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Role of the forebrain commissures in amygdaloid kindling McCaughran, James Arthur 1976

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ROLE OF THE FOREBRAIN COMMISSURES IN AMYGDALOID KINDLING by JAMES ARTHUR McCAUGHRAN, JR. B.A., University of B r i t i s h Columbia, 1976 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE Department of Psychiatry, D i v i s i o n of Neurological Sciences U n i v e r s i t y of B r i t i s h Columbia We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMIBA in THE FACULTY OF GRADUATE STUDIES October, 1976 © J ames Arthur McCaughran, J r . , 1976 In p r e s e n t i n g t h i s t h e s i s in p a r t j a l f u 1 f i l m e n t o f the r e q u i r e m e n t s f o r an advanced degree at the U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r ee t h a t the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and s t u d y . I f u r t h e r ag ree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y pu rpo se s may be g r a n t e d by the Head o f my Department o r by h i s r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Department o f Psychiatry. Division of Neurological Sciences The U n i v e r s i t y o f B r i t i s h Co l umb i a 2075 Wesbrook P l a c e Vancouver, Canada V6T 1W5 Date October 4, 1976 ABSTRACT The r o l e of the f o r e b r a i n commissures i n the developing and developed k i n d l e d amygdaloid s e i z u r e i n the r a t was i n v e s t i g a t e d . In the f i r s t two experiments, b i s e c t i o n of the corpus callosum, hippocampal commissure, and a n t e r i o r commissure p r i o r t o k i n d l i n g caused a s i g n i f -i c a n t f a c i l i t a t i o n i n the r a t e of p r i m a r y - s i t e k i n d l e d s e i z u r e development. In the l a s t experiment, b i s e c t i o n of the corpus callosum and hippocampal commissure a f t e r p r i m a r y - s i t e k i n d l i n g f a c i l i t a t e d the subsequent r a t e of secondary-site k i n d l i n g . I t i s evident, that i n the i n t a c t animal, the nonstimulated hemisphere i s able to exert an i n h i b i t o r y i n f l u e n c e over the development of s e i z u r e a c t i v i t y i n a s t i m u l a t e d hemisphere and that t h i s e f f e c t i s , i n t u r n , mediated v i a the f o r e b r a i n commissures. The corpus callosum and hippocampal commissure were found to p a r t i c i p a t e i n the i n t e r f e r e n c e phenomenon since b i s e c t i o n of these s t r u c t u r e s e i t h e r before or a f t e r p r i m a r y - s i t e k i n d l i n g caused a f a c i l i t a t i o n i n the r a t e of p r i m a r y - s i t e r e k i n d l i n g . In the f i r s t two experiments, an extracommissural, p o s s i b l y brainstem, mechanism i s suggested to mediate the t r a n s f e r e f f e c t between the primary and secondary s i t e s since b i -s e c t i o n of the f o r e b r a i n commissures p r i o r to k i n d l i n g had no e f f e c t on the r a t e of secondary-site k i n d l i n g . The development of primary g e n e r a l i z e d motor se i z u r e s i s i n part dependent on the i n t e g r i t y of the corpus callosum and hippocampal comm-i s s u r e . B i s e c t i o n of these s t r u c t u r e s a f t e r p r i m a r y - s i t e k i n d l i n g , however, abolished the subsequent development of primary g e n e r a l i z e d s e i z u r e s i n a s i g n i f i c a n t number of r a t s . Therefore, i t appears that i f the commissures i i are b i s e c t e d p r i o r t o k i n d l i n g , a l t e r n a t e pathways able to mediate the development of primary g e n e r a l i z e d s e i z u r e s evolve. i i i TABLE OF CONTENTS Page INTRODUCTION 1 EXPERIMENT 1 33 Pr i m a r y - s i t e k i n d l i n g 42 Secondary-site k i n d l i n g 53 Di s c u s s i o n 59 EXPERIMENT 2 67 P r i m a r y - s i t e k i n d l i n g 76 Secondary-site k i n d l i n g 87 P r i m a r y - s i t e r e k i n d l i n g 93 Dis c u s s i o n 98 EXPERIMENT 3 104 P r i m a r y - s i t e k i n d l i n g 110 Secondary-site k i n d l i n g 115 P r i m a r y - s i t e r e k i n d l i n g 120 Secondary-site r e k i n d l i n g 122 Discussi o n 124 GENERAL DISCUSSION 128 SUMMARY 137 REFERENCES 139 iv LIST OF TABLES Page TABLE I 49 TABLE II . 84 TABLE III 112 TABLE IV 116 V LIST OF FIGURES Page Fig. 1 39 Fig. 2 41 Fig. 3 47 Fig. 4 50 Fi g . 5 52 Fig. 6 57 Fig. 7 75 Fig. 8 78 Fig. 9 82 Fig. 10 85 Fig. 11 86 Fig. 12 91 Fig. 13 96 Fig. 14 I l l F ig. 15 113 Fi g . 16 114 Fig. 17 117 Fig. 18 118 v i ACKNOWLEDGEMENT I would l i k e to thank Dr. J.A. Wada f o r h i s as s i s t a n c e i n the prepa r a t i o n of t h i s t h e s i s . S p e c i a l thanks must al s o be extend-ed to Dr. M.E. Corcoran, my colleague and f r i e n d . Many aspects of t h i s study would not have been p o s s i b l e without the t e c h n i c a l a s s i s t a n c e of another f r i e n d , Edward Jung. The typ o g r a p h i c a l e x p e r t i s e of my wife I s a b e l da Silva-McCaughran must a l s o be acknowledged. 1 INTRODUCTION Over the l a s t 100 years an extensive l i t e r a t u r e has evolved concerning the s t r u c t u r e and f u n c t i o n of the f i b r o u s pathways connecting the c e r e b r a l hemispheres. C o l l e c t i v e l y these f i b e r t r a c t s are r e f e r r e d to as commissures and are composed of myelinated f i b e r s a r i s i n g from various areas of the cortex and subcortex o f the b r a i n . These f i b e r s are concentrated at the m i d l i n e , where they form anatomically d i s t i n c t bodies and cross to the opposite hemisphere. In t h i s manner, they serve as important routes f o r the transmission of neural inf o r m a t i o n between e i t h e r homotopic or hetero-t o p i c areas of the hemispheres. The corpus callosum represents most of the f o r e b r a i n commissural f i b e r s , whereas, the remainder are d i s t r i b u t e d between the a n t e r i o r and hippocampal commissures. The corpus callosum can be viewed as a d i f f u s e system o f r a d i a t i o n s p r o j e c t i n g from the m i d l i n e of the b r a i n i n t o the grey matter of the hemispheres. These r a d i a t i o n s i n t e r s e c t with both pro-j e c t i o n and a s s o c i a t i o n f i b e r s and thus form an extensive network of connections r e p r e s e n t i n g a large p o r t i o n of the f o r e b r a i n cortex. Due i n part to the d i v e r s i t y i n connections and the existence o f marked species d i f f e r e n c e s , a d e t a i l e d d e s c r i p t i o n of c a l l o s a l anatomy i s beyond the scope of the present r e p o r t . For s i m i l a r reasons, a d e t a i l e d d i s c u s s i o n of e i t h e r a n t e r i o r commissure or hippocampal commissure anatomy i s not p o s s i b l e . B r i e f Anatomical Ou t l i n e E a r l y i n v e s t i g a t o r s assumed the corpus callosum functioned as a s t r i c t commissural system. That i s , i t served to connect homotopic p o i n t s of the hemispheres. E v e n t u a l l y as knowledge o f c a l l o s a l anatomy grew, h e t e r o t o p i c 2 interh e m i s p h e r i c connections v i a the corpus callosum were subsequently described (Hamilton, 1886; Ransom, 1895; Van Valkenberg, 1911. Today i t i s g e n e r a l l y accepted that the corpus callosum forms an important route f o r the trans m i s s i o n of neural i n f o r m a t i o n between a v a r i e t y of f o r e b r a i n areas. Furthermore, i t i s a l s o recognized that not a l l areas of the mammal-ian f o r e b r a i n are e q u a l l y represented w i t h i n the callosum. For example, r e l a t i v e l y sparse c a l l o s a l r e p r e s e n t a t i o n of the v i s u a l areas i n the neo-cortex has been described i n humans (Van Valkenberg, 1913), primates (McCulloch and Garo l , 1941; G a r o l , 1942; B a i l e y , von Bonin, and McCulloch, 1950; Ebner and Myers, 1962; Myers, 1962), cats (Otsuka and H a s s l e r , 1962; Ebner and Myers, 1965), and r a t s (Nauta and Bucher, 1954). S i m i l a r l y , other areas of the neocortex have been found to vary i n the extent to which they are represented w i t h i n the corpus callosum. A large c a l l o s a l r e p r e s e n t a t i o n of the motor, sensorimotor, and a s s o c i a t i o n areas o f the cortex has been described i n a number of species i n c l u d i n g primates (McCulloch and Garo l , 1941; Ebner and Myers, 1962), cats (Ebner and Myers, 1965), and r a t s (Jacobson, 1965). F i b e r s ending i n h e t e r o t o p i c areas of the c o n t r a l a t e r a l cortex and subcortex have al s o been shown to pass v i a the corpus callosum. Fibers e n t e r i n g the i n t e r n a l and e x t e r n a l capsule and the corpus s t r i a t u m have been described by a number of authors (Hamilton, 1896; Van Valkenberg, 1911; McCulloch and G a r o l , 1941; Ebner and Myers, 1965; Jacobson, 1965). Many of the remaining f o r e b r a i n i n t e r h e m i s p h e r i c connections are pro-vided by e i t h e r the a n t e r i o r or hippocampal commissures. The a n t e r i o r commissure i s a r e l a t i v e l y small bundle of f i b e r s located on the m i d l i n e of the basal f o r e b r a i n . F i b e r s passing through the a n t e r i o r commissure 3 g e n e r a l l y a r i s e from temporal lobe and o l f a c t o r y s t r u c t u r e s . The r e l a t i v e commissural r e p r e s e n t a t i o n of these two areas has been l i n k e d to the p o s i -t i o n of the species on the phylogenic s c a l e . For example, i n mammals lower than primates a n t e r i o r commissure f i b e r s o r i g i n a t e l a r g e l y from s t r u c t u r e s associated with the o l f a c t o r y system ( C a j a l , 1901; Fox and Schmidt, 1943; Brodal, 1948). The temporal areas of the cortex and r e l a t e d temporal lobe s t r u c t u r e s provide a r e l a t i v e l y sparse c o n t r i b u t i o n to the commissure. In primates and humans the m a j o r i t y of f i b e r s i n the a n t e r i o r commissure have been found to o r i g i n a t e from temporal lobe s t r u c t u r e s ( M e t t l e r , 1935; Rundles and Papez, 1938; Bucy and Kluver, 1940, 1955; Garol and McCulloch, 1941; Fox, F i s h e r , and Desalva, 1948; Whitlock and Nauta, 1956). The hippocampal commissure f u n c t i o n s as an important neural connection between the two hippocampi. I t i s a large bundle of f i b e r s a r i s i n g from the hippocampus, b i f u r c a t i n g v e n t r a l to the splenium of the corpus callosum, and descending towards the basal f o r e b r a i n as the f o r n i x . In a d d i t i o n to i t s f u n c t i o n i n connecting the hippocampi, i t a l s o provides an important outflow f o r the t r a n s m i s s i o n of information to other s t r u c t u r e s of the b r a i n . This i s mediated by the f o r n i x . The f o r n i x has been shown to p r o j e c t to a v a r i e t y of s t r u c t u r e s i n c l u d i n g the septum, o l f a c t o r y t u b e r c l e , a n t e r i o r thalamus, mammillary body, and hypothalamus (MacLean, 1949; G u i l l e r y , 1956; V a l e n s t e i n and Nauta, 1959; Green, 1964; L i v i n g s t o n and Escobar, 1971). Role of the Forebrain Commissures i n the Spread of E p i l e p t i f o r m A c t i v i t y A. Pre-electroencephalographic Studies The work of Jackson (1870) and Gowers (1901) showed that e p i l e p t i c s e i z u r e s could be d i v i d e d i n t o a number of c l a s s e s . In one c l a s s , the 4 s e i z u r e appeared to simultaneously i n v o l v e a l l parts of the body; i n another c l a s s , the s e i z u r e appeared i n one h a l f of the body but subsequently spread to i n v o l v e the whole body. Seizures such as these i n which the whole body p a r t i c i p a t e d came to be r e f e r r e d to as g e n e r a l i z e d s e i z u r e s . E a r l y anatomists were p a r t i c u l a r l y concerned w i t h determining which s t r u c t u r e s i n the b r a i n mediated the spread and g e n e r a l i z a t i o n of s e i z u r e s . Lewandowsky (1907) suggested that the corpus callosum was r e s p o n s i b l e f o r the spread of s e i z u r e a c t i v i t y between the motor c o r t i c e s and the subsequent g e n e r a l i z a t i o n of the s e i z u r e . Previous r e p o r t s , however, had f a i l e d to f i n d any s i g n i f i c a n t e f f e c t on the g e n e r a l i z a t i o n of s e i z u r e s evoked by the e l e c t r i c a l s t i m u l a t i o n of the cortex i n callosum-bisected dogs (Un v e r r i c h t , 1883; Frank and P i t r e s , 1883). Karplus (1914) employed s t r i c t e r anatomical c o n t r o l s i n h i s s t u d i e s but a l s o f a i l e d to e f f e c t the g e n e r a l i z a t i o n of s e i z u r e s produced by e l e c t r i c a l s t i m u l a t i o n of the motor cortex i n callosum-b i s e c t e d monkeys and dogs. As an explanation of h i s r e s u l t s he suggested that perhaps the s e i z u r e impulses o r i g i n a t i n g i n the one motor cortex spread to the c o n t r a l a t e r a l cortex by way of pathways s i t u a t e d i n the brainstem. A l t e r n a t e explanations were a l s o o f f e r e d . Some authors b e l i e v e d that the s e i z u r e impulses t r i g g e r e d an e x c i t a t i o n o f the vasomotor centers and these i n t u r n caused increases i n the i n t r a c r a n i a l pressure or changes i n the blood flow which c o n t r i b u t e d to the g e n e r a l i z a t i o n of the s e i z u r e (Krause, 1911; Marburg and Ranzi, 1920; T i l l m a n , 1916). This explanation was l a t e r discarded when i t was found that g e n e r a l i z a t i o n of the s e i z u r e occurred before any s i g n i f i c a n t change i n the i n t r a c r a n i a l pressure was observed (Spiegel and Falkiewz, 1926). Much of the e a r l y research was concerned p r i m a r i l y w i t h determining the r o l e played by the corpus callosum i n the spread of s e i z u r e s . L i t t l e 5 a t t e n t i o n was p a i d to the p o s s i b l e involvement of the other f o r e b r a i n commissures i n t h i s phenomenon. Spiegel and Falkiewz (1926), however, found that b i s e c t i o n of a l l f i b e r connections c r o s s i n g the m i d l i n e r o s t r a l to the rhombencephalon i n the dog f a i l e d to d i s r u p t motor s e i z u r e s e l i c i t e d by e l e c t r i c a l s t i m u l a t i o n of the cortex. S i m i l a r l y , i n l a t e r s t u d i e s b i -s e c t i o n of the f i b r o u s pathways passing through the rhombencephalon was also i n e f f e c t u a l i n d i s r u p t i n g the e l e c t r i c a l l y induced motor s e i z u r e (Spiegel and Takagi, 1927). The r e s u l t s of these s t u d i e s i n d i c a t e d that s e i z u r e g e n e r a l i z a t i o n was able to occur over at l e a s t two d i s t i n c t routes. The one route included pathways r o s t r a l to the rhombencephalon, whereas, the other included pathways i n the rhombencephalon. Both groups of i n v e s t i -gators considered the p o s s i b i l i t y t h a t i n the absence o f a p a r t i c u l a r route f o r propagation and g e n e r a l i z a t i o n of s e i z u r e impulses other, a l t e r n a t e , routes could be r e c r u i t e d i n t o s e r v i c e . The only evidence a v a i l a b l e , how-ever, r e l a t i n g to the spread and g e n e r a l i z a t i o n of the s e i z u r e was der i v e d from the study of i c t a l m a n i f e s t a t i o n s . B. Post-Electroencephalographic Studies The development of the electroencephalograph by Berger i n 1929 enabled researchers to observe the e l e c t r i c a l a c t i v i t y o f the b r a i n f o r the f i r s t time. With the a p p l i c a t i o n of the new rec o r d i n g techniques i t then became p o s s i b l e to observe the s u b c l i n i c a l e p i l e p t o g e n i c process (Lennox, 1936; Lennox, Gibbs, and Gibbs, 1936). The EEG made p o s s i b l e the study of p o t e n t i a l pathways i n v o l v e d i n the propagation of s e i z u r e discharges to surrounding neural t i s s u e and d i s t a n t areas of the b r a i n . In the i n i t i a l stages of these s t u d i e s , s e v e r a l authors 6 Q considered c e r e b r a l blood flow to be important i n t h i s phenomenon sin c e a s s o c i a t e d increases i n the c e r e b r a l blood flow were observed during con-v u l s i o n s (Gibbs, 1933; Gibbs, Lennox, and Gibbs, 1934). I t was found that increases i n blood flow occurred f i r s t i n the v i c i n i t y of e p i l e p t i f o r m f o c i and then r a d i a t e d to more d i s t a n t areas as the c l i n i c a l s e i z u r e general-i z e d ( P e n f i e l d , 1938; P e n f i e l d , von Santha, and C i p r i a n i , 1939).. S i m i l a r increases i n blood flow were a l s o reported f o l l o w i n g increases i n neuronal a c t i v i t y evoked by e l e c t r i c a l s t i m u l a t i o n of the cortex (von Santha and C i p r i a n i , 1938; Serota and Gerard, 1938). The p o s s i b i l i t y that hemodynamic and not neuronal changes were re s p o n s i b l e f o r the development of s e i z u r e s subsequently proved untenable. Kornmuller (1935) concluded that the spread of s e i z u r e impulses evoked by e l e c t r i c a l s t i m u l a t i o n of the r a b b i t cortex were conducted to more d i s t a n t areas v i a neuronal and not hemodynamic path-ways. P e n f i e l d and Boldrey (1939) l a t e r suggested that e p i l e p t i c spread to d i s t a n t s t r u c t u r e s took place over s e l e c t i v e neuronal routes that developed from the c o n t i n u a l neural bombardment generated by the focus. These sens-i t i z e d neural c i r c u i t s , they suggested, could be a c t i v a t e d by e l e c t r i c a l s t i m u l a t i o n of the f o c a l area i n human e p i l e p t i c s . By means of the EEG the c o n t r a l a t e r a l propagation of s e i z u r e a c t i v i t y was shown by many authors to depend on the i n t e g r i t y of the f o r e b r a i n com-missures. Gozzano (1936) found that the a p p l i c a t i o n of strychnine t o the r a b b i t cortex produced spike a c t i v i t y i n homologous areas of the contra-l a t e r a l cortex. He then found that the propagation of these spikes could be blocked by s e c t i o n i n g the corpus callosum. With regard to the c l i n i c a l g e n e r a l i z a t i o n of s e i z u r e s , V o r i s and Adson (1935) reported that g e n e r a l i z e d convulsive episodes were s t i l l observed i n p a t i e n t s s u f f e r i n g an almost 7 t o t a l d e s t r u c t i o n of the corpus callosum by tumors. A l a t e r , more d e t a i l e d d e s c r i p t i o n of s e i z u r e s i n p a t i e n t s with near t o t a l agenesis of the corpus callosum i n d i c a t e d that g e n e r a l i z e d grand mal attacks were r a r e (Hyndman and P e n f i e l d , 1937). The most frequent a t t a c k s tended to be hemiconvulsive or p e t i t mal. E r i c k s o n (1940) was the f i r s t to conduct a d e t a i l e d i n v e s t i g a t i o n of the c l i n i c a l and e l e c t r o g r a p h i c c o r r e l a t e s of s e i z u r e s i n c a l l o s a l - s e c t i o n e d . a c u t e l y prepared cats and monkeys. He observed that b i s e c t i o n of the corpus callosum blocked the spread of e l e c t r i c a l l y induced a f t e r d i s c h a r g e s to the c o n t r a l a t e r a l hemisphere and g e n e r a l i z a t i o n of the motor s e i z u r e . He noted some i p s i l a t e r a l involvement of the hand, but i n general the s e i z u r e was u n i l a t e r a l , confined to the c o n t r a l a t e r a l parts of the body. He suggested that the i p s i l a t e r a l involvement was due to the b i l a t e r a l r e p r e s e n t a t i o n of these areas i n the cortex (Bucy and F u l t o n , 1933; Wyss, 1938). E r i c k s o n concluded h i s study by f u r t h e r suggesting that c e r t a i n i n t r a c o r t i c a l a s s o c i a -t i o n pathways e x i s t e d that represented a r a t h e r elaborate route f o r the conduction of a c t i v i t y v i a the callosum. I t was soon discovered that r e g i o n a l d i f f e r e n c e s e x i s t e d i n the c a l l o s a l r e p r e s e n t a t i o n of p a r t i c u l a r c o r t i c a l areas. Some authors reported the i n -a b i l i t y of strychnine to evoke p r o j e c t e d c o n t r a l a t e r a l spikes from various areas of the cortex (Dusser de Barenne and McCulloch, 1938; Dusser de Barenne, McCulloch and Ogawa, 1938). C u r t i s (1940a,b) found that by e l e c t r i c a l l y stim-u l a t i n g an area of the cortex and simultaneously r e c o r d i n g the evoked p o t e n t i a l s produced i n the c o n t r a l a t e r a l cortex he was able to s y s t e m a t i c a l l y study the r e l a t i v e c a l l o s a l r e p r e s e n t a t i o n of each area. He recorded the greatest p o t e n t i a l s from homotopic areas but a l s o found s e v e r a l areas that 8 d i d not produce p o t e n t i a l s . He reported that s e c t i o n i n g the corpus callosum abolished a l l c o n t r a l a t e r a l p o t e n t i a l s . McCulloch and Garol (1941) r e p o r t -ed that p r o j e c t e d strychnine-evoked p o t e n t i a l s recorded i n the c o n t r a l a t e r a l hemisphere were dependent on the area s t i m u l a t e d . They observed that s t r y c h -n i z a t i o n of areas 1,2,4,8,12,17,19, and 22 d i d not produce c o n t r a l a t e r a l p o t e n t i a l s ; areas 4,6,7,9,10,18, and 21 d i d give r i s e to p o t e n t i a l s but only from homotopical areas; and area 9 d o r s a l to the sulcus p r i n c i p a l i s and the leg and arm areas 5 and 6 produced p o t e n t i a l s d i f f u s e l y s c a t t e r e d over the c o n t r a l a t e r a l cortex. B i s e c t i o n of the corpus callosum abolished a l l of the strychnine spikes i n the c o n t r a l a t e r a l cortex except those that had been generated from the temporal lobe. S e c t i o n i n g of the a n t e r i o r commis-sure e f f e c t i v e l y suppressed c o n t r a l a t e r a l a c t i v i t y a r i s i n g from these areas. The c l i n i c a l g e n e r a l i z a t i o n of s e i z u r e s was found to depend on pathways e x i s t i n g w i t h i n the f o r e b r a i n commissures. Hoefer and Pool (1943) reported that g e n e r a l i z e d s e i z u r e s r e s u l t i n g from e i t h e r e l e c t r i c a l s t i m u l a t i o n of the cortex, surface a p p l i c a t i o n of s t r y c h n i n e , or p i c r o t o x i n could be sup-pressed by s e c t i o n i n g the corpus callosum. An e l e v a t i o n i n the s e i z u r e t h r e s h o l d was a l s o observed a f t e r sectioning, the callosum. They f u r t h e r reported that although the s e i z u r e i n these animals was t y p i c a l l y u n i l a t e r a l , b i l a t e r a l a f t e r d i s c h a r g e s were observed i n most cases. This lead to the suggestion that at l e a s t two routes e x i s t e d that were necessary f o r the g e n e r a l i z a t i o n of s e i z u r e s . The one route, v i a the corpus callosum, was necessary f o r the c l i n i c a l g e n e r a l i z a t i o n of the s e i z u r e , whereas the other route, v i a e x t r a c a l l o s a l pathways, was r e s p o n s i b l e f o r the e l e c t r o g r a p h i c g e n e r a l i z a t i o n of the a f t e r d i s c h a r g e to the c o n t r a l a t e r a l hemisphere. An a l t e r n a t e route from the motor cortex to the temporal cortex and then v i a 9 the a n t e r i o r commissure to the other hemisphere was suggested. Considerable anatomical and e l e c t r o p h y s i o l o g i c a l evidence was then a v a i l a b l e to i n d i c a t e the importance of the a n t e r i o r commissure i n the t r a n s m i s s i o n of a c t i v i t y be-tween the temporal lobes ( M e t t l e r , 1935; Rundles and Papez, 1938; Bucy and Kluver, 1940; McCulloch.and G a r o l , 1941; Fox and Schmidt, 1943). Further-more, Alcade (1942) reported that s e c t i o n i n g the corpus callosum i n cats f a i l e d to suppress the appearance of g e n e r a l i z e d s e i z u r e s r e s u l t i n g from e l e c t r i c a l s t i m u l a t i o n of the cortex. He concluded that the corpus callosum was not an a s s o c i a t i o n system e s s e n t i a l to the propagation of e p i l e p t i f o r m attacks but f a i l e d to elaborate which a l t e r n a t e systems might be i n v o l v e d . Many of the subsequent s t u d i e s concerned w i t h e l a b o r a t i n g the r o l e of the f o r e b r a i n commissures i n e p i l e p s y were done usi n g chronic animal prepar-a t i o n s . Kopeloff, Barrera, and Kopeloff (1942) found that the a p p l i c a t i o n of aluminum hydroxide gel to the cortex of monkeys r e s u l t e d i n the produc-t i o n of a chronic e p i l e p t i f o r m focus. They reported that 3 to 12 weeks after- the g e l a p p l i c a t i o n jacksonian type s e i z u r e s appeared i n the contra-l a t e r a l p a r t s of the body and that these then developed i n t o b i l a t e r a l g e n e r a l i z e d recurrent attacks ( P a c e l l a , Kopeloff, B a r r e r a , and K o p e l o f f , 1944). Ele c t r o c o r t i c o g r a m s i n d i c a t e d f o c a l a b n o r m a l i t i e s around the s i t e of i n j e c t i o n and the appearance of p r o j e c t e d a c t i v i t y i n the homotopic region of the c o n t r a l a t e r a l cortex (Pope, M o r r i s , Jasper, E l l i o t , and P e n f i e l d , 1946). Kopeloff, Kennard, P a c e l l a , K o p e l o f f , and Chusid (1950) examined the e f f e c t s of corpus callosum b i s e c t i o n on r e c u r r e n t spontaneous s e i z u r e s pro-duced by the a p p l i c a t i o n of aluminum hydroxide gel to the cortex of monkeys. They observed that b i s e c t i o n of the s t r u c t u r e e i t h e r before or a f t e r the 10 a p p l i c a t i o n of the gel r e s u l t e d i n the suppression of g e n e r a l i z e d s e i z u r e s . In these monkeys, c o n t r a l a t e r a l hemiconvulsions were most f r e q u e n t l y observ-ed. Furthermore, i t was found that i f the b i s e c t i o n was performed a f t e r the development of s e i z u r e s , the s e v e r i t y of the subsequent hemiconvulsive attacks p r o g r e s s i v e l y increased and, i n some cases, terminated i n status e p i l e p t i c u s . This appeared to suggest that i n the i n t a c t animal the r o l e of the corpus callosum may i n p a r t be concerned with the t r a n s m i s s i o n of i n h i b i t o r y i n f l u e n c e s between the hemispheres. They al s o confirmed the r e s u l t s of previous reports (Hoefer and P o o l , 1943) i n d i c a t i n g that b i s e c -t i o n o f the callosum had no e f f e c t on the e l e c t r o g r a p h i c spread of the s e i z u r e to the c o n t r a l a t e r a l hemisphere. Several explanations have been o f f e r e d as to why b i s e c t i o n of the cor-pus callosum i n monkeys ( E r i c k s o n , 1940; Kopeloff et al. , 1950) but not cats (Alcade,,1942) e f f e c t i v e l y suppresses the c l i n i c a l g e n e r a l i z a t i o n of s e i z u r e s . One explanation concerns the r e l a t i o n s h i p that appears to e x i s t between the s e i z u r e t h r e s h o l d of an area and i t s degree of c a l l o s a l r e p r e s e n t a t i o n . I t has been found that the motor cortex of cats possesses a high s e i z u r e t r i g -g ering t h r e s h o l d (Garner and French, 1958) but a low degree of c a l l o s a l r e p r e s e n t a t i o n (Chang, 1953; Garner and French, 1958). Conversely, the motor cortex of monkeys has a low s e i z u r e t r i g g e r i n g t h r e s h o l d (French, Gernandt, and L i v i n g s t o n , 1956) and a high degree of c a l l o s a l r e p r e s e n t a t i o n (Chang, 1953). Due to the decreased c a l l o s a l coupling of the motor c o r t i c e s i n cats i t seems reasonable to assume that the e l e c t r o g r a p h i c spread and g e n e r a l i z a t i o n of the s e i z u r e may i n v o l v e e x t r a c a l l o s a l pathways. Thus, the increased l e v e l of s t i m u l a t i o n r e q u i r e d to evoke s e i z u r e s from the motor cortex of cats may be s u f f i c i e n t l y high to a l s o a c t i v a t e these e x t r a c a l l o s a l l i n k s . The reverse would apply to the monkey. Because the motor c o r t i c e s are e x t e n s i v e l y coupled by the callosum i n t h i s s p e c i e s , an increased number of d i r e c t pathways are a v a i l a b l e f o r the t r a n s m i s s i o n of a c t i v i t y to the c o n t r a l a t e r a l hemisphere. L i k e l y , the s e i z u r e p r e f e r e n t i a l l y spreads over these more d i r e c t routes. Thus, b i s e c t i o n o f t h i s pathway i n monkeys would sev e r e l y d i s r u p t the e l a b o r a t i o n of seizures from f o c a l to g e n e r a l i z e d a t t a c k s . In c a t s , however, the pathway i s l e s s c r i t i c a l , t h e r e f o r e making the d i s r u p t i o n of the s e i z u r e l e s s l i k e l y a f t e r b i s e c t i o n . The above perhaps suggest that prefered pathways e x i s t that are able to mediate the propagation of s e i z u r e a c t i v i t y from f o c a l areas to more d i s t a n t b r a i n s t r u c t u r e s . The f i r s t task, however, was to determine which areas of the f o r e b r a i n were able to support e p i l e p t o g e n i c a c t i v i t y . The second task was to i n v e s t i g a t e the f u n c t i o n a l and e l e c t r o p h y s i o l o g i c a l char-a c t e r i s t i c s of the neuroanatomical connections that e x i s t e d between the focus and d i s t a n t s t r u c t u r e s . Many authors f e l t that by understanding these two aspects of the problem i t would then become a much simpler process to determine the p r e f e r e d pathways f o r the s e i z u r e spread. The sensorimotor areas of the monkey cortex were found to be the most s e n s i t i v e s t r u c t u r e s to the convulsant e f f e c t s of aluminum hydroxide gel a p p l i c a t i o n (Ward, McCulloch, and Kopeloff, 1948; Kopeloff, Chusid, and Kopeloff,. 1954 ). Recurrent spontaneous s e i z u r e s were al s o observed i n monkeys a f t e r a p p l i c a t i o n of the gel to p a r i e t a l areas (Chusid, K o p e l o f f , and Kopeloff, 1955), p r e o c c i p i t a l areas (Chow and O b r i s t , 1955), and tempor-a l lobe s t r u c t u r e s (Youmans, 1956) although the r e l i a b i l i t y o f the e f f e c t from these areas was somewhat lower than from the sensorimotor areas. Recurrent spontaneous s e i z u r e s have a l s o been e l i c i t e d f o l l o w i n g the i n j e c t i o n of aluminum hydroxide gel i n t o v a r i ous s u b c o r t i c a l s t r u c t u r e s . 12 Sloan, Ransohoff, and Pool (1953) found that i n j e c t i o n s i n t o the amygdala of primates e f f e c t i v e l y produced a recu r r e n t s e i z u r e s t a t e . S i m i l a r r e s u l t s have al s o been reported f o r dogs (Aida, 1956) and cats (Gastaut, Naquet, Meyers, Cavanagh, and Beck, 1959). The thalamus and putamen (Kopeloff, W h i t t i e r , P a c e l l a , and Kope l o f f , 1950), basal g a n g l i a (Faeth and Walker, 1957), and s u b s t a n t i a n i g r a ( S h i r o a , 1969) of cats and primates were found s e n s i t i v e to the convulsant e f f e c t s o f aluminum hydroxide g e l . Although the sei z u r e producing e f f e c t s of aluminum hydroxide g e l are l e s s observable i n species lower than c a t s , S e r v i t and Sterc (1958) were able to render r a t s s u s c e p t i b l e to the convulsant e f f e c t s of au d i t o r y s t i m u l i a f t e r i n j e c t i o n s i n t o the cortex. Forebrain Commissure Involvement i n the Spread o f Temporal Lobe and Limbic  Seizures With the advent of chronic r e c o r d i n g techniques i t became p o s s i b l e to observe and r e l a t e the development o f c l i n i c a l m a n i festations to the e l e c -t r o g r a p h i c a c t i v i t y of the focus and/or more d i s t a n t b r a i n s t r u c t u r e s . For those i n v e s t i g a t i n g the e l e c t r o g r a p h i c spread and subsequent g e n e r a l i z a t i o n of s e i z u r e s , the a c t i v i t y of the c o n t r a l a t e r a l hemisphere during s e i z u r e development was studi e d e x t e n s i v e l y . T h i s , however, became extremely com-plex when attempts were made to study the propagation of s e i z u r e s o r i g i n a t -i n g from s i t e s w i t h i n the temporal lobe or l i m b i c system. Complex p a r t i a l s e i z u r e s r e s u l t i n g from f o c i l ocated w i t h i n the temporal lobe have been a s s o c i a t e d w i t h complex symptomatologies i n v o l v i n g autonomic r e g u l a t i o n , memory, v o l i t i o n a l , and a f f e c t i v e behaviours (Schmidt and Wilder, 1968). E l e c t r o g r a p h i c a l l y , these s e i z u r e s have a l s o been associated w i t h a 13 d i f f u s e spread of a f t e r d i s c h a r g e a c t i v i t y to both i p s i l a t e r a l and contra-l a t e r a l s t r u c t u r e s (Green and Shimamoto, 1953; Gloor, 1957; Walker, 1964). This i n tu r n suggests a marked d i v e r s i f i c a t i o n i n the p r o j e c t i o n pathways from t h i s s t r u c t u r e . For example, pathways o r i g i n a t i n g i n the temporal cortex and p r o j e c t i n g to the brainstem (e.g. Lemmen, 1951; Jasper, Ajmone-marsan, and S t o l l , 1952; French, Hernandez-Peon, and L i v i n g s t o n , 1955; Whitlock and Nauta, 1956; Nauta, 1962), and thalamus (e.g. Jasper, Ajmone-Marsan, and S t o l l , 1952; Gloor 1955a; Whitlock and Nauta, 1956; Nauta and V a l e n s t e i n , 1958; Nauta, 1962) have been i d e n t i f i e d i n a number of species. S i m i l a r l y , c o r t i c a l a s s o c i a t i o n pathways (Adey and Meyer, 1952; Pribram and MacLean, 1953; Bucy and Kluver, 1955; K l i n g l e r and Gloor, 1960) and pathways to the hypothalamus (e.g. Auer and d i V i r g i l i o , 1953; Gloor, 1955a; H a l l , 1959) have a l s o been observed. The amygdala and hippocampus are l i m b i c s t r u c t u r e s most f r e q u e n t l y as-so c i a t e d w i t h the spread of s e i z u r e a c t i v i t y from the temporal lobe i n both humans ( L i c h t e n s t e i n , M a r s h a l l , and Walker, 1959; Jasper, 1964) and labora-t o r y animals (Gloor, 1955a, 1957; Poggio, Walker, and Andy, 1956; Walker and R i b s t e i n , 1957; Guerrero-Figueroa, Barros, Heath, and Gonzalez, 1964; Walker, 1964; Mayangi and Walker, 1974). Some authors have suggested that the t o n i c component of se i z u r e s evoked by e l e c t r i c a l s t i m u l a t i o n of the temporal pole or hippocampus was due to the a c t i v a t i o n o f b r a i n stem centers (Kaada, Pribram, and E p s t e i n , 1949; Kaada, 1951). F e i n d e l and P e n f i e l d (1954) con-s i d e r e d the amygdala to be s i m i l a r to the d i f f u s e p r o j e c t i o n systems of the r e t i c u l a r formation and n o n - s p e c i f i c thalamus. They suggested that a f t e r -discharges invading the amygdala from the temporal cortex were propagated d i f f u s e l y to the c o n t r a l a t e r a l hemisphere, i p s i l a t e r a l diencephalon, and 14 p a r t s of the mesencephalon. I t was. l a t e r found that s t i m u l a t i o n of the amygdala was a l s o capable o f producing c o r t i c a l desynchronization (Feindel and Gloor, 1954) as w e l l as widespread c o r t i c a l , s u b c o r t i c a l , and b r a i n -stem propagation (Gloor, 1955a, 1955b). There i s evidence to suggest that the amygdala and hippocampus are f u n c t i o n a l l y i n v o l v e d i n the dissemination of a f t e r d i s c h a r g e s that have o r i g i n a t e d from other regions of the cortex. Wada and C o r n e l i u s (1960) found that the amygdala and hippocampus were inv o l v e d i n the g e n e r a l i z a t i o n of s e i z u r e discharges o r i g i n a t i n g from chronic f o c i l ocated i n the s e n s o r i -motor cortex of c a t s . Due to the c l o s e anatomical and e l e c t r o p h y s i o l o g i c a l r e l a t i o n s h i p that e x i s t s between the temporal neocortex, the s t r u c t u r e s w i t h i n i t , and the a n t e r i o r commissure, the a n t e r i o r commissure has o f t e n been viewed as a p o t e n t i a l l y important pathway f o r the propagation of temporal lobe a c t i v i t y to the c o n t r a l a t e r a l hemisphere. Studies done i n monkeys (McCulloch and G a r o l , 1941; Fox et al. , 1948; P e t r , Holden, and J i r o u t , 1949; Segundo, Naquet, and Arana, 1955; Whitlock and Nauta, 1956), cats (Fox, 1940; Fox and Schmidt, 1943; Gloor, 1955a, 1955b; Ebner and Myers, 1965) and r a t s (Brodal, 1948; Valverde, 1965; Lammers, 1972; de Olmos, 1972) have demonstrated that temporal lobe f i b e r s pass through the a n t e r i o r commissure. In general, how-ever, the o r i g i n of these f i b e r s w i t h i n the temporal lobe has been found to vary according to the species s t u d i e d . For example, i n cats (e.g. Fox and Schmidt, 1943), and r a t s (e.g. B r o d a l , 1948) the major component of the com-missure i s the pars o l f a c t o r i a or a n t e r i o r limb. The pars interhemispher-i c a or p o s t e r i o r limb i s a r e l a t i v e l y minor component. In primates (e.g. Bucy and Kluver, 1955) and humans ( K l i n g l e r and Gloor, 1960) the r e l a t i o n -15 ship i s reversed. The pars inte r h e m i s p h e r i c a predominates, whereas the c o n t r i b u t i o n of pars o l f a c t o r i a i s r e l a t i v e l y minor. Furthermore, Bucy and Kluver (1955) maintain that the a n t e r i o r commissure i n primates does not connect the amygdalae but passes p o s t e r o l a t e r a l l y to i t and ends i n the temporal pole. F r o s t , Baldwin, and Wood (1958), however, found that a f t e r -discharges evoked by e l e c t r i c a l s t i m u l a t i o n of the amygdala i n monkeys q u i c k l y propagated to the c o n t r a l a t e r a l s t r u c t u r e . They a l s o reported that a f t e r d i s c h a r g e associated with that of the amygdala could be observed i n the a n t e r i o r commissure. S i m i l a r l y , they found that b i s e c t i o n of the com-missure suppressed the propagation of a f t e r d i s c h a r g e s to the c o n t r a l a t e r a l amygdala as w e l l as the b i l a t e r a l i z a t i o n of face and jaw movements oft e n observed f o l l o w i n g r e p e t i t i v e s t i m u l a t i o n . K l i n g l e r and Gloor (1960) reported profuse a n t e r i o r commissure connec-t i o n s between the amygdaloid n u c l e i i n humans, whereas Ebner and Myers (1965) reported only weak connections i n the cat. In the r a t , however, the a n t e r i o r commissure has been found to f u n c t i o n as an important interhemis-p h e r i c connection between the medial, c o r t i c a l , and some of the basal amygda-l o i d n u c l e i (Brodal, 1948). Extensive monosynaptic connections have been found between the amygdala, surrounding c o r t i c a l s t r u c t u r e s , and va r i o u s o l f a c t o r y n u c l e i i n a number of species i n c l u d i n g the r a t (Lammers, 1972; de Olmos, 1972), cat (Fox, 1940; Ebner and Myers, 1965), and monkey (Bucy and Kluver, 1955). Species d i f f e r -ences regarding the r e l a t i v e c o n t r i b u t i o n that each of the above areas makes to the a n t e r i o r commissure have been mentioned p r e v i o u s l y . The poi n t to .be made, however, i s that even i f e p i l e p t i f o r m a c t i v i t y was evoked from an area making a small c o n t r i b u t i o n to the a n t e r i o r commissure, c o n t r a l a t e r a l propa-16 gation would s t i l l take place due to the extensive i p s i l a t e r a l connections that the area has with s t r u c t u r e s that make a large c o n t r i b u t i o n to the a n t e r i o r commissure. Poblete, Ruben, and Walker (1959) found that b i s e c t i o n of the a n t e r i o r commissure i n cats prevented the c o n t r a l a t e r a l propagation of a f t e r d i s c h a r g e s produced by e l e c t r i c a l s t i m u l a t i o n of the temporal pole or second temporal gyrus. Neither the corpus callosum, f o r n i x , massa intermedia, nor p o s t e r i o r commissure appeared to be i n v o l v e d since b i s e c t i o n of these s t r u c t u r e s had no e f f e c t on the propagation. S t i m u l a t i o n of the amygdala produced only weak propagation of a f t e r d i s c h a r g e s to the c o n t r a l a t e r a l s t r u c t u r e . They found that only 3 of 43 s t i m u l a t i o n s of the amygdala evoked a f t e r d i s c h a r g e s i n the c o n t r a l a t e r a l amygdala. This i n p a r t suggests that weak interamyg-d a l a connections e x i s t v i a the a n t e r i o r commissure i n t h i s species (Ebner and Myers, 1965). Straw and M i t c h e l l (1967) found that b i s e c t i o n of the corpus callosum i n cats had no e f f e c t on the c o n t r a l a t e r a l propagation of a f t e r d i s c h a r g e s evoked by e l e c t r i c a l s t i m u l a t i o n of the medial e c t o s y l v i a n gyrus. They suggested that other s u b c o r t i c a l commissural s t r u c t u r e s must mediate the c o n t r a l a t e r a l t r a n s m i s s i o n of t h i s a c t i v i t y . They f e l t that the a n t e r i o r commissure was the most l i k e l y candidate. The hippocampus i s a l i m b i c s t r u c t u r e that may p l a y a r o l e i n the c o n t r a l a t e r a l propagation of temporal lobe s e i z u r e a c t i v i t y (Fox et al. , 1948; Petr et al. , 1949). Adey and Meyer (1952) found that a f t e r d i s c h a r g e s o r i g i n a t i n g from the temporal g y r i spread to the hippocampus and subsequent-l y to the c o n t r a l a t e r a l hemisphere v i a the hippocampal commissure. I t was l a t e r shown that the hippocampal commissure d i d indeed f u n c t i o n i n the c o n t r a l a t e r a l propagation of hippocampal a f t e r d i s c h a r g e s (Simpson,1952; 17 C r e u t z f e l d and M y e r - M i c k e l e i t , 1953), but that the a n t e r i o r commissure s t i l l played a major r o l e (Green and Shimamoto, 1953). Poblete et al. (1959) r e -ported that the c o n t r a l a t e r a l propagation of hippocampal a f t e r d i s c h a r g e i n cats was unaffected by s e c t i o n i n g of the hippocampal commissure. T h e i r r e s u l t s suggest that m u l t i p l e pathways must e x i s t f o r the c o n t r a l a t e r a l propagation of a f t e r d i s c h a r g e s and that when one i s destroyed an a l t e r n a t e pathway may takeover i t s f u n c t i o n . Due to the d i f f u s e nature of the temporal lobe p r o j e c t i o n s and the con-nections these make with a v a r i e t y of s u b c o r t i c a l s t r u c t u r e s that do not cross the m i d l i n e v i a the f o r e b r a i n commissures, many authors have suggested that a l t e r n a t e routes may be used f o r the propagation of s e i z u r e a c t i v i t y to the c o n t r a l a t e r a l hemisphere (e.g. M e t t l e r , 1935; B a i l e y , von Bonin, Garo l , and McCulloch, 1943; Ajmone-Marsan and S t o l l , 1951; Segundo et al. , 1955; Whitlock and Nauta, 1956). These rou t e s , however, g e n e r a l l y tend to be p o l y s y n a p t i c , i n v o l v i n g the thalamus, hypothalamus, or r e t i c u l a r forma-t i o n , and thus seem u n l i k e l y candidates f o r the i n i t i a l propagation of s e i z u r e a c t i v i t y to the c o n t r a l a t e r a l hemisphere. In the e a r l y stages of s e i z u r e development i t seems l i k e l y that the d i r e c t monosynaptic pathways passing v i a the f o r e b r a i n commissures are favoured routes. As s e i z u r e development progresses, there can be l i t t l e doubt that the longer, l e s s d i r e c t connections to the c o n t r a l a t e r a l hemisphere become ' s e n s i t i z e d ' by the p e r s i s t e n t neural bombardment and thus become a c t i v e l y i n v o l v e d i n the spread o f the s e i z u r e discharge. This n o t i o n i s supported by the work of many researchers (e.g. Ajmone-Marsan and S t o l l , 1951; Poggio et al. , 1956; Gloor, 1957; Wada and C o r n e l i u s , 1960). 