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Electrodermal correlates of the dexamethasone suppression test in unipolar and bipolar affective disorders Williams, Karl Munro 1984

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ELEGTRODERMAL CORRELATES OF THE DEXAMETHASONE SUPPRESSION TEST IN UNIPOLAR AND BIPOLAR AFFECTIVE DISORDERS By KARL MUNRO WILLIAMS B.Sc, The University of Calgary, 1981 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF ARTS in THE FACULTY OF GRADUATE STUDIES Department of Psychology We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA Apr i l , 1984 @ Karl Munro Williams, 1984 In presenting t h i s thesis i n p a r t i a l f u l f i l m e n t of the requirements fo r an advanced degree at the University of B r i t i s h Columbia, I agree that the Library s h a l l make i t f r e e l y a v a i l a b l e for reference and study. I further agree that permission for extensive copying of t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the head of my department or by h i s or her representatives. I t i s understood that copying or p u b l i c a t i o n of t h i s thesis f o r f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of f-S JCtfoL*o €~ Y The University of B r i t i s h Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date /Iff i i Abstract To determine whether depressed patients who suppress normally on the Dexamethasone Suppression Test (DST) d i f f e r electrodermally from depressed patients who do not suppress normally on the DST, the skin conductance of 27 unipolar and 9 bipolar (22 DST normal and 11 DST abnormal) depresslves and 15 normal controls was monitored during two experimental conditions. In the f i r s t of these conditions, subjects were exposed to 10, 85-dB, 1,000-Hz, 1-second tones after receiving instructions that were intended to minimize electrodermal responsiveness to the stimuli. In the second experimental condition, subjects were presented with 12, 105-dB, 1,000-Hz, 1-second tones. Half of these tones had a brief gap i n the middle. The subjects were required to monitor the 105-dB tones carefully and to respond to the tones that contained a gap by pressing a foot pedal. No differences i n electrodermal ac t i v i t y between the DST normal and the DST abnormal groups were detected. Moreover, no electrodermal differences between unipolar and bipolar patients and controls were found, and there was no correlation between severity of depression (as measured by the Beck Depression Inventory) and electrodermal act i v i t y . There were also no electrodermal differences between patients who were receiving antidepressant medications when tested and those who were not receiving such medication. i i i Patients who exhibited signs and symptoms of psychomotor retardation were observed to have significantly lower levels of tonic conductance than those patients who had no signs or symptoms of psychomotor retardation or agitation. The sexes also differed, inasmuch as males emitted fewer phasic electrodermal responses to the tones that required the subject to press the foot pedal. Moreover, males habituated to the 1 0 5 - d B tones faster than did females. A number of p o s s i b i l i t i e s are raised i n regard to the absence of electrodermal differences between normal controls and depressives. Two principal p o s s i b i l i t i e s that are discussed are the overall psychomotor status of the present sample of depressives (mostly non-retarded) and the socioeconomic and educational status of the control sample (slightly above average). It i s noted that future research should focus upon reliable demonstrations of electrodermal differences between depressives and controls. It i s further recommended that a heterogeneous sample of normal controls be u t i l i z e d i n such research and that the psychomotor status of the depressed sample be assessed carefully and possibly controlled. TABLE OF CONTENTS TITLE ABSTRACT TABLE OF CONTENTS LIST OF TABLES LIST OF FIGURES ACKNOWLEDGEMENTS CHAPTER ONE - INTRODUCTION Review of the Literature Classification of Depression Dexamethasone Suppression Test Electrodermal Activity Physiological Mechanisms Rationale for Present Study CHAPTER TWO - METHOD Subjects Dexamethasone Suppression Test Electrodermal Measurement Stimuli Electrodermal Measures Procedure CHAPTER THREE - RESULTS Medication Effects Tonic Skin Conductance Levels Phasic Skin Conductance Response to Tones I TABLE OF CONTENTS, continued Psychomotor Retardation 68 Range-Corrected Analyses 79 Sex Effects 82 Cl i n i c a l Status 82 Relationships Among Variables 82 CHAPTER FOUR - DISCUSSION 86 REFERENCES 96 APPENDICES 104 Appendix A.01 - Hamilton Depression Scale 104 Appendix A.02 - Subject Consent Form 108 Appendix A.03 - Beck Depression Inventory 109 Appendix A.04 - Criteria to Subclassify Depressive Episode 112 Appendix B.01 - Instructions for Tone Series I 114 Appendix B.02 - Instructions for Tone Series II 118 v i LIST OF TABLES TABLE 1 Drug Intake of Depressed Patients 41 TABLE 2 Characteristics of Subjects 43 TABLE 3 C l i n i c a l Characteristics of Depressed Subjects 44 TABLE 4 Dexamethasone Suppression Test Status of Depressed Patients 45 TABLE 5 Correlation Coefficients Between Selected Variables 84 TABLE 6 Occupation and Education of Control Subjects 93 v i i LIST OF FIGURES FIGURE 1 Phasic Responses from Right Hand of DST and Control Groups FIGURE 2 Phasic Responses from Left Hand of DST and Control Groups FIGURE 3 Phasic Responses from Right Hand of Unipolar, Bipolar, and Control Groups FIGURE 4 Phasic Responses from Left Hand of Unipolar, Bipolar, and Control Groups FIGURE 5 Phasic Responses from Right Hand of Psychomotor and Control Groups FIGURE 6 Phasic Responses from Left Hand of Psychomotor and Control Groups FIGURE 7 Tonic Conductance Levels i n Right Hand of Psychomotor and Control Groups FIGURE 8 Tonic Conductance Levels i n Left Hand of Psychomotor and Control Groups FIGURE 9 Tonic Conductance Levels i n Right Hand of Unipolar, Bipolar, and Control Groups FIGURE 10 Tonic Conductance Levels i n Left Hand of Unipolar, Bipolar, and Control Groups FIGURE 11 Tonic Conductance Levels i n Right Hand of DST and Control Groups FIGURE 12 Tonic Conductance Levels i n Left Hand of DST and Control Groups 59 60 62 63 70 71 73 74 75 76 77 78 ACKNOWLEDGEMENTS I wish to express my deep appreciation to Dr. William G. Iacono without whose advice, effort, and encouragement this work would not have been possible. I would also l i k e to thank the other members of the thesis committee—Dr. Keith Dobson, Dr. G. James Johnson, and Dr. Ronald A. Remick—for their most generous support and assistance I am grateful to Dr. David Lawson for his kind administrative assistance at Shaughnessy Hospital. I am especially indebted to Eat, who gave me the incentive and the courage to persevere. 1. Depression i s a d i s t u r b i n g l y complex phenomenon which has become one of today ' s most common mental hea l th problems. I t continues to be the subject o f cons iderable research, but nevertheless eludes s a t i s f a c t o r y e t i o l o g i c a l conceptua l i za t i on . In c l i n i c a l p r ac t i ce the d e f i n i t i v e d iagnos i s o f depress ion i s a l s o prob lemat ica l , as i t must contend with a heterogeneous symptomatology that appears to vary a long both quan t i t a t i ve and q u a l i t a t i v e dimensions and may be masked by, or mixed wi th, other types of mental d i s turbance. The trend toward u t i l i z a t i o n of mu l t i p le symptom c r i t e r i a , assessment of i n t e r r a t e r r e l i a b i l i t y , and c o r r e l a t i o n of d iagnos i s with therapeut ic outcome (e.g . Research Diagnost ic C r i t e r i a [RDC] [ Sp i t ze r , End i co t t , & Robins, 19?8]} D iagnost ic and S t a t i s t i c a l Manual o f Mental D i sorders [DSM-III] [American P sych i a t r i c A s soc i a t i on , 1980]) may i n recent years have somewhat enhanced psychodiagnostic p r e c i s i o n . Notwithstanding, the d iagnos i s of depress ion, as i t per ta in s to therapeut ic mode and outcome, remains prob lemat i ca l . Although no s i n g l e method of subc l a s s i f y i ng depress ion has met with un i ve r s a l acceptance, three commonly used methods f o r d i v i d i n g the un ipo la r depress ions have t r a d i t i o n a l l y enjoyed some popu l a r i t y . The o ldes t method i s the endogenous/nonendogenous d ichotomizat ion, f i r s t proposed by G i l l e s p i e (1929). I t d i f f e r e n t i a t e s depress ions that a r i s e spontaneously or endogenomorphically from those which 2. arise in response to environmental factors. The RDC now bases i t s diagnosis of endogenous depression upon the premise that endogenous depressives show a particular cluster of symptoms which has been found to be associated with a good response to somatic therapy. A second way to subdivide depression is by means of neurotic/psychotic differentiation. Psychotic depressives experience a break in reality testing in which hallucinations, delusions, and ideas of reference may be present. Such dichotomization seems unsatisfactory because i t tends to place a relatively small number of depressives in one category while i t attempts to f i t a heterogeneous majority of depressives into the other, and because there remains some doubt as to whether psychotic depressives differ qualitatively or quantitatively from their neurotic counterparts. It should be noted that the DSM-II (American Psychiatric Association, 1968) classification psychotic depressive reaction referred to a depressed mood in which reality testing or functional adequacy is impaired, but which is also distinguished by its being attributable to some precipitating experience. Those studies which employed the DSM-II criteria for psychotic depression would therefore have investigated something different from the current concept of psychotic. It is, however, the impairment in reality testing which is now generally considered to be the hallmark of psychotic depression. A third, relatively recent dichotomization is the primary/secondary one (Robins & Guze, 1972). This division takes into account the patient's previous psychiatric history. The individual is seen to be suffering from a primary depression i f he or she was previously in sound mental 3. health, or experienced only mania or depression; conversely, the diagnosis of secondary depression i s applied when the patient has had some other form of psychiatric i l l n e s s i n the past. The RDC endogenous/nonendogenous dichotomization has been ut i l i z e d i n many studies, i n part due to the evidence which indicates that endogenous and nonendogenous depressives d i f f e r i n their response to somatic forms of therapy. A RDC diagnosis of endogenous depression requires the presence of a major depressive disorder which includes the following featurest From groups A and B a total of at least four symptoms for probable, six for definite, including at least one symptom from group A. A. 1. Distinct quality to depressed mood, i.e. depressed mood i s perceived as disti n c t l y different from the kind of feeling he would have or has had following the death of a loved one. 2. Lack of reactivity to environmental changes (once depressed does not fee l better, even temporarily, when something good happens). 3. Mood i s regularly worse i n the morning. k. Pervasive loss of interest or pleasure. B. 1. Feelings of self-reproach or excessive or inappropriate g u i l t . 2. Early morning awakening or middle insomnia. 4. 3. .Psychomotor retardation or agitation (more than mere subjective feeling of being slowed down or restless). 4. Poor appetite. 5» Weight loss (two pounds a week over several weeks or twenty pounds in a year when not dieting). 6. Loss of interest or pleasure (may or may not be pervasive) in usual activities or decreased sexual drive. Research has also focused upon specific endogenous symptoms such as the presence of psychomotor retardation or agitation. In the present study, classification was made according to endogenous criteria and also specifically on the basis of the patient's psychomotor activity. The rationale behind this dual focus of attention will become apparent later in this paper. Briefly, i t is because endogenous classification has been of concern in studies related to the Dexamethasone Suppression Test, whereas psychomotor status has been of interest in studies of electrodermal activity. From both a theoretical and a practical perspective, i t is important to be able to distinguish between those patients whose problem is severe depression with etiology of possibly a biological nature; those whose depression is severe but possibly attributable to psychological/ environmental factors, or at least amenable to psychological intervention; and those whose pathology lies primarily elsewhere, with perhaps some overlap in symptomatology (e.g. schizophrenia). Because in practice there may be considerable diagnostic uncertainty regarding the 5. category i n which a given individual can best be placed, i t i s also important that reliable and valid indices of depressive subtypes be employed. For example, about 7 0 percent of prescriptions for t r i c y c l i c antidepressant drugs are written by physicians who are i n family practice or internal medicine (Hollister, 1978), and a patient who does not meet the c r i t e r i a for endogenous depression may be given such biologically based therapy when psychotherapy would be more appropriate. (The converse may of course also hold.) In an attempt to improve upon present diagnostic techniques as they relate to depression, and provide information concerning the neurophysiological correlates of depression, a study was conducted in which the pattern of responses of depressives to two different laboratory procedures — t h e Dexamethasone Suppression Test (DST) and the recording of electrodermal ac t i v i t y (EDA)—were examined. The DST i s used to assess the functional integrity of the hypo-thalamo-pituitary adreno-cortical (HPA) system. Dexamethasone phosphate (dex) i s a potent synthetic corticosteroid. In the abbreviated form of the overnight DST, i or 2 milligrams of dex i s administered orally to the patient at about 11:00 p.m. The normal effect of the dex i s to inhibit adrenocorticotrophic hormone secretion, and thus suppress the output of corticosteroid (specifically, Cortisol) from the HPA system. Whether or not this suppression has i n fact occurred i s established by means of one or more samples of blood taken on the day following dex administration. 6. Early escape from HPA/cortisol suppression—that i s , an unusually early rise in Cortisol levels following the suppressive effect obtained by administration of the dex—has come to be recognized as pathognomic. An abnormal plasma Cortisol level, now established to be greater than about 5 micrograms (ug) per deciliter (dL), on any of one to three samplings over the 24-hour period after dex has been ingested may indicate dysfunction of the HPA system. The DST has been used to investigate a variety of pathological states. For example, such investigations have pertained to exogenous obesity and diabetes mellitus (Asfeldt, 1969)» alcoholism (Oxenkrug, 1978), and medical and surgical trauma (Connolly, Gore, Stanley, & Wills, 1968), and have met with particular success in the rapid identification of those individuals suffering from Cushing's Syndrome (Asfeldt, 1969; McHardy-Young, Harris, Lessof, & Lyne, 1967; Meikle, Lagerquist, & Tyler, 1975; Nugent, Nichols, & Tyler, 1965; Bavlatos, Smilo, & Forsham, 1965. Rabhan, 1968). In recent years a growing interest has developed in utilization of the DST with psychiatric populations. Specifically, considerable work has investigated the efficacy of the DST in discriminating those who possess some form of depressive illness and both healthy individuals and those with another form of depressive or psychiatric illness. One of the earliest controlled studies which compared depressed 7. patients with normal controls was conducted by Gibbons and Fahy (1966). These investigators found that the average level of plasma Cortisol in a group of endogenously depressed patients was significantly higher than that of a group of normal controls, when sampled upon three occasions on the same day as intramuscular administration of 2 mg of dex. In a somewhat more ambitious study, Butler and Besser (1968) measured Cortisol levels in patients with severe endogenous depression both before and after administration of varying amounts of dex. Testing was repeated following successful treatment. Their patients demonstrated generally elevated plasma and urinary corticosteroid levels, a disturbed rhythm of Cortisol levels, and resistance to dex suppression at a l l but the highest doses (2 mg every 6 hours for 2 days). Following treatment, the diurnal Cortisol rhythm was normal, and generally normal suppression in response to dex was observed. The tendency for dex suppression to normalize as successful therapy is undergone has been reported by others (Albala & Greden, 1980j Carpenter & Bunney, 1971; Dysken, Pandey, Chang, Hicks, & Davis, 1979; Goldberg, 1980a, 1980b; Greden et a l . , 1980; Greden & Carroll, 1979). Both Goldberg (1980a, 1980b) and Greden et a l . (1980) also observed that the results of a second DST taken upon completion of therapy can be highly indicative of potential for clinical relapse. In addition to obtaining abnormal dex suppression (defined as C o r t i s o l levels greater than 7 ug/dL) in approximately 83 percent of a group of depressive outpatients prior to therapy, Goldberg found that, upon completion of 8. t r i c y c l i c therapy, none of the suppressors on a second DST relapsed within two months, while a l l of the nonsuppressors at the second testing did relapse during that time period. Similarly, Greden et a l . followed endogenously depressed inpatients some of whom did, and others who did not, show normal suppression on a DST prior to discharge ( a l l had been nonsuppressors at the time of admission). They found that upon follow-up 7 to 3 6 months later 80 percent of the normalizers were stable and symptom-free, while