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Both projection and commissural pathways are disrupted in individuals with chronic stroke: investigating… Borich, Michael R; Mang, Cameron; Boyd, Lara A Aug 29, 2012

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RESEARCH ARTICLE Open AccessBoth projection and commissural pathways aredisrupted in individuals with chronic stroke:investigating microstructural white mattercorrelates of motor recoveryMichael R Borich1, Cameron Mang1 and Lara A Boyd1,2*AbstractBackground: Complete recovery of motor function after stroke is rare with deficits persisting into the chronicphase of recovery. Diffusion tensor imaging (DTI) can evaluate relationships between white matter microstructureand motor function after stroke. The objective of this investigation was to characterize microstructural fiber integrityof motor and sensory regions of the corpus callosum (CC) and descending motor outputs of the posterior limb ofthe internal capsule (PLIC) in individuals with chronic stroke and evaluate the relationships between white matterintegrity and motor function.Results: Standardized measures of upper extremity motor function were measured in thirteen individuals withchronic stroke. Manual dexterity was assessed in thirteen healthy age-matched control participants. DTI scans werecompleted for each participant. Fractional anisotropy (FA) of a cross-section of sensory and motor regions of the CCand the PLIC bilaterally were quantified. Multivariate analysis of variance evaluated differences between stroke andhealthy groups. Correlational analyses were conducted for measures of motor function and FA. The stroke groupexhibited reduced FA in the sensory (p = 0.001) region of the CC, contra- (p = 0.032) and ipsilesional (p = 0.001) PLIC,but not the motor region of the CC (p = 0.236). In the stroke group, significant correlations between contralesionalPLIC FA and level of physical impairment (p = 0.005), grip strength (p = 0.006) and hand dexterity (p = 0.036) wereobserved.Conclusions: Microstructural status of the sensory region of the CC is reduced in chronic stroke. Future work isneeded to explore relationships between callosal sensorimotor fiber integrity and interhemispheric interactionspost-stroke. In addition, contralesional primary motor output tract integrity is uniquely and closely associated withmultiple dimensions of motor recovery in the chronic phase of stroke suggesting it may be an important biomarkerof overall motor recovery.Keywords: Diffusion tensor imaging, Stroke, Motor recovery, White matter, Integrity, Corpus callosum, Internalcapsule* Correspondence: lara.boyd@ubc.ca1Department of Physical Therapy, Faculty of Medicine, University of BritishColumbia, 212-2177 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3,Canada2Brain Research Centre, University of British Columbia, Vancouver, BritishColumbia, Canada© 2012 Borich et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.Borich et al. BMC Neuroscience 2012, 13:107http://www.biomedcentral.com/1471-2202/13/107BackgroundDeficits in motor function are common and a primarycontributor to disability after stroke [1]. Approximately80% of individuals with stroke experience hemiparesisand 55-75% experience varying degrees of chronic im-pairment in upper extremity motor function [1]. Whilealtered activity in the sensorimotor cortices is a well-established component of motor recovery followingstroke [2-5], recent evidence from studies using diffusiontensor imaging (DTI) demonstrate that changes in whitematter may also be important [6-10]. The most com-monly reported measure of white matter integrity fromDTI is fractional anisotropy (FA). FA is a quantitative,unit-less measure of the directionality of water diffusionthat indexes the microstructural properties of white mat-ter [11]. Using this measure, relationships between whitematter integrity and various measures of motor functionhave been demonstrated [6-10]. To date, most studieshave focused on descending motor outputs of the pos-terior limb of the internal capsule (PLIC), while themotor and sensory regions of the corpus callosum (CC)have been studied less extensively. Moreover, a system-atic evaluation of relationships between both ipsi- andcontralesional PLIC integrity and a battery of assess-ments of motor recovery in the same patient cohort hasyet to be undertaken. Thus, the present experimentswere designed to explore