18 Commissural P a r t i c i p a t i o n i n Secondary E p i l e p t o g e n e s i s A c t i v e f o c i w i l l o f t e n generate dependent or i n some cases independent spike a c t i v i t y i n more d i s t a n t b r a i n s t r u c t u r e s . The appearance of these spikes i s commonly r e f e r r e d to as secondary e p i l e p t o g e n e s i s (SE). Studies r e l a t e d to t h i s phenomenon have produced data that are v a l u a b l e to the understanding of the r o l e played by the f o r e b r a i n commissures and b r a i n -stem s t r u c t u r e s i n the propagation of e p i l e p t i f o r m discharges. An extensive l i t e r a t u r e e x i s t s on the subject of SE i n human e p i l e p t i c s ( P e n f i e l d and Jasper, 1954; Heath and M i c k l e , 1957; Heath, 1962; Guerrero-Figueroa, G a l l a n t , Robinson, and Heath, 1968), primates (Gozzano, 1936; E r i c k s o n , 1940; P a c e l l a et al. , 1944; Cure and Rasmussen, 1950; Wada, 1964; Nie, Maccabe, E t t l i n g e r , and D r i v e r , 1974), cats (Wada and C o r n e l i u s , 1960; Guerrero-Figueroa et al. , 1964), r a b b i t s ( M o r r e l l , 1960; M o r r e l l , P r o c t o r , and P r i n c e , 1965; P r o c t o r , P r i n c e , and M o r r e l l , 1966), r a t s (Isaacson, Schwartz, P e r s o f f , and Pinson, 1971; A s h c r o f t , Dow, H a r r i s , H i l l , Ingleby, McQueen, and Townsend, 1974), and inframammalians ( S e r v i t and S t r e j c k o v a , 1967, 1971) . There appears to be two stages i n v o l v e d i n the phenomenon of SE: (1) the appearance of discharges temporally dependent on those from the primary focus; and (2) the appearance of discharges temporally independent from those of the primary focus. M o r r e l l (1960) and l a t e r Rutledge and Kennedy (1961) proposed that separate anatomical pathways were r e s p o n s i b l e f o r the mediation of these two stages. I t was suggested that dependent discharges were mediated v i a the corpus callosum, whereas brainstem pathways were r e s p o n s i b l e f o r the mediation of independent discharges. For example, b i -s e c t i o n of the corpus callosum p r i o r to the c r e a t i o n of a primary focus i n 19 the cortex has been found to suppress the appearance of SE i n monkeys (Gozzano, 1936; E r i c k s o n , 1940), r a b b i t s ( M o r r e l l , 1960), and r a t s (Isaacson et al. , 1971; A s h c r o f t et al. , 1974). S i m i l a r l y , Guerrero-Figueroa et al. (1964) found that b i s e c t i o n of the f o r e b r a i n commissures i n the cat p r i o r to implanting alumina gel i n various l i m b i c s t r u c t u r e s prevented the appearance of SE i n c o n t r a l a t e r a l s t r u c t u r e s . In c o n t r a s t , however, Nie et al. (1974) reported that b i s e c t i o n of the corpus callosum i n monkeys p r i o r to the c r e a t i o n of a p o s t e r i o r p a r i e t a l cortex focus only succeeded i n slowing but not stopping SE i n the c o n t r a l a t e r a l homotopic area. D i f f e r e n c e s between the r e s u l t s of Nie et al. and those of e a r l i e r i n v e s t i g a t o r s (e.g. Gozzano, 1936; E r i c k s o n , 1940) may i n p a r t r e f l e c t the n e c e s s i t y of doing s t u d i e s such as these i n chronic p r e p a r a t i o n s . Nie et al. (1974) studied SE i n chronic monkeys whereas the e a r l i e r s t u d i e s were done usi n g acute p r e p a r a t i o n s . I t seems reasonable to speculate that over time a number of pathways may develop i n the chronic p r e p a r a t i o n that become capable of e s t a b l i s h i n g areas of SE i n e i t h e r i p s i l a t e r a l or c o n t r a -l a t e r a l s t r u c t u r e s . Studies done on species not possessing a corpus callosum (e.g. mar-s u p i a l s and inframammalians) i n d i c a t e that a l t e r n a t e , e x t r a c a l l o s a l pathways are capable of e s t a b l i s h i n g areas of SE. For example, S e r v i t and S t r e j k o v a (1967, 1971) found that the f o r e b r a i n of t u r t l e s and frogs was capable of supporting SE. Further studies a l s o showed that b i s e c t i o n of a l l i n t e r -hemispheric connections i n the f r o g b r a i n d i d not a f f e c t the development of SE ( S e r v i t , S t r e j k o v a , and V o l a n s c h i , 1968). Wilder, King, and Schmidt (1968) observed SE i n the f o r e b r a i n of the opposum, a marsupial l a c k i n g a corpus callosum. 20 Studies r e l a t e d to the e f f e c t s of f o r e b r a i n b i s e c t i o n on chronic sec-ondary e p i l e p t o g e n i c areas have shown that the discharge a c t i v i t y of these f o c i i s subjected to both c a l l o s a l and e x t r a c a l l o s a l i n f l u e n c e s (Guerrero-Figueroa et al. , 1964; Isaacson et al. , 1971; Ashc r o f t et al., 1974) . M o r r e l l (1960) found that b i s e c t i o n of the corpus callosum i n r a b b i t s block-ed the development of synchronous spike discharges between the primary and secondary f o c i i n the cortex. B i s e c t i o n o f the corpus callosum a f t e r i n -dependent secondary spike discharges had developed, however, produced no subsequent change i n the discharge p a t t e r n ( M o r r e l l , 1960). M o r r e l l suggest-ed that the development of dependent synchronous spike discharges was mediat-ed by the corpus callosum whereas the development of independent spike d i s -charges depended on a l t e r n a t e s u b c o r t i c a l pathways. To support h i s hypo-t h e s i s he was able to show that the development of independent discharges i n secondary e p i l e p t o g e n i c areas of the r a b b i t cortex could be suppressed by i s o l a t i n g the cortex and corpus callosum from the subcortex. The cortex -corpus callosum s e c t i o n , however, d i d not a f f e c t the development of synchron-ous spike discharges. Commissural P a r t i c i p a t i o n i n the Genesis of Generalized Spike and Wave  A c t i v i t y The f o r e b r a i n commissures have been i m p l i c a t e d i n the interhemispheric g e n e r a l i z a t i o n of bisynchronous spike and wave a c t i v i t y . The 2:5 to 3.5.per second discharge p a t t e r n associated with t h i s a c t i v i t y i s o f t e n observed i n p a t i e n t s e x h i b i t i n g signs of p e t i t mal e p i l e p s y . A c h a r a c t e r i s t i c EEG feature of p e t i t mal attacks i s the simultaneous appearance of g e n e r a l i z e d bisynchronous spike and wave discharges i n most 21 areas of the cortex. In order to e x p l a i n the widespread c o r t i c a l e f f e c t s a s s o c i a t e d with t h i s phenomenon, many i n v e s t i g a t o r s proposed that these attacks were p r e c i p i t a t e d by a p a t h o l o g i c a l c o n d i t i o n i n v o l v i n g e i t h e r the d i f f u s e thalamic p r o j e c t i o n system or brainstem r e t i c u l a r formation (e.g. P e n f i e l d and Jasper, 1954; P o l l e n , 1963; Weir, 1964). A l a r g e body of both c l i n i c a l and experimental data, however, has suggested t h a t the phen-omenon may a l s o be r e l a t e d to the spread of e p i l e p t i f o r m discharges from c o r t i c a l f o c i (Bancaud, T a l a i r a c h , Bonis, Schaub, S z i k l a , Morel, and Bordas-Ferer, 1965; Marcus and Watson, 1966, 1968; Marcus, Watson, and Simon, 1968; Vio c u l e s c u and Popescu-Tisuana, 1969; Mutani, Bergamini, F a r i e l l o , and Quattrocolo, 1972, 1973). Two mechanisms have been proposed to account f o r the extensive propaga-t i o n and r a p i d g e n e r a l i z a t i o n of spike and wave a c t i v i t y generated by a c o r t i c a l f o c i . The one mechanism proposes that discharges a r i s i n g from c o r t i c a l f o c i propagated v i a i n t r a c o r t i c a l routes to i n v o l v e i p s i l a t e r a l s t r u c t u r e s and t r a n s c a l l o s a l routes to i n v o l v e c o n t r a l a t e r a l s t r u c t u r e s . The other proposal i n v o l v e s the spread of f o c a l c o r t i c a l discharges to sub-c o r t i c a l s t r u c t u r e s that i n turn are capable of p r o j e c t i n g the a c t i v i t y to widespread areas of both the i p s i l a t e r a l and c o n t r a l a t e r a l cortex. E x p e r i -mental evidence i n d i c a t e s , however, that i t i s probably a combination of these two that accounts f o r the widespread bisynchronous a c t i v i t y . Marcus and Watson (1966, 1968) and Marcus et al. , (1968) found that t r a n s c a l l o s a l and not the c o r t i c a l - s u b c o r t i c a l pathways were r e s p o n s i b l e f o r the mediation of g e n e r a l i z e d bisynchronous spike and wave discharges o r i g i n a t i n g from b i l a t e r a l l y symmetrical f o c i i n the cortex of acute cats and monkeys. B i s e c t i o n of the corpus callosum was found to d i s r u p t the b i l a t e r a l synchrony of the discharge although each focus continued to d i s -22 charge independently. The independent aspect of the f o c a l a c t i v i t y was found to r e l y on the i n t e g r i t y of the c o r t i c a l - s u b c o r t i c a l systems s i n c e i s o l a t i o n of the cortex and corpus callosum r e s u l t e d i n the suppression of independent a c t i v i t y . This procedure, however, d i d not a f f e c t the b i l a t e r -a l synchrony o f the spike and wave a c t i v i t y . O t t i n o , Meglio R o s s i , and Tercero (1971) reported that s u b c o r t i c a l s t r u c t u r e s were capable of mediating the g e n e r a l i z e d bisynchronous d i s -charges i n the absence of the p r e f e r r e d c a l l o s a l pathways i f the convulsant stimulus was s u f f i c i e n t l y increased. They found that g e n e r a l i z e d bisynchrony could s t i l l be maintained a f t e r b i s e c t i n g a l l f o r e b r a i n commissures to the l e v e l of the midbrain i f the e l e c t r i c a l s t i m u l a t i o n of the cortex was i n -creased concomittantly. Generalized bisynchrony could be permanently a b o l i s h -ed only a f t e r b i s e c t i o n o f the midbrain. I t was p r e v i o u s l y thought that only b i l a t e r a l l y symmetrical c o r t i c a l f o c i were capable of generating g e n e r a l i z e d bisynchronous spike and wave a c t i v i t y . Mutani et al. (1973), however, demonstrated that b i l a t e r a l l y asymmetrical f o c i were e q u a l l y e f f e c t i v e . Furthermore, they found that i t was not necessary to create the f o c i i n areas of the c o r t i c e s e x t e n s i v e l y coupled by the corpus callosum. B i s e c t i o n of the corpus callosum, however, d i s r u p t e d the b i l a t e r a l synchrony a r i s i n g from f o c i created i n the sigmoid gyrus of one hemisphere and the l a t e r a l gyrus of the other. These two areas have been shown to be markedly d e f i c i e n t i n c a l l o s a l connections (Chodoury, Whitteridge, and Wilson, 1965; Hubel and Wiesel, 1965; Jones and Powell, 1968; B e r l u c c h i , 1972). I s o l a t i o n of the cortex and corpus callosum d i d not a f f e c t the bisynchrony of the spike and wave discharges. In view of the above r e p o r t s , i t must be concluded t h a t t r a n s c a l l o s a l and i n t r a ' c o r t i c a l pathways f u n c t i o n p r i m a r i l y i n maintaining the bisynchron-23 ous aspects of the discharge whereas s u b c o r t i c a l pathways are important f o r the establishment of independent discharge p a t t e r n s . Nature of the Information Transmitted V i a the Forebrain Commissures There have been numerous r e p o r t s of e i t h e r enhancement or i n h i b i t i o n of spike discharges i n secondary f o c i f o l l o w i n g drug-induced i n a c t i v a t i o n of the primary focus ( R o v i t , Hardy, and Gloor, 1960; R o v i t , Gloor, and Rasmussen, 1961; Gloor, Garretson, and Rasmussen, 1965; Coceani, Libman, and Gloor, 1966). Subsequent i n v e s t i g a t i o n has shown th a t both t r a n s c a l l o s -a l and c o r t i c a l - s u b c o r t i c a l processes are i n v o l v e d i n t h i s phenomenon. Mutani et al. (1972) observed that b i l a t e r a l asymmetrical c o r t i c a l f o c i o f t e n appeared more a c t i v e than u n i l a t e r a l f o c i . This l e d them to suggest that a f a c i l i t a t o r y i n t e r a c t i o n took p l a c e between b i l a t e r a l f o c i . S e c t i o n -i n g the corpus callosum i n cats was found to produce an even f u r t h e r increase i n the discharge a c t i v i t y of the b i l a t e r a l f o c i . In c o n t r a s t , cortex-corpus callosum i s o l a t i o n r e s u l t e d i n a marked attenuation: i n the f o c a l a c t i v i t y . In view of these r e s u l t s , Mutani et al. (1972) proposed that t r a n s c a l l o s a l pathways were r e s p o n s i b l e f o r an i n h i b i t o r y i n t e r h e m i s p h e r i c i n t e r a c t i o n i n the i n t a c t animal whereas other, s u b c o r t i c a l pathways mediated a f a c i l i t a t o r y i n t e r a c t i o n . There have been few subsequent r e p o r t s concerning the i n h i b i t o r y func-t i o n s of the corpus callosum i n s e i z u r e a c t i v i t y . I t has been shown, how-ever, that b i s e c t i o n of the f o r e b r a i n commissures i n cats (Wada and Sato, 1975) and r a t s (McCaughran, Corcoran, and Wada, 1976) r e s u l t s i n the f a c i l -i t a t i o n of s e i z u r e development. 24 Forebrain Commissurotomy f o r the Control of I n t r a c t i b l e Seizures i n Humans Von Wagenen and Herren (1940) were the f i r s t to use f o r e b r a i n commis-surotomy as a s u r g i c a l treatment f o r the c o n t r o l of i n t r a c t i b l e s e i z u r e s i n human e p i l e p t i c s . The s u r g i c a l procedure was based on a number of c l i n i c a l r e p o r t s that i n d i c a t e d that p a t h o l o g i c a l d e s t r u c t i o n of the corpus callosum often abolished a p r e e x i s t i n g s e i z u r e d i s o r d e r . Of the 10 p a t i e n t s who underwent surgery, the corpus callosum and hippocampal commissure were com-p l e t e l y b i s e c t e d i n only two cases. These s t r u c t u r e s were b i s e c t e d to vary-ing degrees i n the other eight p a t i e n t s . The success of the operation was moderate and postoperative recovery was o f t e n hampered by n e u r o l o g i c a l com-p l i c a t i o n s . Seizures continued i n a number of cases although the frequency of the attacks was g e n e r a l l y reduced. T y p i c a l l y the attacks were no longer g e n e r a l i z e d but u s u a l l y hemiconvulsive and a s s o c i a t e d w i t h jacksonian type c l i n i c a l m anifestations and no l o s s of consciousness. Several p a t i e n t s d i d , however, continue to e x h i b i t g e n e r a l i z e d s e i z u r e s . The longterm success of the operation was not reported, although subsequent study was done on the p s y c h o l o g i c a l e f f e c t s of the surgery ( A k e l a i t i s , 1942; Bridgman, 1945). I t i s d i f f i c u l t to a s c e r t a i n the magnitude of the c l i n i c a l improvement. Bogen and Vogel (1963) and Bogen, F i s c h e r , and Vogel (1965) a l s o attempt-ed to c o n t r o l i n t r a c t i b l e s e i z u r e s i n human e p i l e p t i c s by s u r g i c a l l y b i s e c t -in g the f o r e b r a i n commissures. In t h e i r s e r i e s of p a t i e n t s , a l l were subj e c t -ed to complete t r a n s e c t i o n of the corpus callosum and hippocampal commissure. Some als o underwent b i s e c t i o n of the hippocampal commissure and the massa intermedia of the thalamus. Only one from a group of ten p a t i e n t s f a i l e d to show s i g n i f i c a n t r e -duction i n the frequency of attacks a f t e r f o r e b r a i n b i s e c t i o n . Of the nine 25 showing decreased s e i z u r e frequency, a l l had p r e v i o u s l y shown a high f r e -quency of g e n e r a l i z e d attacks p r i o r to surgery. Generalized attacks f o l l o w -ing surgery were extremely rare over the follow-up p e r i o d ranging from 2-7 years. The few g e n e r a l i z e d attacks that were observed were thought to be p r e c i p i t a t e d by a r e d u c t i o n i n a n t i c o n v u l s a n t medication. Subsequent i n -creases i n medication were reported to suppress these a t t a c k s . I t was a l s o reported that f o c a l , hemiconvulsive attacks were observed s l i g h t l y more f r e q u e n t l y than g e n e r a l i z e d attacks but these a l s o responded fa v o r a b l y to medication. Lussenhop (1970) reported that d i v i s i o n of the f o r e b r a i n commissures was a s u c c e s s f u l a l t e r n a t i v e t o the more r a d i c a l hemispherectomy commonly used f o r the treatment of i n t r a c t i b l e s e i z u r e s a s s o c i a t e d with i n f a n t i l e hemiplegia. Although only two cases were reported and i n both of these adequate follow-up information i s s t i l l l a c k i n g , both cases e x h i b i t e d a marked red u c t i o n i n g e n e r a l i z e d s e i z u r e frequency. U n i l a t e r a l a t t acks were observed although these a l s o decreased i n frequency. K i n d l i n g E l e c t r i c a l s t i m u l a t i o n of the cortex i s probably one of the o l d e s t techniques used i n the study of e p i l e p s y (e.g. F e r r i e r , 1873; L u c i a n i , 1878). Most of the e a r l y knowledge concerning the r o l e of the f o r e b r a i n commissures i n e p i l e p s y was derived from the study of s e i z u r e s produced by e l e c t r i c a l s t i m u l a t i o n of the cortex of l a b o r a t o r y animals ( f o r a review see S p i e g e l , 1931). The convulsant e f f e c t s of b r a i n s t i m u l a t i o n were i n i t i a l l y confined to observations regarding the c l i n i c a l response. I t was not u n t i l Berger (1929) developed the EEG that the e f f e c t s of e l e c t r i c a l s t i m u l a t i o n on the neuron were observed. 26 I t was s h o r t l y a f t e r the development of the EEG t h a t Adrian (1936) ob-served the f i r s t s e l f - s u s t a i n e d a f t e r d i s c h a r g e s r e s u l t i n g from the e l e c t r i c a l s t i m u l a t i o n of the cortex. D e t a i l e d d e s c r i p t i o n s of the morphological f e a -tures of the a f t e r d i s c h a r g e patterns soon followed (e.g. Rosenbleuth and Cannon, 1941-1942; Jasper, 1954; K r e i n d l e r , 1965). S i m i l a r l y , e l e c t r o g r a p h i c studies r e l a t e d to the propagation of a f t e r d i s c h a r g e s from areas of the b r a i n provided a valuable source of inf o r m a t i o n concerning the spread of s e i z u r e a c t i v i t y (e.g. Ajmone-Marsan, and S t o l l , 1951; Jasper, Ajmone-Marsan, and S t o l l , 1952; Poggio et al. , 1956; Udvarhelyi and Walker, 1965; Walker and U d v a r h e l y i , 1965). I t was a l s o found that r e p e t i t i v e s t i m u l a t i o n of an area r e s u l t e d i n the progressive r e d u c t i o n of i t s a f t e r d i s c h a r g e t h r e s h o l d (Pinsky and Burns, 1962; Straw, 1968). The e f f e c t s of repeated b r a i n s t i m u l a t i o n s on freely-moving animals were not known u n t i l r e l a t i v e l y r e c e n t l y . Alonso-de F l o r i d a and Delgado (1958) found that chronic e l e c t r i c a l s t i m u l a t i o n of the amygdala i n cats produced a l a s t i n g behavioural change i n , i n some i n s t a n c e s , motor s e i z u r e s . These r e s u l t s were l a t e r confirmed by Fonberg and Delgado (1961) and extend-ed by Delgado and S e v i l l a n o (1961) , who reported that r e p e t i t i v e s t i m u l a t i o n of the hippocampus evoked p r o g r e s s i v e l y longer a f t e r d i s c h a r g e s and the f r e -quent appearance of g e n e r a l i z e d motor s e i z u r e s . S i m i l a r e f f e c t s were a l s o observed during s e l f - s t i m u l a t i o n s t u d i e s . Wurtz and Olds (1963) observed se i z u r e s i n animals with s e l f - s t i m u l a t i o n electrodes i n the amygdala. Seizures r e s u l t i n g from the s e l f - s t i m u l a t i o n of hypothalamic s i t e s have al s o been reported (Bogacz, St. Laurent, and Olds, 1965) . However, Goddard (1967) and Goddard, Mclntyre, and Leech (1969) were the f i r s t to provide d e t a i l e d i n f o r m a t i o n concerning the p r o g r e s s i v e development of motor se i z u r e s evoked 27 by repeated e l e c t r i c a l s t i m u l a t i o n of the b r a i n . They reported that once-d a i l y a d m i n i s t r a t i o n o f a subconvulsive e l e c t r i c a l stimulus to a v a r i e t y of c o r t i c a l and s u b c o r t i c a l s t r u c t u r e s i n r a t s , c a t s , or monkeys r e s u l t e d i n the gradual development o f ge n e r a l i z e d motor s e i z u r e s . They r e f e r r e d to t h i s phenomenon as the ' k i n d l i n g ' e f f e c t . Kindled s e i z u r e s have now been confirmed i n a number of species i n -c l u d i n g the r a t (Burnham, 1971; Racine, 1972a,b; Corcoran, McCaughran, and Wada, 1973; Mclntyre and Goddard, 1973; P i n e l , P h i l l i p s , and MacNeil, 1973), cat (Wada and Sato, 1974 ; Wada, Sato, and Corcoran, 1974), r a b b i t (Tanaka, 1972), and primate (Wada, Osawa, and M i z o g u i c h i , 1975; Wada and Osawa, 1976). I t was once thought that k i n d l i n g was i n par t the r e s u l t of p a t h o l o g i c a l i n -t e r f e r e n c e of the el e c t r o d e t i p w i t h the surrounding neural t i s s u e . This hypothesis, however, proved to be untenable (Goddard, 1972; Goddard and Mclntyre, 1974). I t now appears that the development o f k i n d l e d s e i z u r e s i s c h a r a c t e r i z e d i n at l e a s t four ways: (1) a re d u c t i o n i n the a f t e r d i s - : charge t h r e s h o l d at the s i t e of s t i m u l a t i o n ; (2) the dependence of motor s e i z u r e development on the production of a f t e r d i s c h a r g e ; (3) the e l a b o r a t i o n i n the morphology of the a f t e r d i s c h a r g e p a t t e r n ; and (4) the spread of af t e r d i s c h a r g e to more d i s t a n t , s y n a p t i c a l l y r e l a t e d s t r u c t u r e s (e.g. Racine, 1972a,b; Wada and Sato, 1974; Wada and Osawa, 1976). Many stu d i e s suggested that k i n d l i n g was able to produce l a s t i n g , i f not permanent, widespread a l t e r a t i o n s i n the f u n c t i o n i n g o f the b r a i n . I t was found that a f t e r g e n e r a l i z e d motor s e i z u r e s had been k i n d l e d , subsequent sei z u r e s f o l l o w i n g nonstimulated periods of v a r i a b l e d u r a t i o n , u s u a l l y r e -s u l t e d on the f i r s t r e s t i m u l a t i o n (Goddard et at., 1969). Seizures i n k i n d l e d cats have been reported f o l l o w i n g n o n s t i m u l a t i o n i n t e r v a l s of up to one year (Wada, Sato, and Corcoran, 1974). Reports of spontaneous rec u r r e n t 28 s e i z u r e s i n k i n d l e d r a t s ( P i n e l , Mucha, and P h i l l i p s , 1975), cats (Wada et al. , 1974), and primates (Wada et al. , 1975), and observations that k i n d l i n g lowers the s e i z u r e t r i g g e r i n g t h r e s h o l d to a v a r i e t y of agents (e.g. P i n e l and Van Oot, 1975; P i n e l , S k e l t o n , and Mucha, 1975; Wada et al. , 1974) supports the n o t i o n that widespread neuronal changes accompany or r e s u l t i n k i n d l e d s e i z u r e s . Transsynaptic changes a l s o appear to accompany the development of k i n d l e d s e i z u r e s . For example, increases i n the s e i z u r e s u s c e p t i b i l i t y of i p s i l a t e r a l and c o n t r a l a t e r a l s t r u c t u r e s have been shown to accompany k i n d l -i n g (Goddard et al. , 1969; Racine, 1972a; Burnham, 1971, 1975). S i m i l a r l y , Wada et al. (1974) reported that independent i n t e r i c t a l discharges p e r s i s t -ing f o r periods up t o one year were observed i n various s u b c o r t i c a l s t r u c -tures of the k i n d l e d cat. Studies have a l s o shown that k i n d l i n g i s able to produce longterm changes i n the behaviour of animals. Mclntyre and Molino (1972) reported that conditioned emotional response l e a r n i n g i n r a t s was di s r u p t e d a f t e r k i n d l i n g . Adamec (1975) a l s o observed changes i n the behaviour o f cat s . He found that a red u c t i o n i n predatory aggression occurred a f t e r e l i c t i n g amygdaloid a f t e r d i s c h a r g e s . R e p e t i t i v e e l e c t r i c a l s t i m u l a t i o n does not appear to be the only agent capable of k i n d l i n g s e i z u r e s . In f a c t considerable evidence e x i s t s which i n d i c a t e s that any stimulus able to cause paroxysmal discharges i n areas of the b r a i n may be capable of k i n d l i n g s e i z u r e s . Kindled s e i z u r e s have been reported f o l l o w i n g i n j e c t i o n s o f carbachol i n t o the amygdala, hippocampus, and caudate n u c l e i o f r a t s (Vosu and Wise, 1975). Mason and Cooper (1972) reported that repeated i n j e c t i o n s of i n i t i a l l y subconvulsive doses o f Metra-29 z o l i n r a t s w i l l e v e n t u a l l y e l i c i t s e i z u r e s . I t has a l s o been shown that r e p e t i t i v e s e i z u r e s induced by f l u o r o t h y l ether ( P r i c h a r d , Gallagher, and Glaser, 1969) or e l e c t r o c o n v u l s i v e shock ( P i n e l and Van Oot, 1975) r e s u l t i n the eventual r e d u c t i o n i n the subsequent s e i z u r e t h r e s h o l d . L i t t l e experimental evidence e x i s t s as to the p o s s i b l e neurophysio-l o g i c a l substrates u n d e r l y i n g the k i n d l i n g phenomenon. As y e t , s t u d i e s have f a i l e d to f i n d morphological changes i n neurons r e l a t e d to k i n d l i n g (Goddard and Douglas, 1975; Racine, T u f f , and Zaide, 1975). Although r e -ports that p o t e n t i a t i o n of neuronal discharge patt e r n s accompanying k i n d l i n g (Douglas and Goddard, 1975; Racine et al. , 1975) have proved i n t r i g u i n g , they are s t i l l i n c o n c l u s i v e . Commissural P a r t i c i p a t i o n i n K i n d l i n g Racine, Okujava, and C h i p a s h v i l i (1972). proposed that k i n d l i n g r e s u l t -ed from the progressive strengthening of i n t e r l i m b i c connections. A f t e r -discharges generated at the s t i m u l a t e d s i t e , i t was proposed, propagated v i a monosynaptic pathways to reach other l i m b i c s t r u c t u r e s . A c t i v i t y i n these s t r u c t u r e s then spread to i n v o l v e more d i s t a n t s t r u c t u r e s and f i n a l l y much of the l i m b i c system. When t h i s p o i n t was reached, there was a f u r t h e r spread of a c t i v i t y to s t r u c t u r e s a s s o c i a t e d w i t h the motor system. I t was a c t i v a t i o n of these motor s t r u c t u r e s that e v e n t u a l l y r e s u l t e d i n the c l i n i c -a l m a n i f e s t a t i o n s . As support f o r the hypothesis, Racine et al. (1972) showed that simultaneous b i l a t e r a l s t i m u l a t i o n of l i m b i c s t r u c t u r e s f a c i l i -t a t e d the development of k i n d l e d s t r u c t u r e s . They a l s o showed that the converse was t r u e . They reported that d i s r u p t i o n of the i n t e r l i m b i c con-nections by t r a n s e c t i n g the f o r e b r a i n commissures s i g n i f i c a n t l y retarded the development of k i n d l e d amygdaloid s e i z u r e s i n the r a t . 30 Wada and Sato (1975) reported that b i s e c t i o n of the f o r e b r a i n com-missures i n the cat r e s u l t e d i n the f a c i l i t a t i o n of k i n d l i n g e l i c i t e d by s t i m u l a t i o n of the amygdala. They a l s o reported that although b i s e c t i o n of the a n t e r i o r commissure d i s r u p t e d the propagation of a f t e r d i s c h a r g e s to the c o n t r a l a t e r a l amygdala i n t h e i r c a t s , k i n d l i n g was s t i l l f a c i l i t a t e d . This seemed to suggest t h a t the c o n t r a l a t e r a l amygdala played l i t t l e i f any r o l e i n the development of k i n d l e d amygdaloid s e i z u r e s . Wada and Sato a l s o reported that since b i s e c t i o n of the f o r e b r a i n commissures d i d not d i s r u p t g e n e r a l i z a t i o n of the s e i z u r e other s u b c o r t i c a l s t r u c t u r e s were l i k e l y r e s p o n s i b l e f o r t h i s aspect of the s e i z u r e development. A l i k e l y s t r u c t u r e , they suggested, was the mesencephalic r e t i c u l a r formation since previous s t u d i e s (e.g. Wada and Sato, 1974) had i m p l i c a t e d t h i s s t r u c t u r e i n the g e n e r a l i z a t i o n o f k i n d l e d amygdaloid s e i z u r e s . They went on to sug-gest that k i n d l i n g may i n part be due to the strengthening of l i m b i c - b r a i n -stem connections r a t h e r than l i m b i c - l i m b i c connections as suggested by Racine et al. (1972)/, In c o n t r a s t to the r e s u l t s of Wada et al. (1974), Mclntyre (1975) r e -ported that b i s e c t i o n of the f o r e b r a i n commissures i n the r a t had no e f f e c t on the r a t e of amygdaloid k i n d l i n g . He als o found that the number o f stim-u l a t i o n s r e q u i r e d to k i n d l e the c o n t r a l a t e r a l amygdala a f t e r k i n d l i n g the primary s i t e ( i e . the t r a n s f e r e f f e c t ) was not s i g n i f i c a n t l y d i f f e r e n t i n e i t h e r the f o r e b r a i n - b i s e c t e d group or the i n t a c t group. B i s e c t i o n of the a n t e r i o r commissure and r o s t r a l corpus callosum, however, d i s r u p t e d propa-gat i o n of a c t i v i t y to the c o n t r a l a t e r a l amygdala. But, the lack of b i l a t e r -a l amygdaloid a f t e r d i s c h a r g e s i n these animals d i d not a f f e c t the t r a n s f e r phenomenon. This r e s u l t suggested that s t r u c t u r e s i n v o l v e d i n t h i s phenom-31 enon are s i t u a t e d e x t r a c a l l o s a l l y . Mclntyre a l s o found that f o r e b r a i n b i -s e c t i o n e l i m i n a t e d the i n t e r f e r e n c e i n s e i z u r e expression that i s t y p i c a l l y observed i n i n t a c t r a t s during the f i r s t s e v e r a l r e s t i m u l a t i o n s of the primary s i t e ( i e . , a f t e r the primary and secondary s i t e s have been k i n d l e d ) . Mclntyre (1975) found that p o r t i o n s o f the f o r e b r a i n commissures par-t i c i p a t e d i n the g e n e r a l i z a t i o n of k i n d l e d amygdaloid s e i z u r e s . He observed that the g e n e r a l i z a t i o n of s e i z u r e s was suppressed i n r a t s i n which the a n t e r i o r commissure and r o s t r a l corpus callosum were b i s e c t e d . These a n i -mals t y p i c a l l y d i s p l a y e d u n i l a t e r a l convulsive manifestations l o c a l i z e d to the c o n t r a l a t e r a l e x t r e m i t i e s o f the body. The Present I n v e s t i g a t i o n The experiments reported i n t h i s t h e s i s were designed to examine the r o l e played by the various f o r e b r a i n commissures i n the development and maintenance of k i n d l e d amygdaloid s e i z u r e s i n the r a t . The f i r s t two ex-periments are concerned with the development and e l e c t r o g r a p h i c spread of k i n d l e d s e i z u r e s i n r a t s possessing v a r y i n g degrees of f o r e b r a i n commissure b i s e c t i o n . The t h i r d experiment determines the e f f e c t s of f o r e b r a i n b i s e c -t i o n on k i n d l e d s e i z u r e s . 32 EXPERIMENT 1 Several c o n f l i c t i n g r e p o rts e x i s t concerning the e f f e c t s of f o r e b r a i n b i s e c t i o n on the development of k i n d l e d amygdaloid se i z u r e s i n l a b o r a t o r y animals (Racine et al. , 1972; Wada and Sato, 1975; Mclntyre, 1975). In view of these r e s u l t s , the present experiment was done i n order to reexamine the r o l e played by the f o r e b r a i n commissures i n the development o f k i n d l e d amygdaloid s e i z u r e s i n the r a t . The goals o f the study were: (1) to deter-mine the e f f e c t that f o r e b r a i n b i s e c t i o n had on various parameters of the c l i n i c a l s e i z u r e (e.g. r a t e of development and duration) and (2) an examin-a t i o n of the e l e c t r o g r a p h i c spread o f the s e i z u r e discharge accompanying the various stages of c l i n i c a l s e i z u r e development. Method Subj e c t s . Approximately 25 male hooded r a t s of the Long-Evans s t r a i n weighing between 250-350 g at the time of surgery were used. They were housed i n d i v i d u a l l y under ad-lib-ltum feeding and d r i n k i n g c o n d i t i o n s , con-stant room temperature, and a 12 hr l i g h t - d a r k c y c l e . Rats were allowed 10-14 days to adjust to the colony environment before undergoing surgery. Surgery. A l l f o r e b r a i n b i s e c t i o n s were done under v i s u a l c o n t r o l . The r a t s were anaesthetized with i n t e r p e r i t o n e a l i n j e c t i o n s of sodium p e n t o b a r b i t a l (25 mg/kg) and c h l o r a l hydrate (300 mg/kg) and a small t r e -phine hole was d r i l l e d over the a n t e r i o r f r o n t a l c o r t e x , l a t e r a l to the mid l i n e . The s a g i t t a l sinus was v i s u a l i z e d and a s l i g h t l y curved s t y l u s constructed from a 23 gauge syringe needle was passed through the opening and i n t o the s a g i t t a l f i s s u r e . The t i p of the s t y l u s was then passed c a u d a l l y u n t i l a poi n t marked on the shaf t of the instrument i n d i c a t e d 33 t h a t the most caudal extent of the corpus callosum had been reached. The s t y l u s was then lowered to the base of the f o r e b r a i n , thus s e c t i o n i n g the corpus callosum, hippocampal commissure, and other m i d l i n e s t r u c t u r e s . The t i p of the s t y l u s was designed with an upward curve to avoid p e n e t r a t i o n of the midbrain. In some cases b i s e c t i o n of the a n t e r i o r commissure was a l s o attempted. In these i n s t a n c e s , the t i p of the s t y l u s was r e t r a c t e d through the diencephalon to the l e v e l of the commissure and then r e i n s e r t e d to the base of the f o r e b r a i n . A s l i g h t l y d i f f e r e n t approach was used, however, i f only b i s e c t i o n o f the a n t e r i o r commissure was d e s i r e d . In t h i s case, the t i p o f the s t y l u s entered the b r a i n r o s t r a l to the corpus callosum and at an oblique angle. This tended to minimize the damage sustained by c a l l o s a l f i b e r s i n a d v e r t e n t l y contacted by the s t y l u s . The t i p of the s t y l u s was r e f l e c t e d up at a l e v e l estimated t o be j u s t d o r s a l t o the a n t e r i o r commis-sure. The e n t i r e s t y l u s was then lowered to the base of the f o r e b r a i n , thus s e c t i o n i n g the s t r u c t u r e . C o n t r o l r a t s were handled s i m i l a r l y except no attempt was made to b i -sect the f o r e b r a i n commissures. In these animals a trephine opening was placed over the l e f t f r o n t a l cortex j u s t l a t e r a l to the m i d l i n e and the s a g i t t a l sinus was v i s u a l i z e d . The dura was then cut but no attempt was made to i n s e r t the s t y l u s . Both groups of r a t s r e c e i v e d i d e n t i c a l p o s t s u r g i c a l treatment. The trephined opening was packed with gelfoam and the scal p i n s c i s i o n was c l o s -ed with s t a i n l e s s s t e e l wound c l i p s . P ostoperative recovery was observed f o r t h i r t y days. Rats that d i s p l a y e d behavioural evidence suggesting gross n e u r o l o g i c a l d y s f u n c t i o n i n g were discarded. 