a l l of the non-normallzers had a complicated c l i n i c a l course. Results of the DST following c l i n i c a l recovery were also assessed by Carroll, Martin, and Davies (1968), who compared the response to 2 mg of dex of groups of severely depressed and non-depressed psychiatric inpatients. A majority of the former group was re-tested upon c l i n i c a l remission. The results of the two blood samples (at 8 : 3 0 a.m. and 4 : 3 0 p.m. on the day after dex administration) indicated significantly higher mean plasma Cortisol levels i n the depressed than i n the non-depressed groups. Upon recovery, however, the formerly depressed patients had somewhat lower average C o r t i s o l levels than the non-depressed psychiatric patients. The investigators employed a rather conservative criterion for nonsuppression (10 ug/dl/), and found that 5 0 percent of the depressives were i n i t i a l l y nonsuppressors, while few of the non-depresslves, and only one of the fourteen recovered depressives, 9. failed to suppress in response to dex. The impressive ability of the DST to distinguish depressed patients from normal controls was exemplified in the results obtained by Stokes, Pick, Stoll, and Nunn (1975)' These workers found that after ingestion of 1 mg of dex at 11:00 p.m., 18 of 22 depressives had plasma Cortisol levels greater than 10 ug/dL at 9*00 a.m. the next day, while a l l of the 23 controls had C o r t i s o l levels less than 5 ug/dL. Furthermore, those patients who did suppress were rated as being less severely depressed than their nonsuppressing counterparts. The reason for such definitive results remains unclear. Possibly, careful diagnosis of the depressives produced a homogeneous patient group which was in turn quite consistent in its response to dex. Much of the fairly recent work with the DST in psychiatric populations has, in fact, tended to emphasize methodological rigor and standardization of administrative and sampling procedures. For example, Carroll, Curtis, and Mendels (l9?6a) noted that 24-hour observation of the suppressive response following dex administration is required, since depressives frequently show abnormal early escape from suppression, rather than simply early morning escape on the day after dex ingestion. Carroll et a l . utilized this technique and monitored the DST response of four depressive patients and one patient without an affective disorder. A l l four of the depressives demonstrated nonsuppression, while the non-depressed patient did not. 1 0 . Moreover, normalization of the DST response i n the depressive group was found to correlate with c l i n i c a l improvement. Less dramatic results were obtained by Brown, Johnstone, and Mayfield (1979), who also sampled blood on three occasions ( 8 : 0 0 a.m., 4 : 0 0 p.m., and 1 1 : 3 0 p.m.) on the day after patients received 2 mg of dex. They found that only 40 percent of the 22 depressives tested were nonsuppressors ( i . e . had post-dex plasma C o r t i s o l levels greater than 6 ug/dL). However, none of a group of non-depressed psychiatric patients f a i l e d to suppress. Brown et a l . again observed the phenomenon of gradual escape from suppression i n the nonsuppressors, with the 1 1 : 3 0 p.m. sample the most sensitive and specific with regard to identification of depressive pathology. A growing body of research has of late focused upon u t i l i z a t i o n of the DST to subclassify depression. Carroll, Curtis, and Mendels (1976b), for instance, made one of the f i r s t attempts to use the DST with quite discrete forms of depressive i l l n e s s . When they compared 42 endogenously depressed patients with an equal number of non-depressed psychiatric patients, these workers found that 5 0 percent of the unipolar depressives and 8 8 percent of the bipolar depressives (i.e. those depressives who had not, and those who had, respectively, a history of a manic episode) had at least one abnormally high suppression level on the day following ingestion of 11. 2 mg of dex. In contrast, only 12 percent of the other psychiatric patients possessed abnormally high levels. Early escape from suppression in the endogenously depressed group was again seen to be progressive on the day after dex administration. A further attempt to distinguish between different forms of depression was made by Brown and Shuey (1980), who divided a group of 4-9 depressed patients into primary and secondary depressives. They found that 50 percent of the primary, but only 6 percent of the secondary, depressives did not suppress normally in response to dex. Their data also indicated that the two groups of depressives did not differ in anxiety as measured by the Hamilton Rating Scale for Depression (Hamilton, I960), the Profile of Mood States (McNair, Lorr, & Droppleman, 1971), or ratings of tension-anxiety and depression made at the time each blood sample was taken. This observation is similar to that of Carroll and Davies (1970), who found anxiety levels to be equivalent in those severely depressed inpatients who did suppress, and those who did not suppress, on the DST. Also, the two groups could not be differentiated in terms of severity of depression. Although nonsuppressors were on average more agitated than suppressors, the observation that individual patients who showed pronounced agitation s t i l l suppressed normally led Carroll and Davies to conclude that, overall, Cortisol abnormality in the DST is not related to apparent differences in anxiety, arousal, or 12. distress. Such information is significant because i t indicates that abnormally high post-dex Cortisol levels cannot be attributed merely to situational or subjective anxiety factors. Carroll et a l . (1980) also worked with endogenously depressed patients, and noted that these individuals had significantly (and abnormally) higher average plasma Cortisol levels during the 2k hours following ingestion of 1 mg of dex than a group of nonendogenous depressives. Moreover, Carroll et a l . observed that although plasma Cortisol levels were significantly reduced and normalized in the four endogenous patients re-tested following clinical recovery, there was no change in the level of circulating dex during the DST. The authors also reported finding no indication of rapid dex clearance from the vascular system of the i l l endogenous patients and, overall, no relationship between plasma Cortisol and plasma dex levels. This suggests that a central neuroendocrine disturbance may be experienced by endogenously depressed patients, rather than factors simply related to the rapid removal of dex from the body by nonsuppressors. However, this observation is in contrast to the results of an earlier study conducted by Carpenter and Bunney (1971). These workers reported that plasma Cortisol levels in depressives are normal following the DST (but, for reasons which are discussed below, the validity of this particular finding can be questioned). Their data also suggested that depressed patients on average produce 13. significantly more plasma C o r t i s o l than recovered depressives—but not normals—and that their metabolic clearance rate for Cortisol is about twice normal levels. In the recovered phase, the production rate for Cortisol drops, say the authors, but clearance remains high, resulting in significantly lower plasma Cortisol concentrations. Carpenter and Bunney concluded that central control mechanisms (presumably this means the HPA system) function normally during depression, but the peripheral metabolic system is in some way abnormal. Which of these conflicting conclusions (i.e. Carpenter & Bunney, 1971» Carroll et a l . , 1980) is correct can only be determined by further investigation. A major DST study was recently conducted by Carroll et a l . (1981), who gave the DST to a total of 438 individuals (of whom 70 were normals) in order to standardize the DST procedure. Of the 368 patients tested, 215 were given a diagnosis of melancholic depression—seen to be equivalent to endogenous depression—on the basis of psychiatric interview, psychiatric and family history, and results obtained from completion of the Schedule for Affective Disorders and Schizophrenia (Spitzer & Endicott, 1977). One hundred of the remaining patients were diagnosed as experiencing nonmelancholic depression, while the other 53 patients were seen to have miscellaneous other psychiatric disorders. Approximately half of the subjects were given the overnight DST utilizing 1 mg of dex, 14. while the other half took the overnight DST with 2 mg of dex. A l l had dex administered orally at 11:30 p.m. on day 1, and had blood sampled for plasma Cortisol determination at 8:00 a.m. and 4:00 p.m. of day 2. About half of the patients also had a blood sample taken at 11:00 p.m. on day 2. Sensitivity was defined as the true-positive rate, or the proportion of melancholic patients with abnormal DST results? while specificity was defined as the true-negative rate, or the proportion of nonmelancholic patients with normal DST results; and diagnostic confidence was the proportion of abnormal test results that were true-positive for melancholia. The following results were obtained: Overall sensitivity was 45 percent; overall specificity was 96 percent; and overall diagnostic confidence was 92 percent. However, when the authors analyzed the results of the 1 mg group separately, utilized a criterion of 5 ug/dL plasma Cortisol as the cut-off for abnormal suppression (6 ug/dL was previously used as the criterion), and included both the 4:00 p.m. and 11:00 p.m. blood sample results, they obtained a sensitivity of 67 percent and a specificity of 96 percent for melancholia. They therefore concluded that the latter criteria yield the most precise diagnostic information. Carroll et a l . also observed that abnormal DST results were not related to age, sex, severity of depressive symptomatology, or recent use of psychotropic medication. (This is in agreement with the findings obtained by, for example, Greden et a l . , 1980; and 15-Shopsln & Gershon, 1971. In fact, a large majority of the DST data suggest that psychotropic medication does not affect the DST response, and that the DST results are unrelated to clinical severity and demographic variables.) DST abnormality is not biologically specific to melancholia, however, and psychiatric patients must be properly screened prior to the DST for optimal diagnostic confidence. Notwithstanding the promise of these data, one of the most recent DST studies, which utilized criteria similar to those employed by Carroll et a l . , obtained less striking results. Rush, Giles, Roffwarg, and Barker (1982) observed that the DST had a sensitivity of 41 percent, specificity of 95 percent, and diagnostic confidence of 87 percent in distinguishing endogenous, non-psychotic unipolar depressives from their nonendogenous counterparts. Possibly, the use of outpatients rather than inpatients, and a slightly more liberal criterion for nonsuppression (4 ug/dL), may account for the discrepancy in results. A study by Schlesser, Winokur, and Sherman (1979) exemplifies the improvement in sensitivity and specificity which may be obtained when the DST is utilized in conjunction with a thorough psychiatric investigation. On the basis of their psychiatric evaluation of 86 unipolar primary depressives and 80 psychiatric patient controls, and following the criteria specified by Winokur, Behar, Van Valkenburg, and Lowry (1978), Schlesser et a l . were able to 16. divide the depressives into those with a family history of depression (familial pure depressives—FPDD), those without such family history (sporadic depressives—SDD), and those with a family history of alcoholism and/or antisocial personality disorder (spectrum disease depressives—DSD). They found that, with a 1 mg overnight DST, nonsuppression was present in 82 percent of the FPDD, 37 percent of the SDD, and 4 percent of the DSD patients, on the basis of only an 8:00 a.m. blood sampling. Overall, nonsuppression (cortisol greater than 5 ug/dL) was present in 43 percent of the depressives and none of the controls. These findings were subsequently closely replicated by these workers in two recent studies (Schlesser et al . , 1980j 1981). However, of two other attempted replications only one obtained data which supported those of Schlesser et a l . Coryell, Gaffney, and Burkhardt (1982) reported results which closely matched those of Schlesser et a l . In contrast, Rudorfer, Hwu, and Clayton (1982) were unable to replicate these results, inasmuch as only 17 percent of the FPDD group in their study were nonsuppressors, while 6? percent of the SDD and 33 percent of the DSD patients failed to suppress normally following the DST. In total, they did obtain abnormal suppression in 42 percent of the endogenous depressives. It is possible that the variability of these results reflects the fact that, in the different studies, different numbers of endogenous depressives 17. comprised each of the Winokur et a l . categories, perhaps due to differences in the care taken to subclassify the depressives (that i s , to take a very careful history). Given the methodological rigor of the research described by Carroll et a l . (1981) and Schlesser et a l . (1979; 1980; 1981), the few reports in the literature of an inability to distinguish between depressives and others on the basis of the DST may be explained in terms of inadequate or inappropriate methodology. For example, negative results were obtained by Shopsin and Gershon (1971) when they attempted to distinguish between mixed depressives and schizophrenics by means of an overnight 2 mg DST. Interpretation of this study is obscured by two factors: First, only one blood sample was obtained (at 8:30 a.m. on day 2), and the report that a l l patients demonstrated normal suppression is explicable in terms of a failure to test for early escape from suppression during the remainder of the day following dex administration. Second, the depressed group was apparently quite heterogeneous in symptomatology, and would probably have possessed considerable variability in both subdiagnosis and DST status. Negative results were also obtained by Shulman and Diewold (1977). When these researchers examined the DST responses of 34 psychiatric inpatients (primary depressives, manics, and schizophrenics) they were unable to distinguish between endogenous depressives and other depressives, despite the fact that, 18. overall, 11 of the patients were nonsuppressors. There again appear to be two possible explanations for these findings: First, blood was sampled only at 8:00 a.m. and 4:30 p.m. This again reflects a failure to check for escape from suppression late in the day following dex ingestion. Second, dex was administered at 6-hour intervals over a period of 48 hours. This would tend to diffuse the effects of dex by spreading the administration period over twice the usual length of time. Carpenter and Bunney's (1971) inability to obtain nonsuppression in 12 depressed patients can also be explained in terms of the methodology employed. These investigators administered dex to their patients over a period of four days (l mg orally twice a day on days 1 and 2; 2 mg orally twice a day on days 3 and 4) and sampled urinary Cortisol levels prior to administration of dex on each day. This procedure would preclude the ability to assess early escape from suppression because sampling was undertaken too soon after previous dex administration (particularly during days 3 and 4, when a relatively high dosage of dex was given) to observe such differential escape from suppression. In short, the DST has been employed with a variety of psychiatric populations and has, despite some variability among studies, usually shown itself to be reasonably successful in its ability to distinguish depressives from normals, depressives from other psychiatric patients, and some types of depressives from other 19. types. It is in the last two areas that research continues to be actively pursued, primarily because considerable clinical utility can potentially be derived from application of the DST in these areas. Prior to such employment, however, considerable effort must be devoted to improvement of the specificity of the DST, either by further enhancing the methodology with which i t is employed (if this i s feasible), or by supplementing i t with additional assessment devices. Electrodermal activity, for instance, has been examined in depressed patients for many years, and a substantial body of research on the psychological and physiological correlates of EDA now exists. It is possible that EDA analysis may shed light upon the differential diagnosis and the etiology of depressive illness. Electrodermal research with depressives has been marked by substantial variability in quality, methodology, subjects, and outcome measures. It is nevertheless possible to note some generally consistent findings throughout the literature. Primary research concerns have focused upon both the average level of skin conductance (tonic EDA) and the skin conductance response to stimuli (phasic EDA), and have usually indicated that both tonic and phasic levels are lower than normal in endogenously depressed patients, while such levels tend to be as high as or higher than normal in nonendogenous depressives. Earlier investigations of EDA in 20. depressive illness tended to be concerned with the electrodermal correlates of both the depressed state and response to treatment. Unfortunately, such early (and some later) work did not distinguish clearly between patients on the basis of clinical symptomatology and history, thus making i t difficult to evaluate outcome. Bassett and Ashby (195^). for example, compared phasic EDA in normals, untreated (mainly depressed) patients, and EOT-treated patients. They observed a failure in both patient groups to show a normal decline in phasic responsiveness (i.e. habituation) to tactile, auditory, and visual stimuli over a five-week testing period. Average electrodermal responses were found to differ significantly between clinically recovered and non-recovered patients at the end of the five-week period (with the recovered