differences in the integrity ofmotor and sensory fibers of the CC and motor outputtracts of the PLIC between individuals with stroke andhealthy age-matched controls, and to evaluate how thesemeasures relate to multiple dimensions of motorrecovery.A primary role of the CC in the motor system is medi-ation of interhemispheric inhibition between the primarymotor (M1) and sensory (S1) cortices to facilitate theperformance of unimanual and coordinated bimanualmovements [12,13]. Impairments in M1-M1 and S1-S1interhemispheric inhibition appear to contribute tomotor deficits after stroke [12,14], but the effects ofstroke on the integrity of CC motor and sensory fibresand their relation to motor function have not been thor-oughly described. Jang et al. [15] found that the presenceof transcallosal fibers projecting from the unaffected cor-ticospinal tract and descending towards the lesion wereassociated with poor motor function, but did not specif-ically evaluate the integrity of fibers within the callosum.Another study demonstrated that transcallosal M1-M1fibre integrity was reduced in individuals with chronicstroke and that lower integrity of these tracts was asso-ciated with less improvement on the Wolf Motor Func-tion Test (WMFT) following 5 consecutive days of non-invasive brain stimulation paired with physical therapy[16]. Interestingly, the integrity of these M1-M1 fibreswas more strongly related to response to rehabilitationthan integrity of the pyramidal tract and alternate des-cending motor tracts, but was not related to baselinelevel of motor function [16]. To our knowledge, no pre-vious studies have specifically investigated alterations inCC sensory fibre integrity post-stroke and how suchreductions may relate to motor recovery. In a longitu-dinal study, a geometric scheme employed by Witelson[17] was used to characterize temporal degeneration ofthe human CC over the period from 0–6 months post-stroke [18]. Gupta and colleagues [18] demonstratedregion-specific reductions in CC integrity but did notevaluate how these reductions related to recovery. Fur-ther, the CC partitioning scheme used by Witelson [17]was predominantly based on experimental work in non-human primates [17] and more recent advances in DTItechniques allowed Hofer and Frahm [19] to re-evaluatethe regional topographic partitioning of the CC inhumans in vivo. The most striking finding of Hofer andFrahm [19] was that regions of the CC comprised offibers projecting to the motor and sensory cortices weremore posterior in the human CC than previously sug-gested by Witelson’s scheme [17]. This finding influ-enced development of a new modified scheme forpartitioning the CC in humans [19]. This scheme moreaccurately characterizes the motor and sensory regionsof the CC in humans, but has not been previously ap-plied to evaluate CC integrity changes post-stroke or toexamine how CC integrity relates to motor recoverypost-stroke.The integrity of corticofugal motor output projec-tions has been more extensively studied in individualswith chronic stroke and has been found to relate tovarious measures of motor function [6-9]. Lower FA ofthe ipsilesional PLIC relative to the contralesional PLIC(i.e. FA asymmetry) relates to greater levels of physicalimpairment [8,9], lower levels of global motor function[9], and less strength in the affected hand [9]. Otherstudies have also reported that lower ipsilesional FAvalues are associated with greater impairments inglobal motor function [6] and hand dexterity [7]. Thesefindings demonstrate that ipsilesional descendingmotor tract integrity is associated with level of post-stroke motor recovery. Schaechter and colleagues [7]also found that lower contralesional PLIC integrity wasassociated with reduced hand dexterity in individualswith chronic stroke, suggesting an important role ofthe contralesional descending motor outputs in mediat-ing motor recovery post-stroke. Nevertheless, the rela-tionship between contralesional PLIC integrity andother global measures of motor function and impair-ment post-stroke have not been previously reported.Additionally, the aforementioned data [6-9] weregenerated from separate investigations with differentpatient group characteristics, functional outcomeBorich et al. BMC Neuroscience 2012, 13:107 Page 2 of 11http://www.biomedcentral.com/1471-2202/13/107measures, and research designs. A systematic evalu-ation of the relationships between both