34 Electrode i m p l a n t a t i o n . T h i r t y days a f t e r surgery a l l s u r v i v i n g r a t s were reanaesthetized w i t h an i n t e r p e r i t o n e a l i n j e c t i o n of sodium pentobarb-i t a l (60 mg/kg) and b i p o l a r s t i m u l a t i n g and rec o r d i n g electrodes were im-planted. The electrodes were constructed o f t w i s t e d nichrome wire and had a f i n a l diameter of 127 ym. Each a l s o had a t i p separation of 0.5 mm and one pole bared of i n s u l a t i o n f o r 0.5 mm along i t s length. M i n i a t u r e male connector pins (Amphenol, P202) were soldered to the leads of each e l e c t r o d e . A l l r a t s r e c e i v e d e l e c t r o d e s aimed b i l a t e r a l l y at the b a s o l a t e r a l nucleus o f the amygdala ([AM] 0.4 mm a n t e r i o r to bregma, 4.3 mm l a t e r a l to the m i d l i n e , 8.5 mm v e n t r a l from the surface of the cort e x , and with the i n s c i s o r bar set at +5.0 mm). In some r a t s electrodes were al s o aimed at the l e f t mesencephalic r e t i c u l a r formation (MRF) at the l e v e l of the super-i o r c o l l i c u l u s (4.4 mm p o s t e r i o r to bregma, 2.0 mm l a t e r a l to the m i d l i n e , 5.5 mm v e n t r a l from the surface o f the cort e x , and with the i n s c i s o r bar set at +5.0 mm). These same r a t s were a l s o prepared with b i p o l a r c o r t i c a l e l ectrodes placed over the motor areas 4 and 6 (MC) of the cortex as shown by Skinner (1971). Each pole of the ele c t r o d e c o n s i s t e d of a c o i l e d loop 2 of nichrome wire that enclosed an area o f approximately 1.0 mm . One pole was placed over Area 4 (1.5 mm p o s t e r i o r to bregma and 1.5 mm l a t e r a l to the m i d l i n e ) , and the other pole was placed over Area 6 (2.5 mm a n t e r i o r to bregma and 1.5 mm l a t e r a l to the m i d l i n e ) . In both cases care was taken not to penetrate the dura. A ground e l e c t r o d e c o n s i s t i n g of a bare s t a i n l e s s s t e e l w i r e, soldered onto a miniature connector p i n , and then t w i s t e d around the head of a miniature screw, was d r i v e n i n t o the f r o n t a l bone of each r a t . Electrodes were h e l d i n place w i t h dental a c r y l i c cement. The temporal muscles along each s i d e of the head were r e t r a c t e d and screws were d r i v e n 35 i n t o the exposed temporal bone. The screws were then covered with a c r y l i c and served as anchors f o r the e l e c t r o d e assembly. The connector pins were arranged i n a s t r a i g h t l i n e running p a r a l l e l to the m i d l i n e ( i f more than two electrodes and a ground e l e c t r o d e were used, then the pins were arrang-ed i n two p a r a l l e l l i n e s ) and held i n place by a s p e c i a l l y constructed tem-p l a t e . The e n t i r e assembly was h e l d together w i t h dental a c r y l i c cement. In an e f f o r t to p r o t e c t the p i n s from being e i t h e r bent or broken by the r a t , a p l a s t i c guard constructed from a 10 mm length of lOcc syringe tubing was f i t t e d and then cemented i n place around the assembly. A l l r a t s were observed f o r a minimum of one week f o l l o w i n g the implant-a t i o n of e l e c t r o d e s . During t h i s time they were p e r i o d i c a l l y handled and checked f o r i n f e c t i o n s . T e s t i n g procedures. T e s t i n g was conducted once d a i l y between 1000 and 1200 hr. The r a t s were transported i n d i v i d u a l l y to the t e s t i n g room and placed i n a s p e c i a l l y constructed cage s h i e l d e d with copper mesh. They were allowed s e v e r a l minutes to adapt to the cage and then b a s e l i n e EEG a c t i v i t y was recorded f o r 2 minutes. E l e c t r i c a l s t i m u l a t i o n c o n s i s t e d of a 1 sec t r a i n of 60 Hz constant current sine wave d e l i v e r e d at a f i x e d current i n t e n s i t y of 160 ya f o r a l l r a t s . S t i m u l a t i o n was i n i t i a l l y a p p l i e d to the r i g h t AM i n most r a t s . Amygdaloid k i n d l i n g . The progressive development of k i n d l e d - s e i z u r e s was c l a s s i f i e d according to the d e s c r i p t i o n by Racine (1972a):, C - l , t w i t c h -i n g of muscles around the mouth and eyes; C-2, the above as w e l l as head nodding; C-3, the above as w e l l as f o r e l i m b clonus; C-4, the above as w e l l as r e a r i n g onto the hindlimbs; C-5, the above as w e l l as l o s s of balance and f a l l i n g . Seizures were recorded only i f the c l i n i c a l m a n i f e s t a t i o n s were sustained f o r s e v e r a l seconds a f t e r the t e r m i n a t i o n of the s t i m u l a t i o n . 36 This c r i t e r i o n was introduced to c o n t r o l f o r the p o s s i b i l i t y of stimulus-bound motor movements being included i n the c l i n i c a l p r ogression. Rats were considered k i n d l e d upon reaching the C-5 stage i n s e i z u r e development. Eight C-5 s e i z u r e s were evoked from the i n i t i a l s i t e of s t i m u l a t i o n (primary s i t e ) . On the f o l l o w i n g s e s s i o n ( i n most cases t h i s was the f o l -lowing day) the s i t e of s t i m u l a t i o n was switched to the c o n t r a l a t e r a l AM (secondary s i t e ) i n order to study the t r a n s f e r e f f e c t . T ransfer r e f e r s to the f a c i l i t a t e d development of secondary s i t e k i n d l i n g that i s produced as a r e s u l t of previous k i n d l i n g at the primary s i t e . Rats were then k i n d -led at the secondary s i t e and allowed to have eight C-5 s e i z u r e s . A f t e r d i s c h a r g e and s e i z u r e d u r a t i o n . The a f t e r d i s c h a r g e and s e i z u r e d u r a t i o n associated with each stage of development were recorded from the s t a r t to the f i n i s h of a l l c l i n i c a l m a n i f e s t a t i o n s , except during stages 4 and 5. During these stages the s e i z u r e d u r a t i o n from the s t a r t to f i n i s h of f o r e l i m b c l o n i c a c t i v i t y was recorded. A f t e r d i s c h a r g e d u r a t i o n , however, was recorded over the e n t i r e s e s s i o n . H i s t o l o g y . F o l l o w i n g the completion of the study, r a t s were k i l l e d w i t h an overdose of sodium p e n t o b a r b i t a l and perfused i n t e r c a r d i a l l y w i t h 0.9% s a l i n e followed by 10% f o r m a l i n . The b r a i n was removed and examined f o r signs of c o r t i c a l damage r e s u l t i n g from b i s e c t i o n of the commissures. The b r a i n was then frozen and coronal s e c t i o n s 40 ym i n thickness were cut on a s l i d i n g microtome. Every f i f t h s e c t i o n (0.2 mm) was kept and s t a i n e d with c r e s y l v i o l e t . The e l e c t r o d e placements were examined and the extent of the f o r e b r a i n b i s e c t i o n was p l o t t e d on s e c t i o n s taken from the a t l a s of P e l l e g r i n o and Cushman (1967) . C o r t i c a l e l e c t r o d e placements were v i s u a l l y determined at the time the b r a i n was removed. Data from animals not having 37 electrodes i n the d e s i r e d s t r u c t u r e s were discarded. Tracings were produced of r e p r e s e n t a t i v e f o r e b r a i n b i s e c t i o n s taken from the samples that remained. S t a t i s t i c a l a n a l y s i s . S t a t i s t i c a l a n a l y s i s of the data was done usi n g standard parametric a n a l y s i s of variance procedures. A l l post hoc compari-sons were achieved us i n g the Scheffe - method f o r m u l t i p l e comparisons. S i g n i -f i c a n t l e v e l s of p were a l l t w o - t a i l e d . A t t e n t i o n was paid to those aspects of the data that d e a l t with the number of s t i m u l a t i o n s to k i n d l e , the a f t e r d i s c h a r g e d u r a t i o n at a l l record-ing s i t e s , and s e i z u r e d u r a t i o n . A n a l y s i s of these v a r i o u s parameters was conducted f o r both primary and secondary s i t e k i n d l i n g . A d e t a i l e d record of the a f t e r d i s c h a r g e development and propagation from the s t i m u l a t e d s i t e i n each r a t was a l s o compiled. Results Eighteen of 25 r a t s s u r v i v e d the f o r e b r a i n b i s e c t i o n and i m p l a n t a t i o n of the e l e c t r o d e s . A l l 10 c o n t r o l r a t s survived the t r e p h i n a t i o n and sub-sequent i m p l a n t a t i o n of e l e c t r o d e s . One-way a n a l y s i s of variance f a i l e d to show any s i g n i f i c a n t d i f f e r e n c e i n the r a t e at which f o r e b r a i n b i s e c t e d and c o n t r o l r a t s k i n d l e d (F=.ll; ci.f=l,23; p>.05). Post hoc h i s t o l o g i c a l examination of the b r a i n , however, showed that b i s e c t i o n of the r o s t r a l corpus callosum, hippocampal, and a n t e r i o r commissures caused a s i g n i f i c a n t f a c i l i t a t i o n i n k i n d l i n g . B i -s e c t i o n of the corpus callosum and hippocampal commissure had no e f f e c t . K i n d l i n g was retarded only i n r a t s s u s t a i n i n g extensive s u b c o r t i c a l , thalamic damage i n a d d i t i o n to f o r e b r a i n b i s e c t i o n . 38 Propagation of a f t e r d i s c h a r g e s (ADs) to the c o n t r a l a t e r a l AM was d i s -rupted by a n t e r i o r commissure b i s e c t i o n whereas corpus callosum b i s e c t i o n d i s r u p t e d propagation of ADs to the c o n t r a l a t e r a l MC. Forebrain b i s e c t i o n had l e s s e f f e c t on the r a t e of secondary s i t e k i n d l i n g than on primary s i t e k i n d l i n g . The e f f e c t s on e l e c t r o g r a p h i c spread of the s e i z u r e , however, remained e s s e n t i a l l y the same during p r i -mary and secondary k i n d l i n g . H i s t o l o g y . The l o c a t i o n of e l e c t r o d e s i s shown i-n F i g . 1. A l l e l e c t r o d e t i p s were found i n or immediately adjacent to the intended s t r u c t u r e s . AM electrodes were found concentrated i n an area surrounding the b a s o l a t e r a l nucleus. Electrodes aimed at the MRF were l o c a l i z e d to an area immediately l a t e r a l to the nucleus of the oculomotor nerve and at the l e v e l of the s u p e r i o r c o l l i c u l u s . V i s u a l a n a l y s i s of the c o r t i c a l e l e c trode placements found these to be o v e r l y i n g the d e s i r e d s t r u c t u r e s : Areas 4 and 6. Post hoc h i s t o l o g i c a l examination of the experimental group i n d i c a t e d that the extent of the f o r e b r a i n b i s e c t i o n was not homogenous. Based on t h i s examination, i t was p o s s i b l e to a s s i g n each of the experimental r a t s to one of the 3 f o l l o w i n g groups: Group CC, b i s e c t i o n of the corpus c a l l o s -um and hippocampal commissure; Group AC, b i s e c t i o n of the a n t e r i o r commis-sure w i t h minimal damage to the r o s t r a l corpus callosum; Group TD, p a r t i a l b i s e c t i o n of the r o s t r a l corpus callosum and hippocampal commissure i n com-b i n a t i o n with extensive extracommissural thalamic damage. Representative h i s t o l o g y from each of these groups i s presented i n F i g . 2. A l l groups d i s p l a y e d some evidence of extracommissural damage. In group CC, damage to the cortex o v e r l y i n g the corpus callosum appeared to be 39 F i g . 1. L o c a l i z a t i o n of s t i m u l a t i n g and r e c o r d i n g e l e c t r o d e s . ATH=anterior thalamus; AM=amygdala; FC=frontal cortex; MC=motor cortex; MRF=mesencephalic r e t i c u l a r formation. 39a 40 s l i g h t and i n most cases l o c a l i z e d to the medial aspects of the r o s t r a l f o r e b r a i n . S u b c o r t i c a l l y there was a s l i g h t d i l a t i o n of the l a t e r a l ven-t r i c a l s but t h i s d i d not appear to be caused by o b s t r u c t i o n of the aque-duct. Damage to the d o r s a l aspects of the l a t e r a l s e p t a l nucleus was evident i n some r a t s although t h i s tended to be u n i l a t e r a l and minimal. There was l i t t l e s i g n of p e n e t r a t i o n of the m i d l i n e thalamic n u c l e i i n t h i s group. S i m i l a r l y , caudal to the hippocampal commissure the hippo-campus appeared undamaged i n most r a t s . The p o s t e r i o r commissure i n a number of r a t s was found to be sectioned whereas the u n d e r l y i n g midbrain appeared to be i n t a c t . Extracommissural damage to the cortex of r a t s i n Group AC was i n some cases n e a r l y nonexistent. A number of r a t s , however, possessed s l i g h t damage to the r o s t r a l c ortex along the medial boundary of Area 10. Sub-c o r t i c a l damage was observed mainly i n the l a t e r a l s e p t a l n u c l e i and anter-i o r hypothalamus. In the septum, i t appeared as though involvement of the l a t e r a l n u c l e i caused widespread degeneration throughout the r e s t of the s t r u c t u r e . P e n e t r a t i o n of the hypothalamus was most f r e q u e n t l y observed i n the p r e o p t i c area and areas r o s t r a l to the a n t e r i o r commissure. Rats i n Group TD possessed the most extracommissural damage. Damage to the cortex of t h i s group d i d not appear to be any more extensive than that observed i n Groups AC and CC. S i m i l a r l y , there was some d e s t r u c t i o n of the dorsomedial aspects of the l a t e r a l s e p t a l n u c l e i and a s l i g h t v e n t r i -c u l a r d i l a t i o n was observed i n a m i n o r i t y of r a t s . By f a r the most exten-s i v e extracommissural damage was i n the v i c i n i t y of the r i g h t r o s t r a l t h a l -amus. Damage to t h i s s t r u c t u r e appeared to be roughly confined to an area bounded r o s t r a l l y by the midportion of the a n t e r o v e n t r a l thalamic nucleus, 41 F i g . 2. Extent of the f o r e b r a i n b i s e c t i o n i n a r e p r e s e n t a t i v e r a t from each group. The b i s e c t i o n i s i n d i c a t e d by the crosshatching. L i g h t l y shaded areas represent v e n t r i c u l a r spaces. Note the large area of d e s t r u c t i o n w i t h i n the r o s t r a l thalamic area of Group TD. 41a 42 m e d i a l l y by the m i d l i n e , and l a t e r a l l y by the i n t e r n a l capsule. The f l o o r of the r i g h t l a t e r a l v e n t r i c l e was the d o r s a l extreme of the damage, and the medial lemniscus formed the v e n t r a l extreme. Caudally, the damage ex-tended to an area approximately at the t i p of the dorsomedial nucleus of the thalamus. N u c l e i w i t h i n t h i s zone of d e s t r u c t i o n appeared to be i n v o l v e d to v a r y i n g degrees. The n u c l e i most a f f e c t e d appeared t o be the r o s t r a l thalamic n u c l e i ( i e . a n t e r o d o r s a l , a n t e r o v e n t r a l , and anteromedial n u c l e i ) . Also a f f e c t e d , however, were p o r t i o n s of the v e n t r a l thalamus i n c l u d i n g the v e n t r o a n t e r i o r nucleus and the r e t i c u l a r nucleus. P o r t i o n s of the m i d l i n e thalamus were a l s o i n v o l v e d . The dorsomedial nucleus sustained the most extensive damage along the m i d l i n e . F i b e r bundles coursing through the above areas of the thalamus were als o d i s r u p t e d by the damage. Both the s t r i a m e d u l l a r i s and the s t r i a t e r m i n a l i s were sectioned as a r e s u l t of the widespread damage. P r i m a r y - s i t e k i n d l i n g A. P r i m a r y - s i t e c l i n i c a l s e i z u r e development. L i t t l e d i f f e r e n c e be-tween the c l i n i c a l s e i z u r e development of f o r e b r a i n - b i s e c t e d r a t s and c o n t r o l r a t s (Group C) was observed during the e a r l y stages of k i n d l i n g . A l l r a t s d i s p l a y e d the p r o g r e s s i v e development of s e i z u r e s commencing with i p s i l a t e r a l eye c l o s u r e , gradual appearance of muscle twitches around the mouth ( C - l ) , and f i n a l l y pronounced head nodding (C-2) . With the appearance of C-3, however, c l i n i c a l d i f f e r e n c e s between the c o n t r o l s and f o r e b r a i n - . b i s e c t e d r a t s became evident. C o n t r o l r a t s at C-3 normally showed a p a t t e r n of a l t e r n a t i n g forelimb clonus whereas r a t s i n a l l three b i s e c t e d groups di s p l a y e d only u n i l a t e r a l f o r e l i m b clonus. C l o n i c a c t i v i t y i n the b i s e c t e d r a t s remained l o c a l i z e d to the f o r e l i m b c o n t r a l a t e r a l to the s t i m u l a t e d 43 s i t e . These d i f f e r e n c e s between the two p e r s i s t e d throughout the subsequent stages 4 and 5. The development of C-3 i n the c o n t r o l group was t y p i c a l l y a s s o c i a t e d w i t h g e n e r a l i z e d s e i z u r e manifestations but these were u s u a l l y secondary ( i e . clonus appeared f i r s t i n the c o n t r a l a t e r a l f o r e l i m b and then became b i l a t e r a l ) . This p a t t e r n predominated through the c l i n i c a l development up to approximately the t h i r d or f o u r t h C-5. At t h i s p o i n t what can only be c a l l e d primary g e n e r a l i z e d C-5 s e i z u r e s developed. The s t i m u l a t i o n t r i g -gered an immediated f u l l - b l o w n , b i l a t e r a l convulsive C-5. This p a t t e r n sub-sequently p e r s i s t e d throughout the f o l l o w i n g C-5s. In f o r e b r a i n - b i s e c t e d r a t s , Groups CC and AC, the development of second-ary g e n e r a l i z a t i o n was retarded: u s u a l l y i t d i d not become evident u n t i l s e v e r a l C-4 s e i z u r e s had been evoked. S i m i l a r l y , the appearance of primary ge n e r a l i z e d C-5s was slowed but not stopped. T y p i c a l l y , t h i s p a t t e r n d i d not emerge u n t i l the s i x t h or seventh C-5. Rats i n Group TD seemed to present a s p e c i a l case. These animals f a i l -ed to d i s p l a y evidence of e i t h e r primary or secondary g e n e r a l i z a t i o n . The c l i n i c a l m a n ifestations i n these r a t s remained asymmetrical, and l o c a l i z e d to the c o n t r a l a t e r a l e x t r e m i t i e s throughout the course of primary s i t e k i n d l i n g . A l l of the r a t s d i s p l a y e d t h i s response r e g a r d l e s s o f the l a t e r -a l i t y of the s t i m u l a t e d AM with respect to the e x t r a c a l l o s a l damage. Three of the 4 r a t s i n t h i s group were i n i t i a l l y k i n d l e d by s t i m u l a t i o n of the AM c o n t r a l a t e r a l to the e x t r a c a l l o s a l damage. Two of the 3 r a t s that were k i n d l e d from s t i m u l a t i o n of the AM contra-l a t e r a l to the e x t r a c a l l o s a l damage developed i n t e r e s t i n g s e i z u r e p a t t e r n s . These con s i s t e d of two d i s t i n c t convulsive episodes w i t h i n a s i n g l e s e s s i o n . 44 This p a t t e r n emerged during the l a t e r C-4s and p e r s i s t e d throughout the f o l l o w i n g C-5s. T y p i c a l l y the s e i z u r e p a t t e r n i n these r a t s began as an asymmetrical C-5 and then terminated w i t h a p e r i o d of immobility. Follow-ing t h i s , however, another asymmetrical C-5 s e i z u r e appeared. The dis-.. t i n g u i s h i n g feature of t h i s attack was that the l a t e r a l i t y of the s e i z u r e was opposite to that of the f i r s t C-5. The e l e c t r o g r a p h i c c o r r e l a t e s of these s e i z u r e s are shown i n F i g . 3. B. P r i m a r y - s i t e e l e c t r o g r a p h i c development and propagation. Bisec-. t i o n of the f o r e b r a i n commissures was found to exert i t s major e f f e c t on the propagation of a f t e r d i s c h a r g e (AD) from the primary s i t e to c e r t a i n c o n t r a l a t e r a l s t r u c t u r e s . V a r i a t i o n s i n the propagation of AD to these s t r u c t u r e s ( i e . AM, MRF, and MC) was i n t u r n found to depend on the extent of the b i s e c t i o n . A l l groups d i s p l a y e d r e l a t i v e l y l o c a l i z e d AD i n the s t i m u l a t e d s i t e during C - l . I t was not u n t i l the appearance of C-2 that appreciable pro-pagated a c t i v i t y to the c o n t r a l a t e r a l s t r u c t u r e s was observed. Group C and r a t s i n Groups CC and TD showed ready propagation of AD i n t o the contra-l a t e r a l AM during stages 2 and 3. Group AC, however, i n which the r o s t r a l corpus callosum and a n t e r i o r commissure were sectioned, d i s p l a y e d l i t t l e i f any evidence of c o n t r a l a t e r a l AM a c t i v i t y . Regardless of t h i s , r a t s i n t h i s group d i s p l a y e d no d e f i c i t i n the c l i n i c a l development of stages 2 and 3 or subsequent stages. Stages 2 and 3 were c h a r a c t e r i z e d by the propagation of AD i n t o the c o n t r a l a t e r a l MC and MRF of a l l groups except Group TD ( r a t s i n t h i s group possessed b i l a t e r a l AM e l e c t r o d e s o n l y ) . A s i g n i f i c a n t . f e a t u r e of t h i s pro-pagation was that b i s e c t i o n of the corpus callosum and hippocampal commis-45 sure (Group CC) d i d not i n h i b i t i t s spread to the c o n t r a l a t e r a l MC. S i m i l a r -l y , r a t s i n Group AC d i s p l a y e d l i t t l e , : i f any, observable c o n t r a l a t e r a l AM AD yet propagation i n t o the c o n t r a l a t e r a l MC and MRF was not a f f e c t e d . During the e a r l y stages of k i n d l i n g ( i e . stages 1, 2, and 3) AD i n the c o n t r a l a t e r a l s t r u c t u r e s was synchronous w i t h that of the st i m u l a t e d s i t e . AD propagated i n t o these s t r u c t u r e s was c h a r a c t e r i z e d by a moderately high amplitude, 3-6/sec spike and wave discharge. A d i s t i n g u i s h i n g f e a t u r e of these e a r l y stages r e l a t e s to the appearance of foreli m b clonus (C-3) i n the b i s e c t e d and c o n t r o l groups. Although AD r e a d i l y propagated i n t o the contra -l a t e r a l MRF and MC of a l l of these groups, the c o n t r o l group d i s p l a y e d b i -l a t e r a l clonus whereas the b i s e c t e d groups d i s p l a y e d u n i l a t e r a l clonus. The e l e c t r o g r a p h i c c o r r e l a t e s o f a t y p i c a l C-5 s e i z u r e i n each group are shown i n F i g . 3. A high amplitude, 6-8/sec p o l y s p i k e and wave discharge was observed i n the c o n t r a l a t e r a l MC of Group C and Group AC with the appear-ance of C-5 ( F i g . 3). O c c a s i o n a l l y , a s i m i l a r p a t t e r n was a l s o observed i n the c o n t r a l a t e r a l MRF. The appearance of t h i s p a t t e r n was c h a r a c t e r i z e d by: (1) i t s independence from that of the st i m u l a t e d s i t e ; (2) i t s appearance during the stage 4 and stage 5 phase o f the s e i z u r e ; (3) the immediate term-i n a t i o n of the p a t t e r n with the end of the C-4 or C-5 c l i n i c a l m a n i f e s t a t i o n s . B i s e c t i o n of the corpus callosum and hippocampal commissure (Group CC) sup-pressed the appearance o f t h i s p a r t i c u l a r AD p a t t e r n i n the c o n t r a l a t e r a l MC ( F i g . 3). AD i n the MC of these r a t s was in s t e a d c h a r a c t e r i z e d by a r e -duced amplitude, 4-6/sec spike and wave p a t t e r n with slow background a c t i v -i t y . The absence of the p o l y s p i k e and wave i n the c o n t r a l a t e r a l MC of Group CC, however, d i d not a f f e c t the c l i n i c a l response. Animals i n t h i s group e v e n t u a l l y d i s p l a y e d a primary g e n e r a l i z e d C-5 as d i d those i n Groups AC and C,:.in which the p o l y s p i k e and wave p a t t e r n was evident. 46 In Groups C and CC l i t t l e subsequent development i n the propagation of AD i n t o the c o n t r a l a t e r a l AM was observed a f t e r the appearance of C-5. Eight C-5 s e i z u r e s were evoked, however, and during t h i s time r a t s i n these two groups d i s p l a y e d a trend towards a complex discharge p a t t e r n c o n s i s t i n g of i r r e g u l a r , high amplitude, 5-8/sec p o l y s p i k e and wave a c t i v i t y i n both the s t i m u l a t e d and c o n t r a l a t e r a l AM ( F i g . 3). Rats i n Group AC showed t h i s trend only at the s t i m u l a t e d s i t e . B i s e c t i o n of the r o s t r a l corpus callosum and a n t e r i o r commissure i n t h i s group i n h i b i t e d the propagation of AD to the c o n t r a l a t e r a l AM ( F i g . 3) even a f t e r e i g h t C-5s had been evoked. This lack of c o n t r a l a t e r a l AM a c t i v i t y , however, d i d not d i s r u p t the eventual appear-ance of primary g e n e r a l i z e d C-5 s e i z u r e s . Propagation of AD i n t o the c o n t r a l a t e r a l AM of Group TD seemed to pre-sent a s p e c i a l case. At the stimulated s i t e , the appearance of C-5 was a s s o c i a t e d with the development of a high amplitude, 5-8/sec p o l y s p i k e and wave discharge not u n l i k e that observed i n the other groups. However, only minimal propagation of AD to the c o n t r a l a t e r a l AM was observed. Following the t e r m i n a t i o n of AD at the s t i m u l a t e d s i t e there was a p e r i o d of immobil-i t y . This i n t u r n was followed by a r e c r u i t i n g - l i k e burst of 7-10/sec, high amplitude spike discharges confined to the c o n t r a l a t e r a l AM. The appearance of t h i s a c t i v i t y was r e l a t e d to a second stage-5 c l i n i c a l response ( F i g . 3). A main feat u r e of t h i s c l i n i c a l response was that during the primary s i t e AD the s e i z u r e was l o c a l i z e d i n the c o n t r a l a t e r a l e x t r e m i t i e s whereas during AD i n the c o n t r a l a t e r a l AM the s e i z u r e was l o c a l i z e d to the i p s i l a t e r a l ex-t r e m i t i e s ( i p s i l a t e r a l to the primary s i t e ) . This phenomenon was observed i n two of the 4 r a t s i n t h i s group. In the remaining 2, s i m i l a r e l e c t r o -graphic features were present but a second c l i n i c a l s e i z u r e was not observed. 47 F i g . 3. E l e c t r o g r a p h i c c o r r e l a t e s of a p r i m a r y - s i t e C-5 s e i z u r e d i s p l a y e d by a t y p i c a l r a t from each group. Arrows i n -d i c a t e the s i t e of s t i m u l a t i o n ; the c i r c l e d numbers under each record i n d i c a t e the c l i n i c a l response being d i s p l a y e d . R=right; L = l e f t . Note that i n Group CC, b i s e c t i o n of the corpus callosum and hippocampal commissure s e v e r l y d i s r u p t s AD propagation i n t o the c o n t r a l a t e r a l R MC but not the R AM or R MRF. In Group AC, propagation of AD to the c o n t r a l a t -e r a l AM (L AM) i s markedly reduced. AD i n R MC and R MRF of t h i s group d i s p l a y s a p o l y s p i k e and wave c o n f i g u r a t i o n t y p i c a l of these s t r u c t u r e s . Note the c o r r e l a t i o n between the end of f o r e l i m b clonus and the disappearance of t h i s p a t t e r n . The record from Group TD shows the AD c o r r e l a t e s of the two se i z u r e s d i s p l a y e d by r a t s o f t h i s group. Note the increase i n c o n t r a l a t e r a l AM (R AM) a c t i v i t y that i s as s o c i a t e d with the appearance of the second s e i z u r e . 47a 48 No evidence of t h i s phenomenon was observed i n r a t s from any of the other b i s e c t e d groups. C. Rate of p r i m a r y - s i t e k i n d l i n g . Data concerning the r a t e of primary s i t e k i n d l i n g i n each group are summarized i n Table I. One-way a n a l y s i s of variance i n d i c a t e d that b i s e c t i o n of the f o r e b r a i n commissures produced an o v e r a l l s i g n i f i c a n t e f f e c t on the r a t e of primary s i t e k i n d l i n g (F=8.22; df=3,21; p<.01). Subsequent a n a l y s i s using the Scheffe" method f o r m u l t i p l e comparisons i n d i c a t e d that Group AC, i n which the r o s t r a l corpus callosum and a n t e r i o r commissure were sectioned, k i n d l e d s i g n i f i c a n t l y f a s t e r than the c o n t r o l group (F=2.95; df=1,21; p<.05). No s i g n i f i c a n t d i f f e r e n c e i n the r a t e of k i n d l i n g between Group C and Group CC was found. Group TD, i n which p a r t i a l b i s e c t i o n of the corpus callosum was accompanied by extensive damage to extracommissural s t r u c t u r e s , k i n d l e d s i g n i f i c a n t l y slower than c o n t r o l s (F=3.31; df =1,21; p<.05). I t was also found that Group TD k i n d l e d s i g n i f i c a n t l y slower than Group CC (^=4.44; cif=l,21; p<.05) and Group AC (F=4.21; df=1,21; p<.05). In Group TD there was no evidence to suggest that the r e t a r d a t i o n i n k i n d l i n g was r e l a t e d to the s t i m u l a t i o n of the AM i p s i -l a t e r a l to the extensive extracommissural damage, and i n f a c t the opposite appeared t r u e . Three of the 4 r a t s i n t h i s group were k i n d l e d by s t i m u l a t -i n g the AM c o n t r a l a t e r a l to the damage. D. P r i m a r y - s i t e s e i z u r e d u r a t i o n . Once k i n d l e d , each r a t was allowed to have an a d d i t i o n a l e i g h t C-5 s e i z u r e s . The mean s e i z u r e d u r a t i o n of each group i s shown i n F i g . 4A. I t i s evident from t h i s f i g u r e that b i -s e c t i o n of the f o r e b r a i n commissures had l i t t l e , i f any, e f f e c t on the s e i z u r e d u r a t i o n . There was a tendency f o r Group TD to d i s p l a y s l i g h t l y longer s e i z u r e s but t h i s was i n p a r t due to the i n c l u s i o n of the second 49 TABLE I MEAN NUMBER OF SESSIONS TO KINDLE AT EACH SITE Group Sessions to k i n d l e primary s i t e Sessions to k i n d l e secondary s i t e C (con t r o l ) 13.3 (10-18) 7.6 (4-15) ri=7 n=5 CC ( r o s t r a l corpus callosum, hippocampal commissure, and a n t e r i o r commissure) 10.0 (4-17) ri=10 4.5 (1-9) n = 10 AC ( a n t e r i o r commissure) 8.5 * (5-12) 8.0 (4-11) n=4 n=4 TD (thalamic damage) 22.0 * (16-27) 12.7 t (1-27) n=4 n=3 * S i g n i f i c a n t l y d i f f e r e n t from Group C, p<0.05 t S i g n i f i c a n t l y d i f f e r e n t from primary s i t e , p<0.05 50 F i g . 4A. P r i m a r y - s i t e k i n d l e d s e i z u r e d u r a t i o n recorded over eig h t successive stage-5 s e i z u r e s . F i g . 4B. Secondary-site k i n d l e d s e i z u r e d u r a t i o n recorded over e i g h t successive stage-5 s e i z u r e s . No s i g n i f i c a n t d i f f e r e n c e s were found between p r i m a r y - s i t e and second-a r y - s i t e s e i z u r e d u r a t i o n s . 50a Se i zure Durat ion (sec) 51 s e i z u r e d u r a t i o n i n the t o t a l s e i z u r e d u r a t i o n . This e f f e c t , however, was not s t a t i s t i c a l l y s i g n i f i c a n t . Group CC tended to d i s p l a y the s h o r t e s t seizures but t h i s a l s o was not s i g n i f i c a n t . No s i g n i f i c a n t e f f e c t s were noted with respect to e i t h e r Group AC or Group C. E. AD d u r a t i o n during p r i m a r y - s i t e k i n d l e d s e i z u r e s . F i g . 5A shows the AD durations recorded from the s t i m u l a t e d and c o n t r a l a t e r a l AM over the eight C-5 s e i z u r e s . The d u r a t i o n of the AD at other s i t e s i s not shown f o r reasons of c l a r i t y but w i l l be discussed i n the t e x t where appropriate. Over the eight sessions there was a marked tendency f o r the AD of the s t i m u l a t e d AM i n the c o n t r o l group to be longer than that of the f o r e b r a i n -b i s e c t e d groups. The d i f f e r e n c e , however, was not c o n s i s t e n t l y s i g n i f i c a n t . B i s e c t i o n of the f o r e b r a i n commissures exerted i t s major e f f e c t on the d u r a t i o n of the AD propagated i n t o the c o n t r a l a t e r a l AM. O v e r a l l , b i s e c t i o n of the commissures was a s s o c i a t e d w i t h a decrease i n AD i n the c o n t r a l a t e r a l AM. This e f f e c t was most obvious i n Group AC, i n which the r o s t r a l corpus callosum and a n t e r i o r commissure were b i s e c t e d . In t h i s group the d u r a t i o n of AD i n the c o n t r a l a t e r a l AM was c o n s i s t e n t l y s h o r t e r than that of the stimulated s i t e . I t was a l s o found that the AD d u r a t i o n of the c o n t r a l a t -e r a l AM i n Group AC was s i g n i f i c a n t l y s h o r t e r than the AD i n the contra-l a t e r a l AM i n the c o n t r o l group f o r the f i r s t s i x sessions (ps<.05). No s i g n i f i c a n t d i f f e r e n c e s were found between the d u r a t i o n of AD i n the ..stimu-l a t e d and c o n t r a l a t e r a l AM i n any o f these groups and Group AC or C. B i s e c t i o n of the f o r e b r a i n commissures d i d not a f f e c t the d u r a t i o n of AD recorded from the c o n t r a l a t e r a l MRF or MC. This was i n contrast to the marked a t t e n u a t i o n of AD i n c o n t r a l a t e r a l AM that was observed i n Group AC. In general, the d u r a t i o n of the AD recorded from e i t h e r the c o n t r a l a t e r a l 52 F i g . 5A. Mean AD dur a t i o n ( i n sees) recorded from the s t i m u l a t e d (primary) and c o n t r a l a t e r a l (secondary) AM during eight successive p r i m a r y - s i t e stage-5 s e i z u r e s . Note the s l i g h t l y lower d u r a t i o n of the secondary-site AD. F i g . 5B. Mean AD du r a t i o n ( i n sees) recorded from the st i m u l a t e d (secondary) and c o n t r a l a t e r a l (primary) AM during eight successive secondary-site stage-5 s e i z u r e s . Note the marked re d u c t i o n i n p r i m a r y - s i t e AD d i s p l a y e d by r a t s i n Groups AC and TD. 52a 100 PRIMARY SECONDARY 2 80 O D DURATI * en o o " AC < • AC < - » C C • TD E , , . 1 1 1 1 1 i i i i i i i — i — 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 SUCCESSIVE STAGE-5 SEIZURES 100 ,SECONDARY \ PRIMARY o 8 0 i K 60 3 0 O 4 0 < -2 20 < l l > 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 SUCCESSIVE STAGE-5 SEIZURES 53 MRF or MC was only m a r g i n a l l y d i f f e r e n t from that recorded from the stimu-l a t e d s i t e . In most cases, the d u r a t i o n of AD i n these s t r u c t u r e s was i d e n t i c a l to that of the s t i m u l a t e d s i t e . Secondary-site k i n d l i n g S t i m u l a t i o n was switched to the c o n t r a l a t e r a l AM (secondary s i t e ) a f t e r e i g h t C-5 s e i z u r e s had been evoked from the primary s i t e . Of the r a t s that survived and d i d not dislodge t h e i r e l e c t r o d e assemblies, only one f a i l e d to k i n d l e with secondary AM s t i m u l a t i o n . A. Secondary-site c l i n i c a l s e i z u r e development. With a few minor ex-c e p t i o n s , the c l i n i c a l development of s e i z u r e s observed during secondary-s i t e k i n d l i n g was e s s e n t i a l l y the same as that observed during primary s i t e k i n d l i n g . No obvious d i f f e r e n c e s were observed between the c o n t r o l and b i s e c t e d r a t s during stages 1 and 2 of secondary-site k i n d l i n g . With the appearance of C-3, however, evidence of secondary g e n e r a l i z a t i o n became n o t i c e a b l e i n the c o n t r o l group but not the b i s e c t e d groups. The c l o n i c component of the s e i z u r e became b i l a t e r a l i n the c o n t r o l group, spreading from the c o n t r a l a t e r a l f o r e l i m b to the i p s i l a t e r a l f o r e l i m b . In the b i -sected groups, however, the c l o n i c component remained u n i l a t e r a l and l o c a l -i z e d to the c o n t r a l a t e r a l f o r e l i m b . L i k e p r i m a r y - s i t e k i n d l i n g , t h i s pat-t e r n p e r s i s t e d up to the development of primary g e n e r a l i z e d C-5 s e i z u r e s . Primary g e n e r a l i z a t i o n i n the c o n t r o l group was found to r e q u i r e fewer s t i m u l a t i o n s to develop during secondary-site k i n d l i n g than during primary-s i t e k i n d l i n g . T y p i c a l l y , i t occurred a f t e r one or two C-5s during second-a r y - s i t e k i n d l i n g but not u n t i l a f t e r three to f i v e C-5s during primary-s i t e k i n d l i n g . In c o n t r a s t , the b i s e c t e d groups r e q u i r e d approximately the same number of C-5s ( i e . 6-7) during secondary-site k i n d l i n g as primary-s i t e k i n d l i n g f o r the development of primary g e n e r a l i z a t i o n . 54 L i k e p r i m a r y - s i t e k i n d l i n g , r a t s i n Group TD a l s o d i d not develop primary g e n e r a l i z e d C-5 s e i z u r e s during secondary-site k i n d l i n g . In t h i s group, the C-5 was t y p i c a l l y of a secondary g e n e r a l i z e d p a t t e r n . In addi-t i o n , 2 of the 4 r a t s d i s p l a y i n g a second convulsive episode during primary-s i t e k i n d l i n g f a i l e d to do so during secondary-site k i n d l i n g . The most obvious d i f f e r e n c e between primary and secondary-site k i n d l i n g was r e l a t e d to the progressive c l i n i c a l development of the s e i z u r e . Seizure development during p r i m a r y - s i t e k i n d l i n g was c h a r a c t e r i z e d by a gradual e l a b o r a t i o n and spread of the c l i n i c a l m a n i f e s t a t i o n s . Secondary-site s e i -zures, however, t y p i c a l l y developed extremely r a p i d l y and subsequently many of the e a r l y c l i n i c a l events were skipped. For example, i t was not unusual to observe r a t s d i s p l a y i n g C-2 on one day and then progress to a C-5 on the f o l l o w i n g day. B. Secondary-site e l e c t r o g r a p h i c development and propagation. The e l e c t r o g r a p h i c c o r r e l a t e s of secondary s i t e k i n d l i n g are shown i n F i g . 6. The gradual development and propagation of AD observed during p r i m a r y - s i t e k i n d l i n g was absent during secondary-site k i n d l i n g . Instead, the AD develop-ment and spread observed during secondary-site k i n d l i n g was c o n s i s t e n t l y more elaborate than that observed during the corresponding stages of primary-s i t e k i n d l i n g . This observation a p p l i e d to a l l groups. AD a s s o c i a t e d with the appearance of C - l and C-2 was c h a r a c t e r i z e d by a high amplitude, 4-6/sec, spike and wave or p o l y s p i k e and wave p a t t e r n that r a p i d l y propagated from the s t i m u l a t e d AM to the i p s i l a t e r a l MRF and MC i n Groups AC, CC, and C. Propagation of AD i n t o these s t r u c t u r e s during p r i m a r y - s i t e k i n d l i n g (they were then c o n t r a l a t e r a l to the s t i m u l a t e d s i t e ) was t y p i c a l l y not observed u n t i l the l a t e r stages of C-2 or the e a r l y stages 55 of C-3. A l s o i n contrast to p r i m a r y - s i t e propagation, AD spread i n t o the primary s i t e during secondary-site k i n d l i n g was minimal u n t i l the appearance of C-3. This at l e a s t a p p l i e d to the c o n t r o l s and Group CC. Rats i n Groups AC and TD f a i l e d to show AD i n the primary s i t e even with the appearance of C-3. AD a c t i v i t y observed i n the primary s i t e of Group CC and C showed a s i m i l a r discharge p a t t e r n to that observed i n the secondary s i t e . No d i s -r u p t i o n i n the c l i n i c a l development of the s e i z u r e was observed i n any of the groups up to stage 3. L i t t l e subsequent AD development occurred at the secondary s i t e f o l l o w -i n g the appearance of C-4 and C-5. The p a t t e r n tended to evolve i n t o a high amplitude, 5-8/sec, p o l y s p i k e and wave discharge t h a t , towards the be-ginning of the s e i z u r e , d i s p l a y e d considerable i r r e g u l a r a c t i v i t y . A s i m i -l a r p a t t e r n g r a d u a l l y emerged from the primary s i t e of the c o n t r o l s although i t took s e v e r a l C-5 s e i z u r e s to f u l l y develop. F i g . 6 shows the e l e c t r o g r a p h i c c o r r e l a t e s of a t y p i c a l C-5 s e i z u r e i n each group. B i s e c t i o n of the f o r e b r a i n commissures exerted a suppressive e f f e c t on the propagation of AD i n t o the primary s i t e that was most evident during the e a r l y stages of C-5. Group CC appeared l e a s t a f f e c t e d , and AD i n the primary s i t e c o n s i s t e d of a 5-8/sec, spike and wave or o c c a s i o n a l l y p o l y s p i k e and wave p a t t e r n synchronous with the secondary s i t e ( F i g . 6). Groups AC and TD were most a f f e c t e d , showing very l i t t l e primary s i t e a c t i v -i t y . Most r a t s i n these groups d i s p l a y e d suppressed AD d u r a t i o n character-i z e d by low amplitude spike and wave a c t i v i t y ( F i g . 