group exhibiting EDA more similar to that of normals), but a majority of patients who were about to demonstrate clinical recovery from their illness showed an increase in phasic EDA independent of therapy. However, patient groups are poorly described, and i t is not specified whether the groups differed in severity of illness prior to testing. Similar findings were obtained by Stern and Sila (1959). who compared phasic electrodermal response to stimulus words in (undefined, but presumably depressed) patients treated with both EOT and chemotherapy, and (undefined but possibly depressed) patients treated with chemotherapy alone. Their results indicated a 21. significant rise in electrodermal responsiveness upon conclusion of the ECT/chemotherapy course, but no such rise in the group which received only chemotherapy. Although replication of these findings was possible (Stern, Sila, & Word, 1961), these results—like those of Bassett and Ashby—are Inconclusive due to factors such as a failure to describe patient groups. Noble and Lader (1971) were unable to replicate the above findings, and in fact noted that EDA showed a trend toward lower levels after a course of EOT. Also, no change in EDA following a course of ECT was found in depressives studied by Dawson, Schell, and Catania (1977). It i s possible that completion of ECT alone is not sufficient for normalization of EDA, and that clinical remission of symptomatology is necessary i f electrodermal normalization is to occur. This explanation remains largely unsatisfactory, however, and the early findings which suggested that electrodermal change accompanies clinical remission are incompatible with recent work in the area (iacono et a l . , 1983), to be discussed below. More plausible i s the possibility that different findings reflect differences in methodology, patient diagnosis, and overall sophistication of experimental technique. For example, Bagg and Crookes (1966) used an interesting, but quite crude, method of electrodermal measurement—in which the investigator literally 22. counts the number of holes created by active sweat glands in a layer of plastic paint applied to the subject's finger—to compare the EDA of 18 depressed patients (17 were endogenous depressives) before and after a course of ECT. Although they found that their patients had reduced EDA while in the depressed condition, and showed a significant increase with recovery, methodological problems such as the absence of a control group (to control, for example, for the effects of repeated exposure to the experimental situation) and the lack of refinement in the technique employed obscured their results. As noted above, EDA in depressives in comparison to normals appears to depend considerably upon the type of depressives under investigation. The possession of more severe, particularly endogenous, symptomatology renders more likely abnormally reduced phasic and tonic skin conductance. However, the literature does contain a few exceptions to this general observation. McCarron (1973) found that a group of nonendogenous depressives had lower amplitude tonic conductance and significantly fewer spontaneous tonic fluctuations than a group of normal subjects. Goldstein (l965)i who examined EDA in a total of 100 psychiatric patients and normals, found that the depressed group was second only to the psychotic group in being electrodermally hyperresponsive to white noise stimuli—relative to both normals and other non-depressed 23. patients. It should be noted, however, that the depressed subjects in this study were nonpsychotic, significantly more anxious than normals, in the early stage of their illness, and were probably a heterogeneous group with regard to endogenous categorization. These factors would tend to elevate their average electrodermal levels. A similar argument can be raised concerning the findings obtained by Lewinsohn, Lobitz, and Wilson (1973) when they compared the response of depressives, psychiatric controls, and normals to electric shock. Results indicated a non-significant trend toward greater overall tonic EDA in the depressed subjects, and significantly greater phasic EDA in response to shock in the depressives. Lewinsohn et a l . used college undergraduates for subjects, however, and allocated subjects to groups on the basis of an interview and results of the Minnesota Multiphasic Personality Inventory (MMPl). Thus, depressives were probably largely of the nonendogenous type, and the observation that they tended to demonstrate hyperresponsive EDA is consistent with the thesis that electrodermal reduction is principally a characteristic of the endogenous subtype of depression. Suarez, Crowe, and Adams (1978) also utilized the MMPI and a population comprised primarily of students to examine the skin conductance of depressives and controls as they rested and as they listened to a tape recording of depressive 24. statements. In this study depressed subjects were again likely to have been of the nonendogenous variety, and the finding that depressives showed a greater number of phasic responses than controls is in keeping with the above thesis. Mixed results were obtained in a correlational study conducted by Zuckerman, Persky, and Curtis (1968). When skin conductance was recorded from psychiatric patients and normal controls both before and after administration of the cold-pressor stress test, i t was found that overt depression in the subjects was positively correlated with spontaneous EDA before and after the stress test, while overt depression was negatively correlated with tonic EDA prior to the test. Although these findings are somewhat complex, the latter observation (reduced tonic activity in more seriously depressed patients) is consistent with the findings of a majority of research. For instance, an earlier study, conducted by Gilberstadt and Maley (1965)» monitored tonic and phasic EDA in psychiatric patients who had been divided into four groups on the basis of their level of anxiety and depression. The authors reported that clinical state did tend to covary with EDA, such that the highest tonic and phasic levels were present in the pure anxiety group, the lowest were present in the pure depression group, and intermediate levels were present in the mixed anxiety/depression groups. Gilberstadt and 25-Maley noted that a failure to distinguish psychiatric groups on the basis of EDA was probably due to the existence of a variety of clinical states within each diagnostic category. This underscores the value of careful diagnostic procedure. Dawson et a l . (197?) appear to have exercised such care in a study in which they monitored EDA in depressed patients and controls while the subjects performed a variety of tasks. As discussed above, the depressives were retested after completion of ECT, at which time no change —beyond the effects of habituation—was observed in the patient group. Of immediate interest is the fact that Dawson et a l . found that, on average, the depressives had lower tonic conductance, smaller phasic responses, and longer latencies of phasic responses in comparison with the controls. Dawson and his colleagues postulated that electrodermal abnormalities reflect a relatively chronic state among those prone to depression. This is a point to which I shall return. Similar findings were obtained by Storrie, Doerr, and Johnson (1981), who noted significantly greater tonic and phasic conductance in controls than in depressives. Moreover, this difference held even after the depressives had received treatment. Noble and Lader (1971) recorded skin conductance from depressed inpatients while the subjects were at rest and while they were performing mental work. 26. Low tonic and phasic skin conductance was found to correlate significantly with severity of depression during illness, and (as noted above) electrodermal levels were unchanged following a course of EGT. Also, when the agitation and retardation of the subjects were assessed on the basis of self- and clinical ratings, i t was found that the agitated subjects had significantly more spontaneous EDA than the retarded subjects. In a later study by Noble and Lader (1972) i t was possible to discriminate endogenous from nonendogenous depressives on the basis of their EDA. Endogenous patients were found to have significantly fewer spontaneous electrodermal fluctuations than nonendogenous patients. This finding is similar to those obtained by Mirkin and Coppen (1980) when they compared endogenous depressives with nonendogenous depressives and controls on their electrodermal response before and during presentation of auditory stimuli. Significantly more of the patients than the controls failed to respond at a l l to the stimuli (67 percent versus 13 percent), and 82 percent of the endogenous group were non-responders. Although the depressives as a whole did not differ from controls in their mean tonic conductance levels, the endogenous group did have significantly lower tonic levels than both the control and nonendogenous groups. Heimann and Straube (1979) reported that generally fast habituation to auditory stimuli was present in a group of nearly 300 "anxious depressed" patients. Twenty-five percent of these patients failed to 27. exhibit any response. This finding takes on particular significance when i t is noted that a general lack of habituation was manifested by a control group of normal subjects. Unfortunately, an absence of diagnostic precision regarding the patient group weakened this study. Byrne (1975) divided acutely depressed patients into neurotic and psychotic depressives on the basis of clinical interviews and monitored the patients' skin conductance as they were presented with visual stimuli. Relative to a group of controls, the neurotic group was found to have significantly greater mean phasic conductance and frequency of phasic activity. In contrast, the psychotic group had significantly less phasic activity than both the controls and neurotics. The patient groups also differed significantly in their rates of habituation, with the neurotic group habituating more slowly than the psychotic group. These findings are similar to those of Lader and Wing (1969), who examined the EDA of agitated depressives, retarded depressives, and matched controls before, during, and after presentation of a series of tones. Lader and Wing found that the agitated group had significantly higher mean tonic conductance than the controls, whereas the retarded group had significantly lower levels. A l l of the agitated patients had more spontaneous fluctuations than both "the retarded patients and controls. Also, the normal controls habituated to the stimuli much more rapidly than the agitated patients, while the retarded depressives tended 28. not to respond to stimuli. However, these results were only-part ially replicated by Lapierre and Butter (1980). They found that retarded endogenous depressives had significantly lower tonic skin conductance than controls while at rest, but that retarded and agitated depressives, and agitated depressives and controls, did not differ from one another. Moreover, the three groups did not differ in phasic conductance while passively or actively responding to auditory stimuli. This study was unfortunately complicated by the use of a control group which was younger than the depressed groups. An important study which examined electrodermal levels in remitted depressives was recently conducted by Iacono and his associates (iacono et a l . , 1983)* These investigators appear to have exercised considerable care in the diagnosis of their patients. Two clinicians made independent diagnoses of patients by utilizing the Schedule for Affective Disorders and Schizophrenia (Spitzer & Endicott, 1977) in conjunction with other rating scales such as the Global Assessment Scale (Endicott, Spitzer, Fleiss, & Cohen, 1976) and the Brief Psychiatric Rating Scale (Overall & Gorham, 1962) for assessment of remitted status. Twenty-five of the 26 unipolar depressives and 17 of the 24 bipolar depressives met the RDC standards for endogenous depression. These patients, when in remission, were then compared with a control group of 46 psychiatrically healthy individuals with regard to their bilateral 29. electrodermal response to a series of pure tones. Iacono et a l . observed that the remitted depressive group had significantly more nonresponders than the control group. Fifty-six percent of this group failed to respond to any stimulus, which is more than twice the corresponding percentage of nonresponding controls. (These findings are comparable to those obtained by Mirkin and Goppen [1980] and Heimann and Straube [1979] with unremitted depressives.) Iacono and his colleagues also reported that the remitted depressives on average produced significantly smaller phasic responses and lower tonic conductance than the controls. Moreover, a significantly smaller proportion of the depressives responded to a dishabituating tone which differed from the others in terms of frequency and duration. This group also habituated to stimuli significantly faster than controls. When tonic conductance levels were further analyzed i t was observed that a criterion level of 6 micromhos discriminated unipolar, bipolar, and control subjects quite well, with less than 4 percent, 20 percent, and 5 0 percent of these subjects, respectively, exhibiting tonic activity above this level. It is important to stress that a l l depressives were in clinical remission at the time of testing. The Iacono group may therefore be justified in interpreting their findings as evidence that reduced electrodermal arousal is a trait characteristic of those individuals with a history of (endogenous) depressive disorder. 30. c A few researchers have f a i l e d to observe significant differences in EDA between depressives and normals or have obtained mixed results. Giedke, Bolz, and Heimann (1980) compared phasic conductance i n primary depressives and normal controls as the subjects were presented with auditory stimuli to which they were, or were not, instructed to respond. No differences among groups were found i n the non-response and rest conditions. In the response condition, however, the controls did increase the number and amplitude of their phasic responses significantly more than the depressives, which suggests that lower levels of EDA were shown by the depressives i n a situation which required an active response. Toone, Cooke, and Lader (1981) f a i l e d to note any differences i n phasic or tonic conductance between depressives and normal controls while the subjects rested or were presented with flashes of l i g h t . However, these workers did not specify how their depressives were classified or divided. This i s unfortunate, because the classification procedure may well have influenced their results. In summary, the evidence that has been discussed here suggests that reduced levels of phasic and tonic skin conductance are f a i r l y reliable correlates of endogenous depression, with a majority of studies showing that this reduction remains despite c l i n i c a l remission. In contrast, i t appears that the DST can be used to identify positively about 50 percent of endogenous depressives 31. (when careful diagnostic screening and optimal criteria and methodology are employed), but that its discriminative ability is restricted to periods of depression. The strength of the DST lies in i ts diagnostic specificity, which is well over 90 percent. Reports concerning EDA in depressives have generally been difficult to analyze carefully due to a frequent failure to report individual electrodermal levels, but Iacono et a l . (1983) indicated that over 90 percent of the unipolar depressives they sampled had conductance levels under 6 micromhos, while 50 percent of normals had similar levels. This implies, however, that the specificity of reduced EDA for depression is only moderate. Certainly, i f a clinician were to employ only electrodermal analysis to diagnose endogenous depressives, he or she would commit an unsatisfactory number of Type II errors. (The converse would hold were the clinician to employ only the DST.) It is possible, however, that a combination of DST and EDA analysis may be of clinical u t i l i t y . Although i t was noted above that psychotropic medication generally has no demonstrable effect upon DST results, nothing has yet been said regarding drug effects upon EDA. In recent years, a majority of investigators have attempted to control for drug effects by keeping patients drug-free for a period of time (usually about 10 days) prior to electrodermal recording (e.g. Mirkin & 32. Goppen, 1980} Noble & Lader, 1972). A few researchers (Giedke et a l . , 1980; Iacono et a l . , 1983) have attempted to compare directly medicated and unmedicated patients. Of 11 studies in which drug effects were controlled, the results of 9 s t i l l indicated that depressives—particularly endogenous depressives—have reduced EDA. The remaining investigators (Goldstein, 1964; Toone et a l . , 1981) reported no significant differences in skin conductance between depressives and normals, but these researchers examined what appeared to be heterogeneous groups of depressives, and a failure to find electrodermal differences may be attributable to this factor. It therefore seems reasonable to assume with some confidence that the differences in EDA between depressives and normals are not related to medication effects. Notwithstanding, in the present study a l l patients had their medication status assessed at the time of testing, and several of the patients were drug-free when tested. Some discussion about the physiological mechanism or mechanisms which may underlie abnormal DST and EDA results is now warranted. In this regard, there appear to be three possibilities: 1. Both DST and EDA abnormalities are mediated by dysfunction in the same anatomical/phyBiological area(s) of the brain. 2. DST and EDA abnormalities reflect dysfunction in distinct anatomical/physiological areas of the brain. 33. 