ipsi- and con-tralesional PLIC integrity and a battery of assessmentsof motor recovery, level of upper extremity impair-ment, strength and manual dexterity has yet to beundertaken in the same patient cohort.The purpose of the present investigation was twofold.First, we evaluated differences in the integrity of callosalmotor and sensory fibers using Hofer and Frahm’smodified geometric scheme [19], and the integrity ofdescending motor output tracts within the ipsi- and con-tralesional PLIC, between individuals with chronicstroke and healthy matched controls. Second, we exam-ined relationships between microstructural integrity ofthese regions with multiple dimensions of motor func-tion in individuals with chronic stroke. We hypothesizedthat FA would be lower in individuals with stroke thanhealthy age-matched controls in each of the regionsevaluated. We also hypothesized that these measures ofwhite matter integrity would be associated with all mea-sures of motor recovery in individuals during thechronic phase of recovery from stroke.Results and discussionComparisons between healthy and chronic strokeindividualsA significant main effect of group on white matter tractFA values was detected by the MANOVA (Wilks’λ=0.406, F(4, 21) = 7.68, p = 0.001). Specifically, mean FAfor the sensory region of the CC was significantly reducedcompared to the healthy group (F(1, 21) = 15.37, p = 0.001),but a significant difference was not observed betweengroups for CC motor region mean FA (F(1, 21) = 1.48,p = 0.236) (Figure 1). For descending motor output tracts,mean FA was reduced in the contra- (F(1, 21) = 5.16,p = 0.032) and ipsilesional PLIC (F(1, 21) = 13.42, p = 0.001)in participants with stroke compared to healthy controls(Figure 1). Greater asymmetry in Box and Blocks test(BBT) performance was observed for individuals withstroke compared to the healthy group (t(23) =−3.96,p = 0.001), indicating impaired manual dexterity in theaffected limb in the chronic stroke group.Associations between assessments of motor function andwhite matter integrityIn the healthy group, there were no significant correlationsbetween age, white matter integrity, or motor performance(BBT score) (p > 0.05). In the stroke group, age was signifi-cantly correlated with Fugl-Meyer (FM) score (r =−0.571,p =0.041), Wolf Motor Function Test (WMFT) asym-metry (r = 0.571, p= 0.042), grip strength asymmetry(r= 0.653, p= 0.021), BBT asymmetry (r = 0.687, p = 0.010),and contralesional PLIC FA (r=−0.668, p= 0.013). Post-stroke duration was correlated with FM (r=−0.723,p =0.008), WMFT asymmetry (r = 0.643, p= 0.024), BBTasymmetry (r = 0.796, p = 0.002), and ipsilesional PLIC FA(r=−0.598, p = 0.040). For measures of white matter integ-rity, only FA of the contralesional PLIC was significantlycorrelated with measures of motor function (FM score:r = 0.722, p = 0.005; grip strength asymmetry: r =−0.740,p =0.006; BBT asymmetry: r =−0.584, p= 0.036) (Figure 2).Summary of primary resultsThe integrity of CC sensory fibers, but not CC motorfibers, was reduced in individuals with chronic strokecompared to healthy controls. Additionally, contrale-sional PLIC integrity was associated with multiple mea-sures of motor function post-stroke.Regional specificity of white matter integrity status in thecorpus callosum is observed after strokeWe utilized the scheme put forth by Hofer and Frahm[19] to partition the human CC to evaluate differencesin the integrity of regions of the CC comprised of inter-hemispheric motor and sensory tracts in individuals withchronic stroke and healthy individuals. This method ofevaluating the CC [19] provides a more accurate meas-ure of CC motor and sensory region integrity in humanspost-stroke compared to previous work [18] utilizing amethod predominantly based on primate research [17].Moreover, by examining individuals with chronic stroke(>1 year post-stroke) we further extend previous researchthat only considered CC integrity changes during theacute phase of stroke recovery (0–6 months post-stroke).Presently, individuals with chronic stroke demon-strated reduced integrity of the sensory CC region, butnot the motor CC region, compared to healthy controls.Using Witelson’s scheme [17], Gupta and colleagues [18]also demonstrated region-specific reductions in CC in-tegrity in the rostrum, genu, rostral body, anterior mid-body and splenium, but not the posterior mid-body andisthmus of the CC, in the acute phase of