6). In the remaining r a t s , propagation to the c o n t r a l a t e r a l AM was prevented. These r a t s d i s -played primary s i t e a c t i v i t y c o n s i s t i n g of slow to f a s t wave forms and independent spike discharges. I n t e r e s t i n g l y , towards the s i x t h to eighth 56 C-5 some recovery i n AD i n the primary s i t e was observed i n Groups CC and TD. These r a t s tended to show the emergence of an AD p a t t e r n that was s i m i -l a r to the secondary s i t e although i t u s u a l l y lacked the amplitude. The development of stages 4 and 5 i n a l l groups (except Group TD) was accompanied by a marked increase i n the i p s i l a t e r a l MRF and MC discharge. A high amplitude, independent, 8-14/sec p o l y s p i k e discharge was observed i n the MRF immediately a f t e r s t i m u l a t i o n . This was accompanied s l i g h t l y l a t e r by a buildup of p o l y s p i k e and wave a c t i v i t y over the MC. The AD i n the MC was t y p i c a l l y independent from the s t i m u l a t e d s i t e at the beginning of the s e i z u r e but tended towards synchrony as the s e i z u r e terminated ( F i g . 6). This p a t t e r n was s i m i l a r to that observed during p r i m a r y - s i t e k i n d l e d s e i -zures, with one exception: there was no evidence of the p o l y s p i k e and wave a c t i v i t y i n the c o n t r a l a t e r a l MC i n Group CC. C. Rate of secondary-site k i n d l i n g . There was no s i g n i f i c a n t d i f f e r -ence between the r a t e at which c o n t r o l and f o r e b r a i n - b i s e c t e d r a t s k i n d l e d (Table I ) . The only s i g n i f i c a n t d i f f e r e n c e i n the r a t e of secondary-site k i n d l i n g was observed between Group CC and Group TD. Rats i n Group CC were found to k i n d l e s i g n i f i c a n t l y f a s t e r than those i n Group TD (F=3.01; df=1,39; p<.05). A l l groups showed a p o s i t i v e t r a n s f e r e f f e c t i n t h a t they u n i f o r m l y r e q u i r e d fewer s t i m u l a t i o n s to k i n d l e the secondary s i t e than the primary s i t e . Group TD, however, was the only group that k i n d l e d s i g n i f i c a n t l y f a s t e r at the secondary s i t e (F=2.93; df=1,39; p<.05). D. Secondary-site s e i z u r e d u r a t i o n . F i g . 4B shows the d u r a t i o n of each C-5 s e i z u r e evoked from secondary s i t e s t i m u l a t i o n . B i s e c t i o n of the f o r e b r a i n commissures produced l i t t l e e f f e c t on the s e i z u r e d u r a t i o n . No 57 F i g . 6. The e l e c t r o g r a p h i c c o r r e l a t e of a secondary-site C-5 s e i z u r e d i s p l a y e d by a t y p i c a l r a t from each group. Arrows i n d i c a t e the s i t e o f s t i m u l a t i o n ; the c i r c l e d numbers under each record i n d i c a t e the c l i n i c a l r e s -ponse being d i s p l a y e d . R=right; L = l e f t . Note that i n b i s e c t e d Group CC, propagation to the R MC i s u n a f f e c t -ed i f the st i m u l a t e d s i t e i s i p s i l a t e r a l to i t . In Group AC, b i s e c t i o n of the r o s t r a l callosum, hippocampal commissure, and a n t e r i o r commissure e l i m i n a t e s propaga-t i o n of AD to the c o n t r a l a t e r a l AM (R AM) but not the R MC or R MRF. Propagation of AD to the c o n t r a l a t e r a l AM (L AM) o f Group TD was a l s o d i s r u p t e d . Note that r a t s i n t h i s group f a i l e d to show two s e i z u r e s during second-a r y - s i t e k i n d l e d s e i z u r e s . 57a 58 s i g n i f i c a n t d i f f e r e n c e s were observed between any of the groups. S i m i l a r l y , the d u r a t i o n of secondary-site s e i z u r e s d i d not d i f f e r s i g n i f i c a n t l y from the d u r a t i o n of p r i m a r y - s i t e s e i z u r e s . E. AD d u r a t i o n during secondary-site k i n d l e d s e i z u r e s . The AD dura-t i o n s recorded from the s t i m u l a t e d and c o n t r a l a t e r a l AM during the eig h t secondary-site C-5s are shown i n Figure 5B. D e t a i l s concerning the AD dur a t i o n at the MC and MRF have been excluded from the f i g u r e f o r the sake of c l a r i t y but w i l l be discussed w i t h i n the t e x t . Considerably more v a r i a t i o n was observed i n the du r a t i o n of the second-a r y - s i t e AD during secondary-site s e i z u r e s than during p r i m a r y - s i t e s e i z u r e s . There were no s i g n i f i c a n t d i f f e r e n c e s between the groups, however, with r e -gard to the AD d u r a t i o n of the stimulated s i t e during secondary-site k i n d l -in g . B i s e c t i o n of the f o r e b r a i n commissures produced i t s greatest e f f e c t on the propagation o f AD i n t o the primary s i t e . The AD i n the primary s i t e i n Groups AC and TD c o n s i s t e n t l y tended to be shorter than the secondary-s i t e AD over the e n t i r e 8 sessions. A s i m i l a r e f f e c t , but of l e s s magnitude, was a l s o observed i n Group CC. In a l l of these groups, however, there were no c o n s i s t e n t l y s i g n i f i c a n t e f f e c t s . The e f f e c t s of f o r e b r a i n b i s e c t i o n on AD i n the primary s i t e were evident i n the b i s e c t e d groups. In Group AC, AD i n the primary s i t e was s i g n i f i c a n t l y shorter than that of the c o n t r o l s on a l l but se s s i o n 2 of the f i r s t s i x sessions (ps<.05). A s i m i l a r but greater e f f e c t was noted i n Group TD. The AD du r a t i o n o f the primary s i t e i n t h i s group was s i g n i f i c a n t -l y s h o r t e r than that of the c o n t r o l s on a l l sessions but session 2 (ps<.05). The AD d u r a t i o n of the primary s i t e i n Group CC jdid not d i f f e r s i g n i f i c a n t l y from that of the c o n t r o l s (ps>.05) or Groups AC and TD (ps>.05) on any of the sessions. 59 No s i g n i f i c a n t d i f f e r e n c e s i n the AD dur a t i o n of the i p s i l a t e r a l MRF and MC were produced by b i s e c t i n g the f o r e b r a i n commissures. S i m i l a r l y , there were no apparent d i f f e r e n c e s i n the AD du r a t i o n of these s t r u c t u r e s between any of the groups (except Group TD). In most cases, the AD dura-t i o n was i d e n t i c a l to that of the st i m u l a t e d s i t e . Therefore, a s i g n i f i c a n t observation was that b i s e c t i o n of the f o r e b r a i n commissures i n Group AC suppresses AD i n the primary s i t e but does not a f f e c t AD i n MC or MRF. Disc u s s i o n The r e s u l t s of the present study i n d i c a t e that i n t e r h e m i s p h e r i c connec-t i o n s v i a the corpus callosum and hippocampal and a n t e r i o r commissures are not c r i t i c a l to the development of ge n e r a l i z e d k i n d l e d amygdaloid convuls-ions. These r e s u l t s are i n agreement with those of Mclntyre (1975) and Wada and Sato (1975) but c o n f l i c t with the e a r l i e r report of Racine et al. (1972) . Racine and colleagues found that b i s e c t i o n of the f o r e b r a i n com-missures i n the r a t s i g n i f i c a n t l y retarded the r a t e of amygdaloid k i n d l i n g . D i f f e r e n c e s i n s t r a i n , s p e c i e s , stimulus i n t e n s i t y , and waveform at f i r s t seem l i k e l y explanations f o r the c o n f l i c t i n g r e s u l t s . However, these pos-s i b i l i t i e s were e l i m i n a t e d by the use of an i n t a c t c o n t r o l group. The present study suggests that extracommissural thalamic damage l i k e that observed i n Group TD may i n par t e x p l a i n the d i f f e r e n c e s between the r a t e s of k i n d l i n g reported here and the e a r l i e r report of Racine et al. (1972) . Racine et al. (1972) f a i l e d to provide the r e s u l t s of an adequate h i s t o -l o g i c a n a l y s i s o f the f o r e b r a i n b i s e c t i o n although he l a t e r acknowledged (personal communication, 1974) that damage to the thalamus was observed i n some of t h e i r r a t s . Therefore, s i n c e r a t s i n Group TD of t h i s study were 60 the only ones to k i n d l e slower than the c o n t r o l s , i t seems reasonable to suggest that the r e s u l t s of Racine et al. (1972) may i n par t have been due to the u n i n t e n t i o n a l d e s t r u c t i o n of thalamic areas c r i t i c a l f o r the develop-ment of k i n d l e d amygdaloid convulsions. Although a complete study of thalamic involvement i n amygdaloid k i n d l -i n g i s s t i l l l a c k i n g , there i s some i n t r i g u i n g p r e l i m i n a r y evidence which suggests that l o c a l i z e d thalamic l e s i o n s are able to exert a d i s r u p t i v e e f f e c t on the development of these s e i z u r e s (McCaughran, Corcoran, and Wada, i n p r e p a r a t i o n ) . P a r t i c i p a t i o n of the thalamus i n other forms o f e p i l e p t i f o r m a c t i v i t y and s e i z u r e development i s w e l l documented. For example, d e s t r u c t i o n of thalamic n u c l e i has been found to attenuate e p i l e p t i -form discharge a c t i v i t y i n cats (e.g. V i l l a b l a n c a , Schlag, and Marcus, 1970; Feeney and G u l l o t t a , 1972), and primates (Kusske, Ojemann, and Ward, 1972). Thalamic l e s i o n s have al s o been reported to block or reduce the frequency of s e i z u r e s i n human e p i l e p t i c s (Mullan, V a i l a t i , K a r a s i c k , and M a i l i s , 1967) . B i s e c t i o n of the r o s t r a l corpus callosum and a n t e r i o r commissure (Group AC) produced a s i g n i f i c a n t f a c i l i t a t i o n i n the r a t e of s e i z u r e development. B i s e c t i o n of the corpus callosum and hippocampal commissure (Group CC), how-ever, d i d not s i g n i f i c a n t l y f a c i l i t a t e the r a t e . In view of these r e s u l t s , i t would appear that s e c t i o n i n g of the a n t e r i o r commissure alone may be suf-f i c i e n t to produce t h i s e f f e c t . The r e s u l t s of Wada and Sato (1975) i n p a r t confirm t h i s . They reported that b i s e c t i o n of the corpus callosum and anter-i o r commissure i n the cat produced the greatest f a c i l i t a t i o n i n k i n d l i n g , although they a l s o observed a f a c i l i t a t e d r a t e o f s e i z u r e development a f t e r b i s e c t i o n o f only the corpus callosum. In co n t r a s t to the above r e p o r t s , 61 Mclntyre (1975) found that b i s e c t i o n of the f o r e b r a i n commissures i n the r a t d i d not f a c i l i t a t e the development of k i n d l e d amygdaloid convulsions. He reported no s i g n i f i c a n t d i f f e r e n c e s between the r a t e s at which b i s e c t e d and c o n t r o l groups k i n d l e d . Further t e s t i n g i s obviously r e q u i r e d i n order to develop an explanation that would s u f f i c i e n t l y account f o r the d i f f e r -ences between t h i s r e p o r t and others. Although no concrete explanation can be o f f e r e d at t h i s time, the p o s s i b i l i t y i s i n t r i g u i n g that the f a c i l i t a t i o n i n the development of k i n d l e d s e i z u r e s f o l l o w i n g f o r e b r a i n b i s e c t i o n a c t u a l -l y r e f l e c t s an i n h i b i t o r y i n t e r h e m i s p h e r i c e f f e c t t r a n s m i t t e d v i a these s t r u c t u r e s i n the normal animal. Such a p o s s i b i l i t y i s not unprecedented i n view of e x i s t i n g data concerning the increase i n c o n v u l s i v e behaviour observed i n animals f o l l o w i n g f o r e b r a i n b i s e c t i o n (e.g. Kopeloff et al., . 1950; Stavraky, 1961; Straw and M i t c h e l l , 1967; Mutani et al. , 1972). The present i n v e s t i g a t i o n found t h a t the i n t e g r i t y of the f o r e b r a i n commissures i s not e s s e n t i a l to the development of b i l a t e r a l g e n e r a l i z e d amygdaloid convulsions. B i s e c t i o n of the commissures retarded but d i d not stop s e i z u r e g e n e r a l i z a t i o n . Mclntyre (1975) reported s i m i l a r f i n d i n g s i n the r a t . In view of these r e s u l t s , i n t e r h e m i s p h e r i c pathways v i a the commissures l i k e l y p a r t i c i p a t e i n s e i z u r e g e n e r a l i z a t i o n , but other, probab-l y s u b c o r t i c a l , s t r u c t u r e s p l a y a c r i t i c a l r o l e . Many previous s t u d i e s have suggested that brainstem s t r u c t u r e s , p a r t i c u l a r l y the r e t i c u l a r forma-t i o n and d i f f u s e thalamic p r o j e c t i o n system, are c r i t i c a l l y i n v o l v e d i n the g e n e r a l i z a t i o n of s e i z u r e s a r i s i n g from temporal lobe s t r u c t u r e s (Kaada, 1951; F e i n d e l and Gloor, 1954; Gloor, 1955a,b). With regard to amygdaloid k i n d l i n g , Wada and Sato (1975) reported that d e s t r u c t i o n of the MRF i n f o r e -b r a i n - b i s e c t e d cats suppressed the appearance of g e n e r a l i z e d amygdaloid con-v u l s i o n s . S i m i l a r l y , Mclntyre (1975) found that t o t a l f o r e b r a i n b i s e c t i o n 62 (including b i s e c t i o n of the thalamus) prevented the development of general-ized amygdaloid convulsions i n r a t s . In the present report, only rats i n Group TD f a i l e d to develop generalized seizures. H i s t o l o g i c a l analysis of the b i s e c t i o n i n t h i s group revealed that large areas of the thalamus had sustained extensive damage. These observations add further support to the hypothesis that structures located e i t h e r i n the brainstem r e t i c u l a r forma-t i o n or thalamus are necessary f o r the generalization of kindled amygdaloid seizures. Some early evidence, however, does not support t h i s hypotheses. For example, the r e s u l t s of Erickson (1940) and Kopeloff et al. (1950) showed that b i s e c t i o n of the forebrain commissures i n animals prevented the generalization of seizures. The r e s u l t s reported here, however, do not provide a strong basis of comparison to these e a r l i e r reports since the early studies dealt with the e f f e c t s of forebrain b i s e c t i o n on epile p t i f o r m a c t i v i t y o r i g i n a t i n g i n the cortex whereas the present report deals with a c t i v i t y o r i g i n a t i n g i n the subcortex. Many previous studies found that the anterior commissure was the major pathway f or the interhemispheric spread of seizure a c t i v i t y o r i g i n a t i n g i n temporal lobe structures (e.g. McCulloch and Garol, 1941; Frost et al. , 1958; Poblete et al. , 1959; Wada and Sato, 1975; Mclntyre, 1975) . In the present study the anterior commissure was found to play a prominent but not exclus-ive r o l e i n the propagation of AD to the c o n t r a l a t e r a l AM. It was found that not only the group i n which the anterior commissure was bisected (Group AC) but also the group i n which extensive damage to the thalamus was observed (Group TD) showed d i s r u p t i v e e f f e c t s on the duration of the AD propagated into the c o n t r a l a t e r a l AM. Because no damage to the anterior commissure was observed i n Group TD, i t must be assumed that the decreased propagation into 63 the contralateral AM was the result of damage to areas of the thalamus that are involved in this phenomenon. Some propagation of AD to the contralater-al AM also occurs via the corpus callosum and hippocampal commissure. It was found that bisection of these structures (e.g. Group CC) had a mildly disruptive effect on AD propagation to the contralateral AM. Mclntyre (1975) reported that the most disruptive effects on propagation of AD to the contralateral AM were observed in rats in which the rostral corpus callosum and anterior commissure were sectioned. Neither the development of bilateral generalized seizures nor the rate of seizure development was affected by the lack of AD in the contralateral AM of Groups AC and TD. In those rats showing the greatest attenuation of AD in the contralateral AM (Group AC), kindling progressed the most rapidly. These results are in contradiction to the interlimbic hypothesis f i r s t pro-posed by Racine et.al. (1972) that suggested that kindling results from the progressive strengthening of interlimbic connections. This would necessit-ate the involvement of the contralateral AM. Clearly in view of the present results and the reports of others (Wada and Sato, 1975; Mclntyre, 1975) this hypothesis no longer appears tenable. Instead, amygdaloid kindling must now be viewed as a strengthening of connections between limbic and other sub-cortical, perhaps brainstem, structure(s). Bisection of the forebrain commissures did not disrupt the transfer effect, in agreement with the results of Mclntyre (1975) . Furthermore, the results of the present study suggest that involvement of the contralateral AM during primary-site kindling is not necessary for transfer. For example, transfer occurred .-in Group AC although rats in this group displayed l i t t l e AD in the contralateral AM. Like kindling i t s e l f , the transfer effect must 64 a l s o make,use of some extracommissural s t r u c t u r e . Those areas of the thalamus destroyed i n Group TD are u n l i k e l y candidates s i n c e t r a n s f e r a l s o occurred i n t h i s group. Previous reports have found that the corpus callosum i s c r i t i c a l f o r the interhemispheric propagation of e p i l e p t i f o r m a c t i v i t y a r i s i n g from s t i m u l a t e d areas of the cortex (e.g. E r i c k s o n , 1940; McCulloch and G a r o l , 1941). The callosum has a l s o been i m p l i c a t e d i n the maintenance of syn-chronous discharges a s s o c i a t e d with secondary e p i l e p t o g e n e s i s ( M o r r e l l , 1960; Isaacson et al. , 1971) and the mediation of g e n e r a l i z e d bisynchronous spike and wave patterns a r i s i n g from b i l a t e r a l c o r t i c a l f o c i (Marcus and Watson, 1966; Marcus et al., 1968; Mutani et al., 1973). The present study found that the corpus callosum and hippocampal commissure were not e s s e n t i a l pathways f o r the interhemispheric t r a n s m i s s i o n of AD i n the MC a s s o c i a t e d with amygdaloid k i n d l i n g . In a previous study (Wada, Sato, and McCaughran, 1975) a unique independent p o l y s p i k e and wave p a t t e r n was described that emerged b i l a t e r a l l y from the MC of the r a t s during the development of k i n d l e d amygdaloid convulsions. This p a t t e r n , i t was observed, was c l o s e l y associated with the f i n a l stage of s e i z u r e development ( i e . C-5). In the present study a s i m i l a r p a t t e r n was observed b i l a t e r a l l y i n the c o n t r o l group but only i n the MC i p s i l a t e r a l to the s t i m u l a t e d s i t e i n Group CC. Although i t has yet to be determined whether t h i s independent a c t i v i t y i s o r i g i n a t i n g i n the MC or spreading there from some deeper s t r u c t u r e , the r e s u l t s of the present study show at l e a s t that (1) i t r e l i e s on t h e i i n -t e g r i t y o f the corpus callosum and hippocampal commissure f o r propagation to the c o n t r a l a t e r a l MC; and (2) i t s absence i n one MC does not d i s r u p t the eventual b i l a t e r a l g e n e r a l i z a t i o n of the convulsion. I t appears l i k e l y 65 that t h i s independent discharge i n the MC i s a r e f l e c t i o n o f a c t i v i t y i n some deeper s t r u c t u r e p o s s i b l y associated with the motor system. This i n part i s supported by the rep o r t that removal of the MC i n r a t s does not d i s r u p t the development of k i n d l e d amygdaloid convulsions i n r a t s (Corcoran, Urstad, McCaughran, and Wada, 1975). Propagation of AD i n t o the MRF was not a f f e c t e d by the b i s e c t i o n of the f o r e b r a i n commissures and no evidence of outstanding e l e c t r o g r a p h i c development, l i k e that reported by Wada and Sato (1974, 1975), was observ-ed i n t h i s s t r u c t u r e . In some r a t s , independent MRF a c t i v i t y was observed during the l a t e r stages of k i n d l i n g but t h i s d i d not c o n s i s t e n t l y occur. Rats having electrodes i n the MRF were a l s o i n the m i n o r i t y of the t o t a l sample and there f o r e made the i n t e r p r e t a t i o n of the e l e c t r o g r a p h i c develop-ment d i f f i c u l t . Obviously, more work w i l l be re q u i r e d to define the r o l e played by the MRF i n the development of k i n d l e d s e i z u r e s i n the r a t . The r e s u l t s of Experiment 1 i n d i c a t e that the f o r e b r a i n commissural pathways i n the r a t are not e s s e n t i a l f o r the development of k i n d l e d amyg-d a l o i d s e i z u r e s and that b i s e c t i o n of these s t r u c t u r e s i s , i f anything, capable of f a c i l i t a t i n g the r a t e of k i n d l i n g . This may be i n t e r p r e t e d to suggest that the f o r e b r a i n commissures f u n c t i o n as i n h i b i t o r y pathways between the c e r e b r a l hemispheres. E x i s t i n g evidence was reported that supports such a hypothesis (e.g. Mutani et dl. , 1972; Wada and Sato, 1975). The o r i g i n a l hypothesis of Racine et al. (1972) that k i n d l i n g r e s u l t e d from the progressive strengthening of i n t e r l i m b i c connections was found to be untenable since the d i s r u p t i o n of the m a j o r i t y o f these connections d i d not a f f e c t the s e i z u r e development. B i s e c t i o n of the r o s t r a l corpus callosum 66 and a n t e r i o r commissure a l s o suppressed the propagation of AD i n t o the c o n t r a l a t e r a l AM but d i d not r e t a r d the r a t e of p r i m a r y - s i t e k i n d l i n g or the p o s i t i v e t r a n s f e r e f f e c t to the secondary s i t e . Experiment 1 showed that d e s t r u c t i o n of areas i n the r o s t r a l thalamus retarded the r a t e of k i n d l i n g and thus i n d i c a t e d t h a t k i n d l i n g may i n s t e a d r e s u l t from the strengthening of l i m b i c - b r a i n s t e m connections as suggested by Wada and Sato (1974, 1975) and Mclntyre (1975). Although the number of r a t s having elec t r o d e s i n s t r u c t u r e s other than the amygdalae were small ( i e . i n the MC and MRF), b i s e c t i o n of the corpus callosum and hippocampal commissure d i s r u p t e d the propagation of AD between the motor c o r t i c e s i n a l l cases. The s i g n i f i c a n c e of the independent p o l y -spike discharge observed i n the MC was not determined but previous evidence suggests that i t i s not i n v o l v e d i n k i n d l i n g (Corcoran et al. , 1975) and, t h e r e f o r e , probably r e f l e c t s a c t i v i t y o c c u r r i n g i n deeper s t r u c t u r e s . Experiment 1 provided l i t t l e evidence of MRF involvement i n k i n d l i n g . A l -though t h i s i s contrary to previous r e p o r t s (Wada and Sato, 1974, 1975) , the r e s u l t s of Experiment 1 must be i n t e r p r e t e d with c a u t i o n due to the small number of r a t s having MRF e l e c t r o d e s . 67 EXPERIMENT 2 The present experiment was designed to examine the r o l e of s p e c i f i c f o r e b r a i n commissures i n the c l i n i c a l and e l e c t r o g r a p h i c development o f k i n d l e d amygdaloid s e i z u r e s . Although Experiment 1 i n d i c a t e d that b i s e c t i o n of the commissures was capable of f a c i l i t a t i n g the development of k i n d l e d s e i z u r e s , i t d i d not provide information r e l a t e d to which of the commissures was r e s p o n s i b l e . This was f e l t to be due, i n p a r t , to the inadequate surg-i c a l procedure since some r a t s (e.g. Group TD) d i s p l a y e d evidence of exten-s i v e extracommissural damage. A more r e f i n e d s u r g i c a l procedure employing s t e r e o t a x i c c o n t r o l over the b i s e c t i o n was used i n the present study. The r e s u l t s of p i l o t s t u d i e s i n d i c a t e d that the new technique provided greater c o n t r o l over the extent of the b i s e c t i o n and minimized the chances of pro-ducing extracommissural damage. Experiment 1 i n d i c a t e d that areas of the r o s t r a l thalamus p a r t i c i p a t e d i n the development of k i n d l e d amygdaloid convulsions. Corcoran et al. (1975) als o showed that the f r o n t a l cortex of the r a t was in v o l v e d i n t h i s process. In view of these data, a d d i t i o n a l e l e c t r o g r a p h i c data were c o l l e c t e d from the f r o n t a l cortex (FC) and the a n t e r i o r n u c l e i of the thalamus (ATH). Method Subjects. F o r t y - f i v e hooded r a t s of the Long-Evans s t r a i n weighing between 325-375 g at the time o f surgery were used. Rats were housed i n d i v i d u a l l y i n s t a i n l e s s s t e e l mesh cages and maintained i n a constant temperature colony room having a 12 hour l i g h t - d a r k c y c l e . Food and water were provided ad libitum except during t e s t i n g . Rats were a l s o allowed a 68 minimum of 10-14 days to adjust to the colony environment before under-going surgery. Surgery. B i s e c t i o n o f a l l f o r e b r a i n commissures, except the a n t e r i o r commissure, was performed using a s t e r e o t a x i c technique. Rats were anaesthetized w i t h sodium p e n t o b a r b i t a l (60.0 mg/kg, i n t r a -p e r i t o n e a l l y ) and placed i n the stereotax. The coordinates corresponding to the a n t e r i o r and p o s t e r i o r extremes of the corpus callosum were marked on the surface of the s k u l l , 1.0 mm l a t e r a l to the m i d l i n e . A 1.0 mm wide s t r i p of bone j o i n i n g these two p o i n t s was then removed by d r i l l i n g a s e r i e s of trephine holes. The dura mater was exposed, dampened p e r i o d i c -a l l y w i t h normal s a l i n e , and o v e r l y i n g chips of bone were removed. The s a g g i t a l sinus.was v i s u a l i z e d and the dura immediately l a t e r a l to i t r e -f l e c t e d . Fine sewing needles (approximately 0.45 mm i n diameter) w i t h the eyes of the needles f a c i n g downward were mounted i n the e l e c t r o d e c a r r i e r s . One needle was then p o s i t i o n e d over the a n t e r i o r extreme of the callosum and the other was p o s i t i o n e d over the p o s t e r i o r extreme. S u r g i c a l s i l k (6-0) was then passed through the eye of each needle. Care was taken to allow enough s l a c k i n the s i l k running between the two needles since i n -s u f f i c i e n t s l a c k was found to produce unwanted t i s s u e d e s t r u c t i o n when the needles were lowered i n t o the b r a i n . The needles were lowered to p o i n t s s l i g h t l y v e n t r a l to the extremes of the callosum and the s i l k was then p u l l e d t a u t . In t h i s manner, a l l t i s s u e l y i n g between the needles was sectioned, i n c l u d i n g the corpus callosum. F o l l o w i n g the b i s e c t i o n , the needles were removed from the b r a i n and the thread was e x t r a c t e d . Exces-s i v e b l e e d i n g was r e a d i l y c o n t r o l l e d by gently a p plying pressure with a 69 cotton swab. The s t r i p of exposed cortex was covered by a t h i n s t r i p of s t e r i l e gelfoam soaked i n normal s a l i n e . The s c a l p wound was then close d with 9.0 mm s t a i n l e s s s t e e l wound c l i p s and the r a t s were allowed a minimum of two weeks to recover before i m p l a n t a t i o n of the e l e c t r o d e s . B i s e c t i o n of the a n t e r i o r commissure, e i t h e r alone or i n a s s o c i a t i o n with the corpus callosum and hippocampal commissure, was achieved by e l e c t r o -l y t i c l e s i o n i n g . An electrode was used that was constructed from 24 guage s t a i n l e s s s t e e l tubing and i n s u l a t e d w i t h Insulex. The c r o s s - s e c t i o n a l diameter of the e l e c t r o d e was l e f t bare. A small hole was d r i l l e d i n the s k u l l , 1.0 mm l a t e r a l to the m i d l i n e and 1.6 mm a n t e r i o r to bregma, and the e l e c t r o d e was lowered 7.0 mm at an angle of 7 degrees to the l e v e l of the commissure. The anode was then attached to the e l e c t r o d e and the cathode was c l i p p e d to the frame of the s t e r e o t a x i c instrument. A 2.0 ma DC c u r r e n t , generated by a Grass constant current l e s i o n maker, was passed through the t i p of the electrode f o r a d u r a t i o n of 25.0 sec. The hole i n the s k u l l was sealed w i t h bone wax and the s c a l p wound was closed w i t h wound c l i p s . The r a t s were al s o allowed a minimum of two weeks to recover before i m p l a n t a t i o n of the e l e c t r o d e s . Two groups of c o n t r o l r a t s were prepared. The f i r s t group c o n s i s t e d of r a t s i n which the corpus callosum and hippocampal commissure were l e f t i n t a c t but the cortex o v e r l y i n g the callosum was sectioned. This was per-formed i n a manner i d e n t i c a l to that described f o r the f o r e b r a i n b i s e c t i o n except that the v e n t r a l p e n e t r a t i o n of the needles was only to the l e v e l of the d o r s a l surface of the callosum. Thus, when the s u r g i c a l s i l k was drawn taut only the cortex o v e r l y i n g the callosum was sectioned. The second group of c o n t r o l s c o n s i s t e d of r a t s prepared i n a manner s i m i l a r 70 to the f i r s t group except no b r a i n t i s s u e was sectioned. A l o n g i t u d i n a l s l i t was d r i l l e d i n the s k u l l , the dura mater exposed but l e f t i n t a c t . In both c o n t r o l groups, the s k u l l opening was packed with s t e r i l e gelfoam soak-ed i n normal s a l i n e and the scalp wound was closed with s t a i n l e s s s t e e l c l i p s . These groups were al s o allowed two weeks to recover before implant-a t i o n of e l e c t r o d e s . Electrode i m p l a n t a t i o n . Implantation o f elect r o d e s was done under a s e p t i c c o n d i t i o n s . Rats were anaesthetized with sodium p e n t o b a r b i t a l (60.0 mg/kg) i n j e c t e d i n t r a p e r i t o n e a l l y , and b i p o l a r s t i m u l a t i n g and record-i n g e lectrodes of the same type as those used i n Experiment 1 were aimed b i l a t e r a l l y at the b a s o l a t e r a l nucleus of the AM (0.4 mm a n t e r i o r to bregma, 4.3 mm l a t e r a l to the m i d l i n e , 8.5 mm v e n t r a l from the surface o f the s k u l l , and the i n s c i s o r bar set at +5.0) of a l l r a t s (N=42). Some r a t s (N=5) were a l s o prepared with electrodes aimed b i l a t e r a l l y at the a n t e r o v e n t r a l nucleus of the thalamus (0.4 mm p o s t e r i o r t o bregma, 1.6 mm l a t e r a l to the m i d l i n e , 5.5 mm v e n t r a l from the surface of the c o r t e x , and the i n s c i s o r bar set at +5.0) i n a d d i t i o n to the b i l a t e r a l AM e l e c t r o d e s . Other r a t s (N=7) a l s o had electr o d e s aimed b i l a t e r a l l y at the MRF (4.4 mm p o s t e r i o r to bregma, 2.0 mm l a t e r a l to the m i d l i n e , 6.0 mm v e n t r a l from the surface of the b r a i n , and the i n s c i s o r bar set at +5.0), i n a d d i t i o n to t h e i r amygdaloid e l e c t r o d e s . The remainder o f the r a t s (N=30) had el e c t r o d e s of s i m i l a r c o n s t r u c t i o n to those used i n Experiment 1 placed over areas of the cortex. In these r a t s electrodes were placed over Area 10 of the FC (3.5 mm and 2.0 mm a n t e r i o r to bregma and 1.5 mm l a t e r a l to the midline) and Areas 4 and 6 ([MC]; 1.5 mm a n t e r i o r to bregma, 1.0 mm p o s t e r i o r to bregma, and 1.5 mm l a t e r a l to the m i d l i n e ) . The el e c t r o d e assembly was then anchored to the s k u l l u s i n g a 71 method i d e n t i c a l to that used i n Experiment 1. Rats were allowed a minimum of 10 days to recover from the e f f e c t s of electrode i m p l a n t a t i o n before being s t i m u l a t e d . During t h i s p e r i o d they were handled and checked o c c a s s i o n a l l y f o r i n f e c t i o n s or n e u r o l o g i c a l impairment. Rats d i s p l a y i n g any n e u r o l o g i c a l d e f i c i t (e.g. abnormal motor movements were dropped from the study. Those with i n f e c t i o n s were t r e a t e d with p e n i c i l l i n ( D e r a f o r t ) . T e s t i n g procedures. The t e s t i n g procedures were the same as those used i n Experiment 1. The r a t s were placed i n a sh i e l d e d wire cage and 2.0 min of b a s e l i n e EEG a c t i v i t y was recorded. Following t h i s , a 1.0 sec, 160 ya, constant current Hz sine wave stimulus was administered to e i t h e r the r i g h t or l e f t AM of a l l r a t s . Rats were s t i m u l a t e d once d a i l y between the hours of 1000 and 1300. Amygdaloid k i n d l i n g . Kindled s e i z u r e development was c l a s s i f i e d ac-cording to the method of Racine (1972a) o u t l i n e d i n Experiment 1. Rats were considered k i n d l e d upon reaching the C-5 stage of s e i z u r e development. Eight C-5 s e i z u r e s were evoked from the primary s i t e and then s t i m u l a t i o n was switched to the secondary s i t e i n order to study the t r a n s f e r e f f e c t . Eight secondary-site C-5 sei z u r e s were evoked before again s t i m u l a t i n g the primary s i t e . The primary s i t e was r e s t i m u l a t e d i n order to study the i n t e r f e r e n c e phenomenon (Mclntyre and Goddard, 1973). Interference r e f e r s to the number of s t i m u l a t i o n s r e q u i r e d to evoke a C-5 s e i z u r e at the primary s i t e a f t e r k i n d l i n g the secondary s i t e . Rats were allowed to have an addi-t i o n a l f i v e C-5 s e i z u r e s before t e r m i n a t i o n of the study. A f t e r d i s c h a r g e and s e i z u r e d u r a t i o n . C r i t e r i a i d e n t i c a l to those used i n Experiment 1 were used i n the present study f o r the purposes of rec o r d i n g 72 the a f t e r d i s c h a r g e and s e i z u r e d u r a t i o n of the various stages of s e i z u r e development. Hi s t o l o g y . Rats were k i l l e d with an overdose of sodium p e n t o b a r b i t a l , perfused through the heart with 0.9% s a l i n e f o l l o w e d by 10% f o r m a l i n . The b r a i n was removed and frozen coronal s e c t i o n s 40 ym i n thickness were taken. Every f i f t h s e c t i o n (0.2 mm) was kept and s t a i n e d w i t h c r e s y l v i o l e t . The l o c a t i o n of the e l e c t r o d e s and the extent of the f o r e b r a i n b i s e c t i o n were p l o t t e d on s e c t i o n s taken from the a t l a s of P e l l i g r i n o and Cushman (1967). C o r t i c a l e l ectrode l o c a t i o n s were i d e n t i f i e d at the time the b r a i n was removed. Tracings of r e p r e s e n t a t i v e h i s t o l o g y were prepared. S t a t i s t i c a l a n a l y s i s . S t a t i s t i c a l a n a l y s i s of the data was done usi n g parametric a n a l y s i s of variance techniques ( i e . one-way and two-way a n a l y s i s of variance) . Post hoc comparisons were accomplished us i n g the Scheffe" method. S i g n i f i c a n t l e v e l s of p were a l l t w o - t a i l e d . Results . Forty-two of the 45 r a t s used i n t h i s study survived the f o r e b r a i n b i -s e c t i o n and i m p l a n t a t i o n of e l e c t r o d e s . None o f the s u r v i v i n g r a t s d i s p l a y -ed overt evidence of n e u r o l o g i c a l d y s f u n c t i o n i n g and i t was not p o s s i b l e to d i s t i n g u i s h between the b i s e c t e d and c o n t r o l s r a t s i n terms of general motor behaviour. Forebrain b i s e c t i o n f a i l e d to r e t a r d the r a t e of amygdaloid-kindled s e i z u r e development. As i n Experiment 1, i t was found that b i s e c t i o n of s p e c i f i c commissures a c t u a l l y f a c i l i t a t e d k i n d l i n g . F o r e b r a i n - b i s e c t e d r a t s , however, d i d not r e a d i l y develop primary g e n e r a l i z e d s e i z u r e s . 73 In p a r t i c u l a r cases, f o r e b r a i n b i s e c t i o n was able to d i s r u p t the con-t r a l a t e r a l propagation of AD. The magnitude of the e f f e c t was subsequently r e l a t e d to the extent of the b i s e c t i o n . The t r a n s f e r e f f e c t was not d i s r u p t e d by f o r e b r a i n b i s e c t i o n ; however, the i n t e r f e r e n c e phenomenon was. In f o r e b r a i n - b i s e c t e d r a t s , the i n t e r -ference phenomenon was markedly reduced. H i s t o l o g y . The t i p s of a l l electrodes were found to be i n or immediate-l y adjacent to the intended s t r u c t u r e s . Electrode l o c a t i o n s are shown i n F i g . 1. AM electrodes were l o c a l i z e d to the regions i n or surrounding the b a s o l a t e r a l and basomedial n u c l e i . MRF e l e c t r o d e s were concentrated i n an area, at the l e v e l of the s u p e r i o r c o l l i c u l u s , and approximately 2.0 mm l a t e r a l to the nucleus of the oculomotor nerve. Electrodes i n the ATH were found s l i g h t l y l a t e r a l to the s t r i a m e d u l l a r i s and i n the v i c i n i t y o f the anterodorsal and a n t e r o v e n t r a l n u c l e i . The i d e n t i f i c a t i o n of c o r t i c a l placements (FC and MC) was done v i s u a l l y at the time the b r a i n was removed from the s k u l l . I t appeared that a l l c o r t i c a l electrodes were s i t u a t e d over the intended c o r t i c a l areas ( i e . Areas 4, 6, and 10). Examination of the f o r e b r a i n b i s e c t i o n s and c o n t r o l operations r e v e a l -ed that 5 h i s t o l o g i c a l l y d i s t i n c t groups were represented i n the sample: Group TSB, b i s e c t i o n of the corpus callosum, hippocampal, and a n t e r i o r : com-missures (N=8); Group CC, b i s e c t i o n of the corpus callosum and hippocampal commissure (N=7); Group AC, b i s e c t i o n o f the a n t e r i o r commissure (N=8); Group SBC, s e c t i o n i n g of the cortex to the l e v e l of the corpus callosum (N=8); Group C, no c o r t i c a l damage (N = l l ) . T r a c i n g of h i s t o l o g y from a r e p r e s e n t a t i v e r a t of each group i s pre-sented i n F i g . 7. Extracommissural damage i n a l l sectioned groups was min-74 imal compared to that i n Experiment 1. Group TSB d i s p l a y e d evidence of . extracommissural damage l o c a l i z e d to the medial aspects of the cerebrum: Areas 24, 25, and 26 of the cingulum. These areas t y p i c a l l y sustained some damage due to the passage of the s u r g i c a l s i l k . However, signs of gross c e l l l o s s were absent except f o r small areas along the border of the s e c t i o n . S u b c o r t i c a l damage was minimized by the use of the s t e r e o t a x i c procedure. No v e n t r i c u l a r d i l a t i o n was observed, nor was p e n e t r a t i o n of the m i d l i n e thalamus or d e s t r u c t i o n o f the medial aspects of the hippocampus noted. Some c e l l l o s s i n v o l v i n g anterodorsal p o r t i o n s of the l a t e r a l s e p t a l nucleus was found. Damage to s t r u c t u r e s i n the v i c i n i t y of the e l e c t r o l y t i c l e s i o n of the a n t e r i o r commissure was minimal and t y p i c a l l y i n v o l v i n g the v e n t r a l p o r t i o n s of the medial s e p t a l n u c l e i and the dorsomedial area of the p r o p r i u s nucleus of the a n t e r i o r commissure. There was no evidence of the l e s i o n invading the r o s t r a l areas of the hypothalamus. Group CC d i s p l a y e d signs of e x t r a c a l l o s a l damage s i m i l a r t o those described f o r Group TSB. Damage to the cortex o v e r l y i n g the callosum was confined to the medial p o r t i o n s of Areas 24, 25, and 26; c e l l l o s s was l o c a l i z e d to the areas immediately adjacent to the s e c t i o n . S u b c o r t i c a l p e n e t r a t i o n i n v o l v e d n e i t h e r the hippocampus nor the mid l i n e areas of the thalamus. However, i n the r o s t r a l area of the f o r e b r a i n there was a s l i g h t p e n e t r a t i o n of the l a t e r a l s e p t a l n u c l e i . Damage to t h i s s t r u c t u r e was s i m i l a r to that described f o r Group TSB. Group AC, i n which the a n t e r i o r commissure was b i s e c t e d , sustained extracommissural damage r e s t r i c t e d to. a small area surrounding the medial p o r t i o n of t h i s s t r u c t u r e . This included the d o r s a l p o r t i o n of the proprius nucleus of the a n t e r i o r commissure, and the ventromedial areas of the medial 75 F i g . 