3. DST and EDA abnormalities reflect dysfunction in the same area of the brain, but are mediated by distinct neural mechanisms and/or neurotransmitters. Greenfield and Sternbach (1972) note that although both the sympathetic and parasympathetic divisions of the autonomic nervous system have in the past been postulated as mediators of EDA, i t is now generally believed that control is actually sympathetic. Although sympathetic activity is controlled by posterior regions of the hypothalamus, stimulation of the tuber cinereum and of the lateral portions of the hypothalamus elicits EDA. Other regions of the brain are also Involved in the mediation of skin conductance. Independent systems which are implicated in the initiation and control of EDA are the premotor cortex and the anterior limbic cortex, for example. In regard to the premotor cortex, the descending pathway from this area passes through the pyramidal tract and by-passes the hypothalamus. Stimulation of this area of the cortex reportedly elicits phasic EDA even after ablation of the hypothalamus (Greenfield & Sternbach, 1972). In short, the inhibitory and facilitating control of EDA appears to be quite complex, and probably involves the frontal cortex, the premotor corticospinal system, the limbic-hypothalamic system, the basal ganglia, pathways in the lateral mesencephalic reticular formation, sensorimotor areas to the spinal sympathetic neurons, and presently 34. unidentified interconnections with other centers. Facilitating components of the electrodermal system include the limbic and infralimbic cortex and the lateral mesencephalic reticular formation, while inhibitory regions include the frontal cortex, the caudate nucleus, the roof nuclei of the cerebellum, and the hippocampus. In contrast, mediation of adrenocortical activity is relatively straightforward. The role of the hypothalamus as a controlling center for anterior pituitary and—via release of adrenocortlcotrophlc hormone (ACTH)—adrenal activity is now well-established (e.g. Keeton, 1972). Although the hypothalamus can exert a facilitating effect upon the anterior pituitary, certain neurons in the hypothalamus also appear to have an inhibitory effect upon pituitary, and thus adrenal, activity. Sachar et a l . (1973) for example, cite evidence which suggests that a noradrenergic neural system in the central nervous system normally inhibits ACTH secretion, and also that serotonin implants in the ventromedial nucleus of the hypothalamus similarly inhibit ACTH secretion. Destruction of serotonergic neurons in this area activates ACTH secretion. It i s therefore possible that abnormalities in adrenocortical output such as those manifested by some depressives reflect either deficient levels of neurotransmitters in the hypothalamic area and/or other hypothalamic dysfunction. This possibility is indirectly supported by evidence which suggests that the hypothalamus is involved in 35. depressive symptomatology. This evidence includes research which indicates that specific hypothalamic lesions are associated with mood disturbance, that hypothalamic stimulation can induce an intense affective state, that the hypothalamus is involved in the regulation of appetite and sexual and autonomic activity (all frequently disturbed in depressives), and that the hypothalamus is part of the link between the cerebral cortex and the neuroendocrine system (Kraines, 1966; Mendels, 1974). There is increasing evidence that a dominance of central cholinergic activity may be implicated in both depressive symptomatology and in the hypersecretion of the HPA system which is characteristic of about one-half of endogenous depressives. Risch (1982) reviewed evidence which suggests that cholinergic mechanisms may be significantly implicated in HPA hyperactivity. On the basis of the research of workers such as Janowsky, El-Yousef, Davis, and Sekerke (1972); Risch, Cohen, Janowsky, Kalin, and Murphy (1980); and Sitaram, Nurnberger, Gershon, and Gillin (1982), evidence has been accrued which indicates that: 1. Cholinomimetics tend to counteract mania and provoke depressive symptomatology in individuals with a history of affective illness. 2. The tricyclic antidepressants, which have anticholinergic properties, often alleviate depression. 36. 3. Physostigmine, a cholinomimetic, produces significant elevations in plasma Cortisol as well as mood changes related to depression, confusion, and hostility. 4. Reserpine, also a cholinomimetic, counteracts mania and may cause depression. Janowsky et a l . (1972) have further proposed that depression involves cholinergic dominance, whereas mania involves adrenergic dominance. This is of interest in light of the (Sachar et al. , 1973) evidence which suggests that central noradrenergic and serotonergic systems may inhibit ACTH secretion. It is quite conceivable that cholinergic dominance and noradrenergic and serotonergic inhibition are working in unison to increase HPA activity and, as a consequence, secretion of Cortisol. Acetylcholine is also involved in the peripheral nervous system in the mediation of skin conductance, but in the central nervous system many pathways and neurotransmitters appear to be implicated in electrodermal control. The hypothalamus alone is innervated by noradrenergic, dopaminergic, serotonergic, and cholinergic pathways. It is therefore possible that the reduction in EDA characteristic of many depressives reflects hyperactivity of those neurotransmitters, receptors, pathways, and/or centers which are inhibitory for EDA (for example, the hippocampus) and/or hypoactivity of those variables 37. which f a c i l i t a t e EDA (such as the hypothalamus). In this regard i t i s of interest to note that one of the best-documented cholinergic pathways i s the septohippocampal one which connects the septum with the hippocampus. Cotman and McCaugh (1980) observed that septal lesions have been found to result i n at least partial loss of cholinergic properties i n the hippocampus, amygdala, hypothalamus, and midbrain. Is i t possible that cholinergic hyperactivity of the septal region results i n both HPA hyperactivity and electrodermal reduction? Since the hippocampus i s inhibitory for EDA, and cholinergic excitation of the hypothalamus appears to be Involved in Cortisol hypersecretion, this would seem to be a plausible hypothesis. If this were true, however, why would cholinergic excitation of the hypothalamus—an area which f a c i l i t a t e s EDA—not counteract the inhibitory effects of (for example) hippocampal excitation? The answer to this question may be that cholinergic dominance i s not confined to the hippocampus and hypothalamus, but also extends to other brain regions which are inhibitory for EDA. The frontal cortex i s such a region, for instance, and this area i s known to contain cholinergic neurons. Overall, the net effect may be inhibitory for EDA. An alternative hypothesis i s that f a c i l i t a t i o n of EDA by the hypothalamus i s governed by noradrenergic and/or serotonergic neurons. In this case cholinergic dominance, and serotonergic and 38. noradrenergic inhibition, would also produce depressive symptomatology and both HPA and electrodermal abnormalities. Indeed, the question as to why the evidence suggests that DST abnormality is a state characteristic, and atypical EDA a trait characteristic, of certain depressives may be better addressed from the perspective of this hypothesis. It may be the case that cholinergic activity normalizes during remission of the depression or as a result of administration of anticholinergics such as tricyclic antidepressants, but that inhibition of noradrenergic and/or serotonergic activity remains. Reduced skin conductance brought about by noradrenergic/serotonergic deficiencies in the hypothalamus would therefore appear as a chronic feature in many depressives. The implicit uncertainty of the above hypotheses makes a combined examination of the DST and EDA particularly interesting. By studying EDA and the DST together i t should be possible to investigate whether electrodermal and Cortisol abnormalities reflect common or distinct neurophysiological mechanisms. (That i s , a strong positive relationship between atypical DST and EDA results would suggest that only one particular brain region or neurotransmitter is dysfunctional. A lack of relationship, or a negative relationship between the two would suggest that either more than one brain region/neurotransmitter is implicated or that 39. different axeas/neurotransmitters in a given region of the brain are affected. The present study therefore provides an opportunity to investigate the neurophyslological basis of DST and electrodermal abnormalities, and thereby provide some insight into the physiology of depression itself. It also makes possible an evaluation of the utility of EDA as a diagnostic tool. Specifically, the following questions can be addressed: 1. Are those individuals who are positive (i.e. nonsuppressors) on the DST also more likely to generate atypical EDA? 2. What are the physiological bases for DST and electrodermal abnormalities? 3. With regard to the approximately 50 percent of endogenous depressives who suppress normally on the DST, does the presence of normal or abnormal EDA in these individuals suggest that EDA would be useful as a diagnostic tool? Furthermore, what are the ramifications of these findings upon the physiological hypotheses discussed above? 4. Given the fact that there have been no direct psychophysiological investigations of the DST and DST suppressors and nonsuppressors, what psychophysiological correlates, i f any, are associated with positive and negative DST results? 40. Method Subjects Thirty-six depressed patients (22 outpatients and 14 inpatients) at Shaughnessy Hospital i n Vancouver were tested. Twenty-five of these patients met the RDC for endogenous depression and the DSM-III c r i t e r i a for major depression with melancholia. An additional eight patients were classified as "probable endogenous" depressives. Only three patients were rated as definitely nonendogenous. Eleven of the depressives were abnormal (positive) and 22 were normal (negative) on the DST. (Three patients had incomplete DST results.) The depressed group was comprised of both unipolar (2?) and bipolar (9) patients — t h a t i s , those who had not, and those who had, respectively, experienced a lifetime episode of mania. Twelve of the patients were receiving antidepressant medication and/or lithium when tested and 24 patients were drug-free for a minimum period of seven days. Eleven of the unmedicated subjects had never received medication for their depression. Three other unmedicated subjects were drug-free for a period of over six months, two others had been unmedicated for between one and six months, two subjects were drug-free for a period of between one and four weeks, and six other subjects were drug-free for a period of seven days prior to testing. The characteristics of the medicated patients are shown i n Table 1. A l l of these individuals had been medicated for a period of more than one year when they participated i n the present study. 41. Table 1 Drug Intake of Medicated Patients Antidepressant Patient Medication Other Medication Duration of Medication (Yrs) 2 3 4 5 6 7 8 9 10 11 12 Lorazepam Doxepin HC1 Phenelzine Sulphate Imipramine Nortriptyline HC1 Doxepin HG1 Phenelzine Sulphate Amitriptyline HC1 Amitriptyline HC1 Maprotiline HC1 Tranylcypromine Sulphate Haloperidol Lithium Carbonate Thioridazine Chloral Hydrate Diazepam Lithium Carbonate Oxazepam Oxazepam Lithium Carbonate Lithium Carbonate Oxazepam Na Amytal 1 5 2 2 . 5 5 1.5 2 3 5*-5 10+ aThe medications specified were not necessarily taken for this period of time. Duration represents the approximate period during which the patient received any psychotropic medication on a continuous basis immediately prior to electrodermal testing. 42. Twenty-three of the patients had no signs or symptoms of psychomotor agitation or retardation, whereas eleven other patients were classified as being psychomotor retarded. Two additional patients met the RDC for psychomotor agitation. The mean age of the 11 male depressives was 43.82 years, with a standard deviation of 11.68 years. The mean age of the 25 female depressives was 37.80 years, with a standard deviation of 12.31 years. Fifteen normal control subjects were also tested. These individuals were recruited at either an Open House at the University of British Columbia or at a local office of the Unemployment Insurance Commission and were paid for their participation in the study. They were screened to eliminate those individuals with a history of psychiatric or serious physical disorder in either themselves or their first-degree relatives and were matched to the depressives on the basis of age and sex. The mean age of the five male and ten female controls was 41.20 years and 37.60 years, respectively. Standard deviations were 11.65 and 11.14 years, respectively. A l l subjects were residents of the Greater Vancouver area. The characteristics of the participants are summarized in Tables 2 to 4. Dexamethasone Suppression Test Nonsuppression on the DST was defined as being a plasma Cortisol level greater than, or equal to, 5 ug/dL when blood was sampled at 4 :00 p.m. on the day following oral ingestion of 1 mg of dex. (Dex 4 3 . Table 2 C h a r a c t e r i s t i c s o f Subjects Number o f Subjects Diagnosis Female Male Age Scores on C l i n i c a l Scales Hamilton Beck Unipolar 20 7 M 37.40 SD 12.52 19.65 7.00 2 2 . 2 7 9-83 B ipo la r M 46.22 SD 10.11 13-86 10.51 22.78 14.18 Normal 10 M 38.80 SD 11.84 6.80 5.80 Note. Hamilton = Hamilton Rat ing Scale f o r Depress ion. Beck = Beck Depression Inventory. The lowest score pos s ib le on the vers ions o f the Hamilton and Beck used i n t h i s study was ze ro . The h ighest scores pos s ib le on the vers ions o f the Hamilton and Beck used i n t h i s study were 61 and 63, r e s p e c t i v e l y . 44. Table 3 Clinical Characteristics of Depressed Subjects Number With Clinical Psychomotor Diagnosis Sex N Prior Episodes Status Status Male 7 7 5 H I 2 Ret 2 Sym 5 Non Unipolar Female 20 16 7 111 1 Ag 5 Sym 5 Ret 8 Rem 14 Non Male 4 4 3 H I 3 Ret 1 Rem 1 Non Bipolar Female 5 5 3 H I 1 Ag 2 Rem 1 Ret 3 Non a I l l = Clinically depressed (Beck greater than, or equal to, 21). Sym = Symptomatic (Beck greater than, or equal to, 13 and less than 21). Rem = Remitted (Beck less than 13). bAg = Agitated Ret = Retarded Non = Non-retarded and non-agitated. Table k Dexamethasone Suppression Test Status of Depressed Patients DST DST ct Sex Diagnosis Normal Abnormal Unipolar 2 4 Male Bipolar k 0 Unipolar 13 Female Bipolar 3 aA post-dexamethasone Cortisol level of less than 5 ug/dL was considered to be normal suppression. 46. was ingested at 11:00 p.m. on the f i r s t day of the test.) To ensure that DST results were not influenced by extraneous factors, these exclusionary c r i t e r i a — f i r s t proposed by Carroll et a l . (1981)—were employed to screen depressed patients: 1. Major physical i l l n e s s such as trauma, fever, dehydration, or nausea. 2. Pregnancy or high-dose estrogen intake. 3. Cushing's Syndrome or other endocrine disease, Addison's disease, hypopituitarism, or corticosteroid therapy. 4. Severe weight loss (less than 80 percent of ideal weight). 5. Hepatic enzyme induction (phenytoin, sodium, barbiturates, or meprobamate). 6. Uncontrolled diabetes mellitus. 7. Temporal lobe epilepsy. 8. Acute withdrawal from alcohol. 9. High-dose benzodiazepines (more than 25 mg per day of diazepam) or cyproheptadine hydrochloride. Laboratory estimates of Cortisol levels utilized the radioimmune assay method. This technique has an assay sensitivity of approximately 0.5 ug/dL. Electrodermal Measurement Electrodermal recording employed the direct measurement techniques standardized by Lykken and Venables (1971). In the depressives, 4 ? . electrodermal testing was conducted as close in time as possible to administration of the DST. (Control subjects did not take the DST.) Approximately 64 percent of the depressives were tested electrodermally within 24 hours of undergoing the DST. An additional 3 0 percent of the patients were tested electrodermally within one week of taking the DST. The remaining 6 percent of the patients (two DST negative subjects) had previously undergone the DST as a routine part of their treatment. These individuals had received the DST several months prior to electrodermal testing. Electrodermal activity was recorded bilaterally from 1-cm Beckman biopotential silver-silver chloride electrodes adhered to 1-cm electrode collars that had a contact diameter of 0 . 8 cm. The collars and the electrodes were mounted on the medial phalanges of the f i r s t and second fingers of each hand. Skin conductance was recorded on a 4-channel Beckman R . 6 1 2 polygraph using two type 9 8 4 4 skin conductance couplers. Maximum sensitivity was 0 . 