stroke recovery.The motor region of the CC in Hofer and Frahm’s modi-fied scheme [19] corresponds to the posterior mid-bodyin Witelson’s scheme [17]. Thus, our finding of no dif-ference in the CC motor region between individuals withchronic stroke and healthy controls is consistent withthe previous finding of no change in posterior mid-bodyintegrity throughout the acute phase of stroke [18]. Onthe other hand, this finding is in contrast to previouswork indicating reduced integrity of trancallosal M1-M1tracts in individuals with chronic stroke [16]. However,Lindenberg et al. [16] utilized tractography techniquesto examine M1-M1 tracts, while the present study uti-lized a cross-sectional ROI approach to evaluate fibre in-tegrity within the CC. In contrast to the CC motorregion, the sensory region of the CC was significantlyreduced in individuals with chronic stroke compared toBorich et al. BMC Neuroscience 2012, 13:107 Page 3 of 11http://www.biomedcentral.com/1471-2202/13/107healthy controls in the present study. The CC sensoryregion identified by Hofer’s scheme [19] corresponds tothe anterior portion of the isthmus from Witelson’sscheme [17]. Gupta et al. [18] found no reduction inisthmus integrity during the acute phase of stroke. Thus,these contradictory findings may represent additionalCC degeneration that occurs following the acute phaseof stroke recovery. Alternatively, any reduction in integ-rity within this specific sensory area may have been un-detected when measured as a small region within thelarger isthmus.Our finding of reduced sensory CC integrity in chronicstroke compliments previous work from our lab demon-strating that rehabilitation strategies designed to targetS1-S1 interhemispheric interactions can have significanteffects on motor system function in individuals withchronic stroke [20]. Repeated applications of inhibitorytheta-burst stimulation over contralesional S1 prior tomotor practice enhanced motor learning compared tosham stimulation in individuals with chronic stroke.Interestingly, individuals who received contralesional S1stimulation demonstrated greater improvement in globalFigure 1 White matter integrity in CC and PLIC in healthy individuals and patients with chronic stroke. In patients with chronic stroke,reduced mean FA values were observed in both the contra- and ipsilesional PLIC and in the primary sensory region of CC. Error bars representone standard deviation from the mean. *p < 0.05.Figure 2 Associations between contralateral PLIC integrity and multiple measures of motor function in patients with chronic stroke. Inpatients with chronic stroke, significant correlations were observed between contralesional PLIC mean FA and FM score, grip strength asymmetryand BBT asymmetry. *p < 0.05.Borich et al. BMC Neuroscience 2012, 13:107 Page 4 of 11http://www.biomedcentral.com/1471-2202/13/107motor function compared to those who received M1stimulation [20]. Thus, these findings demonstrate thattargeting S1-S1 interhemispheric interactions to facilitateipsilesional S1 activity may offer unique strategies to fa-cilitate post-stroke rehabilitation. The present finding ofreduced CC sensory region integrity in individuals withchronic stroke provides additional evidence that the sen-sory system is affected in chronic stroke. Nevertheless,relationships between callosal sensory fibre integrity andmotor function were not observed in the present study,suggesting that the integrity of this white matter regionmay not be particularly important for motor recovery.However, we feel that this is unlikely given the well-established role of inter-hemispheric interactions inmediating motor cortex excitability and function post-stroke [12,14,21-23]. Rather, we believe that therelatively small and homogenous sample of individualspresently studied may have limited the power for detect-ing such a relationship. Further, Lindenberg et al. [16]previously demonstrated that transcallosal M1-M1 tractintegrity related to response to rehabilitation but notbaseline motor function in individuals with chronicstroke. Thus, it is plausible that CC sensory fibre integ-rity may also be more strongly related to response torehabilitation than to baseline measures of motor func-tion. Future research with large heterogeneous samplesexamining callosal motor and sensory region integrity,neurophysiological measures of interhemispheric inhib-ition, bimanual motor tasks and response to