7. Extent of the f o r e b r a i n b i s e c t i o n i n a r e p r e s e n t a t i v e r a t from each group. L i g h t l y shaded areas represent v e n t r i c u l a r spaces. Note that i n Group SBC (operated c o n t r o l s ) the s e c t i o n extends to the d o r s a l surface of the corpus callosum only. 75a 76 s e p t a l n u c l e i . In two cases, the l e s i o n extended c a u d a l l y to i n v o l v e the r o s t r a l f o r n i x . None of the r a t s d i s p l a y e d evidence of damage to the anter-i o r hypothalamus. In Group SBC, damage to the cortex extended the length of the corups callosum, p e n e t r a t i n g to the surface of the s t r u c t u r e . Damage was confined to the medial boundaries of Areas 24, 25, and 26. In many of the r a t s i t appeared that the s i l k had been d e f l e c t e d by the surface of the callosum since these c o r t i c a l areas were 'under-cut' by the s e c t i o n . Group C showed no signs of c o r t i c a l damage. The dura had been v i s u a l -i z e d but not cut i n t h i s group. P r i m a r y - s i t e k i n d l i n g A. P r i m a r y - s i t e c l i n i c a l s e i z u r e development. The appearance of i c t a l a c t i v i t y a s s o c i a t e d with C - l and C-2 was the same f o r a l l groups: mouth movements and head nodding. The e f f e c t s o f f o r e b r a i n b i s e c t i o n d i d not be-come apparent u n t i l r a t s began to d i s p l a y C-3. In the c o n t r o l r a t s , Groups SBC and C, clonus began i n the c o n t r a l a t e r a l f o r e l i m b , spread to the i p s i -l a t e r a l f o r e l i m b , and thus d i s p l a y e d evidence of secondary g e n e r a l i z a t i o n . B i s e c t i o n of e i t h e r the corpus callosum and hippocampal and a n t e r i o r commis-sures (Group TSB) or of the corpus callosum and hippocampal commissure (Group CC) prevented the development of secondary g e n e r a l i z a t i o n . In these groups, the c l o n i c component remained l o c a l i z e d to the c o n t r a l a t e r a l f o r e l i m b . The development of the secondary g e n e r a l i z e d p a t t e r n was subsequently found to depend on the i n t e g r i t y of the c a l l o s a l and hippocampal commissural pathways since b i s e c t i o n of the a n t e r i o r commissure alone (Group AC) d i d not d i s r u p t i t s appearance. 77 Groups AC, SBC, and C d i d not d i f f e r i n c l i n i c a l development throughout the remaining stages of p r i m a r y - s i t e k i n d l i n g . In these groups, s e i z u r e development was c h a r a c t e r i z e d f i r s t by the appearance of secondary-general-i z e d s e i z u r e s ( i e . , the spread of i c t a l a c t i v i t y to the i p s i l a t e r a l p a r t s of the body). Secondary-generalized s e i z u r e s were then followed by the appearance of primary-generalized s e i z u r e s ( i e . , b i l a t e r a l l y symmetrical se i z u r e s from the onset). These bisymmetrical g e n e r a l i z e d s e i z u r e s t y p i c a l l y occurred a f t e r 3 to 4 stage-5 s e i z u r e s had been evoked. The asymmetrical s e i z u r e development observed i n Groups TSB and CC p e r s i s t e d throughout stage 4 and most of stage 5. Rats i n these groups oft e n d i s p l a y e d problems i n r e a r i n g due to the u n i l a t e r a l clonus. A marked d e v i a t i o n i n posture was observed towards the s i d e c o n t r a l a t e r a l to the s i t e of s t i m u l a t i o n . These r a t s d i d , however, begin to show signs of secondary g e n e r a l i z e d s e i z u r e s a f t e r 3 to 4 C-5s had been evoked; i n c o n t r a s t to the c o n t r o l s and Group AC, however, bisymmetrical primary g e n e r a l i z e d s e i z u r e s were not observed u n t i l 5 to 7 stage-5 s e i z u r e s had occurred. There was a latency from the t e r m i n a t i o n of the s t i m u l a t i o n to the appearance of C-5 i n a l l groups of r a t s . T y p i c a l l y t h i s i n t e r v a l was i n i t i a l -l y q uite long but decreased s t e a d i l y with subsequent s t i m u l a t i o n s . By ap-proximately the f i f t h C-5, the d u r a t i o n of the i n t e r v a l appeared to s t a b i l -i z e . This was observed to v a r y i n g degrees i n a l l groups except Group TSB ( F i g . 8A). In t h i s group, l i t t l e r e d u c t i o n i n the i n t e r v a l occurred through-out the e n t i r e C-5 s e i z u r e s . Furthermore, a f t e r reaching stage 5, r a t s o f t e n d i s p l a y e d a number of r e a r i n g and f a l l i n g episodes w i t h i n a s e s s i o n . The number of such episodes was used as an i n d i c a t i o n of s e i z u r e s e v e r i t y , and i s shown i n F i g . 8B. I t was found that r a t s i n Groups TSB and CC tended to 78 F i g . 8A,C,E. The mean latency ( i n sees) from the te r m i n a t i o n of the s t i m u l a t i o n to the appearance of foreli m b clonus during successive p r i m a r y - s i t e , secondary-s i t e , and p r i m a r y - s i t e r e k i n d l e d stage-5 s e i z u r e s . F i g . 8B,D,F. The mean s e i z u r e s e v e r i t y , i n terms of the number of r e a r i n g and f a l l i n g episodes, w i t h i n successive p r i m a r y - s i t e , secondary-site, and p r i m a r y - s i t e r e -k i n d l e d stage-5 s e i z u r e s . 78a 79 d i s p l a y the l e a s t severe s e i z u r e s of any r a t s . Thus, r a t s i n Group TSB tended to show the greatest s e i z u r e l a t e n c i e s and the l e a s t severe s e i z u r e s . B. P r i m a r y - s i t e e l e c t r o g r a p h i c development and propagation. B i s e c t i o n of the f o r e b r a i n commissures had no observable e f f e c t on e i t h e r the develop-ment of p r i m a r y - s i t e AD or AD propagation to the i p s i l a t e r a l MRF, ATH, and FC. During C - l and C-2 a l l groups d i s p l a y e d a s i m i l a r high-amplitude, 2-4/sec spike and wave discharge o r i g i n a t i n g i n the primary s i t e and r e a d i l y spreading to these s t r u c t u r e s . In the c o n t r o l groups, Group SBC and C, sim-i l a r spread to the c o n t r a l a t e r a l MRF, ATH, FC, and AM was observed. However, a l l groups c h a r a c t e r i s t i c a l l y showed l i t t l e a c t i v i t y i n e i t h e r the i p s i l a t e r -a l or c o n t r a l a t e r a l MC. AD was r a r e l y observed i n t h i s s t r u c t u r e u n t i l s e v e r a l C-2 s e i z u r e s had been evoked. The appearance of C-3 or C-4 i n Groups SBC and C was a s s o c i a t e d with a marked increase i n the development and propagation of AD. A high-ampli-tude, 3-6/sec p o l y s p i k e and wave discharge began to emerge from the primary s i t e and spread to other c o r t i c a l and s u b c o r t i c a l s t r u c t u r e s . AD i n the s u b c o r t i c a l s t r u c t u r e s was t y p i c a l l y a lower amplitude but synchronous spike and wave p a t t e r n appearing b i l a t e r a l l y . A p o l y s p i k e and wave c o n f i g -u r a t i o n was observed only i n the i p s i l a t e r a l and c o n t r a l a t e r a l FC and MC. The e l e c t r o g r a p h i c c o r r e l a t e s o f a stage-5 s e i z u r e i n c o n t r o l Group SBC are shown i n F i g . 9. L i t t l e subsequent development occurred at e i t h e r the primary or other s u b c o r t i c a l s i t e s i n groups SBC and C a f t e r the appear-ance of C-5. A notable exception to t h i s was observed i n s e v e r a l r a t s . In these animals, an i r r e g u l a r , 5-8/sec p o l y s p i k e discharge emerged from the primary s i t e and suddenly spread to the c o n t r a l a t e r a l AM. This event t y p i c -a l l y r e q u i r e d s e v e r a l C-5s to develop and seemed to be a s s o c i a t e d with the 80 development of primary g e n e r a l i z e d s e i z u r e s . AD i n other s t r u c t u r e s , except FC and MC, u s u a l l y c o n s i s t e d of p o l y s p i k e and waves synchronized to the primary s i t e . However, i n the FC and MC the development of C-5 was a s s o c i -ated with a buildup of independent high-amplitude, 7-8/sec p o l y s p i k e d i s -charges ( F i g . 9). This a c t i v i t y was observed e i t h e r i n the i p s i l a t e r a l or c o n t r a l a t e r a l FC and MC and disappeared w i t h the t e r m i n a t i o n of the C-5. There were no observable d i f f e r e n c e s between the c o n t r o l groups ( i e . , Groups TSB, CC, and AC) i n terms of the AD development and spread from the primary s i t e to i p s i l a t e r a l s t r u c t u r e s throughout the course of p r i m a r y - s i t e k i n d l i n g . E l e c t r o g r a p h i c c o r r e l a t e s of a t y p i c a l C-5 s e i z u r e i n r a t s from Groups TSB, CC, and AC are shown i n F i g . 9. B i s e c t i o n of the f o r e b r a i n commissures produced a v a r i e t y of e f f e c t s on propagation of AD i n t o c o n t r a l a t e r a l s t r u c t u r e s during the course of p r i m a r y - s i t e k i n d l i n g . B i s e c t i o n of e i t h e r the corpus callosum, hippocampal, and a n t e r i o r commissures (Group TSB) or the a n t e r i o r commissure (Group AC) d i s r u p t e d the spread of a c t i v i t y to the secondary s i t e . In Group TSB, AD i n the secondary s i t e was absent i n a l l r a t s during the e a r l y stages of k i n d l i n g ( i e . stages 1-3); i n Group AC, i t was absent i n only a few r a t s during the e a r l y stages. Rats i n Group AC that d i s p l a y e d AD i n the second-ary s i t e t y p i c a l l y e x h i b i t e d a p a t t e r n that was completely independent of that at the primary s i t e . As k i n d l e d s e i z u r e development progressed there was a gradual increase i n c o n t r a l a t e r a l AM a c t i v i t y i n both Group TSB and Group AC. Secondary-site a c t i v i t y , however, never d i s p l a y e d the high-amp-l i t u d e , p o l y s p i k e and wave p a t t e r n observed i n the c o n t r o l groups ( F i g . 9). Instead, Groups TSB and AC d i s p l a y e d very low-amplitude, s p i k y a c t i v i t y that was o f t e n independent of the primary s i t e . O c c a s i o n a l l y spike and wave a c t i v i t y was observed, but only i n Group AC. 81 B i s e c t i o n o f the corpus callosum and hippocampal commissure (Group CC) d i d not a f f e c t the propagation of AD i n t o the secondary s i t e ( F i g . 9). However, propagation of AD i n t o the c o n t r a l a t e r a l FC and MC i n both t h i s Group and Group TSB was d i s r u p t e d . AD a c t i v i t y i n the c o n t r a l a t e r a l FC and MC during stages 1-3 i n these groups was c h a r a c t e r i z e d by low amplitude, sharp waves intermixed with slow a c t i v i t y . No spike and wave discharges, l i k e those observed i n the c o n t r o l groups, were noted. In c o n t r a s t , spike and wave a c t i v i t y not u n l i k e that observed i n the c o n t r o l groups was observ-ed over the i p s i l a t e r a l FC and MC i n Groups TSB and CC. The 7-8/sec, high amplitude p o l y s p i k e discharge observed b i l a t e r a l l y over the FC and MC i n the c o n t r o l r a t s never developed i n Groups TSB and CC. AD i n the contra-,, l a t e r a l FC and MC i n these groups c o n s i s t e d of moderately high amplitude, sharp waves or spike and waves only o c c a s i o n a l l y independent of the primary s i t e ( F i g . 9). The i p s i l a t e r a l FC and MC, however, d i s p l a y e d the independ-ent p o l y s p i k e features l i k e those observed i n the c o n t r o l groups. The asymmetry of the p a t t e r n i n Groups TSB and CC d i d not a f f e c t the eventual development of primary g e n e r a l i z e d convulsions. B i s e c t i o n of the f o r e b r a i n commissures had i t s major e f f e c t on the morphology of the AD propagated i n t o the c o n t r a l a t e r a l AM, FC, and MC. The duration of the AD i n these s t r u c t u r e s was not permanently d i s r u p t e d ; only during the e a r l y stages of k i n d l i n g was a suppression noted. B i s e c t i o n of the f o r e b r a i n commissures d i d not d i s r u p t the propagation of AD i n t o other s u b c o r t i c a l s t r u c t u r e s . No apparent d i f f e r e n c e s were noted between the c o n t r o l and b i s e c t e d r a t s i n terms of AD spread i n t o the ATH and MRF. 82 F i g . 9. E l e c t r o g r a p h i c c o r r e l a t e s of a p r i m a r y - s i t e C-5 s e i z u r e d i s p l a y e d by a t y p i c a l r a t from each group. Arrows i n -d i c a t e the s i t e of s t i m u l a t i o n ; the c i r c l e d numbers under each record i n d i c a t e the c l i n i c a l response being d i s p l a y -ed. R=right; L = l e f t . B i s e c t i o n o f the a n t e r i o r commissure alone (Group AC) had l i t t l e e f f e c t on the propagation of AD i n the c o n t r a l a t e r a l AM (L AM). Note that propagation i n t o the c o n t r a l a t e r a l AM (L AM) was most severely a f f e c t e d i n Group TSB. Propagation of AD i n t o the c o n t r a l a t e r a l MRF (R MRF) of t h i s group was not a f f e c t e d . B i s e c t i o n of the corpus callosum and hippocampal commissure (Groups CC and TSB) markedly reduced the propagation of AD i n t o the contra-l a t e r a l FC (L FC) and MC (L MC). 82a 83 C. Rate of p r i m a r y - s i t e k i n d l i n g . The r a t e of p r i m a r y - s i t e k i n d l i n g f o r each group i s shown i n Table II. B i s e c t i o n of the f o r e b r a i n commissures was found to have a s i g n i f i c a n t e f f e c t on the r a t e of p r i m a r y - s i t e k i n d l i n g (F=3.52; df=A,37; p<.05). Post hoc a n a l y s i s i n d i c a t e d that b i s e c t i o n of the corpus callosum and hippocampal and a n t e r i o r commissures (Group TSB) caused r a t s to k i n d l e s i g n i f i c a n t l y f a s t e r than c o n t r o l s i n Group SBC / (F=12.57; df=4,37; p<-05) but not i n Group C (F=3.72; df=4 ,37; p>.05). However, no s i g n i f i c a n t d i f f e r e n c e was found between Group SBC and Group C (F=3.57; df =4,37; p>.05). S i m i l a r l y , the r a t e of k i n d l i n g a f t e r b i s e c t i o n of the corpus callosum and hippocampal commissure (Group CC) or the a n t e r i o r commissure (Group AC) d i d not d i f f e r s i g n i f i c a n t l y from e i t h e r Group TSB, Group SBC, or Group C (ps>.05). D. P r i m a r y - s i t e s e i z u r e d u r a t i o n . B i s e c t i o n of the corpus callosum and hippocampal and a n t e r i o r commissures (Group TSB) caused a trend towards c o n s i s t e n t l y longer C-5 s e i z u r e s ( F i g . 10A). Over the f i r s t 4 stage-5 s e i -zures, the d u r a t i o n d i d not s i g n i f i c a n t l y d i f f e r from that of the other groups. However, from the f i f t h to the eighth C-5 the r a t s i n Group TSB d i s p l a y e d c o n s i s t e n t l y longer s e i z u r e s than those r a t s i n Groups SBC and C (ps<.05). Although the s e i z u r e d u r a t i o n i n Group TSB was c o n s i s t e n t l y longer than that of the other b i s e c t e d groups ( i e . , Groups CC and AC), no s i g n i f i -cant d i f f e r e n c e s , were found between Groups CC, AC, SBC, and C. E. AD d u r a t i o n during p r i m a r y - s i t e k i n d l e d s e i z u r e s . A t o t a l of e i g h t C-5 s e i z u r e s were evoked from each r a t . F i g . 11A shows the AD d u r a t i o n of the primary and secondary s i t e a s s o ciated w i t h these s e i z u r e s . Data concern-ing the d u r a t i o n of the AD at other s i t e s ( i e . MRF, ATH, FC, and MC) are not shown f o r reasons of c l a r i t y but w i l l be discussed w i t h i n the t e x t . TABLE I I MEAN NUMBER OF SESSIONS TO KINDLE AT EACH SITE Group Primary S i t e Secondary S i t e Primary S i t e Retest C 15.8 9.1 ** 2.9 (unoperated c o n t r o l s ) (9-29) (4-19) (1-5) n = l l n=10 n=10 SBC 20.5 7.9 t 2.9 (operated c o n t r o l s ) (14-26) (4-11) (2-4) n=8 n=8 n=8 TSB 11.0 * 7.8 1.3 (complete b i s e c t i o n ) (7-15) (1-15) (1-2) n=8 n=5 n=3 CC 16.0 6.6 ** 2.0 (corpus callosum (8-17) (4-10) (1-3) b i s e c t i o n ) n=7 n=5 n=3 AC 18.4 8.4 2.8 ( a n t e r i o r commissure (6-31) (5-13) (1-6) b i s e c t i o n ) n=8 n=8 n=6 * S i g n i f i c a n t l y d i f f e r e n t from operated c o n t r o l s (SBC) p<0.05 ** S i g n i f i c a n t l y d i f f e r e n t from primary s i t e p<0.05 t S i g n i f i c a n t l y d i f f e r e n t from primary s i t e p<0.01 85 F i g . 10A. Mean p r i m a r y - s i t e k i n d l e d s e i z u r e d u r a t i o n ( i n sees) recorded over ei g h t successive stage-5 s e i z u r e s . F i g . 10B. Mean secondary-site k i n d l e d s e i z u r e duration ( i n sees) recorded over ei g h t successive stage-5 s e i z u r e s . F i g . IOC. Mean p r i m a r y - s i t e r e k i n d l e d s e i z u r e d u r a t i o n ( i n sees) recorded over ei g h t successive stage-5 s e i z u r e s . SEIZURE DURATION S g g 8 — i 1 1 r— *S2 86 Fig. 11A. Mean AD duration ( i n sees) recorded from the stimulated (primary) and c o n t r a l a t e r a l (secondary) AM during eight successive primary-site stage-5 seizures. Fig. 11B. Mean AD duration (in sees) recorded from the stimulated (secondary) and c o n t r a l a t e r a l (primary) AM during eight successive secondary-site stage-5 seizures. Note the marked reduction i n primary-site AD duration i n the rats possessing the most extensive b i s e c t i o n (Group TSB). Fig . 11C. Mean AD duration ( i n sees) recorded from the stimulated (primary) and c o n t r a l a t e r a l (secondary) AM during eight successive primary-site rekindled stage-5 seizures. Note that i n Group TSB the secondary-site AD duration i s considerably shortened during primary-site rekindled seizures. AM AD DURATION ^ ro A o> oo o o o o o 5 ^98 87 B i s e c t i o n of the f o r e b r a i n commissures produced no c o n s i s t e n t l y s i g n i -f i c a n t e f f e c t s on the d u r a t i o n of the AD recorded from the secondary s i t e . Furthermore, f o r e b r a i n b i s e c t i o n d i d not appear to a f f e c t the AD d u r a t i o n of e i t h e r the MRF, ATH, FC, or MC. In these s t r u c t u r e s , whether i p s i l a t e r a l or c o n t r a l a t e r a l to the s i t e of s t i m u l a t i o n , the d u r a t i o n of the AD was t y p i c a l l y s i m i l a r i f not i d e n t i c a l to that of the primary s i t e . Although i n Groups TSB and CC the propagation of AD i n t o the c o n t r a l a t e r a l FC and MC was a f f e c t e d by the b i s e c t i o n , only the morphology of the AD was changed. Secondary-site k i n d l i n g A. Secondary-site c l i n i c a l s e i z u r e development. Secondary-site k i n d l -i n g was i n p a r t c h a r a c t e r i z e d by an a c c e l e r a t i o n i n the c l i n i c a l development of s e i z u r e s i n a l l groups. U n l i k e the p r o g r e s s i v e i c t a l development d i s p l a y -ed by the groups during p r i m a r y - s i t e k i n d l i n g , stages i n s e i z u r e development during k i n d l i n g of the secondary s i t e were often missed. Rats o f t e n d i s -played C-3 s e i z u r e s on the f i r s t secondary-site s t i m u l a t i o n or 'skipped' from C-2 to C-5 from one s e s s i o n t o the next. Rats i n Groups AC, SBC, and C showed a r a p i d secondary g e n e r a l i z a t i o n of the c l o n i c component a s s o c i a t e d w i t h C-3: clonus i n i t i a l l y appeared i n the c o n t r a l a t e r a l f o r e l i m b but subsequently g e n e r a l i z e d to a l s o i n c l u d e the i p s i l a t e r a l f o r e l i m b . Groups TSB and CC a l s o developed secondary general-i z e d c l i n i c a l m anifestations but, l i k e p r i m a r y - s i t e k i n d l i n g , they were slower to appear. Secondary ge n e r a l i z e d c h a r a c t e r i s t i c s t y p i c a l l y d i d not develop u n t i l the l a t e r stages of C-4 or e a r l y C-5. Up to t h i s p o i n t , the c l o n i c component of the s e i z u r e was l o c a l i z e d to the c o n t r a l a t e r a l extrem-i t i e s . I t was found, however, that the development of secondary g e n e r a l i z e d c h a r a c t e r i s t i c s was, o v e r a l l , s l i g h t l y f a s t e r during secondary-site k i n d l i n g than during p r i m a r y - s i t e k i n d l i n g . 88 The development of primary g e n e r a l i z e d convulsions appeared i n Groups AC, SBC, and C a f t e r one or two C-5 s e i z u r e s had been evoked. This was s l i g h t l y f a s t e r than that observed during p r i m a r y - s i t e k i n d l i n g (e.g., dur-in g p r i m a r y - s i t e k i n d l i n g t h i s development u s u a l l y occurred a f t e r 3 to 5 stage-5 s e i z u r e s ) . Groups TSB and CC a l s o d i s p l a y e d a. s l i g h t l y a c c e l e r a t e d r a t e . o f primary g e n e r a l i z e d s e i z u r e development w i t h the appearance of C-5. T y p i c a l l y by the appearance of the f i r s t C-5, secondary g e n e r a l i z a t i o n of clonus to the i p s i l a t e r a l e x t r e m i t i e s was observed. Primary g e n e r a l i z e d s e i z u r e s u s u a l l y followed t h i s by one or two sessions. Thus, primary ge n e r a l i z e d s e i z u r e s i n these groups developed a f t e r 3 to 4 C-5 s e i z u r e s : s l i g h t l y f a s t e r than during p r i m a r y - s i t e k i n d l i n g . Most groups d i s p l a y e d a much longer l a t e n c y from the t e r m i n a t i o n of the s t i m u l a t i o n to the appearance o f the C-5 during secondary-site k i n d l e d s e i z u r e s than during p r i m a r y - s i t e k i n d l e d s e i z u r e s ( F i g . 8C). However, the notable exceptions were Groups TSB and CC. In these groups, the l a t e n c y d i d not appear to d i f f e r g r e a t l y between primary and secondary-site C-5s. The other groups ( i e . Groups AC, SBC, and C) showed a gradual r e d u c t i o n i n latency over the eight C-5s; but even by the eighth C-5, the latency i n these groups was approximately twice that observed a f t e r a comparable number of primary s i t e C-5s. Secondary-site C-5 s e i z u r e s e v e r i t y i n a l l groups, except Group TSB, was s l i g h t l y greater than p r i m a r y - s i t e C-5 s e v e r i t y . In Group TSB, s e i z u r e s e v e r i t y was reduced s l i g h t l y during secondary-site C-5s ( F i g . 8D). However, l i k e p r i m a r y - s i t e C-5s the trend towards increased s e v e r i t y with successive stage-5 s e i z u r e s was observed i n a l l groups, i n c l u d i n g Group TSB, during secondary-site C-5s. 89 B. Secondary-site e l e c t r o g r a p h i c development and propagation. The development and spread of AD associated with the e a r l y stages of secondary-s i t e k i n d l i n g ( i e . , C - l and C-2) was considerably more advanced than that observed during s i m i l a r stages of p r i m a r y - s i t e k i n d l i n g . A l l groups d i s p l a y -ed a high amplitude, 3-4/sec spike and wave or p o l y s p i k e and wave discharge appearing f i r s t i n the secondary s i t e and then r a p i d l y spreading to the i p s i l a t e r a l MRF, ATH, FC, MC, and the c o n t r a l a t e r a l MRF and ATH. Groups AC, SBC, and C, but not Groups TSB and CC, a l s o e x h i b i t e d a r a p i d propaga-t i o n of t h i s p a t t e r n i n t o the c o n t r a l a t e r a l FC and MC. In Groups TSB and CC, c o n t r a l a t e r a l c o r t i c a l a c t i v i t y u s u a l l y c o n s i s t e d of low amplitude slow waves. Spread of AD i n t o the primary s i t e of Groups CC, SBC, and C was unaffected but of very low amplitude, much lower than that observed during s i m i l a r stages of p r i m a r y - s i t e k i n d l i n g . Many of the r a t s i n Group CC d i s -played no AD i n c o n t r a l a t e r a l AM. However, the most s t r i k i n g e f f e c t on propagation of AD i n t o the primary s i t e was observed i n Groups TSB and AC. None of the r a t s i n these groups e x h i b i t e d AD spread i n t o t h i s s t r u c t u r e . The l a t e r stages of secondary-site k i n d l i n g ( i e . , C-3, C-4, and C-5)-were marked by the gradual emergence, from the secondary s i t e i n a l l groups, of a high amplitude, high frequency, i r r e g u l a r p o l y s p i k e p a t t e r n . This p a t t e r n f i r s t became evident during C-3 and was f u l l y developed by the ap-pearance of C-5. A l l groups a l s o showed evidence of the b i l a t e r a l propaga-t i o n of t h i s AD p a t t e r n i n t o the ATH and MRF. In these s t r u c t u r e s , however, the p a t t e r n was more r e g u l a r and c o n s i s t e d of p o l y s p i k e and wave discharges. During C-4 and C-5, an independent p o l y s p i k e p a t t e r n , l i k e t hat observed during p r i m a r y - s i t e k i n d l i n g , was observed b i l a t e r a l l y over the FC and MC i n Groups AC, SBC, and C ( F i g . 12). The discharge appeared with the s t a r t of 90 the C-4 or C-5 and g r a d u a l l y ceased with the te r m i n a t i o n of the s e i z u r e . Groups TSB and CC d i s p l a y e d a s i m i l a r development but only u n i l a t e r a l l y over the FC and MC i p s i l a t e r a l to the sti m u l a t e d AM ( F i g . 12). The contra -l a t e r a l FC and MC AD f a i l e d to e x h i b i t a p o l y s p i k e p a t t e r n and i n s t e a d d i s -played mainly lower frequency spike and waves. This asymmetry, however, d i d not d i s r u p t the appearance o f bisymmetrical g e n e r a l i z e d convulsions. Propagation o f AD i n t o the primary s i t e appeared most a f f e c t e d by secondary-site k i n d l i n g . Even Groups CC, SBC, and C showed a marked sup-p r e s s i o n i n propagated a c t i v i t y i n t o t h i s s t r u c t u r e . T y p i c a l l y , the dura-t i o n of AD i n the c o n t r a l a t e r a l AM i n these groups was not as a f f e c t e d as the amplitude of the AD. U n l i k e the r e l a t i v e l y high amplitude spike and wave or p o l y s p i k e and wave p a t t e r n that evolved during stages 3-5 of primary-s i t e k i n d l i n g , the primary s i t e during s i m i l a r stages of secondary-site k i n d l i n g d i s p l a y e d a very low amplitude sharp wave or spiky discharge ac-companied by f a s t background a c t i v i t y . T his p a t t e r n dominated the primary s i t e u n t i l s e v e r a l C-5 sei z u r e s had been evoked. Associated w i t h these s e i z u r e s there was a r a p i d development i n primary s i t e a c t i v i t y and a grad-u a l emergence of the i r r e g u l a r spike and wave or p o l y s p i k e and wave p a t t e r n observed i n the primary s i t e ( F i g . 12). The development of AD i n the contra-l a t e r a l AM i n r a t s o f Group AC was s i m i l a r to that described f o r Groups CC, SBC, and C. However, the amplitude of AD i n the c o n t r a l a t e r a l AM i n Group AC f a i l e d to develop with the appearance of C-5. Instead, the amplitude remained low and co n s i s t e d of high frequency s p i k y a c t i v i t y ( F i g . 12). Rats i n Group TSB dis p l a y e d a lack of AD i n the primary s i t e which p e r s i s t e d throughout the course of secondary-site k i n d l i n g . The d u r a t i o n increased s l i g h t l y during the appearance of C-5 but i t was o f t e n only h a l f 91 F i g . 12. E l e c t r o g r a p h i c c o r r e l a t e o f a secondary-site C-5 s e i z u r e d i s p l a y e d by a t y p i c a l r a t from each group. Arrows i n -d i c a t e the s i t e of s t i m u l a t i o n ; the c i r c l e d numbers under each record i n d i c a t e the c l i n i c a l response being d i s p l a y -ed. R=right; L = l e f t . Note that i n Group AC, b i s e c t i o n of the a n t e r i o r commissure had l i t t l e e f f e c t on the pro-pagation of AD i n t o the c o n t r a l a t e r a l AM (R AM). In Group TSB, b i s e c t i o n of the corpus callosum, hippocampal commissure, and a n t e r i o r commissure se v e r e l y d i s r u p t e d propagation of AD i n t o the c o n t r a l a t e r a l AM. Propagation i n t o the c o n t r a l a t e r a l MRF (L MRF) i n t h i s group was un-a f f e c t e d . Note al s o i n Groups CC and TSB propagation of AD i n t o the MC and FC i p s i l a t e r a l to the sti m u l a t e d AM i s unaffected. 91a 92 of that recorded from the secondary s i t e . Rats i n t h i s group a l s o f a i l e d to develop any high amplitude AD i n the primary s i t e ( F i g . 12). AD a c t i v i t y recorded from t h i s s t r u c t u r e t y p i c a l l y c o n s i s t e d of independent s p i k y a c t i v -i t y or slow waves. C. Rate of secondary-site k i n d l i n g . No s i g n i f i c a n t d i f f e r e n c e i n the r a t e o f secondary-site k i n d l i n g was observed between any of the groups (F=.36; df=4,31; p>.05). However, a l l groups required fewer s t i m u l a t i o n s to k i n d l e s e i z u r e s during secondary-site k i n d l i n g than during p r i m a r y - s i t e k i n d l i n g and thus showed a p o s i t i v e t r a n s f e r e f f e c t (Table II) . In a l l groups, except Group TSB, the r a t e o f secondary-site k i n d l i n g was s i g n i f i c a n t l y f a s t e r than primary s i t e : Group TSB - F=1.19; df'=4,72; p>.05; Group CC - F=3.38; df=4,72; p<.05; Group AC - F=4.64; df=4,72; p<.01; Group SBC - F=5.32; df=4,72; p<.01; Group C - F=3.24; df=4,72; p<.05. Group TSB presumably d i d not d i s p l a y a s i g n i f i c a n t t r a n s f e r e f f e c t because the r a t e of p r i m a r y - s i t e k i n d l i n g was al s o f a c i l i t a t e d . D. Secondary-site s e i z u r e d u r a t i o n . F i g . 10B shows the du r a t i o n o f the e i g h t successive stage-5 s e i z u r e s evoked by secondary-site k i n d l i n g . L i t t l e v a r i a b i l i t y i n s e i z u r e d u r a t i o n between the groups was observed and no s i g n i f i c a n t d i f f e r e n c e s were found. Although secondary-site s e i z u r e s tended to be longer than p r i m a r y - s i t e s e i z u r e s , no s i g n i f i c a n t d i f f e r e n c e s were found. E. AD dur a t i o n during secondary-site k i n d l e d s e i z u r e s . The AD dur a t i o n recorded from the secondary and primary s i t e during the 8 secondary-site C-5s i s shown i n F i g . 11B. For reasons of c l a r i t y the d u r a t i o n of the AD recorded from the MRF,ATH, FC, and MC i s not shown but w i l l be discussed w i t h i n the t e x t . 93 B i s e c t i o n of the f o r e b r a i n commissures produced v a r i a b l e e f f e c t s on the d u r a t i o n of the AD recorded from the primary s i t e . The du r a t i o n of AD propagated i n t o the primary s i t e i n a l l groups, except Group TSB, was not s i g n i f i c a n t l y d i f f e r e n t from that of the secondary s i t e . In Group TSB, the d u r a t i o n o f AD i n the primary s i t e was s i g n i f i c a n t l y s h o r t e r than that of the secondary s i t e (ps<.05) on a l l but the t h i r d , seventh, and eighth sessions. The d u r a t i o n of the AD recorded from the primary s i t e of Groups CC, AC, SBC, and C was not s i g n i f i c a n t l y d i f f e r e n t . However, the du r a t i o n of AD i n the primary s i t e of Group TSB was s i g n i f i c a n t l y s h o r t e r than that of c o n t r o l Group SBC on a l l sessions (ps<.05) and c o n t r o l group C on a l l ses-sions (ps<.05) but the f i r s t , t h i r d , and seventh. The du r a t i o n of the AD recorded from the primary s i t e o f Group TSB was not c o n s i s t e n t l y s h o r t e r than that of the other b i s e c t e d groups ( i e . , Groups CC and AC). B i s e c t i o n of the f o r e b r a i n commissures d i d not d i s r u p t e i t h e r the i p s i l a t e r a l or c o n t r a l a t e r a l propagation of AD i n t o the MRF, ATH, MC, or FC. The AD d u r a t i o n recorded from these s i t e s d i d not d i f f e r g r e a t l y from that recorded from the st i m u l a t e d s i t e . In many cases, the durations were i d e n t i c a l . Therefore, the dur a t i o n of the AD recorded from the primary s i t e i n Group TSB was oft e n s i g n i f i c a n t l y s h o r t e r than that recorded from any of these s t r u c t u r e s . R e k i n d l i n g of the primary s i t e A. C l i n i c a l s e i z u r e development. Primary g e n e r a l i z e d s e i z u r e s occurred very r a p i d l y i n a l l groups when the primary s i t e was again s t i m u l a t e d . A l l groups, but p a r t i c u l a r l y Groups TSB and CC, possessed a m a j o r i t y o f r a t s that d i s p l a y e d e i t h e r C-4 or C-5 s e i z u r e s on the f i r s t s t i m u l a t i o n . I t was r a r e to observe r a t s e x h i b i t i n g l e s s than a C-3 on the f i r s t s t i m u l a t i o n . 94 Signs of secondary g e n e r a l i z a t i o n were absent i n a l l r a t s except f o r a few i n Groups TSB and CC. T y p i c a l l y , most r a t s d i s p l a y e d a primary g e n e r a l i z e d s e i z u r e on the f i r s t C-5. Some r a t s i n Groups TSB and CC, how-ever, r e q u i r e d one, but r a r e l y more than two, C-5s i n order to develop t h i s p a t t e r n . In a l l groups but Group TSB, the late n c y from the te r m i n a t i o n of the s t i m u l a t i o n to the appearance o f the C-5 was i n i t i a l l y q u i t e long but stead-i l y decreased with subsequent C-5s. The late n c y i n Group TSB was i n i t i a l l y q u i t e short and changed very l i t t l e w i t h subsequent C-5s ( F i g . 8E) . A sim-i l a r e f f e c t was observed during p r i m a r y - s i t e C-5 s e i z u r e s . However, during these the l a t e n c i e s i n Group TSB were i n i t i a l l y longer than the other groups and remained so throughout the subsequent C-5s ( F i g . 8A). In general, the l a t e n c i e s recorded during r e k i n d l i n g o f the primary s i t e were s i m i l a r to those recorded during secondary s i t e k i n d l i n g ( F i g . 8C). Rats i n Groups TSB and CC showed l e s s severe s e i z u r e s than other r a t s during r e k i n d l i n g of the primary s i t e ( F i g . 8F). Furthermore, r a t s i n Groups TSB and CC showed l i t t l e d i f f e r e n c e between the s e v e r i t y of primary-s i t e , secondary-site, and p r i m a r y - s i t e - r e t e s t C-5s. In c o n t r a s t , r a t s i n the other groups showed a trend towards increased s e v e r i t y over these phases of the study (e.g. F i g s . 8B, 8D, and 8F). B. E l e c t r o g r a p h i c development and propagation. The development and spread of AD evoked by r e s t i m u l a t i o n of the primary s i t e was i n general s i m i l a r to that observed during the l a t e r stages ( i e . C-4 and C-5) of secondary-site k i n d l i n g . A l l groups i n i t i a l l y developed a high amplitude, 3- 4/sec, spike and wave discharge that subsequently evolved i n t o a complex, 4- 6/sec, i r r e g u l a r s pike and wave or p o l y s p i k e and wave with the appearance of C-5 s e i z u r e s . 95 During C-5, an independent, i r r e g u l a r p o l y s p i k e and wave discharge was observed b i l a t e r a l l y over the FC and MC of Groups AC, SBC, and C ( F i g . 13). In Groups TSB and CC a s i m i l a r p a t t e r n was observed but was r e s t r i c t e d to the c o r t i c a l areas i p s i l a t e r a l to the s t i m u l a t e d AM ( F i g . 13). The contra-l a t e r a l FC and MC i n these groups was c h a r a c t e r i z e d by a low frequency spike and wave discharge w i t h high amplitude slow wave background a c t i v i t y . Rats i n Groups CC, SBC, and C i n i t i a l l y d i s p l a y e d a suppression i n AD propagation i n t o the secondary s i t e . However, the suppression d i d not appear i n the d u r a t i o n of AD but r a t h e r i n the amplitude of AD. The second-ary s i t e was dominated by very low amplitude s p i k y a c t i v i t y w i t h intermixed low amplitude sharp waves or spikes. This p a t t e r n o f t e n p e r s i s t e d up u n t i l s e v e r a l C-5 s e i z u r e s had been evoked, at which time i t r a p i d l y assumed the c h a r a c t e r i s t i c s of the s t i m u l a t e d s i t e ( F i g . 13). Propagation of AD i n t o the secondary s i t e of Group TSB was s e v e r e l y d i s r u p t e d by the f o r e b r a i n b i s e c t i o n . C o n t r a l a t e r a l AM a c t i v i t y i n t h i s group u s u a l l y c o n s i s t e d of independent low amplitude spike discharges of short d u r a t i o n ( F i g . 13). The d u r a t i o n increased s l i g h t l y during the appear-ance of C-5 but o v e r a l l i t remained very short. Rats i n Group AC i n i t i a l l y d i s p l a y e d a s i m i l a r p a t t e r n of development ( F i g . 13) except that the dura-t i o n of the AD recorded from the secondary s i t e g r a d u a l l y increased. During the appearance of C-5, the morphology of the AD p a t t e r n i n the secondary s i t e was l i k e that observed i n Groups CC, SBC, and C except there appeared to be a tendency towards more independent a c t i v i t y . Propagation of AD i n t o the i p s i l a t e r a l and c o n t r a l a t e r a l ATH and MRF d i d not vary between the groups ( F i g . 13). In most cases the discharge morphology i n these s t r u c t u r e s was s i m i l a r to the s t i m u l a t e d s i t e . 96 F i g . 13. E l e c t r o g r a p h i c c o r r e l a t e s o f a p r i m a r y - s i t e r e k i n d l e d C-5 s e i z u r e d i s p l a y e d by a t y p i c a l r a t from each group. Arrows i n d i c a t e the s i t e of s t i m u l a t i o n ; the c i r c l e d numbers under each record i n d i c a t e the c l i n i c a l response being d i s p l a y e d . R=right; L = l e f t . B i s e c t i o n o f the a n t e r i o r commissure caused a s l i g h t r e d u c t i o n i n the AD d u r a t i o n of the c o n t r a l a t e r a l AM (L AM). Note that i n Groups CC and TSB propagation to the c o n t r a l a t e r a l MC (L MC) and FC (L FC) has been sev e r e l y d i s r u p t e d by b i -s e c t i o n o f the corpus callosum and hippocampal commissure. S i m i l a r l y , i n Group TSB, propagation of AD i n t o the contra-l a t e r a l AM (R AM) was d i s r u p t e d . Propagation of AD i n t o the c o n t r a l a t e r a l MRF (R MRF) i n t h i s group was not a f f e c t -ed. 96a 97 C. Rate of r e k i n d l i n g . The r a t e at which the groups r e k i n d l e d when the primary s i t e was again s t i m u l a t e d i s shown i n Table I I . The magnitude of the i n t e r f e r e n c e e f f e c t was determined by the number of s t i m u l a t i o n s r e q u i r e d to evoke a C-5. For example, the greatest number of s t i m u l a t i o n s r e q u i r e d s i g n i f i e d the greatest i n t e r f e r e n c e e f f e c t . As can be seen i n Table 2, r a t s i n Groups TSB and CC k i n d l e d the f a s t e s t and thus showed the l e a s t i n t e r f e r e n c e . Groups AC, SBC, and C showed the g r e a t e s t i n t e r f e r e n c e . However, no s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e s i n the r a t e . o f k i n d l i n g were found (F=1.04; eif=4,25; p>.05). This i n p a r t may have been due to the small number of r a t s i n Groups TSB and CC that progressed to t h i s stage. D. Seizure d u r a t i o n . Five C-5 s e i z u r e s were evoked from the primary s i t e before t e r m i n a t i o n of the experiment. F i g . IOC shows the s e i z u r e d u r a t i o n of the group on each of these sessions. No s i g n i f i c a n t d i f f e r e n c e s i n the s e i z u r e d u r a t i o n were found between any of the groups on any of the f i v e C-5s. Furthermore, the d u r a t i o n of these s e i z u r e s d i d not d i f f e r s i g n i -f i c a n t l y from those recorded during e i t h e r primary or secondary-site k i n d l i n g . E. AD d u r a t i o n . F i g . 