5 micromhos per cm. Stimuli Skin conductance was monitored while subjects were exposed to two series of tones. These series differed with respect to the amplitude of the tones and with respect to the instructions that were given immediately prior to each series. In the f i r s t series, 1 0 , 85-decibel (dB), 1 , 0 0 0 - H e r t z (Hz) tones were presented pseudo-randomly to the subject, with an average interval between tones of 3 0 seconds 48. (range: 20 to 40 seconds). The penultimate tone in the f i r s t series was a dishabituating stimulus. It had the same characteristics as the other tones but contained a 0.1-second gap in the middle of the tone. The second series of stimuli was comprised of 12, 105-dB, 1,000-Hz tones that varied as to whether or not they contained a 0.1-second gap in the middle of the tone. The f i r s t , fourth, fi f t h , seventh, eighth, and eleventh tones did not contain such a gap, whereas the remainder had a gap. These tones were again presented on a pseudo-random basis, with an average interval between tones of 30 seconds (range: 20 to 40 seconds). A l l tones were of 1-second duration, had a rise/fall time of 0.04 seconds, and were presented against a 50-dB white noise background. Tones were generated by a Goulbourn Instruments Precision Signal Generator type S81-06 that was triggered by signals recorded on Maxell UDXL-II tape and played on a Realistic SCT-24 stereo cassette deck. Instructions were also pre-recorded on the tape. Instructions and tones were presented binaurally to the subject by means of Koss Pro-4 stereo headphones. The headphones had been calibrated using a Bruel and Kjaer Precision Sound Level Meter 2203 with a 1560-P83 earphone coupler. Calibration was made in terms of voltages that were a l l measured with a digital voltmeter to a 1,000-Hz continuous tone. Two readings were taken from the left and right earpieces during calibration; these readings were then averaged. (Using the mean value, accuracy should be within • 0.5 dB.) 49. Electrodermal Measures To be counted as such, a l l skin conductance responses had to have a minimum amplitude of 0.05 micromhos. Phasic responses to tones were defined as those occurring between 1 and 3 seconds of stimulus onset. Tonic skin conductance readings were taken immediately prior to each tone. Procedure A l l subjects were tested between May and December, 1983• Control subjects were tested i n the same time period as the depressives, on an ongoing basis. Depressed subjects were interviewed and rated on the Hamilton Rating Scale for Depression (Hamilton, I960 [see Appendix A.01]) by R. Remick, M.D., Director of the Affective Disorders Clinic at Shaughnessy Hospital. Dr. Remick then referred the patient to the laboratory for the DST and to the author for electrodermal testing. Such testing occurred within 1 to 5 days (usually within 3 days) of psychiatric interview and rating on the Hamilton. Skin conductance was recorded i n i t i a l l y (May to July) i n a room on the psychiatric ward and subsequently (July to December) in a room near the Psychiatric Outpatient Department at Shaughnessy Hospital. Subjects were seated i n a comfortable recliner chair (maintained i n an upright position) with their backs to the experimenter and the equipment, facing a blank wall. The recording apparatus was calibrated prior to testing each subject. Subjects were shown the 50. equipment and informed that they would have their bodily responses recorded while they relaxed and listened to tones and while they pressed a switch i n response to some of the tones. Subjects then signed a consent form that repeated this information (Appendix A.02) and completed the Beck Depression Inventory (Beck, 1972; Beck, Ward, Mendelson, Mock, & Erbaugh, 1961 [Appendix A.03]). Depressed subjects were then interviewed briefly by the experimenter to identify the presence of vegetative signs indicative of endogenous depression and to note features of psychomotor agitation or retardation (see Appendix A.04 for the c r i t e r i a employed i n this regard). Skin conductance electrodes were then attached i n the following manner: Each electrode was affixed by f i r s t attaching an adhesive electrode collar to the subject's finger. A second collar was affixed to the electrode, that was then f i l l e d with a Unibase/physiological saline electrode paste prepared following the instructions outlined i n Fowles et a l . (1981). Finally, the collar with electrode attached was affixed firmly to the coll a r already on the finger. Approximately 10 minutes was allowed to elapse between the time the skin conductance electrodes were attached and the time electrodermal recording began. Prior to the f i r s t series of instructions and tones the subject was requested to cough three times and then to hold his/her breath for a period of 15 seconds. The purpose of this was to activate f u l l y 51. the sweat glands before presentation of the stimuli. As noted above, the instructions that were given to the subject were of two types. The instructions given prior to the f i r s t series of tones were designed to minimize responsiveness, and included directions to focus attention upon becoming relaxed and ignoring the tones (Appendix B.Ol). Conversely, the instructions given immediately before the second set of tones were designed to maximize responsiveness. These directions emphasized the need to pay careful attention to the stimuli and to respond to some of the tones (the ones in which there was a gap) by pressing a pedal located in front of the subject's right foot (Appendix B.02). The rationale behind these different instructions can be found in Iacono and Lykken (1979). Basically, i t was postulated that the f i r s t set of instructions would minimize differences between normals and depressives whereas the second set of instructions would maximize such differences. The instructions and tones for the second series followed immediately the conclusion of the f i r s t series of tones. The entire sequence (the f i r s t set of instructions; the 85-dB tones; the second set of instructions; the 105-dB tones) lasted approximately 17 minutes. 5 2 . Results Of primary interest when the following analyses were conducted were comparisons between: (a) DST normal and DST abnormal groups; (b) unipolar, bipolar, and control groups; and (c) psychomotor groups. To understand these comparisons i t was necessary f i r s t to determine the effects of medication upon electrodermal ac t i v i t y . The approach that was then taken was to seek overall differences between groups on the basis of factors such as tonic skin conductance and phasic responsiveness to tones. In this regard, univariate analyses of variance with a conservative test of significance were usually employed (see below). After such investigation, particularly when results differed markedly from those of prior research, more detailed analyses—such as an examination of phasic responsiveness i n each hand for specific tones—were performed. I n i t i a l l y , to investigate the equality of depressed and control group variances, Bartlett's test for homogeneity of variance was performed on the skin conductance data. No significant differences among groups were detected for phasic or tonic skin conductance, F(2,3i43) = 1.98, £ > . 0 5 and F(2, 31^3) < 1, £ > . 0 5 , respectively. The following analyses are therefore mostly parametric i n nature. To correct for correlated repeated measures effects i n repeated measures designs, however, the sphericity test reported i n Anderson (1958) was u t i l i z e d . This was followed, when appropriate (i.e. when 53. the sphericity test was significant, indicating that the orthogonal polynomials for the within factor were not independent with equal variances), by the Greenhouse-Geiser (1959) correction. This correction factor, called can range from 1 to l / ( q - l ) , where q i s the number of levels of the repeated measures factor. It w i l l be equal to 1 i f there exists homogeneity of variances for the within factor. Winer((l9?l) notes that the Greenhouse-Geiser procedure ca l l s for using the c r i t i c a l values F. ([q-l]£, p[n-l][q-i]£) and F, _/[p-l][q-l]£, p[n-l][q-i]£), where p i s the number of levels of l — the between factor, to conduct tests on the within-subject effects when i t i s necessary to correct for correlated repeated measures effects. Medication Effects To determine whether the anticholinergic effects of antidepressant medications affected electrodermal activity, two preliminary 2(unipolar/bipolar) X 2(medication status) analyses of variance were performed. These analyses revealed that there were no significant differences between medicated and unmedicated depressives i n mean skin conductance level (defined as the average of the tonic skin conductance levels immediately preceding each tone), F ( l , 32) = 3*17. £ > .05, or i n amplitude of phasic response to the f i r s t 105-dB tone, 1 32) < 1, £ "> .05. An analysis of variance also revealed no differences i n mean skin conductance level or i n mean phasic responsiveness to tones (defined as the average of the phasic responses to a l l tones) between depressives who had never received 54. antidepressant medication, depressives who had been medicated i n the past but were drug-free when tested, and depressives who were medicated when tested, P(2, 33) = i . ? 3 , £ > .05 and F(2, 33) = i.11, _ > .05, respectively. Finally, a chi-square test detected no significant relationship between medication status and positive or negative DST response,% 2(l, N = 33) < 1. £ > .05. In l i g h t of these results, for subsequent analyses medication status was collapsed across groups. Tonic Skin Conductance Levels Analyses of variance with repeated measures for hands and t r i a l s were conducted on the tonic skin conductance data. These analyses were performed to determine whether significant differences existed between groups i n skin conductance level over t r i a l s ( i . e . over tones), to determine whether there were differences among groups i n skin conductance level i n each hand, and to determine whether there were any significant interactions between these variables. As noted above, for analyses with repeated measures the epsilon-correction procedure of Greenhouse and Geiser (1959) was employed to correct for correlated repeated measures effects. The unadjusted degrees of freedom are presented together with the value of £ and the corrected 2 value. A 2(sex) X 2(DST) X 2(hands) X lO(trials) analysis of variance with repeated measures on the la s t two factors was performed for tonic 55. skin conductance level ( i . e . the skin conductance level immediately prior to each tone) during presentation of the 85-dB tone series. A significant t r i a l s effect and a significant hands X t r i a l s interaction were observed, F(9, 2 6 l ) = 16.35. £ = .15. £ < -0001 and F(9, 261) = 3«17. £ = .25. £ < .05. respectively. These results indicate that tonic skin conductance level declined significantly over the course of the 85-dB t r i a l s and that this drop i n tonic level over t r i a l s was greater for the right than for the l e f t hand. However, no significant differences due to sex, DST status, or hands were noted, F ( l , 29) = 1.37, £ > .05. _ ( l , 29) < 1, £ > .05, a n d F ( l , 29) < 1, £ . 0 5 , respectively. There were also no other significant interactions between variables. To determine i f the different instructions, amplitude, and task demands associated with the loud tones affected tonic levels, a 2(sex) X 2(DST) X 2(hands) X 12(trials) analysis of variance was performed for tonic conductance levels during presentation of the 105-dB tone series. A significant t r i a l s effect was again observed, F ( l l , 319) = 7.52, £ = .32, £ < .0001. This indicated that tonic skin conductance level declined significantly during the 105-dB series. However, the analysis revealed no significant differences due to sex, DST status, or hand, F ( l , 29) < 1, £ > .05, F ( l , 29) < 1, £ > .05, and F ( i , 29) < 1, £ > .05, respectively. There were also no significant interactions between variables. 5 6 . Results similar to the above were obtained i n two, sex X diagnostic group (i.e. unipolar, bipolar, and control) analyses of variance. These analyses were designed to investigate the tonic conductance differences between diagnostic groups and between a l l male and female subjects over t r i a l s and between hands. A 2(sex) X 3(group) X 2(hands) X lO(trials) analysis of variance was performed on tonic skin conductance levels during the 8 5-dB series and an analogous 2(sex) X 3(group) X 2(hands) X 1 2 ( t r i a l s ) analysis of variance was conducted on tonic levels during the 1 0 5 - d B series. In the former analysis, a significant t r i a l s effect, F ( 9 t 4 0 5 ) = 1 7 . 1 2 , £ = . 1 5 , £ < . 0 0 0 1 , and a significant hands X t r i a l s interaction, F ( 9 , 4 0 5 ) = 3 . 2 0 , £ = . 3 0 , £ < . 0 0 1 , were detected. These significant effects indicated, as did the preceding parallel set of analyses in which DST outcome was substituted for diagnosis, that the tonic skin conductance level showed a significant decline during the course of the 8 5-dB tone series and also that the right hand measures declined at a faster rate than those of the l e f t hand. The diagnostic, sex, and hands effects were nonsignificant, F ( 2 , 4 5 ) < 1 , £ > - 0 5 , F ( l , 4 5 ) < 1 , £ > . 0 5 , and F ( l , 4 5 ) = 1 . 4 9 , £ > . 0 5 , respectively. Also, no other interactions were significant. In the analysis of variance performed on tonic levels during the 1 0 5 - d B series the t r i a l s effect was significant, confirming once again that tonic skin conductance levels declined over the 1 0 5 - d B series, F ( l l , 4 9 5 ) = 1 1 . 9 2 , £ = . 3 2 , £ < . 0 0 0 1 . However, the group, sex, and hands effects were not significant. In order, the s t a t i s t i c s 57. associated with these variables were F(2, 45) < 1, _ > .05, F ( l , 45) < i , 2 > '°5. and F ( l , 45) = 1.37, £ > .05. No interactions reached significance. In summary, the above results indicated that, in regard to tonic skin conductance levels: 1. There was no difference between male and female depressives or between male and female subjects overall. 2. There was no difference between DST normal and DST abnormal depressives. 3. There was no difference between unipolar, bipolar, and control groups. 4. There were significant declines (in tonic conductance) over both the 85-dB and the 105-dB tone series. 5. For the 85-dB series, the right and l e f t hands had different rates of tonic skin conductance decline. The right hand conductance declined at a faster rate than that of the l e f t hand. It w i l l be recalled that an investigation of electrodermal differences between DST normal and DST abnormal depressives i s of particular interest i n the present study. The absence of significant differences between these groups i n tonic conductance i s therefore noteworthy. Also of considerable interest i s the finding that there were no differences between depressed and control groups i n their tonic skin conductance. These issues are discussed at length below. 58. Phasic Skin Conductance Response to Tones Phasic responses to tones were defined as those occurring between i and 3 seconds of stimulus onset. Descriptive s t a t i s t i c s based on phasic response amplitudes revealed a number of interesting trends that were then investigated i n further s t a t i s t i c a l analyses. One such trend i s depicted i n Figures 1 and 2. The groups under inspection i n these figures are the DST normal, DST abnormal, and control groups. Figure i displays for each group mean phasic response amplitudes i n the right hand and Figure 2 displays the corresponding amplitudes i n the l e f t hand. It was apparent from the descriptive s t a t i s t i c s that there existed a trend such that the DST abnormal group had lower average responses to tones than did the DST normal group. The DST normal group's responses were i n turn somewhat lower than those of the control group. This trend was particularly evident for the right hand. Separate 2(sex) X 2(DST) X 2(hands) X iO(trials) and 2(sex) X 2(DST) X 2(hands) X 12(trials) analyses of variance with repeated measures on the last two factors were therefore performed on phasic responses to tones during the 85-dB and the 105-dB tone series, respectively. The purpose of these analyses was to evaluate the hypothesis of differential electrodermal responsiveness i n the DST groups. Specifically, i t was possible to determine whether (male and female depressive; DST normal and DST abnormal) groups differed significantly i n the amplitude of their phasic responses over t r i a l s , 1.1 Figure 1. Mean amplitude of phasic skin conductance response from the right hand of DST normal, DST abnormal, and control groups. O X % a H 1.H 1.0 .9-.8-.7-.6-.5-.4 .3-.2-.1 Control DST Normal DST Abnormal TRIALS ~6 7 § 5" 105 dB lb II 12 Figure 2 . Mean amplitude of phasic skin conductance response from the l e f t hand of DST normal, DST abnormal, and control groups. 61. to determine whether there were any differences between hands over t r i a l s , and to determine whether there were any significant interactions between variables. A significant t r i a l s effect was / found for both the 85-dB and the 105-dB tone series, F ( 9 , 2 6 1 ) = 4.14, £ = .16, £ < . 0 0 0 1 and F ( l l , 3 1 9 ) = 9 . 7 2 , £ = . 2 9 , £ < . 0 0 0 1 , respectively. These results indicated that there was a significant decline i n amplitude of phasic responsiveness as both tone series progressed. However, no sex or DST effects were significant. For the 85-dB series, the sex and DST s t a t i s t i c s were both F ( l , 2 9 ) < 1 , £ > . 0 5 * For the 105-dB series, the corresponding sex and DST st a t i s t i c s were F ( l , 2 9 ) = 2 . 4 9 , £ > . 0 5 and F ( l , 2 9 ) < 1 , £ > . 0 5 , respectively. Thus, no differences between DST groups were found i n overall phasic responsiveness to tones. Attention was therefore focused next upon a comparison of diagnostic (unipolar, bipolar, and control) groups. Figures 3 and 4 depict the mean phasic response amplitudes of the right and l e f t hands, respectively, for the unipolar, bipolar, and control groups. A trend was again apparent for both hands. In this case the bipolar group had lower amplitude responsiveness than the unipolar and control groups (there appeared to be l i t t l e or no difference between the latt e r groups). Separate 2(sex) X 3(diagnostic groups) X 2(hands) X 1 0 ( t r i a l s ) and 2(sex) X 3(<liagnostic groups) X 2(hands) X 1 2 ( t r i a l s ) analyses of variance were conducted for phasic responses during the 85-dB and the 105-dB series, respectively, to 1.1 O a i.oH .9-.8-.7-.6-.5-.4-.3-.2-.1-3 4 5 6 7 8 9 1C - Control • Unipolar • Bipolar 85 dB 0 1 TRIALS ~T~ 3 5 » 7. 105 dB -r -8 9 10 l'l IT Figure 3» Mean amplitude of phasic skin conductance response from the right hand of unipolar, bipolar, and control groups. 1.1 1.<H .9 .8-.7-.6 .5-.4 .3 .2 .1 .0 A Control • Unipolar • Bipolar — i 1 1— 10 11 12 85 dB TRIALS 105 dB Figure 4. Mean amplitude of phasic skin conductance response from the l e f t hand of unipolar, bipolar, and control groups. 64. determine what differences or interactions, i f any, existed between groups and hands over t r i a l s . Once again, as the similar analysis based on DST grouping showed, a significant t r i a l s effect for both series of tones indicated that phasic responsiveness declined significantly as the 8 5-dB and 1 0 5 - d B series progressed, F ( 9 » 4 0 5 ) = 8 . 