rehabilita-tion will provide further insights into the functionalrelevance of post-stroke CC integrity changes.Contralesional descending motor outputs are associatedwith motor recovery after strokeIn addition to evaluating post-stroke callosal integritychanges, we also measured changes in the integrity ofdescending motor outputs within the PLIC. Previouswork has demonstrated that reduced integrity of thecontra- and ipsilesional PLICs are associated with anumber of different functional measures in individualswith chronic stroke [6-10]; however, these findings havebeen compiled from multiple studies examining cohortswith different patient group characteristics, functionaloutcome measures, and research designs. Here, we eval-uated the integrity of the contra- and ipsilesional PLICand multiple measures of motor recovery in a single co-hort of patients with chronic stroke. In our data, bothcontra-and ipsilesional PLIC integrity were decreased inindividuals with chronic stroke compared to healthyage-matched controls. Degenerative changes of the con-tralesional PLIC were associated with greater level ofphysical impairment, lower hemiparetic upper extremitystrength, and lower hand dexterity in chronic stroke.Similarly, Schaechter and colleagues [7] observed thatreduced contralesional white matter integrity was asso-ciated with lower hand dexterity and finger tappingspeed. The present study extends the findings ofSchaechter et al. [7] by demonstrating that in addition tohand dexterity and finger tapping speed, contralesionalwhite matter integrity is also associated with overall levelof physical impairment and grip strength. Evidence fromanimal models of stroke recovery indicate that changesin white matter microstructure in the contralesionalhemisphere including axonal sprouting, formation ofnew synapses and increased myelinating activity arepotentiated by treatments that also improve motor re-covery [24-26]. Thus, it is possible that similar processesoperated in our cohort of individuals with chronicstroke, which may explain the relationships we note be-tween contralesional PLIC integrity and motor function.These relationships were not observed in a matchedgroup of healthy individuals suggesting a unique rela-tionship between microstructural changes in descendingmotor output integrity and physical impairment,strength and manual dexterity in well-recovered indivi-duals after stroke.In contrast to previous work [7-9], ipsilesional motoroutput tract integrity was not significantly associatedwith measures of motor function in the present study.These differences may stem from differences in strokeparticipant characteristics in past studies. In the presentstudy, the sample was fairly homogenous in terms of le-sion location, level of recovery and, to a lesser extent,time since stroke onset. In other investigations, motorfunction and lesion location were more heterogeneous[7-9]. Additionally, the difference between the level ofresidual physical impairment in our patient sample andthat of previous work may also contribute to this dis-crepancy. Our participants demonstrated higher FMscores indicating reduced upper extremity impairmentand greater motor recovery in comparison to subjects inrelated investigations [8,27]. Taken together, these differ-ences in patient characteristics may, in part, explain theobservation of a relationship between contralesional, butnot ipsilesional, tract integrity and motor function.We also evaluated relationships between age and post-stroke duration of our stroke participants with measuresof motor function and white matter integrity. Consistentwith previous work [28], we observed that advancing ageis associated with reduced motor function. Likewise, agewas negatively correlated with contralesional PLIC integ-rity. We also observed that greater time since stroke wasassociated with lower motor function and lower ipsile-sional PLIC integrity in individuals with chronic stroke.Previous work by Stinear et al. [8] indicated that longertime since stroke was associated with smaller improve-ments in FM score after motor practice. On the otherhand, a recent systematic review determined that theBorich et al. BMC Neuroscience 2012, 13:107 Page 5 of 11http://www.biomedcentral.com/1471-2202/13/107evidence that time since stroke influences upper limbmotor recovery is inconclusive [28]. The present findingssuggest that motor function declines with greater timesince stroke and