11C shows the AD d u r a t i o n recorded at the primary and secondary s i t e during the f i v e C-5 s e i z u r e s evoked by s t i m u l a t i o n of the primary s i t e . The d u r a t i o n of AD recorded from s i t e s other than the AM i s not shown f o r the sake of c l a r i t y . Relevant data concerning these s t r u c t u r e s w i l l be presented i n the t e x t . No s i g n i f i c a n t d i f f e r e n c e s i n the d u r a t i o n of the primary s i t e AD were found between any of the groups. S i m i l a r l y , i n a l l groups except TSB the d u r a t i o n of AD i n the secondary s i t e was not s i g n i f i c a n t l y d i f f e r e n t from that of the primary s i t e . In Group TSB, the d u r a t i o n of AD i n the secondary s i t e was s i g n i f i c a n t l y s h o r t e r (ps<;05) than that of the s t i m u l a t e d AM on 98 a l l s essions. I t was a l s o found to be c o n s i s t e n t l y s h o r t e r that that of the secondary s i t e i n any of the other groups (ps<.05). B i s e c t i o n of the f o r e b r a i n commissures d i d not a f f e c t the d u r a t i o n of the AD propagated i n t o e i t h e r the i p s i l a t e r a l or c o n t r a l a t e r a l MRF, ATH, FC, and MC. In most cases, the d u r a t i o n of the AD recorded from these s t r u c t u r e s was s i m i l a r i f not i d e n t i c a l to that recorded from the s t i m u l a t e d s i t e . D i s c u s s i o n The r e s u l t s of the present study complement and extend those of Experiment 1. I t i s evident t h a t the f o r e b r a i n commissural pathways i n the r a t are not c r i t i c a l f o r the development of bisymmetrical g e n e r a l i z e d con-v u l s i o n s evoked by k i n d l i n g of the amygdala. In view of these r e s u l t s , the p o s s i b i l i t y must be considered that other, extracommissural s t r u c t u r e s may be e i t h e r c r i t i c a l f o r or at l e a s t capable of mediating the development of k i n d l e d s e i z u r e s . B i s e c t i o n of the corpus callosum and hippocampal and a n t e r i o r commis-sures (Group TSB) was found to s i g n i f i c a n t l y f a c i l i t a t e the development of p r i m a r y - s i t e k i n d l e d s e i z u r e s when compared to the appropriate c o n t r o l group, one i n which the cortex o v e r l y i n g the callosum had been sectioned (Group SBC) i n order to c o n t r o l f o r the e f f e c t s of c o r t i c a l damage. The present experiment a l s o succeeded i n d e l i n e a t i n g which of the f o r e b r a i n commissures were re s p o n s i b l e f o r the f a c i l i t a t i o n i n p r i m a r y - s i t e k i n d l i n g . The r e s u l t s i n d i c a t e d that b i s e c t i o n of the corpus callosum and hippocampal and a n t e r i o r commissures (Group TSB) was c r i t i c a l s ince b i s e c -t i o n of the corpus callosum and hippocampal commissure (Group CC) or the a n t e r i o r commissure alone (Group AC) d i d not a f f e c t the r a t e of s e i z u r e 99 development. In Experiment 1, b i s e c t i o n of the r o s t r a l corpus callosum and hippocampal and a n t e r i o r commissures s i g n i f i c a n t l y f a c i l i t a t e d k i n d l i n g . Therefore, i f the r e s u l t s of the two experiments are combined i t becomes apparent that b i s e c t i o n of the r o s t r a l corpus callosum and hippocampal and a n t e r i o r commissures i s a l l that i s necessary f o r the e f f e c t . I t f u r t h e r shows that the e n t i r e corpus callosum i s not i n v o l v e d but only those areas of the s t r u c t u r e r o s t r a l to Area 4. Interhemispheric pathways v i a the f o r e b r a i n commissures were not s i g n i -f i c a n t l y i n v o l v e d i n determining the r a t e of secondary-site k i n d l i n g since i t was found that b i s e c t e d r a t s k i n d l e d at approximately the same r a t e as the i n t a c t c o n t r o l s . However, the commissural pathways appeared t o par-take i n the mediation of the i n t e r f e r e n c e e f f e c t that i s commonly observed during r e k i n d l i n g of the primary s i t e (e.g., Mclntyre and Goddard, 1973). The present r e s u l t s i n d i c a t e that .bisected Groups TSB and CC d i s p l a y e d a r e d u c t i o n i n i n t e r f e r e n c e . B i s e c t i o n of the a n t e r i o r commissure alone (Group AC) had no e f f e c t on i n t e r f e r e n c e . In view of these data, i t i s evident that the i n t e r h e m i s p h e r i c pathways r e s p o n s i b l e f o r the mediation of the i n t e r f e r e n c e e f f e c t are contained w i t h i n the corpus callosum or hippo-campal commissure but not w i t h i n the a n t e r i o r commissure. Previous r e s u l t s (e.g. Mclntyre, 1975) have l e d to s i m i l a r conclusions. The r e s u l t s presented here a l s o show that c o l l e c t i v e l y the corpus callosum, hippocampal commissure, and a n t e r i o r commissure p l a y a s i g n i f i c a n t r o l e i n determining the p r i m a r y - s i t e AD and s e i z u r e d u r a t i o n . However, there was no suggestion of t h e i r involvement i n e i t h e r secondary-site k i n d l i n g or r e k i n d l i n g of the primary s i t e . B i s e c t i o n of these s t r u c t u r e s , as possessed by r a t s i n Group TSB, s i g n i f i c a n t l y increased the d u r a t i o n of 100 the p r i m a r y - s i t e AD and s e i z u r e . Other b i s e c t i o n s were without e f f e c t . Although the present study i n d i c a t e s that the i n t e g r i t y of the f o r e -b r a i n commissures i s not e s s e n t i a l f o r the development of k i n d l e d convul- . s i o n s , there are strong i n d i c a t i o n s t h a t access of s t r u c t u r e s i n one hemi-sphere to those i n the other hemisphere ( v i a the f o r e b r a i n commissures) i s important f o r determining (1) the l a t e n c y to the onset of the s e i z u r e ; (2) the s e v e r i t y of the i c t a l episode; and (3) the mediation of an ' i n t e r f e r e n c e -type' e f f e c t a c t i n g on the l a t e n c y to s e i z u r e onset during secondary-site C-5s. A l l groups except Groups TSB and CC showed an inverse r e l a t i o n s h i p between the s e i z u r e s e v e r i t y and the l a t e n c y to onset of the s e i z u r e : as the latency decreased the s e v e r i t y increased. B i s e c t e d r a t s i n Groups TSB and CC c o n s i s t e n t l y d i s p l a y e d l i t t l e change i n latency.or s e i z u r e s e v e r i t y during the primary, secondary, and primary r e t e s t phases of the study; i n c o n t r a s t , the other groups showed a p r o g r e s s i v e l y more severe s e i z u r e but a decreasing latency only during the primary and primary r e t e s t phases. In these groups, the l a t e n c y during secondary-site k i n d l e d s e i z u r e s was t y p i c a l l y longer,than that recorded during p r i m a r y - s i t e k i n d l e d or primary-s i t e r e k i n d l e d s e i z u r e s . This e f f e c t was not observed i n Groups TSB and CC, suggesting that i t i s mediated by e i t h e r the corpus callosum, hippocampal commissure, or both. S i m i l a r l y , the decreased s e i z u r e s e v e r i t y observed i n Groups TSB and CC s t r o n g l y suggests that i n t e r h e m i s p h e r i c pathways v i a the corpus callosum and hippocampal commissures are e s s e n t i a l i n determining the s e v e r i t y of the convulsive a t t a c k . The present study i n d i c a t e s that the corpus callosum, hippocampal commissure, and a n t e r i o r commissure p l a y a s i g n i f i c a n t r o l e i n the propa-gat i o n of AD i n t o the c o n t r a l a t e r a l AM. Previous r e p o r t s have found that 101 b i s e c t i o n of the a n t e r i o r commissure alone i s s u f f i c i e n t to block the spread of AD between the amygdalae (e.g., F r o s t et al. , 1958; Poblete et al. , 1959). However, the data reported here suggest t h a t a l t e r n a t e routes are a v a i l a b l e through which the AD may spread to the c o n t r a l a t e r a l AM s i n c e b i s e c t i o n of t h i s s t r u c t u r e alone ( r a t s i n Group AC) d i d not a f f e c t the d u r a t i o n of AD i n the c o n t r a l a t e r a l AM. The present r e p o r t suggests that r a t h e r than se r v i n g as a c r i t i c a l route f o r AD propagation, the a n t e r i o r commissure functi o n s mainly as a s t r u c t u r e i n v o l v e d i n maintaining the synchrony of the AD between the two amygdalae. B i s e c t i o n of t h i s s t r u c t u r e blocked the development of bisynchronous AD between the amygdalae. Propagation of AD i n t o the c o n t r a l a t e r a l AM was most d i s r u p t e d by the extensive b i s e c t i o n of the f o r e b r a i n commissures (Group TSB). I f these data are considered along wi t h those from Experiment 1, i t becomes apparent tha t b i s e c t i o n of the r o s t r a l corpus callosum, hippocampal commissure, and a n t e r i o r commissure i s s u f f i c i e n t to produce the e f f e c t . Mclntyre (1975) a r r i v e d at a s i m i l a r c o n c l u s i o n . In s p i t e of the depression i n c o n t r a l a t e r a l AM a c t i v i t y that was observed i n Group TSB during p r i m a r y - s i t e k i n d l i n g , no s i g n i f i c a n t e f f e c t i n the r a t e o f secondary-site t r a n s f e r was found between t h i s group and any of the other groups. These r e s u l t s i n d i c a t e , as do the previous r e s u l t s of Experiment 1 and those of Mclntyre (1975), that the ap-pearance of AD i n the c o n t r a l a t e r a l AM d u r ing p r i m a r y - s i t e k i n d l i n g i s not c r i t i c a l f o r the t r a n s f e r e f f e c t and that the t r a n s f e r e f f e c t must th e r e f o r e be mediated by some extracommissural s t r u c t u r e . Furthermore, the bisynchron-ous discharge of the amygdalae was not found to be c r i t i c a l to the develop-ment of primary ge n e r a l i z e d s e i z u r e s since these developed i n a l l groups regardless of the s t a t e of the AD i n the c o n t r a l a t e r a l AM. 102 An i n t e r e s t i n g e f f e c t was observed throughout t h i s study with regard to the du r a t i o n of AD i n the c o n t r a l a t e r a l AM of Group TSB. I t appeared as though the depression i n propagation to the c o n t r a l a t e r a l AM increased wit h subsequent phases of the study. For example, the depression appeared greatest d u ring the secondary-site and p r i m a r y - s i t e r e t e s t phases of the study. A s i m i l a r observation was made during secondary-site k i n d l i n g i n Experiment 1. The corpus callosum and hippocampal commissure were found to be c r i t i c a l f o r the b i l a t e r a l propagation of a p o l y s p i k e and wave discharge p a t t e r n that was observed i n the FC and MC. In Groups TSB and CC t h i s p a t t e r n was l o c a l i z e d to the FC and MC i p s i l a t e r a l to the s t i m u l a t e d s i t e , whereas i n the other groups the p a t t e r n was observed b i l a t e r a l l y . Although t h i s p a t t e r n i s c l o s e l y a s s o c i a t e d with the appearance o f C-5 s e i z u r e s , i t s importance i n the expression of these s e i z u r e s remains u n c e r t a i n . As sug-gested i n Experiment 1, the p a t t e r n i s l i k e l y a r e f l e c t i o n of a c t i v i t y o c c u r r i n g i n some lower s t r u c t u r e . However, i n the present study the asym-m e t r i c a l nature of t h i s p a t t e r n i n Groups TSB and CC d i d not d i s r u p t the eventual g e n e r a l i z a t i o n of the s e i z u r e . B i s e c t i o n of the f o r e b r a i n commissures d i d not d i s r u p t the b i l a t e r a l propagation of AD i n t o the ATH and MRF. No d i f f e r e n c e i n AD spread to these s t r u c t u r e s was observed between any of the groups. In Experiment 1, the data suggested that areas of the r o s t r a l thalamus were c r i t i c a l l y i n v o l v e d i n the development of k i n d l e d s e i z u r e s ; y e t , i n the present study, no out-standing e l e c t r o g r a p h i c features were noted i n t h i s s t r u c t u r e . Admittedly, however, only a small area of the r o s t r a l thalamus was monitored i n the present study, which may suggest that l a r g e r areas of the s t r u c t u r e are 103 i n v o l v e d i n k i n d l i n g . Furthermore, i f brainstem s t r u c t u r e s are c r i t i c a l to k i n d l i n g , as has been hypothesized, then perhaps recordings from the MRF would have provided an i n d i c a t i o n . C l e a r l y , i n the present study no signs of outstanding e l e c t r o g r a p h i c a c t i v i t y were observed i n the MRF, contrary to observations made i n cats (Wada and Sato, 1974, 1975). Two p o s s i b i l i t i e s may account f o r t h i s discrepency: (1) species d i f f e r e n c e s with regard to MRF p a r t i c i p a t i o n i n k i n d l i n g ; and (2) the areas of the MRF monitored were not comparable. Of the two p o s s i b i l i t i e s the l a t t e r i s favoured since MRF el e c t r o d e placements i n the present study were q u i t e r o s t r a l to those o f Wada and Sato (1974). This i n t u r n may i n d i c a t e that only p a r t i c u l a r areas of the MRF p a r t i c i p a t e i n k i n d l i n g . The f o r e b r a i n commissures p a r t i c i p a t e i n , but are not c r i t i c a l f o r , the development o f bisymmetrical g e n e r a l i z e d convulsions. B i s e c t i o n of the corpus callosum and hippocampal commissure r e t a r d s but does not stop the development of bisymmetrical g e n e r a l i z a t i o n . The present r e s u l t s i n d i c a t e that a l t e r n a t e extracommissural pathways are capable of mediating t h i s p a r t i c u l a r aspect of s e i z u r e development. The question that must be asked i s , What r o l e do these a l t e r n a t e routes p l a y i n the i n t a c t r a t ? Unfortun-a t e l y , t h i s cannot be as c e r t a i n e d on the b a s i s of the data contained w i t h i n the present study. 104 EXPERIMENT 3 The two previous experiments have i n d i c a t e d that the f o r e b r a i n comis-sures i n the r a t are not e s s e n t i a l f o r the development of k i n d l e d amygdaloid s e i z u r e s . The r e s u l t s of these studies show, i n f a c t , that b i s e c t i o n of these pathways i s capable of f a c i l i t a t i n g the r a t e of p r i m a r y - s i t e k i n d l i n g , i n c r e a s i n g the d u r a t i o n of the s t i m u l a t e d s i t e AD, and i n c r e a s i n g the s e i z -ure d u r a t i o n . Furthermore, bisymmetrical g e n e r a l i z e d convulsions were shown to develop i n the b i s e c t e d r a t s , although the r a t e of development was r e t a r d -ed i n the absence of the commissural pathways. There are s e v e r a l r e p o r t s that b i s e c t i o n of the f o r e b r a i n commissures i n humans s u f f e r i n g from i n t r a c t i b l e s e i z u r e s i s a b e n e f i c i a l t h e r a p e u t i c technique (Bogen and Vogel, 1963; Bogen et al. , 1965; Lussenhop, 1970). The reported b e n e f i c i a l e f f e c t s range from an enhanced a b i l i t y to c o n t r o l the s e i z u r e w i t h a n t i c o n v u l s a n t medication, to the l a t e r a l i z a t i o n of the s e i z u r e and subsequent r e t e n t i o n of consciousness. To my knowledge none of the authors have reported an increase i n s e i z u r e a c t i v i t y , as might be suggested by the r e s u l t s of Experiments 1 and 2. I t may, however, be s i g n i -f i c a n t to note that a r e d u c t i o n i n p o s t o p e r a t i v e medication has been assoc-i a t e d w i t h the appearance of g e n e r a l i z e d s e i z u r e s i n some of these p a t i e n t s (Bogen, Sperry, and Vogel, 1969). This i n part supports the suggestion made e a r l i e r that the commissural pathways are i n v o l v e d i n , but not e s s e n t i a l t o , the development of g e n e r a l i z e d s e i z u r e s . The p o i n t at which the f o r e b r a i n commissures are sectioned, i n r e l a t i o n to the development of the e p i l e p t o g e n i c process, may be an important f a c t o r i n e x p l a i n i n g the i n c o n g r u i t y that e x i s t s between the r e s u l t s of the human 105 c l i n i c a l s t u d i e s and Experiments 1 and 2. In the human c l i n i c a l s t u d i e s , b i s e c t i o n of the commissures was performed f o l l o w i n g the maturation of the e p i l e p t i c process, whereas i n Experiments 1 and 2 b i s e c t i o n was done p r i o r to the development of the process. Perhaps i n the i n t a c t b r a i n an i n t e r -hemispheric i n h i b i t o r y i n f l u e n c e , l i k e that suggested by Mutani et al. (1972), i s maintained by the f o r e b r a i n commissures and t h i s i n turn func-t i o n s i n the c o n t r o l of abnormal e l e c t r i c a l a c t i v i t y i n the b r a i n ( i e . , paroxysmal d i s c h a r g e s ) . The s e c t i o n i n g of the f o r e b r a i n commissures would remove the i n h i b i t o r y e f f e c t thereby f a c i l i t a t i n g the development of s e i z u r e a c t i v i t y . Kopeloff et al. (1950) found that b i s e c t i o n of the f o r e b r a i n commissures a f t e r the maturation of a c o r t i c a l focus i n the monkey r e s u l t e d i n an increased s t a t e of s e i z u r e s u s c e p t i b i l i t y . A l t e r n a t i v e l y , i n the i n -t a c t b r a i n the commissural pathways might be the pathways c r i t i c a l l y i n v o l v e d i n the maintenance of s e i z u r e a c t i v i t y a f t e r the e p i l e p t o g e n i c process has matured. A mutually f a c i l i t a t o r y e f f e c t may occur between the hemispheres that i s mediated v i a the f o r e b r a i n commissures. I f these connections are then severed the r e s u l t may be a severe d i s r u p t i o n i n the s e i z u r e . In order to c l a r i f y the various i s s u e s , the present experiment was designed to examine the e f f e c t s of f o r e b r a i n b i s e c t i o n on secondary-site k i n d l i n g i n r a t s already k i n d l e d from a primary s i t e . I f these pathways are i n v o l v e d i n the media-t i o n of an i n t e r h e m i s p h e r i c i n h i b i t i o n , b i s e c t i o n of the commissures a f t e r p r i m a r y - s i t e k i n d l i n g should r e s u l t i n f a c i l i t a t e d secondary-site k i n d l i n g . On the other hand, i f the f o r e b r a i n commissural pathways f u n c t i o n i n the mediation of a mutual f a c i l i t a t i o n between hemispheres, by s e c t i o n i n g them secondary-site k i n d l i n g should be retarded. I t was decided that r a t h e r than examining the r o l e played by a l l the f o r e b r a i n commissures, only the e f f e c t s of b i s e c t i n g the corpus callosum 106 and hippocampal commissure would be examined. These two connections were chosen f o r a v a r i e t y of reasons. F i r s t l y , i t was f e l t t hat since these s t r u c t u r e s are most f r e q u e n t l y sectioned i n human p a t i e n t s , i t would be appropriate to do the same i n t h i s study. Secondly, there are many tech-n i c a l c o n s i d e r a t i o n s i n v o l v e d i n the b i s e c t i o n of these s t r u c t u r e s i n the r a t . For example, p i l o t s t u d i e s i n d i c a t e d that s e l e c t i v e b i s e c t i o n of the a n t e r i o r commissure i n a k i n d l e d r a t would be extremely d i f f i c u l t and im-p o s s i b l e to achieve on a c o n s i s t e n t b a s i s . However, b i s e c t i o n of the corpus callosum and hippocampal commissure was c o n s i s t e n t l y achieved. Methods Subjects. Seventeen male hooded r a t s of the Long-Evans s t r a i n weigh-in g between 300-350 g were used. Rats were housed i n d i v i d u a l l y i n a temper-ature c o n t r o l l e d colony room with a 12 hour l i g h t - d a r k c y c l e . They had fr e e access to food and water except during t e s t i n g and were allowed 10-14 days to adjust to the colony environment before undergoing surgery. Electrode i m p l a n t a t i o n . Rats were anaesthetized w i t h sodium pento-b a r b i t a l (60.0 mg/kg, i n t r a p e r i t o n e a l l y ) and b i p o l a r nichrome electrodes were aimed b i l a t e r a l l y at the b a s o l a t e r a l nucleus o f the amygdala (0.4 mm a n t e r i o r to bregma, 4.3 mm l a t e r a l to the m i d l i n e , 8.5 mm v e n t r a l from the surface of the s k u l l , and the i n s c i s o r bar set at +5.0) of a l l r a t s . D e t a i l s concerning the c o n s t r u c t i o n of e l e c t r o d e s , t h e i r i m p l a n t a t i o n , and postoper-a t i v e care of r a t s has been o u t l i n e d i n Experiments 1 and 2. Te s t i n g procedures. The t e s t i n g procedure used i n t h i s study was i d e n t i c a l to that used i n the previous experiments, 1 and 2. Rats were placed i n a sh i e l d e d wire cage and 2.0 min of b a s e l i n e EEG a c t i v i t y was 107 recorded. A 1.0 sec, 160 ya constant current 60-Hz sine wave stimulus was then administered to e i t h e r the r i g h t or l e f t amygdala of each r a t . The s t i m u l a t i o n was d e l i v e r e d once d a i l y between the hours of 1000 and 1300. Amygdaloid k i n d l i n g and f o r e b r a i n b i s e c t i o n . Kindled s e i z u r e develop-ment was c l a s s i f i e d according to the method of Racine (1972a) o u t l i n e d i n Experiment 1. Rats were considered k i n d l e d a f t e r reaching the C-5 stage i n se i z u r e development. Eight stage-5 s e i z u r e s were evoked from the primary s i t e . F o llowing the ei g h t h C-5, r a t s were anaesthetized with sodium p e n t o b a r b i t a l (60 mg/kg, i n t r a p e r i t o n e a l l y ) , f i x e d i n the s t e r e o t a x , and a m i d l i n e craniotomy was performed. The s a g g i t a l sinus was v i s u a l i z e d and the f o r e b r a i n commissures were b i s e c t e d u s i n g the method described i n Experiment 2. Eight of the 15 r a t s were randomly chosen f o r b i s e c t i o n . No record was kept of which r a t s had undergone b i s e c t i o n i n order to r e -duce experimenter b i a s . The remaining r a t s were t r e a t e d i n a s i m i l a r manner, but i n s t e a d of b i s e c t i n g the commissures only the cortex o v e r l y i n g the corpus callosum was sectioned. These r a t s served as a c o n t r o l group. F o l l o w i n g surgery the craniotomy was packed with s t e r i l e gelfoam soaked i n normal s a l i n e , and the s k u l l was then covered w i t h a t h i n l a y e r of dent a l a c r y l i c . Rats were allowed a minimum of 10 days to recover from surgery before being stimulated. F o l l o w i n g recovery, the s i t e of s t i m u l a t i o n was switched to the secondary s i t e i n order to study the e f f e c t s of f o r e b r a i n commissur-otomy on t r a n s f e r . Rats were then k i n d l e d and eight C-5 s e i z u r e s were evok-ed. F o l l o w i n g the eighth C-5, s t i m u l a t i o n was then switched back to the o r i g i n a l s i t e (primary s i t e ) and the e f f e c t s of f o r e b r a i n b i s e c t i o n on the i n t e r f e r e n c e phenomenon was examined. Eight C-5 s e i z u r e s were evoked by s t i m u l a t i n g the primary s i t e . The s i t e of s t i m u l a t i o n was then again 108 switched back to the secondary s i t e where eight C-5 s e i z u r e s were evoked p r i o r to the termination of the experiment. A f t e r d i s c h a r g e and s e i z u r e d u r a t i o n . The c r i t e r i a used i n the present study f o r the re c o r d i n g of a f t e r d i s c h a r g e and s e i z u r e d u r a t i o n a s s o c i a t e d with the va r i o u s stages of k i n d l i n g were the same as those used i n Exper-iments 1 and 2. A d d i t i o n a l parameters of the k i n d l e d s e i z u r e . The r e s u l t s of E x p e r i -ments 1 and 2 suggested that a record of s e v e r a l a d d i t i o n a l aspects of the k i n d l e d s e i z u r e would be h e l p f u l i n determining the e f f e c t s of f o r e b r a i n b i s e c t i o n . Thus, a record was made of the latency from the t e r m i n a t i o n of the s t i m u l a t i o n to the appearance of the C-5 i c t a l manifestations f o r each sessi o n . S i m i l a r l y , the number of C-5 s e i z u r e s evoked p r i o r to the b i l a t -e r a l g e n e r a l i z a t i o n of the response were a l s o noted. A measure of the s e v e r i t y of the s e i z u r e was a l s o attempted on each s e s s i o n ; t h i s was estim-ated by recording the number of r e a r i n g and f a l l i n g episodes e x h i b i t e d by each r a t on each sess i o n . H i s t o l o g y . Rats were k i l l e d with an overdose of sodium p e n t o b a r b i t a l , perfused through the heart w i t h 0.9% s a l i n e that was followed by 10% form-a l i n . The b r a i n was removed and stored i n 10% f o r m a l i n . Frozen coronal s e c t i o n s 40 ya i n thickness were taken. Every f i f t h s e c t i o n (0.2 mm) was kept and st a i n e d w i t h c r e s y l v i o l e t i n order to i d e n t i f y the el e c t r o d e l o c a t i o n and extent of the b i s e c t i o n . The el e c t r o d e l o c a t i o n and extent of the b i s e c t i o n were then p l o t t e d on s e c t i o n s taken from the s t e r e o t a x i c a t l a s of P e l l i g r i n o and Cushman (1967). Tracings of r e p r e s e n t a t i v e h i s t o l -ogy were prepared. 109 Results Because no record was kept concerning which r a t s had undergone commis-surotomy, the experimental and c o n t r o l groups were not assembled u n t i l a h i s t o l o g i c a l a n a l y s i s of the b r a i n had been made. A l l r a t s were i n t a c t during p r i m a r y - s i t e k i n d l i n g ; t h e r e f o r e , the d i v i s i o n of the p r i m a r y - s i t e k i n d l i n g data i n t o experimental and c o n t r o l s e c t i o n s was done i n order to show that e f f e c t s observed between these groups i n subsequent phases of the study were not due to inherent d i f f e r e n c e s . B i s e c t i o n of the corpus callosum and hippocampal commissure f a c i l i t a t -ed the r a t e of secondary-site k i n d l i n g . Forebrain b i s e c t i o n was a l s o found to d i s r u p t the development of primary g e n e r a l i z e d motor s e i z u r e s . AD dura-t i o n was not a f f e c t e d by f o r e b r a i n b i s e c t i o n ; however, secondary-site k i n d l e d s e i z u r e s were t y p i c a l l y l e s s severe and of longer l a t e n c y to onset. I n t e r -ference was a l s o markedly reduced by the b i s e c t i o n . H i s t o l o g y . A l l e l e c t r o d e t i p s were found i n or immediately adjacent to the b a s o l a t e r a l nucleus of the AM ( F i g . 1). B i s e c t i o n of the f o r e b r a i n commissures i n the experimental group ([CC]; N=8) appeared r e l a t i v e l y con-s t a n t , with most r a t s possessing a complete b i s e c t i o n of the corpus callosum and hippocampal commissure. To be in c l u d e d i n the experimental group r a t s had to possess a complete b i s e c t i o n of the hippocampal commissure and at l e a s t the r o s t r a l h a l f of the callosum: the r e s u l t s of Experiment 1 and 2 suggested that the r o s t r a l aspects of the callosum were most i n v o l v e d i n k i n d l i n g . Extracommissural damage i n the experimental group was minimal. In most r a t s i t was confined to the t i s s u e o v e r l y i n g the callosum ( i e . , c i n g u l a t e c o r t e x ) . S u b c o r t i c a l damage a l s o appeared n e g l i g i b l e . The hippo-campus appeared r e l a t i v e l y f r e e of d e s t r u c t i o n , although some r a t s d i s p l a y e d 110 minor damage to the medial aspects of Ammons Horn. No evidence of m i d l i n e thalamic damage was observed, nor was any obvious disturbance of the v e n t r i -c u l a r system apparent. O v e r a l l , the b i s e c t i o n was very clean. Representa-t i v e s e c t i o n s are shown i n F i g . 14. There were no signs of c a l l o s a l damage i n the c o n t r o l group ( [ C ] ; N=7) . The t r a n s e c t i o n i n t h i s group was confined to a small s t r i p of c i n g u l a t e cortex, adjacent to the m i d l i n e . In a few r a t s the l o c a t i o n and extent of the t r a n s e c t i o n were s i m i l a r to the above except that some 'undercutting' of the cortex was noted, apparently r e s u l t i n g from the d e f l e c t i o n of the s u r g i c a l s i l k by the f i b e r s of the callosum. Representative c o n t r o l sec-t i o n s are shown i n F i g . 14. P r i m a r y - s i t e k i n d l i n g A. P r i m a r y - s i t e e l e c t r o c l i n i c a l development and propagation. There were no outstanding d i f f e r e n c e s between the c o n t r o l and experimental groups with regard t o the e l e c t r o c l i n i c a l development of p r i m a r y - s i t e k i n d l e d s e i -zures. The progressive e l a b o r a t i o n of s e i z u r e s i n both groups followed a p a t t e r n s i m i l a r to that described f o r the c o n t r o l r a t s of Experiments 1 and 2. By the eighth C-5 a l l but one r a t from each group had developed primary ge n e r a l i z e d s e i z u r e s (Table I I I ) . T y p i c a l l y t h i s p a t t e r n emerged around the f o u r t h or f i f t h C-5 and remained throughout subsequent sessions. Both groups a l s o d i s p l a y e d marked but s i m i l a r reductions i n the C-5 l a t e n c i e s over the f i r s t to eighth s e i z u r e s ( F i g . 15A). S i m i l a r l y , both groups showed a progressive increase i n s e i z u r e s e v e r i t y over the eight C-5 sessions ( F i g . 15B). The o v e r a l l . p a t t e r n of AD development and propagation was s i m i l a r i n both groups. Perhaps the most evident e l e c t r o g r a p h i c f e a t u r e was the some-I l l F i g . 14. Extent of the f o r e b r a i n b i s e c t i o n on a r e p r e s e n t a t i v e r a t from each group. L i g h t l y shaded areas represent v e n t r i c u l a r spaces. In Group C, the s e c t i o n extends to the d o r s a l surface o f the corpus callosum only. 111a 112 TABLE I I I EFFECT OF FOREBRAIN BISECTION ON THE DEVELOPMENT OF PRIMARY GENERALIZED MOTOR SEIZURES _. . „ , Primary Secondary Primary Secondary R e t e s / R e t e s t Group CC No. showing primary g e n e r a l i z e d 7 1 4 3 s e i z u r e T o t a l 8 8 t 7 7 * Group C No. showing primary g e n e r a l i z e d 6 7 7 7 s e i z u r e T o t a l 7 7 7 7 * S i g n i f i c a n t l y d i f f e r e n t from Group C (c o n t r o l s ) p<0.05 t S i g n i f i c a n t l y d i f f e r e n t from Group C ( c o n t r o l s ) p<0.01 113 F i g . 15A,C,E,G. Mean latency ( i n sees) from the ter m i n a t i o n o f the s t i m u l a t i o n to the appearance o f f o r e l i m b clonus during successive p r i m a r y - s i t e k i n d l e d , secondary-site k i n d l e d , p r i m a r y - s i t e r e k i n d l e d , and secondary-site r e k i n d l e d stage-5 s e i z u r e s . F i g . 15B,D,F,H. Mean s e i z u r e s e v e r i t y i n terms of the number of r e a r i n g and f a l l i n g episodes, w i t h i n successive p r i m a r y - s i t e k i n d l e d , secondary-site k i n d l e d , p r i m a r y - s i t e r e k i n d l e d , and secondary-site r e -k i n d l e d stage-5 s e i z u r e s . 113a 114 Fi g . 16. Records from a r e p r e s e n t a t i v e r a t i n each group show-in g the e l e c t r o g r a p h i c c o r r e l a t e s of a stage-5 s e i z u r e during the va r i o u s se c t i o n s o f the experiment. Arrows i n d i c a t e the s i t e of s t i m u l a t i o n ; the c i r c l e d numbers under each record i n d i c a t e the c l i n i c a l response being d i s p l a y e d . R=right; L = l e f t . 114a 115 what slow development of propagated a c t i v i t y i n the c o n t r a l a t e r a l AM. Although the AD p a t t e r n i n t h i s s t r u c t u r e was t y p i c a l l y synchronous with that of the st i m u l a t e d s i t e , the amplitude of the discharge was consider a b l y lower. The a c t i v i t y o f the c o n t r a l a t e r a l AM i n both groups d i d not u s u a l l y mature ( i e . , assume the same high amplitude c h a r a c t e r i s t i c s of the s t i m u l a t -ed s i t e ) u n t i l s e v e r a l stage-5 s e i z u r e s had been evoked. F i g . 16 shows the e l e c t r o g r a p h i c c o r r e l a t e s of a p r i m a r y - s i t e C-5 s e i z u r e f o r each group. B. Rate of p r i m a r y - s i t e k i n d l i n g . Table IV shows the r a t e o f primary-s i t e k i n d l i n g f o r each group. As expected, there was no s i g n i f i c a n t d i f f e r -ence between the r a t e at which the c o n t r o l and experimental groups k i n d l e d (F=.29; df=1,13; p>.05). C. P r i m a r y - s i t e s e i z u r e d u r a t i o n . The p r i m a r y - s i t e s e i z u r e d u r a t i o n observed during each o f the eigh t C-5s i s shown i n F i g . 17A. No s i g n i f i c a n t d i f f e r e n c e s were found between the two groups over these eight sessions. Both groups tended to d i s p l a y longer s e i z u r e s during the f i r s t s e v e r a l C-5s but wit h subsequent s t i m u l a t i o n s the durations appeared to s t a b i l i z e . D. AD d u r a t i o n during p r i m a r y - s i t e k i n d l e d s e i z u r e s . F i g . 18A d i s -plays the AD du r a t i o n recorded from the primary and secondary s i t e s during the eight p r i m a r y - s i t e C-5 s e i z u r e s . As i s evident, l i t t l e d i f f e r e n c e be-tween the st i m u l a t e d and c o n t r a l a t e r a l AM AD dur a t i o n i n e i t h e r group e x i s t -ed. Furthermore, no s i g n i f i c a n t d i f f e r e n c e s were found between e i t h e r group with regard to the d u r a t i o n of the primary or secondary-site AD. Secondary-site k i n d l i n g A. Secondary-site e l e c t r o c l i n i c a l development and propagation. B i s e c -t i o n of the corpus callosum and hippocampal commissure was found to severely d i s r u p t the development of primary g e n e r a l i z e d C-5 s e i z u r e s . This f i n a l 116 TABLE IV MEAN NUMBER OF SESSIONS TO KINDLE AT EACH SITE „ n . c , Primary S i t e Secondary S i Group Primary S i t e Secondary S i t e „ Ketest Ketest CC 14.6 4.0* 1.6 1.3 t (11-20) (2-9) (1-4) (1-2) n=8 n=8 n=8 n=7 C 15.9 7.0 2.4 2.4 (8-26) (6-9) (1-4) (2-3) n=7 n=7 n=7 n=7 * S i g n i f i c a n t l y d i f f e r e n t from the ra t e of secondary-site k i n d l i n g of the c o n t r o l s (Group C) p<0.05 t S i g n i f i c a n t l y d i f f e r e n t from the ra t e of secondary-site r e k i n d l i n g of the c o n t r o l s (Group C) p<0.01 117 F i g . 17A. Mean s e i z u r e d u r a t i o n ( i n sees) of eigh t successive stage-5 p r i m a r y - s i t e s e i z u r e s . F i g . 17B. Mean s e i z u r e d u r a t i o n ( i n sees) of e i g h t successive stage-5 secondary-site s e i z u r e s . F i g . 17C. Mean p r i m a r y - s i t e r e k i n d l e d s e i z u r e d u r a t i o n ( i n sees) recorded over eight successive stage-5 s e i z u r e s . F i g . 17D. Mean secondary-sees) recorded s i t e over r e k i n d l e d s e i z u r e d u r a t i o n ( i n eight successive stage-5 s e i z u r e s . 117a 80 < 60 ce 3 ° 4 0 UJ tc 3 N 20 UJ (A PRIMARY S E C O N D A R Y A C • C C i — i — i i « • > • • 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 S U C C E S S I V E STAGE -5 SEIZURES PRIMARY R E T E S T - SECONDARY RETEST m m 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 S U C C E S S I V E STAGE-5 SE IZURES 118 Mean AD du r a t i o n ( i n sees) recorded from the st i m u l a t e d (primary) and c o n t r a l a t e r a l (secondary) AM during e i g h t successive p r i m a r y - s i t e stage-5 s e i z u r e s . Mean AD du r a t i o n ( i n sees) recorded from the st i m u l a t e d (secondary) and c o n t r a l a t e r a l (primary) AM during eight successive secondary-site stage-5 s e i z u r e s . Mean AD d u r a t i o n ( i n sees) recorded from the s t i m u l a t e d (primary) and c o n t r a l a t e r a l (secondary) AM during eight successive p r i m a r y - s i t e r e k i n d l e d stage-5 s e i z u r e s . Mean AD du r a t i o n ( i n sees) recorded from the st i m u l a t e d (secondary) and c o n t r a l a t e r a l (primary) AM during e i g h t successive secondary-site r e k i n d l e d stage-5 s e i z u r e s . 118a 100 O 80 5= 6 0 Q Q 40 < 2 20 PRIMARY SITE • • • •'' v' A C • cc PRIMARY -— - SECONDARY r^j 1 1 1 1 — SECONDARY — - PRIMARY 11 4 6 8 2 4 6 8 SUCCESS IVE STAGE -5 SEIZURES 100 z 0 80 < 6 0 D O Q 40 < AM 20 PRIMARY-SITE RETEST PRIMARY SECONDARY _i 1 1 — SECONDARY-SITE RETEST V — SECONDARY — - PRIMARY 8 2 4 6 8 SUCCESS IVE STAGE -5 SEIZURES 119 stage i n development was d i s p l a y e d by a l l c o n t r o l r a t s by the eighth C-5; i n c o n t r a s t , primary g e n e r a l i z a t i o n was evident i n only one of the 8 r a t s i n the experimental group (Table 3). This d i f f e r e n c e was found to be h i g h l y s i g n i f i c a n t (X =8.24; df=l; p<.01). Experimental and c o n t r o l groups both showed s i m i l a r e f f e c t s on the C-5 s e i z u r e l a t e n c i e s . Secondary-site s e i -zures were t y p i c a l l y , accompanied by much longer l a t e n c i e s to develop. The major d i f f e r e n c e , however, was that f o r e b r a i n - b i s e c t e d r a t s d i s p l a y e d c o n s i s t e n t l y longer l a t e n c i e s than those of the c o n t r o l group ( F i g . 15C). Furthermore, f o r e b r a i n b i s e c t i o n a l s o produced a marked r e d u c t i o n i n the s e v e r i t y of the secondary-site s e i z u r e ( F i g . 15D). However, the e f f e c t was not permanent and tended to d i s s i p a t e by the eighth C-5. Therefore, i n summary, secondary-site c l i n i c a l s e i z u r e s may be c h a r a c t e r i z e d by: (1) lack of primary g e n e r a l i z a t i o n ; (2) longer l a t e n c y to appear; and (3) a marked r e d u c t i o n i n s e i z u r e s e v e r i t y . B i s e c t i o n of the f o r e b r a i n commissures had very l i t t l e e f f e c t on the e l e c t r o g r a p h i c c o r r e l a t e s of secondary-site k i n d l i n g . Experimental and c o n t r o l groups both showed a s i m i l a r f a c i l i t a t i o n i n the development of secondary-site AD that has proved to be a c h a r a c t e r i s t i c o f secondary-site k i n d l i n g (e.g., Experiments 1 and 2). S i m i l a r l y , both groups showed a r e t a r d a t i o n i n the propagation of AD i n t o the primary s i t e . The d u r a t i o n of AD i n the primary s i t e was d i s r u p t e d only during the i n i t i a l stages of k i n d l i n g ( i e . C - l to C-3). As k i n d l i n g progressed, the d u r a t i o n of the AD approached that of the secondary s i t e , but the amplitude and complexity of the discharge remained depressed. This e f f e c t appeared most evident i n the b i s e c t e d group but p e r s i s t e d throughout many o f the i n i t i a l C-5s i n both groups. AD morphology i n the secondary s i t e d i d not approach that of the primary s i t e ( i e . , 4-6/sec, high amplitude, p o l y s p i k e and wave or i r r e g u l a r 120 polyspike) u n t i l approximately f i v e C-5 s e i z u r e s had been evoked. E l e c t r o -graphic f e a t u r e s of a t y p i c a l C-5 s e i z u r e f o r each group are shown i n F i g . 16. B. Rate of secondary-site k i n d l i n g . The r a t e of secondary s i t e k i n d l -i n g i n each group i s shown i n Table IV. B i s e c t i o n of the corpus callosum and hippocampal commissure s i g n i f i c a n t l y f a c i l i t a t e d the r a t e of secondary-site k i n d l i n g (F=8.83; df=1,13; p<.05). The c o n t r o l group d i d , however, show a s i g n i f i c a n t t r a n s f e r e f f e c t (.F=5.05; df=1,13; p<.05). C. Secondary-site s e i z u r e d u r a t i o n . The d u r a t i o n a s s o c i a t e d w i t h each of the secondary-site C-5 s e i z u r e s i s shown i n F i g . 17B. Both groups d i s -played s i m i l a r increases i n s e i z u r e d u r a t i o n as compared to those of primary-s i t e s e i z u r e s . Although the b i s e c t e d r a t s d i s p l a y e d longer secondary-site s e i z u r e s than the c o n t r o l s , no c o n s i s t e n t l y s i g n i f i c a n t d i f f e r e n c e s between the groups were found. D. AD d u r a t i o n during secondary-site k i n d l e d s e i z u r e s . B i s e c t i o n of the f o r e b r a i n commissures had l i t t l e e f f e c t on the d u r a t i o n of the AD r e -corded from the secondary and primary s i t e . F i g . 