1 0 , £ = .18, 2 < - 0 0 0 1 and F ( l l , 4 9 5 ) = 1 4 . 8 2 , £ = . 3 0 , £ < . 0 0 0 1 , respectively. No significant differences were detected for sex, diagnosis, or hand for either the 8 5-dB or the 1 0 5 - d B tone series, however. In order, the s t a t i s t i c s for these variables were F ( l , 4 5 ) < 1 , £ > . 0 5 and F ( l , 4 5 ) = 2 . 7 3 , £ > . 0 5 ; F ( 2 , 4 5 ) = 1 . 2 0 , £ > . 0 5 and F ( 2 , 4 5 ) < 1 , £ > . 0 5 ; and F ( l , 4 5 ) < 1 , £ > . 0 5 and F ( l , 4 5 ) < 1 , £ > . 0 5 . Furthermore, no interactions reached significance. Figures 1 to 4 indicate that the f i r s t few 1 0 5 - d B tones appeared to best differentiate groups with regard to their phasic responsiveness. The amplitude of phasic response to these tones was therefore used as the dependent variable i n a further series of analyses. Three analyses used the amplitude of phasic response to the f i r s t 1 0 5 - d B tone as the dependent variable. These analyses examined whether the following groups differed i n their response to the f i r s t loud tone: (a) Depressives and normals (one-way analysis of variance); (b) male and female depressives and unipolar and bipolar patients ( 2[sex] X 2[unipolar/bipolar] analysis of variance); and (c) DST normal and DST abnormal patients (one-way analysis of variance). (Analysis [c] was not incorporated into one of the other analyses because of small c e l l size i n the DST abnormal, bipolar group.) However, none of these analyses revealed significant results. In order, the s t a t i s t i c s associated with analyses (a), (b), and (c) were* F ( l , 49) < 1, £ > .05; F ( l , 32) < 1, £ > .05 (sex) and F ( l , 32) = 1.39, £ > -05 (diagnosis); and F ( l , 32) < 1, £ > .05-More specific analyses were designed to test for differences between DST abnormal and control subjects i n phasic responsiveness to the f i r s t 105-dB tone i n each hand separately. (Hands were analyzed separately because the descriptive s t a t i s t i c s indicated that the distinction between groups was more apparent i n the right hand than i n the l e f t hand [see Figures 1 and 2].) No significant differences were observed for the response to the f i r s t loud tone, however. For the right and l e f t hands the relevant s t a t i s t i c s were, in order, F ( l , 24) = 1.34, £ > .05 and F ( l , 24) < 1, £ > .05. No significant effects (except for t r i a l s ) were detected i n a series of analyses of variance designed to investigate phasic responsiveness to the 105-dB tones that required a physical response ("response" tones: those tones for which the subject had to press a foot pedal) and the 105-dB tones that required no response ("nonresponse" tones). Two (one analysis for the response tone series and one analysis for the nonresponse tone series), 2(sex) X 2(DST) X 2(hands) X 6(trials) analyses of variance with repeated measures on the last two factors f a i l e d to detect significant 66. differences on the basis of sex, DST status, or hands. For the response and nonresponse tones the relevant s t a t i s t i c s were, i n order, F ( i , 29) = 2.79, £ > .05 and F ( i , 29) = 1.58, £ > .05; F ( i , 29) < 1, £ > .05 and F ( i , 29) < 1, £ > .05; and F ( l , 29) < 1, £ > .05 and _ ( l , 29) = 1.68, £ > .05. The significant t r i a l s effect for both the response and the nonresponse series confirmed that the amplitude of phasic responsiveness declined over the course of both the response and the nonresponse t r i a l s , F(4, 145) = 12.11, £ = .42, £ < .0001 and F(4, 145) = 10.70, <£ = .40, £ < .0001, respectively. Similar results were obtained i n two, 2(unipolar/bipolar) X 2(hands) X 6(trials) analyses of variance that were performed separately on the response and nonresponse t r i a l s to determine whether diagnostic groups differed i n their phasic responsiveness across response and nonresponse t r i a l s . The t r i a l s effect was again significant for both the response and the nonresponse series, F(5. 170) = 12.92, £ = .41, £ < .0001 and F(5, 170) = 10.95, £ = .41, £ < .0001, respectively. For the response tones neither the group nor the hands effect was significant, F ( l , 34) = 1.84, £ > .05 and F ( i , 34) < 1, £ > .05, respectively. Similarly, the group and hands effects f a i l e d to reach significance i n the nonresponse series, F ( l , 34) = 3.02, £ > .05 and F ( l , 34) = 1.04, £ > .05, respectively. No interactions were significant. To determine whether there were any differences between male and 67. female, and DST normal, DST abnormal, and control subjects in frequency (rather than amplitude) of phasic responsiveness to tones, a 2(sex) X 3(DST and control groups) analysis of variance was performed. This analysis used as dependent variables the number of phasic responses given by subjects to response tones and the number of phasic responses given to nonresponse tones. For both the response and the nonresponse t r i a l s males gave fewer phasic electrodermal responses than females, F ( l , 42) = 4.41, p_ < .05 and F ( i , 42) = 4.07, 2 < .05, respectively. There was no significant difference between diagnostic groups, however, F(2, 42) < i , £ > .05 and F(2, 42) < 1, £ > .05 for the response and nonresponse t r i a l s , respectively. There were no significant interactions. To summarize, a majority of the analyses that u t i l i z e d phasic responses to tones as the dependent variable did not detect significant differences among groups. The results of these analyses may be summarized as follows: 1. No significant difference between male and female depressives or between DST normal and DST abnormal patients i n phasic responsiveness over both the 85-dB and the 105-dB tone series. 2. No significant difference between males and females (overall) or between unipolar, bipolar, and control groups i n phasic responsiveness over the 85-dB and 105-dB tone series. 3. No significant difference between depressives and normals, 68. male and female depressives, or DST normal and DST abnormal patients in amplitude of phasic responsiveness to the f i r s t 105-dB tone. 4. No significant difference between male and female depressives, DST normal and DST abnormal patients, or unipolar and bipolar patients in amplitude of phasic responsiveness to response (i.e. those requiring pedal press) and nonresponse tones when these series were analyzed separately. 5. Males emitted significantly fewer phasic responses to response and nonresponse tones than did females. 6. No significant difference between DST normal, DST abnormal, and control subjects in number of phasic responses given to the response and nonresponse tones. 7 . A l l trials effects for repeated measures designs indicated a significant decline in phasic responsiveness over trials. As with the tonic conductance data, the analyses of phasic electrodermal activity provide no evidence that DST normal and DST abnormal patients differ electrodermally. Moreover, depressives and normals do not appear to be distinguishable on the basis of their phasic conductance. Psychomotor Retardation It was noted in the introductory section of this paper that the psychomotor status of depressives has been of considerable interest in previous electrodermal research. Some workers have attributed 69. their electrodermal results to the presence of psychomotor symptomatology (e.g. Lader & Wing, 1969). In the present study, descriptive statistics based upon the psychomotor activity of the depressed subjects revealed that the psychomotor retarded patients appeared to have reduced levels of skin conductance relative to both psychomotor non-retarded, non-agitated depressives and control subjects. As an example of this, the trend in amplitude of phasic responses to tones in the psychomotor and control groups i s illustrated in Figures 5 and 6. To determine whether depressives who possessed signs and symptoms of psychomotor retardation differed electrodermally from non-retarded, non-agitated depressives, two, 2(psychomotor retarded/psychomotor normal) X 2(hands) X lO(trials) analyses of variance were performed for the 85-dB tone series and two, 2(psychomotor retarded/psychomotor normal) X 2(hands) X 12(trials) analyses of variance were performed for the 105-dB series. These analyses were designed to compare the psychomotor groups on their phasic and tonic electrodermal activity. For phasic activity, only the trials effects were significant for the 85-dB and 105-dB series, F(9, 288) = 8.74, £ = .21, £ < .001 and _ ( 1 1 , 352) = 17.45, £ = .29, £ < .0001, respectively. Neither the group nor the hands effect was significant for either series, F(l, 32) = 1.29, £ > .05 (85-dB groups), F(i, 32) = 1.21, £ > .05 (85-dB hands), F(l, 32) = 1.78, £ > .05 (105-dB groups), and F(l, 32) < 1, £ > .05 (105-dB hands). The retarded group had 1 a Cu 1.1-1.0-.9-.8-.7-.6-.5-A .3 .2 .1-1 • Control • Psychomotor Normal • Psychomotor Retarded - r -2 T 3 85 dB TRIALS 105 dB r r 10 11 12 Figure 5» Mean amplitude of phasic skin conductance response from the right hand of psychomotor normal, psychomotor retarded, and control groups. -N3 o I 3 H CU 1H 1.0 .9-1 • Control • Psychomotor Normal • Psychomotor Retarded i 3 5 105 dB ITT ib i i i i Figure 6. Mean amplitude of phasic skin conductance response from the l e f t hand of psychomotor normal, psychomotor retarded, and control groups. 7 2 . significantly lower levels of tonic conductance for both the 8 5-dB and the 1 0 5 - d B tone series, however, P ( i , 3 2 ) = 5 « 0 6 , £ < . 0 5 and F ( l , 3 2 ) = 4 . 8 7 , £ < . 0 5 , respectively. Moreover, significant t r i a l s effects indicated a decline i n tonic conductance over the course of both the 8 5-dB and the 1 0 5 - d B series of tones, F ( 9 , 2 8 8 ) = 2 4 . 0 5 , £ = . 1 5 . £ < - 0 0 0 1 and F ( l l , 3 5 2 ) = 1 0 . 9 2 , £ = .31, £ < . 0 0 1 , respectively. A significant hands X t r i a l s interaction for the 8 5-dB series showed that the tonic conductance from the l e f t hand declined at a greater rate than that of the right hand, F ( 9 » 288) = 3 . 6 7 , £ = . 2 1 , £ < . 0 5 , but there were no other differences between hands for either the soft or the loud series, F ( l , 3 2 ) < 1 , £ > . 0 5 and F ( l , 3 2 ) < 1 , £ > . 0 5 . There were also no other significant interactions. Tonic conductance levels for the psychomotor and control groups are depicted i n Figures 7 and 8 . For i l l u s t r a t i v e purposes the tonic conductance levels of the diagnostic groups and the DST groups are shown i n Figures 9 to 1 2 . In l i g h t of the significant differences between retarded depressives and non-retarded, non-agitated depressives i n tonic conductance, i t was necessary to ensure that previous results i n the present study (both significant and non-significant) were not attributable to the retardation factor. In this regard a series of chi-square tests was performed. These tests revealed that there were no significant relationships between psychomotor status and sex, DST status, medication status, or diagnosis. In order, the relevant 2.0-1.5-•Q. 1.0-A Control • Psychomotor Normal • Psychomotor Retarded 0.5-T 8 T" 10 85db TRIALS T r 6 7 lOSdb - l 1 r 9 10 11 Figure ?. Mean tonic skin conductance level in the right hand of psychomotor normal, psychomotor retarded, and control groups. 2.0-1.5-1.0-• Control P Psychomotor Normal • Psychomotor Retarded 0.5-T" 10 12 4 85db 9 TRIALS 7 105db 8 Figure 8. Mean tonic skin conductance level in the l e f t hand of psychomotor normal, psychomotor retarded, and control groups. 10 11 cn O X _ _ — _ u z H U Q g _ c/i 3.0-2.5H 2.0 1.5H i.oH 0.5 • Control O Unipolar • Bipolar - i 1 1 i — — I r 2 3 4 5 6 7 T" 9 10 1 2 85db TRIALS 1 1 r 6 7 8 105db Figure 9» Mean tonic skin conductance level i n the right hand of unipolar, bipolar, and control groups. 10 11 12 -o 0\ O X -4 -J Ed u z H U Q 3.(H 2.5H 2.(H 1.5H l.(H 0.5H A Control • Unipolar • Bipolar C/3 Figure 10. 1 — i r 4 5 85db 8 10 1 105db 8 TRIALS Mean tonic skin conductance level in the left hand of unipolar, bipolar, and control groups. ' 10 11 12* ON 2.0-1.5-1.0-0.5-• Control a DST Normal • DST Abnormal H 1 r 3 4 5 85db 10 TRIALS 6 7 105db 10 11 12 Figure 11. Mean tonic skin conductance level in the right hand of DST normal, DST abnormal, and control groups. cn •O X V a s C/3 2.5-2.0-15-1.0-0.5 A Control • DST Normal • DST Abnormal 10 11 12 "l r T 8 " T -10 1 2 3 8 9 85 db TRIALS 105db Figure 12. Mean tonic skin conductance level in the l e f t hand of DST normal, DST abnormal, and control groups. 00 79. statistics were: X2(l, N = 36) = 1.27, £ > . 0 5 , X 2 ( l , N = 33) = 1.71, £ > . 0 5 , X 2 ( i , N = 3 4 ) < 1, £ > .05, andX^l, N = 36) = 1.49, £ > .05. Range-Corrected Analyses The rationale behind range correction can be found in Lykken, Rose, Luther, and Marley (1966). In brief, i t is believed that such correction provides values that reflect more accurately an individual's response to a stimulus by compensating for factors such as the number of sweat glands that are active in the individual and the quality of monitoring of the sweat glands by the electrodes. Phasic responses to the f i r s t and second 105-dB tones were range-corrected by dividing the subject's response to the tone in question by that individual's maximum phasic response. Analysis was performed on the f i r s t two loud tones because the responses to these stimuli appeared to differentiate best the DST and control groups. In this analysis DST abnormal patients were compared with control subjects because descriptive statistics had indicated that the electrodermal separation between these groups was greater than that between DST normals and controls or between DST normals and DST abnormals. It was f e l t that the discovery of a significant (or even substantial) difference between DST abnormal patients and controls would provide justification for additional range-corrected analyses. Range-corrected phasic responses in each hand were analyzed separately because preliminary investigation had indicated that the 80. right hand provided more distinction between groups than did the left hand (see Figures i and 2). However, no differences between DST abnormal patients and control subjects were detected for either the f i r s t or the second 105-dB tone, F(l, 24) < 1, _ > .05 (right) and F(i, 24) = 1.18, £ > .05 (left); and F(l, 24) = 1.00, £ > .05 (right) and F(i, 24)< 1, £ > .05 (left), respectively. Dishabituation Effects It will be recalled that the penultimate tone in the 85-dB series was a dishabituating stimulus that differed from the other 85-dB tones inasmuch as i t contained a 0.1-second gap. As can be seen from Figures 1 to 6, the phasic response to this tone was exaggerated in the control group. To establish whether depressives and controls differed in-their phasic responsiveness to this stimulus, a 3(diagnostic groups) X 2(hands) X 3(trials 8,9,10) analysis of variance was performed. Of particular interest in this analysis was examination of the trials X groups interaction, because a significant interaction would have indicated differential responsiveness of the groups to the dishabituating stimulus. However, this interaction f e l l short of significance, F(4, 96) = 2.38, H = .?8, £ > .05. Habituation Effects For the 105-dB tone series habituation was analyzed in terms of both the number of trials to two, and the number of trials to three, 81. consecutive zero phasic responses. The rationale for this dual definition was to establish as accurately as possible when subjects ceased to respond to stimuli, (in the present study time to two consecutive zero responses may not reflect as precisely overall habituation as does time to three consecutive zero responses. This i s because of the pseudorandom presentation of "response" [ i . e . pedal press required] and "nonresponse" tones. The former tended to e l i c i t somewhat greater phasic responsiveness than the latter.) Two, 2(sex) X 3(DST and control groups) analyses of variance were performed to determine whether male and female, and DST and control, groups differed i n the number of t r i a l s to two, and the number of t r i a l s to three, consecutive zero responses during the 105-dB series. (The 105-dB responses were employed i n these analyses because the louder and more complex 105-dB stimuli differentiated groups better than did the 85-dB series. The rapidity of habituation i n the latt e r series precluded meaningful analysis of group differences.) In the analysis of time to two consecutive zero responses, a significant sex difference indicated that males habituated more quickly than females, F ( l , 42) = 4.47, £ < .05- However, no differences among DST and control groups were detected, F(2, 42)< 1, £ > «05» and there were no significant interactions. When time to three consecutive zero responses was used as the dependent variable, no sex or group differences emerged, F ( l , 42) = 1.91. £ > .05 and F(2, 42) < 1, £ > .05, respectively. There were no significant 82. interactions. Sex Effects To ensure that the presence or absence of significant differences among groups was not a result of differential sex composition of the groups, chi-square tests were performed for both the DST and the diagnostic (unipolar/bipolar) groups. The results of these tests indicated that there was no significant relationship between sex and DST status or sex and unipolar/bipolar diagnosis, X ( l , N = 33) = 0.29, £ > .05 and % 2 ( 1 , N = 36) = 1.09, £ > .05, respectively. C l i n i c a l Status To determine whether severity of depression (as assessed by the score on the Beck Depression Inventory) affected electrodermal activity, an analysis of variance was performed to compare patients who obtained scores below 13 (N = 11), between 13 and 20 (N = 7 ) , or over 21 (N = 18) on the Beck. No differences among these groups were detected on the basis of mean tonic or mean phasic electrodermal activity, F ( l , 35) < 1, £ > .05 for both tonic and phasic a c t i v i t y . Relationships Among Variables The following Pearson correlations were computed: 1. Between score on the Beck and score on the Hamilton. 2. Between score on the Beck and mean tonic conductance (for depressives and controls separately). 83. 3. Between score on the Beck and phasic response to the f i r s t 105-dB tone (for depressives and controls separately). 4. Between score on the Beck and post-dex Cortisol l e v e l . 5. Between mean tonic conductance and post-dex Cortisol l e v e l . 6. Between mean tonic conductance and phasic response to the f i r s t 105-dB tone (for depressives and controls separately). 7. Between mean tonic conductance and score on the Hamilton. The coefficients of correlation are shown i n Table 5« The Beck score was found to be significantly and positively related "to the Hamilton score, r = .50, £ < .01. Mean tonic conductance was related positively to the amplitude of phasic response to the f i r s t 105-dB tone i n both the depressives and the controls, r = .56, £ < .0001 and r = .64, £ < .0001, respectively. However, no significant relationship was found between the Beck score and (a) mean tonic conductance, (b) phasic response to the f i r s t 105-dB tone, or (c) post-dex Cortisol l e v e l . In order, the st a t i s t i c s associated with these variables are: r = .02, £ > .05 (depressives) and r = -.08, £ > .05 (controls); r = .03, £ > .05 (depressives) and r = -.04, £ > .05 (controls); and r = -.26, £ > .05. Similarly, the relationships between mean tonic conductance and (a) post-dex Cortisol l e v e l , and (b) the Hamilton also lacked significance, r = .12, £ > .05 and r = .06, £ > .05, respectively. Finally, a one-way analysis of variance revealed no significant differences among DST normal and DST abnormal groups i n severity of depression Table 5 Correlation Coefficients Between Selected Variables Beck Hamilton 1 s t 105-dB tone Post-dex Cortisol Beck — .50 .03(D) -.26 -.04(C) Mean tonic . 0 2(D) .06 .56(D) . 1 2 conductance - . 0 8 ( c ) . 6 4(C) Note. D = Depressed group. C = Control group. 85. as measured by the Beck and the Hamilton, F ( l , 30) = 1.97. £ > .05 and F ( l , 24) < 1, £ > .05, respectively. 86. Discussion To summarize, the results indicate that there are no significant differences between DST normal, DST abnormal, and control subjects i n tonic or phasic electrodermal a c t i v i t y . Similarly, no significant electrodermal differences between unipolar and bipolar patients and controls were detected. Psychomotor retarded depressives were found to have significantly lower levels of tonic conductance than their non-retarded, non-agitated counterparts. In regard to comparisons between the sexes, males emitted significantly fewer phasic responses from the l e f t hand during the nonresponse tones than did females. Moreover, males habituated faster than females (when time to two consecutive zero responses was used as the criterion for habituation). No differences were found i n the composition of the DST, diagnostic, and control groups on the basis of sex or psychomotor status. One of the major hypotheses under investigation i n the present study was whether patients who are normal on the DST d i f f e r electrodermally from those who are abnormal on the DST. The results suggest that they do not so d i f f e r . This i n turn suggests that central mechanisms that govern the suppressive response during the DST are distinct from those mechanisms that influence skin conductance—or at least that HPA hyperactivity and electrodermal hypoarousal are not controlled by a single, discrete area of the central nervous system. Taken alone, the electrodermal similarity between DST normal and DST 82. abnormal patients does not detract from the biochemical theories of depression that were discussed in the introductory section of this paper. It is conceivable, for example, that cholinergic hyperactivity in the hypothalamic region is responsible for HPA hyperactivity and (because the hypothalamus tends to facilitate skin conductance) offsets severe electrodermal reduction produced by cholinergic excitation of areas such as the hippocampus (an area that, i t will be recalled, is inhibitory for EDA). If this were to be the case, i t is possible that individuals who are normal on the DST do not show lower EDA than do those who are abnormal on the DST because cholinergic hyperactivity of the hypothalamus is characteristic of both DST normals and DST abnormals, but that another (unknown) variable is necessary for the HPA abnormality to become manifest. An alternative explanation for the results of this study is that depression—and perhaps HPA abnormality—is a result of cholinergic inbalance, whereas electrodermal abnormalities reflect a second neural abnormality. One such possibility is the serotonergic and noradrenergic inhibition that was discussed in the introduction to this paper. In this case, individuals who are abnormal on the DST (and experience cholinergic hyperactivity) may or may not exhibit concomitant serotonergic and noradrenergic inbalance and resultant reduction in electrodermal levels. This may also explain why i t has been observed that electrodermal reduction appears to be a trait characteristic of depression (iacono et a l . , 1983), whereas DST abnormality is confined 88. to the depressed state. Unfortunately, such hypotheses are rendered somewhat redundant by a second major finding of the present study—namely, that depressed patients and normal controls did not d i f f e r electrodermally from one another. Although this result i s not consistent with that obtained by several other researchers (Dawson et a l . , 1977? Heimann & Straube, 1979; Iacono et a l . , 1983; McCarron, 1973; Storrie et a l . , 1981), i t i s c r i t i c a l to note that other workers have obtained results that suggest that normal control subjects do not d i f f e r electrodermally from depressives, or that controls may on average even have lower skin conductance than the depressed group. It i s important to keep i n mind that several studies have been marred by inadequate or inappropriate subject classification and description, and that the research as a whole has util i z e d a plethora of experimental techniques and measures. Nevertheless, i t i s s t i l l necessary to account for the following: In two studies no difference was found between depressives and controls on one or more electrodermal measures (Giedke et a l . , 1980; Toone et a l . , 1981); i n five other studies i t was reported that the depressed group had higher skin conductance levels than the controls (Bassett & Ashby, 1954; Goldstein, 1965; Lewinsohn et a l . , 1973; Suarez, 1978; Zuckerman, 1968); i n three studies i t was observed that the depressed group had both higher and lower skin conductance than the controls, depending upon how the depressives were subclassified (Byrne, 19755 Gilberstadt & Maley, 1965; Lader & Wing, I969); and i n two other studies i t was stated that the depressives had skin conductance 89. that was lower than and equal to that of the controls, again contingent upon subclassification of the depressives (Lapierre & Butter, 1980? Mirkin & Coppen, 1980). Subclassification of the patient group on the basis of both manifest and reported signs and symptoms would appear to be essential i n electrodermal studies and may provide a key to understanding what seem to be confusing and contradictory data. A number of workers (e.g. Mirkin & Coppen, 1980; Noble & Lader, 1972) have reported differences between depressives on the basis of patients' endogenous features and other workers (e.g. Lader & Wing, 1969; Noble & Lader, 1971) have observed electrodermal differences between agitated and retarded depressives (the former on average had higher levels of EDA than both the latt e r and, sometimes, controls). As noted i n the Method section of the present paper, there were too few nonendogenous depressives i n the present study to compare s t a t i s t i c a l l y endogenous and nonendogenous depressives (see Appendix A.Ok for the c r i t e r i a used to determine endogenous depression). With regard to psychomotor activ i t y , a majority of the patients ( 2 3 ) did not possess features of retardation or agitation at the time of testing. Another 11 patients exhibited signs of retardation and two other patients appeared to be agitated when tested. (Classification on the basis of psychomotor acti v i t y was c l i n i c a l . The c r i t e r i a used to rate agitation and retardation are also l i s t e d i n Appendix A.Ok.) A comparison of the skin conductance of depressives on the basis of their psychomotor status revealed that the retarded depressive group had significantly lower levels of tonic conductance than those depressives who had no signs of retardation or agitation. (There were too few agitated patients to compare this group with psychomotor retarded and psychomotor normal patients.) There also existed a (nonsignificant) trend i n phasic responsiveness to tones, such that the retarded group had lower average responses than did the psychomotor normal group and controls (see Figures 5 and 6). In the present study, nearly two-thirds of the depressives appeared to be neither retarded nor agitated. On the basis of the above results i t could be postulated that the lack of electrodermal difference between the depressed and control groups i s due to the fact that there were relatively few retarded depressives i n the depressed group. At the very least, i t i s clear that the assessment of the psychomotor status of the depressed patients i s important i n psychophysiological studies of this nature. It seems l i k e l y that psychomotor status i s one of perhaps several variables that contribute to electrodermal differences between depressives and controls. Another variable that may be implicated i n the i n a b i l i t y i n the present study to distinguish depressives from controls on the basis of their skin conductance i s the way i n which normal controls were recruited (posters at a university open house and at an unemployment insurance o f f i c e ) . The method of recruitment may have produced a less arousable sample than has been uti l i z e d i n prior research. In this regard, i t i s interesting to note the source of the control subjects used i n previous electrodermal investigations. Of those studies i n which i t was observed that depressives had reduced EDA relative to normals, one had students as control subjects (McCarron, 1973), one had hospital workers as controls (Dawson et a l . , 1977), and one had family practice c l i n i c attendees as the normal group (iacono et a l . , 1983). Two a r t i c l e s did not identify the source of the control subjects (Heimann & Straube, 1979; Storrie et a l . , 1981). Similarly, of those studies i n which i t was found that depressives had higher skin conductance than normals two had hospital employees as controls (Bassett & Ashby, 195^; Goldstein, 1965), two had students as control subjects (Lewinsohn et a l . , 1973; Suarez et a l . , 19?8), and one did not identify the control source (Zuckerman et a l . , 1968). Very similar sources of control subjects were uti l i z e d i n the research that has found no, or equivocal, differences between depressives and controls: In three studies hospital staff were enlisted as controls (Lader & Wing, 1969; Lapierre & Butter, 1980; Toone et a l . , 1981), in one study the psychology staff were used as controls (Gilberstadt & Maley, 1965)» and i n three studies the control source was not described (Byrne, 1975; Giedke et a l . , 1980; Mirkin & Goppen, 1980). It i s readily apparent from the above that strikingly similar sources have been tapped i n the quest for supposedly normal and representative control subjects. However, because those sources have been relatively few i n number, and thus quite restricted i n nature, their adequacy i n providing f u l l y representative control samples can be questioned. Is the skin conductance of hospital employees, for instance (the most convenient and popular source of control subjects), representative of the skin conductance of the population i n general, or do variables such as socioeconomic status, the physical condition of the depressives' and employees' hands, the degree of competitiveness of the employees, and the familiarity of the employees with the research, the researcher, and tests i n general influence the results in some unknown but significant manner? The socioeconomic status of the control subjects may i n particular be a variable that i s worthy of future study. It i s conceivable, for example, that a less educated and sophisticated sample than the one used i n the present study would tend to be more aroused by factors such as elaborate electronic hardware, an examiner i n a white coat, written and verbal questions, and a hospital location. (Table 6 shows the occupation and education of each of the control subjects tested i n the present study.) There are several other factors that might account for differences in the results of electrodermal studies. These include the c l i n i c a l state, chronicity, and medical status of the depressives, the type and intensity of stimuli and task demands, and the location of the electrodes from which electrodermal activity was monitored. In the 93. Table 6 Occupation and Education of Control Subjects 3* Subject Occupation Education 1 Nurse's Aide High School 2 C i v i l Servant High School + Specialty 3 Research Assistant University 4 Counselor Master's Degree 5 Secretary (Unemployed) High School 6 University Student Some University 7 Pilot (Retired) High School + Specialty 8 Restaurant Manager High School 9 Secretary High School 10 Actor (Unemployed) High School 11 Nurse High School + Specialty 12 Child Care Worker Some University 13 Speech Therapist University 14 Government Researcher University 15 Homemaker High School Approximate level completed. 94. present study, no differences i n skin conductance due to severity of depression or medication status were detected. It nevertheless remains a possibility that these variables interact with others (such as psychomotor status) to affect electrodermal activity. In regard to the stimuli employed and the overall demands of the experimental situation, i t i s possible that stimuli that are more meaningful than are tones would have influenced group differences. For instance, the meaningful stimuli might have enhanced the involvement of normal controls more than that of the depressives, with resultant increases i n the skin conductance of the controls relative to the conductance of the depressives. It i s also possible that the location of the electrodes has some influence on electrodermal a c t i v i t y . In the present study, the influence would have been to create a ceiling effect that resulted i n an overall reduction i n the electrodermal arousability of the control group to a level at which the depressed and control groups had skin conductance levels that were indistinguishable from each other. In summary, the results of the present study indicate that DST normal and DST abnormal patients do not d i f f e r significantly i n their tonic or phasic electrodermal ac t i v i t y , although group averages for phasic responses to tones do exhibit a trend indicative of somewhat lower levels of phasic responsiveness i n depressed, and i n particular DST abnormal, patients. As a diagnostic tool, however, an examination of electrodermal a c t i v i t y — e i t h e r alone or i n conjunction with the DST—does not appear to be of u t i l i t y due to the substantial overlap i n skin conductance between depressives and controls. The results also suggest that the psychomotor status of the patients may influence their phasic electrodermal ac t i v i t y and that psychomotor status should therefore be monitored carefully, and possibly controlled, i n future studies. Groups should also be matched on the basis of sex. 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Depression: Avoidance learning and physiological correlates in c l i n i c a l and analog populations. Behavior Research and Therapy, 16, 21-31. Toone, B.K., Cooke, E., & Lader, M.H. (1981). Electrodermal activity i n the affective disorders and schizophrenia. Psychological  Medicine, 11, 497-508. Winer, B.J. (1971)• St a t i s t i c a l principles i n experimental design (2nd ed.). New York: McGraw-Hill. Winokur, G., Behar, D., Van Valkenburg, C , & Lowry, M. (1978). Is a familial definition of depression both feasible and valid? Journal of Nervous and Mental Disease, 166, 764-768. Zuckerman, M., Persky, H., & Curtis, G.C. (1968). Relationships among anxiety, depression, h o s t i l i t y , and autonomic variables. Journal of Nervous and Mental Disease, 146, 481-487. Appendix A.01 Hamilton Depression Scale For each item, write the correct number (only one response). 