18B shows the d u r a t i o n of the AD recorded from AM during the 8 secondary-site C-5 s e i z u r e s i n each group. Although the AD d u r a t i o n at the secondary s i t e i n the b i s e c t e d group tended to be longer than that of the c o n t r o l s , no s i g n i f i c a n t d i f f e r e n c e s were found. S i m i l a r l y , no d i f f e r e n c e s were found between the d u r a t i o n of AD i n the primary s i t e and the secondary s i t e i n e i t h e r group. R e k i n d l i n g of the primary s i t e A. E l e c t r o c l i n i c a l development and propagation. The e f f e c t s of f o r e -b r a i n b i s e c t i o n on the development of s e i z u r e s was l e s s apparent during r e -k i n d l i n g of the primary s i t e than during secondary-site k i n d l i n g . Both 121 groups d i s p l a y e d s i m i l a r s e i z u r e l a t e n c i e s that were, i n general, s h o r t e r than those observed during secondary-site k i n d l i n g ( F i g . 15E). No s i g n i f i -cant d i f f e r e n c e s were found between the groups, although b i s e c t e d r a t s continued to d i s p l a y longer l a t e n c i e s than the c o n t r o l s ( F i g . 15E) . Sever-i t y o f the s e i z u r e was a l s o unaffected by the f o r e b r a i n b i s e c t i o n ( F i g . 15F). B i s e c t i o n of the corpus callosum and hippocampal commissure d i s r u p t e d the development of primary g e n e r a l i z e d C-5 s e i z u r e s . Only 4 of the 8 r a t s i n the experimental group e v e n t u a l l y developed t h i s type of C-5; i n c o n t r a s t , a l l r a t s i n the c o n t r o l group e x h i b i t e d primary g e n e r a l i z e d C-5 se i z u r e s (Table I I I ) . No s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e was found between the groups with regard to t h i s p a r t i c u l a r aspect of s e i z u r e development. A l s o , more r a t s i n the experimental group developed primary g e n e r a l i z e d C-5s dur-i n g r e k i n d l i n g of the primary s i t e than during k i n d l i n g of the secondary s i t e . Very few c o n t r a s t i n g e l e c t r o g r a p h i c features were observed between the experimental and c o n t r o l group during p r i m a r y - s i t e r e k i n d l i n g . The e l e c t r o -graphic c o r r e l a t e s of a t y p i c a l C-5 s e i z u r e are shown i n F i g . 16. Both groups showed a r a p i d development of s e i z u r e s . This was accompanied by a f a c i l i t a t e d development i n the o v e r a l l morphology of the st i m u l a t e d s i t e . Most r a t s d i s p l a y e d high amplitude, 4-6/sec, p o l y s p i k e and wave discharges that became p r o g r e s s i v e l y more i r r e g u l a r with subsequent C-5 s e i z u r e s . Propagation i n t o the secondary s i t e o f both groups i n i t i a l l y c o n s i s t e d of very low amplitude spike and wave or sharp wave discharges synchronized with the primary s i t e . However, a f t e r four to f i v e C^5 s e i z u r e s had been evoked, t h i s p a t t e r n g r a d u a l l y evolved i n t o a high amplitude i r r e g u l a r discharge s i m i l a r to th a t observed at the primary s i t e . 122 B. Rate of p r i m a r y - s i t e r e k i n d l i n g . The r a t e of p r i m a r y - s i t e r e k i n d l -i n g i s shown i n Table IV. B i s e c t i o n of the corpus callosum and hippocampal commissure produced a r e d u c t i o n i n the i n t e r f e r e n c e e f f e c t that i s commonly observed when a s i t e i s r e k i n d l e d (e.g., Experiments 1 and 2). However, due to the v a r i a b i l i t y w i t h i n the two groups, the e f f e c t was not s t a t i s t i c a l l y s i g n i f i c a n t . C. Rekindled p r i m a r y - s i t e s e i z u r e d u r a t i o n . No s i g n i f i c a n t d i f f e r -ences were found between the C-5 s e i z u r e d u r a t i o n of e i t h e r group. The d u r a t i o n i n both groups appeared to s t a b i l i z e during t h i s phase of the study ( F i g . 17C). Both groups showed a n o n s i g n i f i c a n t r e d u c t i o n i n s e i z u r e d u r a t i o n as compared to secondary-site C-5s. D. AD d u r a t i o n during p r i m a r y - s i t e r e k i n d l e d s e i z u r e s . F i g . 18C shows the d u r a t i o n of AD i n the primary and secondary s i t e a s s o c i a t e d with each of the p r i m a r y - s i t e r e k i n d l e d C-5 s e i z u r e s . B i s e c t i o n of the f o r e b r a i n commissures d i d not a f f e c t the AD d u r a t i o n . No s i g n i f i c a n t d i f f e r e n c e s were found i n the AD d u r a t i o n of primary or secondary s i t e s e i t h e r w i t h i n or between the two groups. R e k i n d l i n g of the secondary s i t e A. E l e c t r o c l i n i c a l development and AD propagation. S i g n i f i c a n t l y fewer r a t s i n the experimental group developed primary g e n e r a l i z e d C-5 s e i z u r e s during secondary-site r e k i n d l i n g (X=3.22; df=l; p<.05). Only 3 of the 7 r a t s i n the f o r e b r a i n - b i s e c t e d group developed t h i s type of s e i z u r e ; a l l of the r a t s i n the c o n t r o l group, however, e x h i b i t e d the eventual development of t h i s p a t t e r n (Table I I I ) . B i s e c t i o n of the f o r e b r a i n commissures was found to have l i t t l e e f f e c t on the s e v e r i t y or l a t e n c y of the s e i z u r e . Although the s e i z u r e latency i n previous phases of the study t y p i c a l l y decreased as 123 a f u n c t i o n of the number of C-5 s e i z u r e s , i t appeared to s t a b i l i z e during secondary-site k i n d l e d s e i z u r e s ( F i g . 15G)^. The s e i z u r e s e v e r i t y i n the c o n t r o l group appeared to s t a b i l i z e , whereas i n the experimental group the c h a r a c t e r i s t i c increase with subsequent C-5 s e i z u r e s was observed ( F i g . 15H). The e l e c t r o g r a p h i c c o r r e l a t e s of a secondary-site r e k i n d l e d C-5 are shown i n F i g . 16, There was no d i f f e r e n c e between the groups i n terms of s t i m u l a t e d - s i t e AD development. Both groups d i s p l a y e d w e l l developed, high amplitude, 4-6/sec, p o l y s p i k e and wave c o n f i g u r a t i o n s with the f i r s t stimu-l a t i o n . An outstanding feature of secondary-site r e k i n d l i n g was the lack of propagation i n t o the primary s i t e observed i n the f o r e b r a i n - b i s e c t e d group. Not only was the amplitude of the discharge d r a s t i c a l l y reduced i n t h i s group but the d u r a t i o n of the discharge was a l s o severely a f f e c t e d . This lack of p r i m a r y - s i t e a c t i v i t y was most evident during the f i r s t s e v e r a l C-5 s e i z u r e s . Some signs of recovery were noted with subsequent sessions. U s u a l l y by the s i x t h to eighth C-5, a p a t t e r n s i m i l a r to that recorded from the primary s i t e was observed i n t h i s s t r u c t u r e . A s i m i l a r but l e s s con-s i s t e n t e f f e c t was a l s o observed i n the c o n t r o l group. In the c o n t r o l group, propagation i n t o the primary s i t e was sometimes depressed during the e a r l y C-5s but i n a l l cases i t r a p i d l y recovered. P r i m a r y - s i t e a c t i v i t y i n both groups was c h a r a c t e r i z e d by extremely low amplitude sharp wave d i s -charges imposed on a background of f a s t a c t i v i t y . These discharges, however, were only r a r e l y independent from those of the s t i m u l a t e d s i t e . B. Rate of secondary-site r e k i n d l i n g . B i s e c t i o n of the corpus callosum and hippocampal commissure s i g n i f i c a n t l y reduced the i n t e r f e r e n c e e f f e c t as-s o c i a t e d w i t h the r e k i n d l i n g of the secondary s i t e (F=17.65; df=l,l2; p<.01). The r a t e of secondary s i t e r e k i n d l i n g i s shown i n Table IV. No s i g n i f i c a n t 124 d i f f e r e n c e s were observed between the r a t e s of primary and secondary-site r e k i n d l i n g i n e i t h e r group. C. Rekindled secondary-site s e i z u r e d u r a t i o n . The s t a b i l i z a t i o n i n s e i z u r e d u r a t i o n noted during p r i m a r y - s i t e r e k i n d l e d C-5s was a l s o evident during secondary-site C-5s. The d u r a t i o n of these secondary-site r e k i n d l e d s e i z u r e s i s shown i n F i g . 17D. No s i g n i f i c a n t d i f f e r e n c e s i n s e i z u r e dura-t i o n were found between e i t h e r the c o n t r o l or f o r e b r a i n - b i s e c t e d groups. D. AD d u r a t i o n during secondary-site r e k i n d l e d s e i z u r e s . B i s e c t i o n of the f o r e b r a i n commissures caused a c o n s i s t e n t r e d u c t i o n i n the d u r a t i o n of AD i n the primary s i t e ( F i g . 18D). A s i g n i f i c a n t r e d u c t i o n from that of the s t i m u l a t e d s i t e was found on s e s s i o n 2, 4, 5, 6, and 7 (ps<.05). No s i g n i f i c a n t d i f f e r e n c e s were found i n AD durations of the c o n t r o l group primary and secondary s i t e . Furthermore, the AD durations of the secondary s i t e i n the c o n t r o l and experimental group were not s i g n i f i c a n t l y d i f f e r e n t . Discussion The r e s u l t s of the present study again confirmed t h a t the corpus c a l l -osum and hippocampal commissure i n the r a t are not e s s e n t i a l pathways f o r the development of k i n d l e d amygdala s e i z u r e s . B i s e c t i o n of these s t r u c t u r e s , f o l l o w i n g p r i m a r y - s i t e k i n d l i n g , produced a s i g n i f i c a n t f a c i l i t a t i o n i n the r a t e of secondary-site k i n d l i n g ( i e . , t r a n s f e r e f f e c t ) . These data suggest that i n the i n t a c t animal the commissural connections i n t e r f e r e w i t h or i n -h i b i t the interhemispheric t r a n s f e r of s e i z u r e s u s c e p t i b i l i t y . The present r e s u l t s a l s o i n d i c a t e that although the i n t e g r i t y of the f o r e b r a i n commissures i s not necessary f o r the development of s e i z u r e s , these s t r u c t u r e s do p a r t i c i p a t e i n determining s e v e r a l c l i n i c a l aspects of 125 the k i n d l e d s e i z u r e . F i r s t l y , the f o r e b r a i n commissural pathways are i n v o l v -ed i n determining the latency from te r m i n a t i o n of the s t i m u l a t i o n to C-5 c l i n i c a l m a n i f e s t a t i o n s . B i s e c t i o n of these pathways produced much longer l a t e n c i e s . Secondly, s i n c e the s e v e r i t y o f the k i n d l e d s e i z u r e was markedly reduced i n the b i s e c t e d r a t s , commissural pathways p r o v i d i n g access to the c o n t r a l a t e r a l hemisphere must be viewed as important l i n k s f o r the transmis-s i o n o f a c t i v i t y concerned with determining the s e v e r i t y of the c o n v u l s i v e attack. The d i s r u p t i v e e f f e c t s that f o r e b r a i n b i s e c t i o n has on latency and s e v e r i t y of the attack are most evident during secondary-site k i n d l i n g . The d i s r u p t i v e e f f e c t s diminished w i t h subsequent phases o f the study: primary-and secondary-site r e k i n d l i n g . In view of these data, i t i s worthwhile co n s i d e r i n g the p o s s i b i l i t y that t h i s diminuation i n the d i s r u p t i v e e f f e c t s i s a r e f l e c t i o n of the establishment of a l t e r n a t e , extracommissural routes which i n turn are able to support these two aspects of k i n d l e d s e i z u r e ex-p r e s s i o n . F i n a l l y , i n the i n t a c t r a t the neuronal mechanisms r e s p o n s i b l e f o r the development of p r i m a r y - s i t e primary g e n e r a l i z e d s e i z u r e s are l i k e l y to i n v o l v e the f o r e b r a i n commissures. Furthermore, i f r a t s are k i n d l e d p r i o r to f o r e b r a i n b i s e c t i o n , these commissural connections may become the p r e f e r r e d , i f not permanent, pathways concerned with the primary g e n e r a l i z -a t i o n of the s e i z u r e . This i s supported by the present f i n d i n g that b i s e c -t i o n of the commissures produces a longterm d i s r u p t i o n i n the expression of t h i s type of s e i z u r e . The present r e s u l t s i n d i c a t e that perhaps both i n h i b i t o r y and f a c i l i -t o r y processes are evoked during k i n d l i n g and t h a t b i s e c t i o n of the f o r e -b r a i n commissures can s u c c e s s f u l l y separate these. For example, an i n t e r -hemispheric i n h i b i t o r y e f f e c t , mediated v i a the commissures, may be a c t i v e l y 126 i n v o l v e d i n the suppression of e p i l e p t o g e n e c i t y i n the i n t a c t animal. B i -s e c t i o n of the commissures would e l i m i n a t e t h i s i n f l u e n c e and may thus ex-p l a i n the f a c i l i t a t e d r a t e of secondary-site k i n d l i n g that was observed i n the experimental group. As k i n d l e d s e i z u r e development progresses i n the i n t a c t animal, an i n t e r h e m i s p h e r i c f a c i l i t a t o r y i n t e r a c t i o n may be evoked that a l s o i s mediated v i a the f o r e b r a i n commissures. This i n t u r n may i n -fluence such aspects of the s e i z u r e as s e v e r i t y and latency to expression. This would account f o r the decreased s e v e r i t y and increased latency observed i n the b i s e c t e d r a t s . Whether or not t h i s i s an a c t i v e process cannot be deduced at t h i s time. I t i s p o s s i b l e that a f a c i l i t a t o r y i n t e r a c t i o n i s not a c t u a l l y o c c u r r i n g , and the e f f e c t s on l a t e n c y and s e i z u r e s e v e r i t y noted i n the b i s e c t e d group are due to a d i s r u p t i o n i n the spread t o , and subsequent recruitment of, a g r e a t e r number of c o n t r a l a t e r a l s t r u c t u r e s (e.g., areas of the c o n t r a l a t e r a l c o r t e x ) . The f o r e b r a i n commissures were a l s o found to be i n v o l v e d i n the med-i a t i o n of the i n t e r f e r e n c e e f f e c t observed during the r e k i n d l i n g of the primary s t r u c t u r e . The r e s u l t s showed th a t b i s e c t i o n of the commissures s i g n i f i c a n t l y reduced the i n t e r f e r e n c e e f f e c t ( i e . , b i s e c t e d r a t s r e q u i r e d fewer s t i m u l a t i o n s than c o n t r o l s to r e k i n d l e ' a s i t e ) . These data may a l s o be viewed as support f o r the hypothesis that f o r e b r a i n b i s e c t i o n d i s r u p t s the m a n i f e s t a t i o n of an i n t e r h e m i s p h e r i c i n h i b i t o r y process. P a r t i c i p a t i o n of the f o r e b r a i n commissures i n determining the C-5 s e i -zure d u r a t i o n was not i n d i c a t e d by the present r e s u l t s . No d i f f e r e n c e s were observed between the experimental and c o n t r o l groups. However, some evidence of commissural involvement i n the propagation of AD i n t o the c o n t r a l a t e r a l AM was observed, but only during the r e k i n d l i n g of the secondary s i t e . 127 I t was found that the AD d u r a t i o n i n the c o n t r a l a t e r a l AM during t h i s phase of the study was s i g n i f i c a n t l y reduced on many o f the sessions. An explan-a t i o n f o r t h i s e f f e c t i s l a c k i n g f o r the moment. 128 GENERAL DISCUSSION Racine et al. (1972) proposed that k i n d l i n g r e s u l t e d from the pro-gre s s i v e strengthening of i n t e r l i m b i c connections. To support t h i s hypo-t h e s i s , they showed that i f the m a j o r i t y of the i n t e r l i m b i c connections were severed by t r a n s e c t i n g the f o r e b r a i n commissures, the r a t e of amygdaloid k i n d l i n g was retarded. The present s e r i e s of experiments shows, however, that the f o r e b r a i n commissures of the r a t are not c r i t i c a l pathways f o r the development of s e i z u r e s evoked by r e p e t i t i v e s t i m u l a t i o n of the amygdala. This f i n d i n g i s not unprecedented and has been observed i n previous s t u d i e s (Mclntyre, 1975; Wada and Sato, 1975). The r e s u l t s of Racine et al. (1972) may i n p a r t have been due to the u n i n t e n t i o n a l damage of extracommissural s t r u c t u r e s as suggested by Experiment 1. Although present and previous r e s u l t s ( i e . , M clntyre, 1975; Wada and Sato, 1975) i n d i c a t e that the i n t e r l i m b i c hypothesis of Racine does not adequately account f o r amygdaloid k i n d l i n g , the hypothesis cannot be t o t a l -l y discarded; even i n the f o r e b r a i n - b i s e c t e d animal many a l t e r n a t e i n t e r -l i m b i c and p o t e n t i a l i n t e r l i m b i c routes e x i s t v i a s t r u c t u r e s such as the thalamus and hypothalamus (e.g., Bucy and Kluver, 1955; Nauta, 1962; Lammers, 1972; de Olmos, 1972). Nevertheless, the acceptance of the i n t e r l i m b i c hypothesis should remain guarded. In view of the present r e s u l t s , an a l t e r -nate explanation i s advanced. This hypothesis proposes that amygdaloid k i n d l i n g i s a f u n c t i o n of the strengthening of l i m b i c - b r a i n s t e m connections. I t has been proposed that the r e p e t i t i v e e l i c i t a t i o n of AD r e s u l t s i n the pr o g r e s s i v e p o t e n t i a t i o n of p a r t i c u l a r pathways (e.g., Goddard and Douglas, 1975; Racine et al. , 1975). I t i s p o s s i b l e that some of these pathways may i n v o l v e routes to the brainstem. Many e a r l y r e p o r t s suggested that r e t i c u l a r 129 and thalamic elements of the brainstem are important f o r the development of seiz u r e s a r i s i n g from the temporal lobe s t r u c t u r e s (Kaada, 1951; F e i n d e l and Gloor, 1954; Gloor, 1955a,b). Wada and Sato (1974, 1975) have a l s o demonstrated the p a r t i c i p a t i o n of the MRF i n amygdaloid k i n d l i n g . Brainstem involvement i n other aspects of convulsive behaviour such .as secondary e p i -leptogenesis (e.g., M o r r e l l , 1960; Isaacson et al. , 1971; Nie et al. , 1974) and bisymmetrical g e n e r a l i z a t i o n of discharges a r i s i n g from b i l a t e r a l c o r t -i c a l f o c i (e.g., Marcus and Watson, 1966; Ot t i n o et al. , 1971; Mutani et al. , 1973) has a l s o been shown. Furthermore, i n Experiment 1 of t h i s t h e s i s , d e s t r u c t i o n o f large areas o f the thalamus s i g n i f i c a n t l y retarded amygdaloid k i n d l i n g . B i s e c t i o n o f the corpus callosum, hippocampal commissure, and a n t e r i o r commissure s i g n i f i c a n t l y f a c i l i t a t e d the r a t e of p r i m a r y - s i t e k i n d l i n g (Experiments 1 and 2); b i s e c t i o n of the corpus callosum and hippocampal commissure s i g n i f i c a n t l y f a c i l i t a t e d the r a t e o f secondary-site k i n d l i n g (Experiment 3). Wada and Sato (1975) a l s o found that b i s e c t i o n of these s t r u c t u r e s f a c i l i t a t e d the r a t e of amygdaloid k i n d l i n g i n the cat. These r e s u l t s support the hypothesis that w i t h i n the i n t a c t animal one hemisphere i s able to exert an i n h i b i t o r y i n f l u e n c e on the development of e p i l e p t i f o r m a c t i v i t y i n the other. In a d d i t i o n , t h i s i n f l u e n c e appears to be mediated v i a the f o r e b r a i n commissures. This hypothesis does not go unsupported by e a r l i e r i n v e s t i g a t i o n s . For example, a number o f st u d i e s have shown that e i t h e r enhancement or i n h i b i t i o n of spike discharges i n secondary f o c i can occur f o l l o w i n g the i n a c t i v a t i o n of primary f o c i (e.g., Rovit et al. , 1960; M o r r e l l , 1960; Gloor et al. , 1965; Coceani et al. , 1966). These s t u d i e s demonstrate the f a c t that b i l a t e r a l f o c i possess the a b i l i t y to i n t e r a c t . 130 Mutani et al. (1972) l a t e r showed that the a c t i v i t y of b i l a t e r a l c o r t i c a l f o c i i s enhanced f o l l o w i n g the s e c t i o n i n g of commissural connections and reduced f o l l o w i n g cortex-corpus callosum i s o l a t i o n from the subcortex. This l e d to the suggestion that t r a n s c a l l o s a l pathways were r e s p o n s i b l e f o r the transmission of an interhemispheric i n h i b i t o r y i n f l u e n c e and that b r a i n -stem pathways mediated a s i m i l a r but f a c i l i t a t o r y e f f e c t . Although Mutani's hypothesis was derived from observations of c o r t i c a l e p i l e p t o g e n i c processes i n a c u t e l y prepared animals, the r e s u l t s presented i n t h i s t h e s i s suggest that the same i s true f o r s u b c o r t i c a l processes i n chronic p r e p a r a t i o n s . The present r e s u l t s suggest that the f a c i l i t a t e d r a t e of k i n d l e d s e i -zure development may i n p a r t be the r e f l e c t i o n of the precoccious develop-ment o f li m b i c - b r a i n s t e m pathways i n the b i s e c t e d r a t . The f a c i l i t a t i v e nature of these pathways and the importance of brainstem s t r u c t u r e s has already been discussed ( i e . , Mutani etal. , 1972; Wada and Sato, 1974, 1975). Therefore, the f o l l o w i n g hypothesis i s advanced: In the i n t a c t animal, shorter monosynaptic and o f t e n commissural routes are the p r e f e r r e d routes f o r the e a r l y spread of e p i l e p t i f o r m a c t i v i t y o r i g i n a t i n g i n the amygdala. For example, F r o s t et al. (1958) showed that the importance of the a n t e r i o r commissure i n monkeys f o r the e a r l y spread of amygdaloid AD to the contra-l a t e r a l amygdala. However, these are not c r i t i c a l pathways f o r the develop-ment of k i n d l e d s e i z u r e s and f u n c t i o n mainly as avenues f o r the dissemination of the discharge to other n o n e s s e n t i a l s t r u c t u r e s . The c r i t i c a l pathways f o r k i n d l i n g are those connecting the l i m b i c - b r a i n s t e m s t r u c t u r e s . Because these routes are o f t e n long and p o l y s y n a p t i c , they are slow to develop i n the i n -t a c t animal; and do so only through the repeated bombardment by AD from the AM. In the e a r l y stages of k i n d l i n g , AD propagation l i k e l y occurs f i r s t over 131 the short monosynaptic routes since these are more a c c e s s i b l e . As k i n d l i n g progresses, however, the l e s s a c c e s s i b l e brainstem pathways are g r a d u a l l y ' s e n s i t i z e d ' by the repeated i n v a s i o n of AD a c t i v i t y . Therefore, k i n d l e d s e i z u r e development i n the i n t a c t animal i s a r e f l e c t i o n of the gradual ' s e n s i t i z a t i o n ' o f these limb i c - b r a i n s t e m connections. In the b i s e c t e d animal, many of the s h o r t e r , more a c c e s s i b l e monosynaptic routes are sever-ed. Thus, AD i n these animals i s unable to make use of these pathways. Instead, AD that would normally use these routes i s , i n a sense, 'funnelled' i n t o the brainstem c i r c u i t s . This increased l e v e l of AD bombardment i n tu r n r e s u l t s i n an increased r a t e of ' s e n s i t i z a t i o n ' . The increased r a t e of limbic-brainstem ' s e n s i t i z a t i o n ' , t h e r e f o r e , i s r e f l e c t e d as an increase i n the r a t e of amygdaloid k i n d l i n g . One might a l t e r n a t i v e l y e x p l a i n the f a c i l i t a t i o n i n k i n d l i n g as a mani-f e s t a t i o n of denervation s u p e r s e n s i t i v i t y and not the removal of transcomis-s u r a l i n h i b i t i o n and p o t e n t i a t i o n of limbic - b r a i n s t e m connections, since the e f f e c t was observed i n completely b i s e c t e d ( i e . , b i s e c t e d i n the corpus callosum, hippocampal commissure and a n t e r i o r commissure) r a t s of Experiments 1 and 2 and callosotomized r a t s of Experiment 3. This i n d i c a t e s that only those r a t s with the most extensive b i s e c t i o n s show the e f f e c t . Stavraky (1961) found an increase i n the s u s c e p t i b i l i t y o f callosomotized r a t s and cats to the convulsive e f f e c t s of p e n t y l e n e t e t r a z o l . S i m i l a r l y , Sharpless (1969) has suggested that denervation s u p e r s e n s i t i v i t y i s capable of pro-ducing increases i n s e i z u r e s u s c e p t i b i l i t y . The r e s u l t s presented here, however, c o n t r a i n d i c a t e s u p e r s e n s i t i v i t y as a cause f o r the f a c i l i t a t e d k i n d l i n g . F i r s t l y , only p r i m a r y - s i t e k i n d l i n g i n Experiments 1 and 2 and secondary-site k i n d l i n g i n Experiment 3 were f a c i l i t a t e d . I f denervation 132 s u p e r s e n s i t i v i t y were the explanation f o r t h i s increase i n s e i z u r e suscept-i b i l i t y , a f a c i l i t a t i o n i n secondary-site k i n d l i n g i n Experiments 1 and 2 might a l s o have been expected. Secondly, i n Experiments 1 and 2 the s e i z u r e s e v e r i t y i n the r a t s with b i s e c t i o n s i n e i t h e r the corpus callosum, a n t e r i o r commissure, and hippocampal commissure or corpus callosum and hippocampal commissure d i d not appr e c i a b l y increase through subsequent phases of the s t u d i e s , u n l i k e the other b i s e c t e d and c o n t r o l r a t s . Furthermore, i n Exper-iment 3 the s e i z u r e s e v e r i t y during secondary-site k i n d l i n g a c t u a l l y decreas-ed. An o v e r a l l increase i n s e i z u r e s e v e r i t y would presumably be i n d i c a t e d i f denervation s u p e r s e n s i t i v i t y were the cause of the f a c i l i t a t e d s e i z u r e development. F i n a l l y , Wada and Sato (1975) found no d i f f e r e n c e i n the gene r a l i z e d s e i z u r e t r i g g e r i n g t h r e s h o l d of f o r e b r a i n - b i s e c t e d k i n d l e d cats and i n t a c t k i n d l e d cats. The f o r e b r a i n commissures are i m p l i c a t e d i n the mediation of the i n t e r -ference e f f e c t . However, only b i s e c t i o n s i n v o l v i n g at l e a s t the corpus callosum and hippocampal commissure d i s r u p t e d t h i s e f f e c t , suggesting that these s t r u c t u r e s and not the a n t e r i o r commissure are c r i t i c a l . Mclntyre (1975) reported a s i m i l a r r e s u l t . Although the r e s u l t s o f Experiments 1, 2, and 3 i n d i c a t e that b i s e c t i o n of the f o r e b r a i n commissures e i t h e r before or a f t e r k i n d l i n g produces many s i m i l a r e f f e c t s , they f u r t h e r i n d i c a t e that q u i t e d i f f e r e n t e f f e c t s can be produced. The most obvious d i f f e r e n c e s were noted with regard to the devel-opment of primary g e n e r a l i z e d convulsions. The r e s u l t s of Experiments 1 and 2 showed that the corpus callosum and hippocampal commissure p a r t i c i p a t e d i n but were not c r i t i c a l f o r the development of primary g e n e r a l i z a t i o n . B i s e c -t i o n of these s t r u c t u r e s retarded but d i d not stop the gradual emergence of 133 t h i s convulsion. However, b i s e c t i o n of these s t r u c t u r e s a f t e r k i n d l i n g rendered the animals incapable of developing primary g e n e r a l i z e d convul-sions during subsequent phases o f k i n d l i n g ( i e . , secondary s i t e , e t c . ) . These c o n t r a s t i n g r e s u l t s may i l l u s t r a t e an inherent property of the cen-t r a l nervous system: neural p l a s t i c i t y . Because the development of primary g e n e r a l i z e d convulsions i s severely d i s r u p t e d by f o r e b r a i n commissurotomy a f t e r k i n d l i n g , the f o r e b r a i n commissures appear c r i t i c a l l y i n v o l v e d i n t h i s phenomenon i n the i n t a c t r a t . On the other hand, i f the commissural path-ways are severed p r i o r t o k i n d l i n g the r e s u l t s support the neural p l a s t i c i t y suggestion i n that a l t e r n a t e , s u b c o r t i c a l pathways are able to assume the f u n c t i o n s of the commissures and thus mediate the development of primary ge n e r a l i z e d convulsions. In the k i n d l e d r a t , the commissural connections appear to be the major routes f o r primary g e n e r a l i z a t i o n of the s e i z u r e and the ' p o t e n t i a l ' a l t e r n a t e pathways are presumably i n v o l v e d i n some other aspect of k i n d l i n g (e.g., propagation of AD). Therefore, the number of ' p o t e n t i a l ' a l t e r n a t e pathways i n the k i n d l e d r a t are n e c e s s a r i l y fewer than i n the nonkindled r a t . As a r e s u l t , f o r e b r a i n b i s e c t i o n has a considerably greater, i f not permanent, e f f e c t on primary g e n e r a l i z a t i o n of the s e i z u r e i n k i n d l e d as opposed to nonkindled r a t s . Most of the r e p o r t s concerning the e f f e c t s of f o r e b r a i n b i s e c t i o n i n humans s u f f e r i n g from i n t r a c t i b l e s e i z u r e s have i n d i c a t e d t h e r a p e u t i c bene-f i t s ranging from enhanced a b i l i t y to c o n t r o l s e i z u r e s w i t h anticonvulsant drugs to a r e d u c t i o n i n g e n e r a l i z e d s e i z u r e frequency, l a t e r a l i z a t i o n of the c l i n i c a l m a n ifestations and a r e t e n t i o n of consciousness (Bogen and Vogel, 1963; Bogen et al. , 1965; Lussenhop, 1970). None of the authors have thus f a r reported an increase i n s e i z u r e a c t i v i t y as might be suggested by 134 the r e s u l t s of the present s t u d i e s ( i e . , Experiments 1 and 2). However, the only f a i r t e s t o f t h i s was represented by Experiment 3, i n which the e f f e c t s of f o r e b r a i n b i s e c t i o n on the mature e p i l e p t i f o r m process were t e s t e d . The r e s u l t s of t h i s study i n d i c a t e that b i s e c t i o n of the f o r e b r a i n commissures was indeed capable of e x e r t i n g a degree of c o n t r o l over subsequent s e i z u r e development. Although the b i s e c t e d r a t s i n t h i s study d i s p l a y e d a s i g n i f i -cant f a c i l i t a t i o n i n secondary-site k i n d l i n g , i t i s important to note that the c l i n i c a l aspects of these s e i z u r e s i n d i c a t e d that an o v e r a l l decrease i n the i n t e n s i t y of the evoked s e i z u r e s had occurred. This decrease i n se i z u r e i n t e n s i t y was manifest as: (1) a s i g n i f i c a n t r e d u c t i o n i n the number of r a t s d i s p l a y i n g primary g e n e r a l i z a t i o n ; (2) a marked increase i n the latency to convulsion; and (3) a r e d u c t i o n i n the s e i z u r e s e v e r i t y . An explanation as to why the r a t s d i s p l a y e d f a c i l i t a t e d s e i z u r e development and the human p a t i e n t s did.not may be a f u n c t i o n of: (1) a d i f f e r e n c e i n species; or (2) the maintenance of the human p a t i t e n t s on a posto p e r a t i v e regimen of anticonvulsant medication. In the human p a t i e n t , b i s e c t i o n of the f o r e b r a i n commissures may increase the se i z u r e t r i g g e r i n g t h r e s h o l d to the p o i n t where anticonvulsant medication becomes e f f e c t i v e . With regard to the gen e r a l i z e d s e i z u r e , Bogen et al. (1969) have reported that general-i z e d s e i z u r e s have occurred i n p a t i e n t s f o l l o w i n g a red u c t i o n i n medication. This supports the suggestion that the f o r e b r a i n commissures are the p r i n c i -p a l mediators i n t h i s phenomenon, but that a l t e r n a t e pathways are a l s o able to serve as mediators. The e l e c t r o g r a p h i c observations seemed t o bear no r e l a t i o n s h i p to the c l i n i c a l aspects o f k i n d l i n g , although the importance o f p a r t i c u l a r pathways f o r the inter h e m i s p h e r i c propagation of AD was i n d i c a t e d . In con t r a s t to 135 many of the e a r l y reports (e.g., McCulloch and Garol, 1941; F r o s t et al. , 1958; Poblete et al., 1959) the a n t e r i o r commissure was found not to be the major pathway f o r the spread of AD between the amygdalae. Experiments 1 and 2 showed that b i s e c t i o n of the a n t e r i o r commissure alone had l i t t l e longterm e f f e c t on propagation i n t o the c o n t r a l a t e r a l AM. Because propaga-t i o n was most d i s r u p t e d by s e c t i o n i n g of the corpus callosum, hippocampal commissure and a n t e r i o r commissure, the importance of these a d d i t i o n a l routes was c l e a r l y i n d i c a t e d . Furthermore, the p a r t i c i p a t i o n of thalamic areas i n t h i s phenomenon was i n d i c a t e d by Experiment 1. The lack of AD a c t i v i t y i n the c o n t r a l a t e r a l AM had no e f f e c t on (1) t r a n s f e r ; (2) i n t e r f e r e n c e ; or (3) g e n e r a l i z a t i o n . In view of these data, not only does the i n t e r l i m b i c hypothesis of k i n d l i n g become l e s s ten-able but the importance of c o n t r a l a t e r a l l i m b i c s t r u c t u r e s i n k i n d l i n g be-comes questionable. Further s t u d i e s should be done to determine t h e i r p a r t i c i p a t i o n . The corpus callosum and hippocampal commissure are i n v o l v e d i n the b i l a t e r a l propagation of an independent p o l y s p i k e discharge observed i n the MC. This p a t t e r n of a c t i v i t y has been described p r e v i o u s l y (Wada et al. , 1975) and t y p i c a l l y occurs i n a s s o c i a t i o n w i t h the appearance of C-5 s e i -zures. I t was not p o s s i b l e to determine whether t h i s a c t i v i t y o r i g i n a t e d i n the MC or was a r e f l e c t i o n of a c t i v i t y o c c u r r i n g i n some deeper s t r u c t u r e . However, the asymmetrical appearance of t h i s p a t t e r n i n the b i s e c t e d r a t s d i d not appear to a f f e c t the c l i n i c a l development. For example, the p a t t e r n was present i n these animals even a f t e r g e n e r a l i z e d s e i z u r e s had developed. Forebrain b i s e c t i o n had no e f f e c t on the b i l a t e r a l propagation of AD i n t o the MRF and ATH. S i m i l a r l y , no outstanding e l e c t r o g r a p h i c features 136 were observed during k i n d l i n g i n e i t h e r of these s t r u c t u r e s . Wada and Sato (1974, 1975) showed that the MRF i n cats d i s p l a y e d a unique e l e c t r o -graphic p a t t e r n of development, as s o c i a t e d w i t h the b i l a t e r a l g e n e r a l i z a -t i o n of the convulsion and the appearance of spontaneous rec u r r e n t s e i z u r e s . The lack of such development in_the present Experiments 1 and 2 i s l i k e l y i n part due to a d i f f e r e n c e i n electrode l o c a t i o n w i t h i n the MRF. 137 SUMMARY The r o l e of the f o r e b r a i n commissures i n the development of k i n d l e d amygdaloid se i z u r e s i n the r a t was i n v e s t i g a t e d i n the f i r s t two e x p e r i -ments. B i s e c t i o n of the corpus callosum, hippocampal commissure, and a n t e r i o r commissure s i g n i f i c a n t l y f a c i l i t a t e d the r a t e of p r i m a r y - s i t e s i e z u r e development. The r e s u l t s suggest that i n t e r h e m i s p h e r i c connections v i a the f o r e b r a i n commissures are able to i n h i b i t the devleopment of k i n d l -ed s e i z u r e s . In the b i s e c t e d r a t , an increase i n the r a t e of formation of limbic-brainstem pathways c r i t i c a l to k i n d l i n g was suggested as a f u r t h e r explanation f o r the f a c i l i t a t e d s e i z u r e development. The present s t u d i e s a l s o found that the f o r e b r a i n commissures p a r t i c i p a t e i n the i n t e r f e r e n c e phenomenon but not i n the t r a n s e r e f f e c t . In the l a s t experiment, the r o l e of the corpus callosum and hippocampal commissure i n the k i n d l e d r a t was i n v e s t i g a t e d . B i s e c t i o n of these s t r u c -tures caused a s i g n i f i c a n t f a c i l i t a t i o n i n secondary-site k i n d l i n g but a marked red u c t i o n i n the i n t e n s i t y of the s e i z u r e . The r e s u l t s of the present s t u d i e s suggest that the corpus callosum and hippocampal commissure are l i k e l y the p r i n c i p l e routes used i n the development of g e n e r a l i z e d k i n d l e d motor s e i z u r e s . B i s e c t i o n of these pathways a f t e r k i n d l i n g renders a s i g n i f i c a n t number of r a t s subsequently incapable of d i s p l a y i n g t h i s type of s e i z u r e . However, i f these s t r u c t u r e s are b i s e c t e d p r i o r to k i n d l i n g , the development of g e n e r a l i z e d convulsions i s retarded but not stopped. These d i f f e r e n c e s are presumably a t t r i b u t a b l e to the establishment of a l t e r n a t e routes f o r s e i z u r e g e n e r a l i z a t i o n , i n the r a t that has undergone f o r e b r a i n b i s e c t i o n p r i o r to k i n d l i n g . 138 B i s e c t i o n of the a n t e r i o r commissure alone was not s u f f i c i e n t to d i s -rupt the propagation of a f t e r d i s c h a r g e i n t o the c o n t r a l a t e r a l amygdala (Experiments 1 and 2). The r o s t r a l corpus callosum and hippocampal commis-sure are a d d i t i o n a l pathways f o r the interamygdaloid propagation o f a f t e r -discharge. Furthermore, the lack of a f t e r d i s c h a r g e i n the c o n t r a l a t e r a l amygdala d i d not d i s r u p t the t r a n s f e r e f f e c t . 139 REFERENCES Adamec, R. Behavioral and e p i l e p t i c determinants of predatory attack behavior i n the cat. Canadian Journal of Neurological Sciences, 1975, 2, 457-466. Adey, W.R. and Meyer, M. Hippocampal and hypothalamic connections of the temporal lobe i n the monkey. Brain, 1952, 75, 358-384. Adrian, E.D. The spread of a c t i v i t y i n the c e r e b r a l cortex. Journal of Physiology, 1936, 88, 127-161. Aida, S. Experimental research on the f u n c t i o n of the amygdaloid n u c l e i i n psychomotor e p i l e p s y . Folia Psychiatrica et Neurologica Japonica, 1956, 10, 181-207. Ajmone-Marsan, C. and. S t o l l , J . S u b c o r t i c a l connections of the temporal pole i n r e l a t i o n t o temporal lobe s e i z u r e s . Archives of Neurology and Psychiatry, 1951, 66, 669-686. A k e l a i t i s , A.J. A study of gnosis, p r a x i s , and language f o l l o w i n g s e c t i o n of the corpus callosum and a n t e r i o r commissure. Journal of Neuro-... surgery, 1944, 1, 94-102. A l c a l d e , Obrador S. Corpus callosum and e p i l e p t i c f i t s . Biol. Labovat. estud. med. mex., 1942, 1, 29. A l o n s o - D e f l o r i d a , F. and Delgado, J.M.R. L a s t i n g b e h a v i o r a l and EEG changes i n cats induced by prolonged s t i m u l a t i o n of amygdala. American Journal of Physiology, 1958, 193, 223-229. A s h c r o f t , G.W., Dow, R.C., Emson, P.C, H a r r i s , P., Ingleby, J . , Joseph, M.H., and McQueen, J.K. A c o l l a b o r a t i v e study of cob a l t l e s i o n s i n the r a t as a model f o r e p i l e p s y . In: Epilepsy. Proceedings of the Hans Berger centenary symposium. P. H a r r i s and C. Mawdsley (Eds), C h u r c h i l l L i v i n g s t o n e , New York, 1974, 115-124. Auer, J . and d i V i r g i l i o , G. Some a f f e r e n t connections of the hypothalamus i n the cat. Anatomical Record, 1953, 115, 277. B a i l e y , P.G., von Bonin, G., Gar o l , H.E., and McCulloch, W.S. Long a s s o c i -a t i o n f i b e r s i n c e r e b r a l hemispheres of monkey and chimpanzee. Journal of Neurophysiology, 1943, 6, 129-134. B a i l e y , P.G., von Bonin, G., and McCulloch, W.S. The Isocortex of the Chimpanzee. The. U n i v e r s i t y of I l l i n o i s Press, 1950, 377. Bancaud, J . , T a l a i r a c h , J . , Bonis, A., Schaub, C , S z i k l a , G., Morel, P., and Bordas-Ferer, M. La ster&o-electroence'phalographie dans I'epilepsie. Masson, P a r i s , 1965, 321. 