1. DEPRESSED MOOD (Sadness, hopeless, worthless) 0=Absent l=These feeling states indicated only on questioning 2=These feeling states spontaneously reported verbally 3=Communicates feeling states non-verbally—i.e. through f a c i a l expression, posture, voice, and tendency to weep 4=Patient reports VIRTUALLY ONLY these feeling states i n his spontaneous verbal and non-verbal communication 2. FEELINGS OF GUILT 0=Absent l=Self reproach, feels he has l e t people down 2=Ideas of g u i l t or rumination over past errors or sin f u l deeds 3=Present il l n e s s i s a punishment. Delusions of guilt 4=Hears accusatory or denunciatory voices and/or experiences threatening visual hallucinations 3. SUICIDE 0=Absent l=Feels l i f e i s not worth l i v i n g 2=Wishes he were dead or any thoughts of possible death to self 3=Suicide ideas or gesture 4=Attempts at suicide (Any serious attempt rates 4) 4. INSOMNIA EARLY 0=No d i f f i c u l t y f a l l i n g asleep l=Complains of occasional d i f f i c u l t y f a l l i n g asleep—i.e. more than l/2 hour 2=Complains of nightly d i f f i c u l t y f a l l i n g asleep 5. INSOMNIA MIDDLE 0=No d i f f i c u l t y l=Batient complains of being restless and disturbed during the night 2=Waking during the night—any getting out of bed rates 2 (except for purposes of voiding) 105. Appendix A.01, continued 6. INSOMNIA LATE p=No d i f f i c u l t y i-Waking i n early hours of the morning but goes back to sleep 2=Unable to f a l l asleep again i f he gets out of bed 7. WORK AND ACTIVITIES 0=No d i f f i c u l t y l=Thoughts and feelings of incapacity, fatigue or weakness related to a c t i v i t i e s , work or hobbies 2=Loss of interest i n activity, hobbies or work—either directly reported by patient; or indirect i n listlessness, indecision and vacillation (feels he has to push self to work or act i v i t i e s ) 3=Decrease i n actual time spent i n a c t i v i t i e s or decrease i n productivity. In hospital, rate 3 i f patient does not spend at least three hours a day i n a c t i v i t i e s (hospital job or hobbies) exclusive of ward chores 4=Stopped working because of present i l l n e s s . In hospital, rate 4 i f patient engages i n no a c t i v i t i e s except ward chores, or i f patient f a i l s to perform ward chores unassisted 8. RETARDATION (Slowness of thought and speech; impaired a b i l i t y to concentrate; decreased motor activity) 0=Normal speech and thought 1=Slight retardation at interview 2=Obvious retardation at interview 3=Interview d i f f i c u l t ^-Complete stupor 9. AGITATION 0=None 1="Playing with" hands, hair, etc. 2=Hand-wringing, nail-biting, hair-pulling, biting of l i p s 10. ANXIETY PSYCHIC 0=No d i f f i c u l t y 1=Subjective tension and i r r i t a b i l i t y 2=Worrying about minor matters 3=Apprehensive attitude apparent i n face or speech 4=Fears expressed without questioning 106. Appendix A.01, continued 11. ANXIETY SOMATIC 0=Absent Physiological concomitants of anxiety, such as: l=Mild Gastro-Intestinal—dry mouth, wind, 2=Moderate indigestion, diarrhea, cramps, belching 3=Severe Cardio-vascular—palpitations, headaches 4=Incapacitating Respiratory—hyperventilation, sighing Urinary frequency Sweating 12. SOMATIC SYMPTOMS GASTROINTESTINAL 0=None l=Loss of appetite but eating without staff encouragement. Heavy feelings i n abdomen. 2=Dlfficulty eating without staff urging. Requests or requires laxatives or medication for bowels or medication for G.I. symptoms 13. SOMATIC SYMPTOMS GENERAL 0=None l=Heaviness i n limbs, back or head. Backaches, headache, muscle aches. Loss of energy and fa t i g a b i l i t y 2=Any clear-cut symptom rates 2 14. GENITAL SYMPTOMS 0=Absent Symptoms such as: Loss of libido l=Mild Menstrual 2= Severe disturbances 15. HYPOCHONDRIASIS 0=Not present 1=Self-absorption (bodily) 2= Preoccupation with health 3=Frequent complaints, requests for help, etc. ^Hypochondriacal delusions 16. LOSS OF WEIGHT Rate either A or B A. When Rating By History: 0=No weight loss l=Probable weight loss associated with present i l l n e s s 2=Definite (according to patient) weight loss B. On Weekly Ratings By Ward Psychiatrist. When Actual Weight Changes Are Measured: 0=Less than or equal to 1 l b . weight loss i n week l=Greater than 1 l b . but less than or equal to 2 l b . weight loss i n week 2=Greater than 2 l b . weight loss i n week Appendix A.01, continued 17. INSIGHT 0=Acknowledges being depressed and i l l l=Acknowledges ill n e s s but attributes cause to bad food, climate, overwork, virus, need for rest, etc. 2=Denies being i l l at a l l 18. DIURNAL VARIATION Rate both A and B, but ADD 18B only into total score A, Note whether symptoms are worse i n morning or evening. If NO diurnal variation, mark none 0=No variation l=Worse i n A.M. 2=Worse i n P.M. B. When present, mark the severity of the variation. Mark "None i f NO variation 0=None l=Mild 2=Severe 19. DEPERSONALIZATION AND DEREALIZATION 0=Absent Such as: Feelings of unreality l=Mild 2=Moderate 3=Severe 4=Incapacitating 20. PARANOID SYMPTOMS 0=None l=Suspicious 2=Ideas of reference 3=Delusions of reference and persecution 21. OBSESSIONAL AND COMPULSIVE SYMPTOMS 0=Absent l=Mild 2=Severe 108. Appendix A.02 Subject Consent Form I have been asked to participate in a study in which my body's responses will be recorded while I perform a simple task. This task involves comfortably relaxing while listening to brief tones and pressing a switch in response to some of the tones. The responses of my body that will be recorded are the activity of my sweat glands and heart. To make these recordings, sensors will be attached to my arms and leg and to two fingers of each hand, but no discomfort or danger to myself is involved. I understand that a l l the information obtained in this project will be kept confidential and used only for the purposes of this study. By signing this form, I agree to participate, although I realize I am free to withdraw from this study at any time without prejudice to current and future care and treatment. Signature Witness Bale Assigned I.D. 109. Appendix A . 0 3 Beck Depression Inventory Name Date On this questionnaire are groups of statements. Please read each group of statements carefully. Then pick out the one statement i n each group which best describes the way you have been feeling the PAST WEEK, INCLUDING TODAY1 Circle the number beside the statement you picked. If several statements i n the group seem to apply equally well, c i r c l e each one. Be sure to read a l l the  statements In each group before making your choice. 1. 0 I do not feel sad. 1 I feel sad. 2 I am sad a l l the time and I can't snap out of i t . 3 I am so sad or unhappy that I can't stand i t . 2 . 0 I am not particularly discouraged about the future. 1 I fee l discouraged about the future. 2 I fee l I have nothing to look forward to. 3 I feel that the future i s hopeless and that things cannot improve. 3 . 0 I do not fe e l l i k e a fai l u r e . 1 I feel I have f a i l e d more than the average person. 2 As I look back on my l i f e , a l l I can see i s a l o t of failures. 3 I fee l I am a complete failure as a person. 4 . 0 I get as much satisfaction out of things as I used to. 1 I don't enjoy things the way I used to. 2 I don't get real satisfaction out of anything anymore. 3 I am dissatisfied or bored with everything. 5 . 0 I don't fe e l particularly guilty. 1 I fee l guilty a good part of the time. 2 I fee l quite guilty most of the time. 3 I fee l guilty a l l of the time. 6 . 0 I don't fe e l I am being punished. 1 I feel I may be punished. 2 I expect to be punished. 3 I fee l I am being punished. 110. Appendix A.03, continued 15. 0 I can work about as well as before. 1 It takes an extra effort to get started at doing something. 2 I have to push myself very hard to do anything. 3 I can't do any work at a l l . 16. 0 I can sleep as well as usual. 1 I don't sleep as well as I used to. 2 I wake up 1-2 hours earlier than usual and find i t hard to get back to sleep. 3 I wake up several hours earlier than I used to and cannot get back to sleep. 17. 0 I don't get more tired than usual. 1 I get tired more easily than I used to. 2 I get tired from doing almost anything. 3 I am too tired to do anything. 18. 0 My appetite i s no worse than usual. 1 My appetite i s not as good as i t used to be. 2 My appetite i s much worse now. 3 I have no appetite at a l l anymore. 19« 0 I haven't lost much weight, i f any, lately. 1 I have lost more than 5 pounds. I am purposely 2 I have lost more than 10 pounds. trying to lose 3 I have lost more than 15 pounds. weight by eating less. Yes No 20. 0 I am no more worried about my health than usual. 1 I am worried about physical problems such as aches and pains, or upset stomach, or constipation. 2 I am very worried about physical problems and i t ' s hard to think of much else. 3 I am so worried about my physical problems that I cannot think about anything else. 21. 0 I have not noticed any recent change i n ray interest i n sex. 1 I am less interested i n sex than I used to be. 2 I am much less interested i n sex now. 3 I have lost interest i n sex completely. Appendix A.03, continued ?. 0 I don't feel disappointed in myself. 1 I am disappointed in myself. 2 I am disgusted with myself. 3 I hate myself. 8. 0 I don't feel I am any worse than anybody else. 1 I am critical of myself for my weaknesses or mistakes. 2 I blame myself a l l the time for my faults. 3 I blame myself for everything bad that happens. 9. 0 1 don't have any thoughts of killing myself. 1 I have thoughts of killing myself, but I would not carry them out. 2 I would like to k i l l myself. 3 I would k i l l myself i f I had the chance. 10. 0 I don't cry anymore than usual. 1 I cry more now than I used to. 2 I cry a l l the time now. 3 I used to be able to cry, but now I can't cry even though I want to. 11. 0 I am no more irritated now than I ever am. 1 I get annoyed or irritated more easily than I used to. 2 I feel irritated a l l the time now. 3 I don't get irritated at a l l by the things that used to irritate me. 12. 0 I have not lost interest in other people. 1 I am less interested in other people than I used to be. 2 I have lost most of my interest in other people. 3 I have lost a l l of my interest in other people. 13. 0 I make decisions about as well as I ever could. 1 I put off making decisions more than I used to. 2 I have greater difficulty in making decisions than before. 3 I can't make decisions at a l l anymore. 14. 0 I don't feel I look any worse than I used to. 1 I am worried that I am looking old or unattractive. 2 I feel that there are permanent changes in my appearance that make me look unattractive. 3 I believe that I look ugly. Appendix A. 04 Criteria Employed to Subclassify Depressive Episode MELANCHOLIC DSM-III - loss of pleasure in a l l or almost a l l activities - lack of reactivity to usually pleasurable stimuli 3 of the following symptoms: (1) depressed mood distinctly different from that associated with the death of a loved one (2) depression worse in the morning (3) early morning awakening (2 hours before usual) (4) marked psychomotor retardation or agitation (5) significant anorexia or weight loss (6) excessive or inappropriate guilt ENDOGENOUS RDC i symptom from A, plus 4 symptoms from A and B for probable, 6 for definite: A. (l) depressed mood distinctly different from that associated with the death of a loved one (2) lack of reactivity to environmental changes (3) mood worse in the morning (4) pervasive loss of interest or pleasure B. (l) feelings of self-reproach or excessive or inappropriate guilt (2) early morning awakening or middle insomnia (3) psychomotor retardation or agitation (4) poor appetite (5) weight loss (2 lb. a week for several weeks or 20 lb. a year when not dieting) (6) loss of interest or pleasure or decreased sex drive PRIMARY Episode not preceded by other non-affective psychiatric disorder, serious physical illness, or physical illness often associated with psychological symptoms. SECONDARY Episode preceded by one of the above. Appendix A.C4, continued AGITATED 2 of the following symptoms axe present for at least several days: 1) pacing 2) handwringing (3) unable to s i t s t i l l (4) pulling or rubbing on hair, skin, clothing, or other objects 5) outbursts of complaining or shouting 6) talks on and on or can't seem to stop talking RETARDED 2 of the following symptoms are present for at least 1 week: (1) slowed speech (2) increased pauses before answering (3) low or monotonous speech (4) mute or markedly decreased amount of speech (5) slowed body movements 114. Appendix B.01 Instructions for Tone Series I Okay. We're ready to begin. The f i r s t thing we want to t e l l you is that there's nothing for you to worry about. Those wires connected to you just measure tiny signals that your body generates. Nothing unpleasant will happen. I ' l l t e l l you about everything in advance so there will be no surprises. The f i r s t thing we want to do is check the recording equipment to make sure i t is working correctly. We would like to see how your body reacts when you cough—just an ordinary cough like this (cough). Please cough once now . . . cough again . . . and one more time. Good. Now take a deep breath and hold i t . Take a deep breath now . . . hold i t , don't let any air out . . . okay, you can breathe normally now. (Total duration of breath hold 15 seconds.) Alright. For about the next 10 minutes we'll ask you to sit perfectly s t i l l , so take a few moments now to get comfortable in your chair. Next, we want to measure your ability to Ignore distracting sounds while you concentrate on becoming completely relaxed. Every so often you will hear a short tone. The tones will come at unpredictable times. Our equipment will record your body's reactions to these tones. At fi r s t you'll probably respond to them. As they are repeated you'll get used to them and soon you won't react to them at a l l . We want to see how quickly you can stop responding to these sounds. Some people can stop responding to a meaningless, distracting sound very Appendix B.01, continued quickly. For others i t takes longer. We want to see how quickly you can stop responding. It's easier to ignore something that's distracting and unimportant i f you have something else to focus your attention on. This will require some concentration. One way to concentrate on relaxing, to become deeply relaxed, is to repeat over and over to yourself sentences like "I feel deeply relaxed; my whole body is completely relaxed". This is what we want you to do while listening to the tones. Keep repeating these sentences over and over in your mind. The more you do, the more relaxed you will become and the easier i t will be to ignore the tones. Take a moment now to get comfortable. Close your eyes now and let your whole body start to relax. Let the day's tensions just drain out of your body. Breathe easily, in a steady, regular way. Swallow i f you have to, but try not to move any other muscles. I'm going to give you some instructions now to help you become deeply relaxed. Since I want you to concentrate on relaxing by saying things to yourself in your mind, the instructions you will hear next are spoken as though you were saying them to yourself. After I say each sentence, repeat i t to yourself in your thoughts. Here we go. us. Appendix B.01, continued quickly. For others i t takes longer. We want to see how quickly you can stop responding. It's easier to ignore something that's distracting and unimportant i f you have something else to focus your attention on. One way to concentrate on relaxing, to become deeply relaxed, is to repeat over and over to yourself sentences like "I feel deeply relaxed} my whole body is completely relaxed". This is what we want you to do while listening to the tones. Keep repeating these sentences over and over in your mind. The more you do, the more relaxed you will become and the easier i t will be to ignore the tones. Take a moment now to get comfortable. Close your eyes now and let your whole body start to relax. Let the day's tensions just drain out of your body. Breathe easily, in a steady, regular way. Swallow i f you have to, but try not to move any other muscles. I'm going to give you some instructions now to help you become deeply relaxed. Since I want you to concentrate on relaxing by saying things to yourself in your mind, the instructions you will hear next are spoken as though you were saying them to your self. After I say each sentence, repeat i t to your self in your thoughts. Here we go. 117. Appendix B.01, continued My whole body i s becoming limp and relaxed. My feet f e e l heavy and relaxed. My legs f e e l heavy and relaxed. My ankles, knees, and hips f e e l heavy, relaxed, and comfortable. My hands fee l heavy and relaxed. My arms f e e l heavy and relaxed. My wrists, elbows, and shoulders f e e l heavy and relaxed. My stomach and chest feel deeply relaxed. The muscles i n my face and neck fee l heavy and relaxed. My neck, jaw, and my forehead f e e l comfortable and deeply relaxed. My whole body feels completely relaxed. Remember, the more you concentrate on relaxing the easier i t w i l l be to ignore the tones. Keep saying to yourself over and over "I feel deeply relaxed; my whole body feels heavy and relaxed". If you f e e l tension anywhere i n your body—for example, i n your jaw—keep saying to yourself "My jaw feels heavy and relaxed" u n t i l you can f e e l the tension melt away. Then continue to repeat to yourself "I fe e l deeply relaxed; my whole body feels heavy and relaxed". Start saying that now. You'll know when this part of the session i s over because I ' l l speak to you again. Here we go. 118. Appendix B.02 Instructions for Tone Series II Okay. That concludes the f i r s t series of tones. Now open your eyes and wake yourself up a b i t . You w i l l see that I'm now placing what looks a bit l i k e a sewing machine foot pedal just in front of your right foot. The purpose of this pedal w i l l be explained in just a moment. For now, to get the fee l of i t , I want you to place your toes on the pedal and tap i t down. When I say the word "tap", tap. Okay. Tap . . . tap . . . tap . . . tap. Good. We're going to l i s t e n to some more tones, but this time the tones w i l l be much louder than before. In the last part of our session we were measuring your a b i l i t y to ignore sounds. Now, however, we want you to do the opposite. It's important to pay careful attention to the following tones because they aren't a l l alike. Some of the tones have a very short gap i n the middle, just li k e one of the tones you heard near the end of the last series, while others don't have this gap. What we want you to do i s the following: When you hear a tone which you're sure has a gap i n i t , tap the pedal down with your foot and then release i t . This sends a signal to our equipment which t e l l s us that you identified the tone as one with a gap i n i t . On the other hand, when you hear a tone which i s continuous—that i s , one that has no gap i n i t — d o nothing. The tones, and the kind of tone, w i l l come at unpredictable times. I ' l l repeat the instructions. When you hear a tone which you're Appendix B.02, continued sure has a l i t t l e break or gap i n i t , press the pedal, then release i t . It's more important that you try to be correct than you be fast, so try to be sure that there i s i n fact a gap before you tap. When you hear a tone which has no gap, do nothing. So, i f there's a gap, tap. If not, don't. Here we go. 

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