140 Berger, H. Uber das Elektrenkephalogramm des Menschen. Archiv fur Psychiatrie und Nervenkrank, 1929, 87, 527-570. B e r l u c c h i , G. Anatomical and p h y s i o l o g i c a l aspects of v i s u a l f u n c t i o n s of corpus callosum. Brain Research, 1972, 37, 371-392. Bogacz, J . , St. Laurent, J . , and Olds, J . D i s s o c i a t i o n of s e l f - s t i m u l a -t i o n and e p i l e p t i f o r m a c t i v i t y . Electroencephalography and Clinical Neurophysiology, 1965, 19, 75-87. Bogen, J.E., F i s h e r , E.D., and Vogel, P.J. Cerebral commissurotomy: A second case r e p o r t . Journal of the American Medical Association, 1965, 194, 1328. Bogen, J.E., Sperry, R.W., and Vogel, P.J. Commissural s e c t i o n and propa-gation of s e i z u r e s . In: The Basic Mechanisms of the Epilepsies. H. H. Jasper, A. Pope, A.A. Ward (Eds), L i t t l e , Brown, and Company, Boston, 1969, 439-440. Bogen, J.E. and Vogel, P.J. Treatment o f gen e r a l i z e d s e i z u r e s by c e r e b r a l commissurotomy. Surgical Forum, 1963, 14, 431. Bridgeman, C.S. and Smith, K.L). B i l a t e r a l n eural i n t e g r a t i o n of v i s u a l p e rception a f t e r s e c t i o n of the corpus callosum. Journal of Compara-tive Neurology, 1945, 83, 57-68. Brodal, A. The o r i g i n of the f i b e r s o f the a n t e r i o r commissure i n the r a t . Experimental s t u d i e s . Journal of Comparative Neurology, 1948, 88, 157-200. Bucy, P.C. and F u l t o n , J.F. I p s i l a t e r a l r e p r e s e n t a t i o n i n the motor and premotor cortex of monkeys. Brain, 1933, 56, 318-342. Bucy, P.C. and Kluver, H. Anatomic changes secondary to temporal lobectomy. Archives of Neurology and Psychiatry, 1940, 44, 1142-1146. Bucy, P.C. and Kluver, H. An anatomical i n v e s t i g a t i o n of the temporal lobe i n the monkey (Macaca mulatta). Journal of Comparative Neurology, 1955, 103, 151-252. Burnham, W.M. E p i l e p t o g e n i c m o d i f i c a t i o n o f the r a t f o r e b r a i n by d i r e c t and t r a n s y n a p t i c s t i m u l a t i o n . Unpublished Doctoral Dissertation, M c G i l l U n i v e r s i t y , Quebec, Canada, 1971. Burnham, W.M. Primary and " t r a n s f e r " s e i z u r e development i n the k i n d l e d r a t . Canadian Journal of Neurological Sciences, 1975, 2, 417-428. y C a j a l , R.S. E s t r u c t u r a de l a c o r t e z a o l f a c t i v a d e l hombre y mamiferos. Trabajos del laboratorio de investigaoidn biologia (Madrid), 1901, I, 1-140. 141 Chang, H.T. C o r t i c a l response to a c t i v i t y of c a l l o s a l neurons. Journal of Neurophysiology, 1953, 16, 117, 131. Chodoury, B.P., Whitteridge, D., and Wilson, M.E. The f u n c t i o n of the c a l l o s a l connections of the v i s u a l cortex. Quarterly Journal of Experimental Physiology, 1965, 50, 214-219. Chow, K.L. and O b r i s t , W.D. EEG and b e h a v i o r a l changes on a p p l i c a t i o n of A1(0H) cream on p r e o c c i p i t a l cortex of monkeys. Archives of Neurology and Psychiatry, 1954, 72, 30-87. Chusid, J.G., Kop e l o f f , L.M., and Kopeloff> N. Motor e p i l e p s y o f p a r i e t a l lobe o r i g i n i n the monkey. Neurology, 1955, 5, 108-112. Coceani, F., Libman, I . , and Gloor, P. The e f f e c t of i n t r a c a r o t i d amobarb-i t a l i n j e c t i o n s upon experimentally induced e p i l e p t i f o r m a c t i v i t y . Electroencephalography and Clinical Neurophysiology, 1966, 20, 542-558. Corcoran, M.E., McCaughran, J.A., J r . , and Wada, J.A. Acute a n t i e p i l e p t i c e f f e c t s of delta-9 tetrahydrocannabinol i n r a t s with k i n d l e d s e i z u r e s . Experimental Neurology, 1973, 40, 471-483. Corcoran, M.E., Urstad, H., McCaughran, J.A., J r . , and Wada, J.A. F r o n t a l lobe and k i n d l i n g i n the r a t . Canadian Journal of Neurological Sciences, 1975, 2, 501-508. C r e u t z f e l d t , O.D. and Meyer-Mickeleit, R.W. Patterns of convulsive discharges of the hippocampus and t h e i r propagation. Electroencephalography and Clinical Neurophysiology, 1953, Supp. 3, 43. Cure, C. and Rasmussen, T. Experimental e p i l e p t o g e n i c l e s i o n s of the c e r e b r a l motor cortex and the i n s u l a r cortex i n monkeys. Electroencephalography and Clinical Neurophysiology, 1950, 2, 254. C u r t i s , H.J. I n t e r c o r t i c a l connections of the. corpus callosum as i n d i c a t e d by evoked p o t e n t i a l s . Journal of Neurophysiology, 1940a, 3, 404-413. C u r t i s , H.J. An a n a l y s i s o f c o r t i c a l p o t e n t i a l s mediated by the corpus callosum. Journal of Neurophysiology, 1940b, 3, 414-422. Delgado, J.M.R. and S e v i l l a n o , M. E v o l u t i o n of repeated hippocampal s e i -zures i n the cat. Electroencephalography and Clinical Neurophysiology, 1961, 13, 722-733. Douglas, R.M. and Goddard, G.V. Long term p o t e n t i a t i o n of the p e r f o r a n t path granule c e l l synapse ; i n the r a t hippocampus. Brain Research, 1976, In press. Dusser de Barenne, J.G. and McCulloch, W.S. Sensorimotor co r t e x , nucleus caudatus and thalamus o p t i c u s . Journal of Neurophysiology, 1938, 1, 364-377. 142 Dusser de Barenne, J.G., McCulloch, W.S., and Ogawa, T. F u n c t i o n a l organiz-a t i o n i n the f a c e - s u b d i v i s i o n of the sensory cortex of the monkey (Macaca mulatta). Journal of Neurophysiology, 1938, 1, 436-441. Ebner, F.F. and Myers, R.E. Commissural connections i n the neocortex of monkey. Anatomical Record, 1962, 142, 229. Ebner, F.F. and Myers, R.E. D i s t r i b u t i o n o f corpus callosum and a n t e r i o r commissure i n cat and racoon. Journal of Comparative Neurology, 1965, 124, 353-366. E r i c k s o n , T.C. Spread of e p i l e p t i c discharge: An experimental study o f the a f t e r d i s c h a r g e induced by e l e c t r i c a l s t i m u l a t i o n of the c e r e b r a l cortex. Archives of Neurology and Psychiatry, 1940, 43, 429-452. Faeth, W.H. and Walker, A.E. Studies oh e f f e c t of the i n j e c t i o n of alumina (alumina oxide) cream i n t o the bas a l g a n g l i a . Archives of Neurology and Psychiatry, 1957, 78, 562-567. Feeney, D.M. and G u l l o t t a , F.P. Suppression of s e i z u r e discharges and sleep s p i n d l e s by l e s i o n s o f the r o s t r a l thalamus. Brain Research, 1972, 45, 254-259. F e i n d e l , W. and Gloor, P. Comparison of e l e c t r o g r a p h i c e f f e c t s o f s t i m u l a -t i o n of the amygdala and b r a i n stem r e t i c u l a r formation i n cat s . Electroencephalography and Clinical Neurophysiology, 1954, 6, 389-402. F e i n d e l , W. and P e n f i e l d , W. L o c a l i z a t i o n of discharge i n temporal lobe automatism. Archives of Neurology and Psychiatry, 1954, 6, 389-402. F e r r i e r , D. Experimental researches i n c e r e b r a l physiology and pathology. Vest Riding Lunatic Asylum Medical Report (London), 1873, 3, 1-50. Fonberg, E. and Delgado, J.M.R. Avoidance and alimentary r e a c t i o n s during amygdala s t i m u l a t i o n . Journal of Neurophysiology, 1961, 24,. 651-664. Fox, C A . C e r t a i n b a s a l t e l e n c e p h a l i c centers i n the cat. Journal of Comparative Neurology, 1940, 72, 1-62. Fox, C.A., F i s h e r , R.R., and Desalva, S.J. The d i s t r i b u t i o n of the a n t e r i o r commissure i n the monkey (Macaca mulatta). Journal of Comparative Neurology, 1948, 89, 245-261T Fox, C A . and Schmitz, J.T. A Marchi study of the d i s t r i b u t i o n of the a n t e r i o r commissure i n the cat. Journal of Comparative Neurology, 1943, 79, 297-314. Franck, M.R. and P i t r e s , L.S. Recherches experimentales et c r i t i q u e s sur le s convulsions e p i l e p t i f o r m e s d ' o r i g i n e c o r t i c a l e . Archives de Physiologie, 1883, 12, 2. 143 French, J.D., Gernandt, B.E., and L i v i n g s t o n , R.B. Regional d i f f e r e n c e s i n s e i z u r e s u s c e p t i b i l i t y i n monkey c e r e b r a l cortex. Archives of Neurology and Psychiatry, 1956, 72, 260-274. French, J.D., Hernandez-Peon, R., and L i v i n g s t o n , R.B. P r o j e c t i o n s from the cortex to the c e p h a l i c brainstem ( r e t i c u l a r formation) i n monkey. Journal of Neurophysiology, 1955, 18, 74-95. F r o s t , L.L., Baldwin, M., and Wood, C.D. I n v e s t i g a t i o n o f the primate amygdala: Movements of the face and jaws. Neurology, 1958, 8, 543-546. Garner, J . and French, J.D. Regional d i f f e r e n c e i n s e i z u r e s u s c e p t i b i l i t y i n cat cortex. Archives of Neurology and Psychiatry, 1958, 80, 675-681. G arol, H.W. C o r t i c a l o r i g i n and d i s t r i b u t i o n of the corpus callosum and a n t e r i o r commissure i n the cat. Journal of Neuropathology and Experi-mental Neurology, 1942, 1, 422-429. Gastaut, H., Naquet, R., Meyer, A., Cavanagh, J.B., and Beck, E. E x p e r i -mental psychomotor e p i l e p s y i n the cat. E l e c t r o c l i n i c a l and anatomo-p a t h o l o g i c a l c o r r e l a t i o n s . Journal of Neuropathology and Experimental Neurology, 1959, 18, 270-293. Gibbs, F.A. Cerebral blood flow preceeding and accompanying experimental convulsions. Archives of Neurology and Psychiatry., 1933, 30, 1003-1010. Gibbs, F.A., Lennox, W.G., and Gibbs, E.L. Cerebral blood flow preceeding and accompanying e p i l e p t i c s e i z u r e s i n man. Archives of Neurology and Psychiatry, 1934, 32, 257-272. Gloor, P. E l e c t r o p h y s i o l o g i c a l s t u d i e s on the connections of the amygda-l o i d nucleus i n the cat. I. The neuronal o r g a n i z a t i o n of the amygda-l o i d p r o j e c t i o n system. Electroencephalography and Clinical Neuro-physiology, 1955a, 7, 223-242. Gloor, P. E l e c t r o p h y s i o l o g i c a l s t u d i e s on the connections of the amygda-l o i d nucleus i n the cat. I I . The e l e c t r o p h y s i o l o g i c a l p r o p e r t i e s of the amygdaloid p r o j e c t i o n system. Electroencephalography and Clinical Neurophysiology, 1955b, 7, 243-264. Gloor, P. The p a t t e r n of conduction o f amygdaloid s e i z u r e discharge: An experimental study i n the cat. Archives of Neurology and Psychiatry, 1957, 77, 247-258. Gloor, P., Garretson, H., and Rasmussen, T. Further s t u d i e s of the e f f e c t s of i n t r a c a r o t i d amobarbital and metrazol i n j e c t i o n s upon e p i l e p t i c d i s -charges i n man. In: Abstracts from the VI International Congress of Electroencephalography and Clinical Neurophysiology, 1965, 45-47. 144 Goddard, G.V. Development of e p i l e p t i c s e i z u r e s through b r a i n s t i m u l a t i o n at low i n t e n s i t y . Nature, 1967, 214, 1020-1021. Goddard, G.V. Long term a l t e r a t i o n f o l l o w i n g amygdaloid s t i m u l a t i o n . In: The Neurobiology of the Amygdala. B.E.. E l e f t h e r i o u \(Ed), Plenum Pub-l i s h i n g Corporation, New York, 1972, 581-596. Goddard, G.V. and Douglas, R.M. Does the engram of k i n d l i n g model the engram of normal long term memory. Canadian Journal of Neurological Sciences, 1975, 2, 385-394. Goddard, G.V. and Mclntyre, D.C. Some p r o p e r t i e s of a l a s t i n g e p i l e p t o -genic tr a c e k i n d l e d by repeated e l e c t r i c a l s t i m u l a t i o n of the amygdala i n mammals. In: Surgical Approaches in Psychiatry. L.V. L a i t i n e n and K.E. L i v i n g s t o n (Eds)v U n i v e r s i t y Park Press, B a l t i m o r e , 197'4, 109-115. Goddard, G.V., Mclntyre, D.C, and Leech, C.K. A permanent change i n b r a i n f u n c t i o n r e s u l t i n g from d a i l y e l e c t r i c a l s t i m u l a t i o n . Experimental Neurology, 1969, 25, 295-330. Gowers, W.R. Epilepsy and Other Chronic Convulsive Diseases: Their Causes, Symptoms, and Treatment (2nd ed.). London, J . and A. Church, 1901. Gozzano, ,M. B i o l e k t r i s c h e Erscheinungen b e i der R e f l e x e p i l e p s i e . Journal flXr Psychologie und Neurologie, 1936, 47, 24-39. Green, J.D. The hippocampus. Physiological Reviews, 1964, 44, 561-608. Green, J.D. and Shimamoto, T. Hippocampal s e i z u r e s and t h e i r propagation. Archives of Neurology and Psychiatry, 1953, 70, 687-702. Guerrero-Figueroa, R., Barros, A., Heath, R.C, and Gonzales, E.Z. E x p e r i -mental s u b c o r t i c a l e p i l e p t i f o r m focus. Epilepsia, 1964, 5, 112-139. Guerrero-Figueroa, R., G a l l a n t , D., Robinson, W., and Heath, R.G. Changes of hippocampal and amygdaloid complex a c t i v i t i e s during wakefulness and n a t u r a l sleep i n the cat: n e u r o p h y s i o l o g i c a l and c l i n i c a l c o r r e l a -t i o n s i n p a t i e n t s with true temporal lobe e p i l e p s y . In: Clinical and Experimental Approaches to Problems in Mental Illness. R. Guerrero-Figueroa (Ed), Lo u i s i a n a State U n i v e r s i t y Press, Baton Rouge, 1968. G u i l l e r y , R.W. Degeneration i n the postcommissural f o r n i x and the mammil-l a r y peduncle of the r a t . Journal of Anatomy, 1956, 89, 19-32. H a l l , E. Ph.D. Thesis. U n i v e r s i t y of Ottawa, 1959. Hamilton, D.J. On the corpus callosum i n the embryo. Brain, 1885, 8, 145-163. 145 Heath, R.G. Common c h a r a c t e r i s t i c s of e p i l e p s y and schizophrenia: c l i n i c a l observations and depth electrode s t u d i e s . American Journal of Psychi-atry, 1962, 118, 1013-1026. Heath, R.G. and M i c k l e , W.A. E l e c t r i c a l a c t i v i t y from s u b c o r t i c a l , c o r t i -c a l , and scalp e l e c t r o d e s before, and during c l i n i c a l e p i l e p t i c s e i -zures. Transactions of the American Neurological Association, 1957, 82, 63-65. Hoefer, P.E.A. and P o o l , J.L. Conduction of c o r t i c a l impulses and motor management of convulsive s e i z u r e s . Archives of Neurology and Psychi-atry, 1943, 50, 381-400. Hubel, D.H. and Wiesel, T.N. Receptive f i e l d s and f u n c t i o n a l a r c h i t e c t u r e i n two n o n s t r i a t e v i s u a l areas (18 and 19) of the cat. Journal of Neurophysiology, 1965, 28, 229-289. Hyndman, O.R. and P e n f i e l d , W. Agenesis of the corpus callosum: I t s r e c o g n i t i o n by ventriculography. Archives of Neurology and Psychiatry, 1937, 37, 1251-1270. Isaacson, R.L., Schwarz, H., P e r s o f f , N., and Pinson, L. The r o l e of the corpus callosum i n the establishment of areas of secondary e p i l e p t i -form a c t i v i t y . Epilepsia, 1971, 12, 133-146. Jackson, J.H. Selected Writings of John Hughlings Jackson. Vol. 1. On epilepsy and epileptiform convulsions. J . T a y l o r (Ed), London, Hodder and Stoughton, 1931. Jacobson, S. I n t r a l a m i n a r , i n t e r l a m i n a r , c a l l o s a l , and t h a l a m o c o r t i c a l con-nections i n f r o n t a l and p a r i e t a l areas o f the a l b i n o r a t c e r e b r a l cor-tex. Journal of Comparative Neurology, 1965, 124, 131-146. Jasper, H.H. F u n c t i o n a l p r o p e r t i e s of the thalamic r e t i c u l a r system. In: Brain Mechanisms and Consciousness (A Symposium). E.D. Adrian and J.F. Delafresnaye (Eds), Charles C. Thomas ( B l a c k w e l l S c i e n t i f i c P u b l i c a t i o n s ) , S p r i n g f i e l d , 111., 1954, 374-401. Jasper, H.H., Ajmone-Marsan, C , and S t o l l , J . C o r t i c o f u g a l p r o j e c t i o n s to the brainstem. Archives of Neurology and Psychiatry, 1952, 67, 155-166. Jones, E.G. and Powell, T.P.S. The commissural connections of the somatic sensory cortex i n the cat. Journal of Anatomy (London), 1968, 103, 433-455. Kaada, B.R. Somato-motor, autonomic, and e l e c t r o c o r t i c o g r a p h i c responses to e l e c t r i c a l s t i m u l a t i o n s of " r h i n e n c e p h a l i c " and other s t r u c t u r e s i n primates, cat and dog. Acta Physiologica Scandanavia,: Siipp. 83y 1951, 1-285. 146 Kaada, B.R., Pribram, K.H., and E p s t e i n , J.A. R e s p i r a t o r y and v a s u l a r responses i n monkeys from temporal p o l e , i n s u l a , o r b i t a l s u r f a c e , and c i n g u l a t e gyrus. Journal of Neurophysiology, 1949, 12, 347-356. Karplus, I.P. E x p e r i m e n t e l l e r B e i t r a g zur Kenntnis der Gehirn vorgange beim e p i l e p t i s c h e n A n f a l l e . Wiener Klinisohe Wochensahrift, 1914, 27, 645-651. K l i n g l e r , J . and Gloor, P. The connections of the amygdala and of the a n t e r i o r temporal cortex i n the human brain.. Journal of Comparative Neurology, 1960, 115, 333-369. Kopel o f f , L.M., B a r r e r a , S.E., and K o p e l o f f , N. Recurrent convulsive s e i z u r e s i n animals produced by immunologic and chemical means. American Journal of Psychiatry, 1942, 98, 881-902. Kopeloff, L.M., Chusid, J.G., and K o p e l o f f , N. Chronic experimental e p i l e p s y i n Macaca mulatta. Neurology, 1954, 4, 218-227. Kopel o f f , N., Kennard, M.A., P a c e l l a , B.L., and Chusid, J.G. Secion of corpus callosum i n experimental e p i l e p s y i n the monkey. Archives of Neurology and Psychiatry, 1950, 63, 719-727. Kopeloff, N., W h i t t i e r , J.R., P a c e l l a , B.L., and K o p e l o f f , L.M. The e p i l e p t o g e n i c e f f e c t of s u b c o r t i c a l alumina cream i n the rhesus monkey. Electroencephalography and Clinical Neurophysiology, 1950, 2, 163-168. Krause, R. C h i r u r g i e des Gehirns. Urban-Schwarzenberg, 1911. K r e i n d l e r , A. Experimental E p i l e p s y . Progress in Brain Research, V o l . 19, E l s e v i e r , Amsterdam, 1965. Kusske, J.A., Ojemann, G.A., and Ward, A.A., J r . E f f e c t s of l e s i o n s i n v e n t r a l a n t e r i o r thalamus on experimental f o c a l e p i l e p s y . Experimental Neurology, 1972, 34, 279-290. Lammers, H.J. The neural connections of the amygdaloid complex i n mammals. In: The Neurobiology of the Amygdala. B.E. E l e f t h e r i o u (Ed),. Plenum P u b l i s h i n g Corporation, New York, 1972. Lemmen, L.J. An anatomical and experimental study of temporal and o c c i p i -t a l a s s o c i a t i o n areas. Journal of Comparative Neurology, 1951, 95, 521-547. Lennox, W.G. The p h y s i o l o g i c a l pathogenesis of e p i l e p s y . Brain, 1936, 59, 113-121. Lennox, W.G., Gibbs, F.A., and Gibbs, E.L. E f f e c t on the electroencephalo-gram o f drugs and c o n d i t i o n which i n f l u e n c e s e i z u r e s . Archives of Neurology and Psychiatry, 1936, 36, 1236-1250. 147 Lewandowski, G.S. Funktionen des Zentralnervensystems. Jena, 1907. L i c h t e n s t e i n , R.S., M a r s h a l l , C , and Walker, A.E. S u b c o r t i c a l r e c o r d i n g i n temporal lobe e p i l e p s y . A.M.A. Archives of Neurology, 1959, 1, 289-302. L i v i n g s t o n , K.E. and Escobar, A. Anatomical b i a s o f the l i m b i c system concept. Archives of Neurology, 1971, 24, 17-21. L u c i a n i , L. S u l l a patogenesi d e l l ' e p i l e s s i a . Rivista Sperimentale di Freniatria e Medicina Legale, 1878, 4, 617-646. Luessenhop, A.J. Interhemispheric Commissurotomy: (The s p l i t b r a i n operation) as an a l t e r n a t e to hemispherectomy f o r c o n t r o l of i n t r a c t -able s e i z u r e s . The American Surgeon, May 1970, 265-268. McCaughran, J.A., J r . , Corcoran, M.E., and Wada, J.A. Development of k i n d l e d s e i z u r e s a f t e r s e c t i o n of the f o r e b r a i n commissures i n r a t s . Folia Psychiatrica et Neurologica Japonica, 1976, 30, 65-71. McCulloch, W.S. and G a r o l , H.W. C o r t i c a l o r i g i n and d i s t r i b u t i o n of corpus callosum and a n t e r i o r commissure i n the monkey (Macaca mula t t a ) . Journal of Neurophysiology, 1941, 4, 555-563. Mclntyre, D.C. S p l i t - b r a i n r a t : Transfer and i n t e r f e r e n c e of k i n d l e d •amygdala convulsions. The Canadian Journal of Neurological Sciences, 1975, 2, 429-437. Mclntyre, D.C. and Goddard, G.V. T r a n s f e r , i n t e r f e r e n c e and spontaneous recovery of convulsions k i n d l e d from the r a t amygdala. Electroencephalo-graphy and Clinical Neurophysiology, 1973, 35, 533, 543. Mclntyre, D.C. and Molino, A. Amygdala l e s i o n s and CER learning-longterm e f f e c t of k i n d l i n g . Physiology and Behavior, 1972, 8, 1055-1058. MacLean, P.D. Psychosomatic disease and the " v i s c e r a l " b r a i n . Recent developments bearing on the Papez theory of emotions. Psychosomatic Medicine, 1949, 11, 338-353. Marburg, K. and Ranzi, P. C i t e d by: E. S p i e g e l . American Journal of Psychiatry, 1931, 87, Part 2, 595-605. Marcus, E.M., and Watson, CW. B i l a t e r a l synchronous spike wave e l e c t r o -graphic p a t t e r n s i n the cat: i n t e r a c t i o n of b i l a t e r a l c o r t i c a l f o c i i n the i n t a c t , the b i l a t e r a l c o r t i c a l - c a l l o s a l and ad i e n c e p h a l i c p r e p a r a t i o n . Archives of Neurology, 1966, 14, 601-610. Marcus, E.M. and Watson, CW. B i l a t e r a l symmetrical e p i l e p t o g e n i c f o c i i n monkey c e r e b r a l cortex: mechanisms of i n t e r a c t i o n and r e g i o n a l v a r i a t i o n s i n capacity f o r synchronous spike slow wave discharges. Archives of Neurology, 1968, 19, 99-116. 148 Marcus, E.M., Watson, C.W., and Simon, S. Behavioral c o r r e l a t e s of acute b i l a t e r a l symmetrical e p i l e p t o g e n i c f o c i i n monkey c e r e b r a l cortex. Brain Research, 1968, 9, 370-373. Marcus, E.M., Watson, C.W., and Simon, S. An experimental model of some v a r i e t i e s of p e t i t mal epi l e p s y : E l e c t r i c a l - b e h a v i o r a l c o r r e l a t i o n s of acute b i l a t e r a l e p i l e t o g e n i c f o c i i n c e r e b r a l cortex. Epilepsia, 1968, 9, 233-248. Mason, C.R., and Cooper, R.M. A permanent change i n convulsive t h r e s h o l d i n normal and b r a i n damaged r a t s with small repeated doses of pentylene-t e t r a z o l . Epilepsia, 1972, 13, 663-674. Mayanagi, Y., and Walker, A.E. Experimental temporal lobe e p i l e p s y . Brain, 1974, 97, 423-446. M e t t l e r , F.A. C o r t i c o f u g a l f i b e r connections of the cortex of Macaca  mulatta. The temporal region. Journal of Comparative Neurology, 1935, 63, 25-47. M o r r e l l , F. Secondary e p i l e p t o g e n i c l e s i o n s . Epilepsia, 1960, 1, 535-560. M o r r e l l , F., Pr o c t o r , F., and P r i n c e , D.A. E p i l e p t o g e n i c p r o p e r t i e s of s u b c o r t i c a l f r e e z i n g . Neurology, 1965, 15, 744-751. Mullan, S., V a i l a t i , G., Karasick, J . , a n d M a i l i s , M. Thalamic l e s i o n s f o r the c o n t r o l of e p i l e p s y . Archives of Neurology, 1967, 16, 277-288. Mutani, R., Bergamini, L., F a r i e l l o , R., and Quattrocolo, G. An experimental i n v e s t i g a t i o n on the mechanisms of i n t e r a c t i o n o f asymmetrical acute e p i l e p t i c f o c i . Epilepsia, 1972, 13, 597-608. Mutani, R., Bergamini, L., F a r i e l l o , R., and Quattrocolo, G. B i l a t e r a l synchrony of e p i l e p t i c discharge a s s o c i a t e d w i t h chronic asymmetrical c o r t i c a l f o c i . Electroencephalography and Clinical Neurophysiology, 1973, 34, 53-59. Myers, R.E. Commissural connections between o c c i p i t a l lobes of the monkey. Journal of Comparative Neurology, 1962, 118, 1-16. Nauta, W.J.H. Neural a s s o c i a t i o n s of the amygdaloid complex i n monkey. Brain, 1962, 85, 505-520. Nauta, W.J.H., and Bucher, V.M. E f f e r e n t connections of the s t r i a t e c ortex i n the a l b i n o r a t . Journal of Comparative Neurology, 1954, 100, 257-286. Nauta, W.J.H., and V a l e n s t e i n , E. Some p r o j e c t i o n s of the amygdaloid complex i n the monkey. Anatomical Record, 1958, 130, 346. 149 Nie, V., Maccabe, J . J . , E t t l i n g e r , G., and D r i v e r , M.V. The development of secondary e p i l e p t i c discharges i n the rhesus monkey a f t e r comm-i s s u r e s e c t i o n . Electroencephalography and Clinical Neurophysiology, 1974, 37, 473-481. de Olmos, J.S. The amygdaloid p r o j e c t i o n f i e l d i n the r a t as studi e d with the c u p r i c - s i l v e r method. In: The Neurobiology of the Amygdala. B.E. E l e f t h e r i o u (Ed), Plenum P u b l i s h i n g Corporation, New York, 1972. Otsuka, R., and H a s s l e r , R. Uber Aufbau und Gliederung der C o r t i c a l e n Sehsphare b e i der Katze. Archiv fur Psychiatrie und Zietschrift fur die Gesammte Neurologie, 1962, 203, 212-234. O t t i n o , C.A., Meglio, M., R o s s i , G.F., and Tercero, E. An experimental study of the s t r u c t u r e s mediating b i l a t e r a l synchrony of e p i l e p t i c discharges of c o r t i c a l o r i g i n . Epilepsia, 1971, 12, 299-311. P a c e l l a , B.L., Kopel o f f , N., Barrera, S.E., and Kopeloff, L.M. Exper-imental production o f f o c a l e p i l e p s y . Archives of Neurology and Psychiatry, 1944, 52, 189-196. P e l l e g r i n o , L .J., and Cushman, A.J. A Stereotaxic Atlas of the Rat Brain. Appleton-Century-Crofts, New York, 1967. P e n f i e l d , W. The c i r c u l a t i o n of the e p i l e p t i c b r a i n . Research Publication for the Association for Research into Nervous and Mental Disease, 1938, 28, 605. P e n f i e l d , W., and Jasper, H. Epilepsy and the Functional Anatomy of the Human Brain. L i t t l e , Brown and Co., Boston, 1954. P e n f i e l d , W., von Santha, K., and C i p r i a n i , A. Cerebral blood flow during induced e p i l e p t i f o r m s e i z u r e s , human and mammalian. Journal of Neurophysiology, 1939, 2, 257-267. P e t r , P., Holden, L.B., and J i r o u t , J . The e f f e r e n t i n t e r c o r t i c a l connections of the s u p e r f i c i a l cortex of the temporal lobe. (Macaca mulatta). Journal of Neuropathology and Experimental Neurology, 1949, 8, 100-103. P i n e l , J . P . J . , Mucha, R.F., and P h i l l i p s , A.G. Spontaneous s e i z u r e s generated i n r a t s by k i n d l i n g : a p r e l i m i n a r y r e p o r t . Physiological Psychology, In pre s s , 1976. P i n e l , J.P.J., P h i l l i p s , A.G., a n d M a c N e i l l , B. Blockage of h i g h l y s t a b l e " k i n d l e d " s e i z u r e s i n r a t s by antecedent footshock. Epilepsia, 1973, 14, 29-37. P i n e l , J.P.J., S k e l t o n , R., and Mucha, R.F. E f f e c t s of current i n t e n s i t y on a f t e r d i s c h a r g e t h r e s h o l d during k i n d l i n g . Paper presented at Canadian P s y c h o l o g i c a l A s s o c i a t i o n , Quebec C i t y , 1975. 150 P i n e l , J.P.J., and Van Oot, P.H. G e n e r a l i t y of the k i n d l i n g phenomenon: Some c l i n i c a l i m p l i c a t i o n s . Canadian Journal of Neurological Sciences, 1975, 2, 467-475. Pinsky, C., and Burns, D.B. Production of e p i l e p t i f o r m a f t e r d i s c h a r g e s i n cat's c e r e b r a l cortex. Journal of Neurophysiology, 1962, 25, 359-379. Poblete, R., Ruben, R.J., and Walker, A.E. Propagation of a f t e r d i s c h a r g e between temporal lobes. Journal of Neurophysiology, 1959, 22, 538-553. Poggio, G.F., Walker, A.E., and Andy, O.J. The propagation of c o r t i c a l a f t e r - d i s c h a r g e through s u b c o r t i c a l s t r u c t u r e s . Archives of Neurology and Psychiatry, 1956, 75, 350-361. P o l l e n , D.A., Perot, P., and Reid, K.M. Experimental b i l a t e r a l wave and spike from thalamic s t i m u l a t i o n i n r e l a t i o n to l e v e l of a r o u s a l . Electroencephalography and Clinical Neurophysiology, 1963, 15, 1017-1028. Pope, A., M o r r i s , A.A., Jasper, H., E l l i o t t , K.A.C., and P e n f i e l d , W. Histochemical and a c t i o n p o t e n t i a l s t u d i e s on e p i l e p t o g e n i c areas of c e r e b r a l cortex i n man and the monkey. Association for Research into Nervous and Mental Disease Proceedings, 1946, 26, 218. Pribram, K.H., and MacLean, P.D. Neuronographic a n a l y s i s of medial and basal c e r e b r a l cortex. I I . Monkey. Journal of Comparative Neurology, 1953, 16, 324-340. P r i c h a r d , J.W., Gallagher, B.B., and Glaser, G.H. Experimental s e i z u r e t h r e s h o l d t e s t i n g with f l u r o t h y l . Journal of Pharmacology and Experimental Therapy, 1969, 166, 170. P r o c t o r , F., P r i n c e , D., and M o r r e l l , F. Primary and secondary spike f o c i f o l l o w i n g depth l e s i o n s . Archives of Neurology, 1966, 15, 151-162. Racine, R.J. M o d i f i c a t i o n of s e i z u r e a c t i v i t y by e l e c t r i c a l s t i m u l a t i o n : 1. A f t e r d i s c h a r g e t h r e s h o l d . Electroencephalography and Clinical Neurophysiology, 1912a, 32, 269-279. Racine, R.J. M o d i f i c a t i o n of s e i z u r e a c t i v i t y b y e l e c t r i c a l s t i m u l a t i o n : I I . Motor s e i z u r e . Electroencephalography and Clinical Neuro-physiology. 1972b, 32, 281-294. Racine, R.J., Okujava, V., and C h i p a s h v i l i , S. M o d i f i c a t i o n of s e i z u r e a c t i v i t y by e l e c t r i c a l s t i m u l a t i o n : I I I . Mechanisms. Electro-encephalography and Clinical Neurophysiology, 1972, 32, 295-299. Racine, R.J., T u f f , L., and Zaide, J . K i n d l i n g , u n i t discharge p a t t e r n s and neural p l a s t i c i t y . Canadian Journal of Neurological Sciences, 1975, 2, 395-405. 151 Ransom, W.B. On tumors of the corpus callosum. Brain, 1895, 18, 532-550. Rosenblueth, A., and Cannon, W.B. C o r t i c a l responses to e l e c t r i c a l s t i m u l a t i o n . American Journal of Physiology, 1941-42, 135, 690-741. R o v i t , R.L., Gloor, P., and Rasmussen, T. I n t r a c a r o t i d amobarbital i n e p i l e p t i c p a t i e n t s . A new d i a g n o s t i c t o o l i n c l i n i c a l e l e c t r o -encephalography. Archives of Neurology (Chicago), 1961, 5, 606-626. Ro v i t , R.L., Hardy, J . , and Gloor, P. Electroencephalographic e f f e c t s of i n t r a c a r o t i d amobarbital on e p i l e p t i c a c t i v i t y . An experimental study using p e n i c i l l i n - i n d u c e d e p i l e t i c f o c i i n r a b b i t s . Archives of Neurology (Chicago), 1960, 3, 642-655. Rundles, R.W., and Papez, J.W. F i b e r and c e l l u l a r degeneration f o l l o w i n g lobectomy i n the monkey. Journal of Comparative Neurology, 1938, 68, 267-296. Rutledge, L.T., and Kennedy, T.T. Brain-stem and c o r t i c a l i n t e r a c t i o n s i n the i n t e r h e m i s p h e r i c delayed response. Experimental Neurology, 1961, 4, 470-483. von Santha, K., and C i p r i a n i , A. Focal a l t e r a t i o n s i n s u b c o r t i c a l c i r c u l a t i o n r e s u l t i n g from s t i m u l a t i o n o f the c e r e b r a l cortex. Association for the Research of Nervous and Mental Disease Proceedings, 1937, 18, 346-362. Schmidt, R.P., and Wilder, B.J. (Eds). Epilepsy. F.A. Davis Company, P h i l a d e l p h i a , 1968. Segundo, J.P., Naquet, R., and Arana, R. S u b c o r t i c a l connections from temporal cortex of monkey. Archives of Neurology and Psychiatry, 1955, 73, 515-524. Serota, H.M., and Gerard, R.W. L o c a l i z e d thermal changes i n the cats' b r a i n . Journal of Neurophysiology, 1938, 1, 115-124. S e r v i t , Z., and S t e r c , J . Audiogenic e p i l e p t i c s eizures evoked i n r a t s by a r t i f i c i a l e p i l e p t o g e n i c f o c i . Nature, 1958, 181, 1475-1476. S e r v i t , Z., and S t r e j c k o v a , A. E p i l e p t o g e n i c focus i n the f r o g t e l e n -cephalon. Seizure i r r a d i a t i o n from the focus. Physiologia Bohemoslovaca, 1967, 16, 522-530. S e r v i t , Z., and S t r e j c k o v a , A. Thalamocortical r e l a t i o n s and the genesis of e p i l e p t i c e l e c t r o g r a p h i c phenomena i n the f o r e b r a i n of the t u r t l e . Experimental Neurology, 1971, 35, 50-60. S e r v i t , Z., S t r e j c k o v a , A., and V o l a n s c h i , D. An e p i l e p t o g e n i c focus i n the f r o g telencephalon. Pathways of propagation of f o c a l a c t i v i t y . Experimental Neurology, '.1968, 21, 383-396. 152 Sharpless, S.K. I s o l a t e d and deafferented neurons: Disuse s u p e r s e n s i t i v i t y . In: Basic Mechanisms of the Epilepsies. H.H. Jasper, A.A. Ward, and A. Pope (Eds). L i t t l e , Brown, and Company, Boston, 1969. Sh i r o a , T. E f f e c t s of alumina cream l e s i o n s i n the s u b s t a n t i a n i g r a or on the cortex o f cat s . Acta Mealica Kagoshima, 1969, 11, 79-96. Simpson, D.A. The p r o j e c t i o n of the p u l v i n a r to the temporal lobe. Journal of Anatomy, 1952, 86, 20-28. Skinner, J.E. Neuroscience: A Laboratory Manual. W.B. Saunders, P h i l a d e l p h i a , 1971. Sloan, N., Ransohoff, J . , and Po o l , J.L. C l i n i c a l and EEG s e i z u r e s f o l l o w i n g chronic i r r i t a t i v e l e s i o n s of the medial temporal region i n monkeys. Electroencephalography and Clinical Neurophysiology, 1953, 5, 320-321. S p i e g e l , E. The c e n t r a l mechanism of gen e r a l i z e d e p i l e p t i c f i t s . American Journal of Psychiatry, 1931, 87, 595-605. S p i e g e l , E.A., and F a l k i e w i c z , T. Experimentelle Untersuchungen iiber d i e Ausbreitung der Erregung im e p i l e p t i s c h e n A n f a l l . Kleiner Wochen-schrift, 1926, 5, 606-607. S p i e g e l , E., and Takagi, M. C i t e d by: E. S p i e g e l . American Journal of Psychiatry, 1931, 87, Part 2, 595-605. Stavraky, G.W. Neuronal i s o l a t i o n of the c e r e b r a l cortex and c o n v u l s i b i l i t y i n animals and man. A s e c t i o n of the corpus callosum. In: Super-sensitivity Following Lesions of the Nervous System. G.W. Stavraky (Ed). U n i v e r s i t y of Toronto Press, Toronto, 1961. Straw, R.N., and M i t c h e l l , C L . E f f e c t of s e c t i o n of the corpus callosum on c o r t i c a l a f t e r d i s c h a r g e patterns i n the cat. Proceedings of the Society of Experimental Biology and Medicine, 1967, 125, 128-132. Udavarhelyi, G.B., and Walker, A.E. Dissemination of acute f o c a l s e i z u r e s i n the monkey. I. From c o r t i c a l f o c i . Archives of Neurology, 1965, 12, 33-356. U n v e r r i c h t , H. Experimentelle un k l i n i s c h e Untersuchungen liber d i e E p i l e p s i e . Archiv fUr Psychiatrie, 1183, 14, 175-265. V a l e n s t e i n , E.S., and Nauta, W.J.H. A comparison of the d i s t r i b u t i o n of the f o r n i x system i n the r a t , guinea p i g , c a t , and monkey. Journal of Comparative Neurology, 1959, 113, 337-363. Valverde, F. Studies on the Piriform Lobe.Harvard U n i v e r s i t y Press, Cambridge, 1965. Van Valkenberg, G.T. The o r i g i n of the f i b r e s o f the corpus callosum and the p s a l t e r i u m . Royal Academy of Amsterdam. 1911. 153 Van Valkenberg, G.T. Experimental and pathologico-anatomioal researches on the corpus callosum. Brain, 1913, 36, 119-165. Van Wagenen, W.P., and Herren, R.Y. S u r g i c a l d i v i s i o n of commissural pathways i n the corpus callosum. Archives of Neurology and Psychiatry, 1940, 44, 740-759. V i l l a b l a n c a , J . , Schlag, J . , and Marcus, R. Bl o c k i n g of experimental spike and wave by a l o c a l i z e d f o r e b r a i n l e s i o n . Epilepsia, 1970, 11, 163-177. Vo i c u l e s c u , V., V o i c u l e s c u , I . , and Papescu-Tisuana, G. Experimental e p i l e p t o g e n i c f o c i i n the mesial cortex of the cat. Excevpta Medica, Amsterdam, 1969, 295. V o r i s , H.C, and Adson, A.W. Tumors of the corpus callosum: P a t h o l o g i c a l and c l i n i c a l study. Archives of Neurology and Psychiatry, 1935, 34, 965-972. Vosu, H., and Wise, R.A. C h o l i n e r g i c s e i z u r e k i n d l i n g i n the r a t : Comparison of caudate, amygdala and hippocampus. Behavioral Biology, In p r e s s , 1976. Wada, J.A. Chronic e p i l e p t o g e n i c b r a i n processes. In: Epileptology. J.A. Wada (Ed). Igaku-Shoin, Tokyo, 1964. Wada, J.A., and C o r n e l i u s , L.R. F u n c t i o n a l a l t e r a t i o n of deep s t r u c t u r e s i n cats with chronic f o c a l c o r t i c a l i r r i t a t i v e l e s i o n s . Archives of Neurology, 1960, 3,. 425-447. Wada, J.A., and Osawa, T. Generalized convulsive s e i z u r e s t a t e induced by d a i l y e l e c t r i c a l amygdaloid s t i m u l a t i o n i n senegalese baboons, Papio papio. Neurology, In press, 1976. Wada, J.A., Osawa, T., and Mizoguchi, T. Recurrent spontaneous s e i z u r e s s t a t e induced by p r e f r o n t a l k i n d l i n g i n senegalese baboons, Papio  papio. Canadian Journal of Neurological Sciences, 1975, 2, 477-492. Wada, J.A., and Sato, M. Generalized convulsive s e i z u r e s induced by d a i l y e l e c t r i c a l s t i m u l a t i o n of the amygdala i n cat s : C o r r e l a t i v e e l e c t r o -graphic and b e h a v i o r a l f e a t u r e s . Neurology, 1974, 24, 564-574. Wada, J.A., and Sato, M. The g e n e r a l i z e d convulsive s e i z u r e s t a t e induced by . . d a i l y . e l e c t r i c a l s t i m u l a t i o n of the amygdala i n ; s p l i t - b r a i n . c a t s . Epilepsia, 1975, 16, 417-430. Wada, J.A., Sato, M., and Corcoran, M.E. P e r s i s t e n t s e i z u r e s u s c e p t i b i l i t y and r e c u r r e n t spontaneous s e i z u r e s i n k i n d l e d cats. Epilepsia, 1974, 15, 465-478. 154 Wada, J.A., Sato, M., and McCaughran, J.A., J r . C o r t i c a l e l e c t r o g r a p h i c c o r r e l a t e s of convulsive s e i z u r e development induced by d a i l y e l e c t r i c a l s t i m u l a t i o n of the amygdala i n r a t s and c a t s . Folia Psychiatrica et Neurologica Japonic, 1976, 29, 329-339. Walker, A.E. The patte r n s of propagation of e p i l e p t i c discharge. In: Cerebral Localization and Organization. G. Schaltenbrand and C.N. Woolsey (Eds). The U n i v e r s i t y of Wisconsin Press, Milwaukee, 1964. Walker, A.E., and R i b s t e i n , M. Chronic depth r e c o r d i n g i n f o c a l and g e n e r a l i z e d e p i l e p s y : An e v a l u a t i o n of the technique. Archives of Neurology and Psychiatry, 1957, 78, 44-45. Walker, A.E., and Udvarhelyi, G.B. Dissemination of acute f o c a l s e i z u r e s i n the monkey. I I . From s u b c o r t i c a l f o c i . Archives of Neurology, 1965, 12, 357-380. Ward, A.A., J r . , McCulloch, W.S., and Kopeloff, N. Temporal and s p a t i a l d i s t r i b u t i o n of changes during spontaneous se i z u r e s i n monkey b r a i n . Journal of Neurophysiology, 1948, 11, 377-386. Weir, B. Spike-wave from s t i m u l a t i o n of r e t i c u l a r core. Archives of Neurology, 1964, 11, 209-218. Whitlock, D.G., and Nauta, W.J.H. S u b c o r t i c a l p r o j e c t i o n s from temporal neocortex i n Macaca mulatta. Journal of Comparative Neurology, 1956, 106, 183-212. Wilder, B.J., King, R.L., and Schmidt, R.P. A comparative study of secondary e p i l e p t o g e n e s i s . Epilepsia, 1968, 9, 275-289. Wurtz, R.H., and Olds, J . Amygdaloid s t i m u l a t i o n and operant reinforcement i n the r a t . Journal of Comparative and Physiological Psychology, 1963, 56, 941-949. Wyss, O.A.M. On an i p s i l a t e r a l motor e f f e c t from c o r t i c a l s t i m u l a t i o n i n the Macaque monkey. Journal of Neurophysiology, 1938, 1, 125-126. Youmans, J.R. Experimental production of s e i z u r e s i n the macaque by temporal lobe l e s i o n s . Neurology, 1956, 6, 179-186. Publications:: Wada, J.A., M.E. Corcoran, M. Sato, and J.A. McCaughran, Jr. Antiepil-eptic properties of tetrahydrocannabinol. Presented at the American Epilepsy Society, November, 1972. Corcoran, M.E., J.A. McCaughran, Jr., and J.A. Wada. Acute antiepilep-tic effects of delta 9-tetrahydrocannabinol in rats with kindled seizures. Exp. Neurol., 40, 471-483, 1973. McCaughran, J.A., Jr., M.E. Corcoran, and J.A. Wada. Anticonvulsant activity of delta 8- and delta 9-tetrahydrocannabinol in rats. Pharmacol., Biochem., Behav., 2, 227-233, 1974. Corcoran, M.E., H.C. Fibiger, J.A. McCaughran, Jr., and J.A. Wada. Potentiation of amygdaloid kindling and metrazol-induced seizures by 6-hydroxydopamine in rats. Exp. Neurol., 45, 118-133, 1974. Wada, J.A., M. Sato, and J.A. McCaughran, Jr. Cortical electrographic correlates of amygdaloid seizure development. Presented at the Eastern EEG Association Meeting, December, 1974. Corcoran, M.E., I. Bolotow, Z. Amit, and J.A. McCaughran, Jr. Condi-tioned taste aversions produced by active and inactive cannabinoids. Pharmacol., Biochem., Behav., 2, 725-728, 1974. McCaughran, J.A., Jr., M.E. Corcoran, and J.A. Wada. Development of kindled amygdaloid seizures after section of the forebrain commis-sures in rats. Folia Psychiatrica et Neurologica Japonica, In Press, 1975. Corcoran, M.E., H. Urstad, J.A. McCaughran, Jr., and J.A. Wada. Frontal lobe and kindling in the rat. Canadian Journal of Neurological Sciences, 2, 501-508, 1975. Wada, J.A., M. Sato, and J.A. McCaughran, Jr. Cortical electrographic correlates of convulsive seizure development induced by daily electrical stimulation of the amygdala. Folia Psychiatrica et Neurologica Japonica, 29, 329-339, 1975. 

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