that this decline may relate to degener-ation of ipsilesional PLIC integrity. These data, in com-bination with previous work [8,28], demonstrate thatsimple demographic information may help explain therelationships observed between level of recovery andwhite matter degeneration.LimitationsSeveral limitations may impact the conclusions drawnfrom this study. Our sample of participants with strokewas relatively small and homogenous and thus may limitgeneralizability to the stroke population as a whole. Wealso limited our investigation of descending motor out-put tracts to a subsection of the motor output projectionsystem previously shown to have reduced integrity fol-lowing stroke [8,9] and shown to be reliable and sensi-tive in a subset of the present cohort of patients [29].Other work has used alternative analysis techniques toevaluate this sub-section of tract but also other whitematter regions within the brain [6,7,27,30]. Currentlythere is no gold standard for DTI analysis techniques instroke and further work is needed to determine optimalimaging and analysis parameters.ConclusionsThe present study demonstrates that the integrity of thesensory region of the CC is reduced in individuals withchronic stroke, but that the integrity of this region didnot directly relate to the measures of motor functionemployed here. Future work is needed to elucidate rela-tionships between CC integrity and interhemisphericsensorimotor interactions in the chronic phase of stroke.In addition, the present study demonstrates that con-tralesional descending motor output tract integrity, aswell as demographic characteristics, are associated withmultiple dimensions of motor function after stroke.Thus, contralesional motor output tract integrity may bean important biomarker of level of motor recovery inthe chronic phase of stroke and may provide insightsinto future investigations of response to rehabilitationstrategies.MethodsParticipantsThirteen well-recovered individuals with chronic stroke(mean age ± SD: 63.8 ± 6.4) and thirteen age and gender-matched healthy control participants (mean age ± SD:62.9 ± 7.4) were recruited from community and localpostings. Participant characteristics are listed in Table 1.A subset of the individuals with stroke (n = 9) was partof a previous method development study [29]. Informedconsent was obtained from each participant in accord-ance with the Declaration of Helsinki. University ofBritish Columbia research ethics boards approved allaspects of the study protocol.Research designEach participant completed motor function assessmentsand magnetic resonance imaging (MRI) on separatedays.Functional assessmentsParticipants in the stroke group completed a battery ofassessments to comprehensively measure upper extrem-ity motor impairment, motor function, grip strength andmanual dexterity. These assessments were administeredby a licensed physical therapist. Physical impairmentlevel of the involved arm was assessed using the upperextremity motor portion of the FM assessment (range ofscores 0–66) containing 33 items scored from 0–2 withhigher scores indicating less physical impairment [31].The WMFT has been shown to be a reliable and validcomprehensive assessment of upper extremity motorfunction [32]. Testing consisted of fifteen timed move-ment tasks and two tests of strength. Movement timefor each task was averaged over three trials and medianmovement time was calculated across all tasks. Max-imum grip strength was averaged over three trials usinga calibrated handheld dynamometer. The BBT reliablymeasures hand dexterity in stroke [33]. For the BBT,participants grasped a 2.54 cm3 wooden block on oneside of a divided box using the thumb and index fingerand released it on the other side. Performance was quan-tified by number of blocks transferred in 60s [34]. Indi-viduals in the healthy group completed the BBT toprovide a comparison of motor performance betweengroups. The WMFT, grip strength assessment and BBTwere conducted bilaterally for each participant in thestroke group. Asymmetry scores were calculated foreach participant:WMFTaff WMFTunaffWMFTaff þWMFTunaffGripunaff  GripaffGripunaff þ GripaffBBTunaff  BBTaffBBTunaff þ BBTaffAsymmetry values could range from −1.0 to +1.0 withpositive values indicating greater impairment and nega-tive values indicating less impairment of the affectedupper extremity compared to the less affected extremity.Values of 0.0 were indicative of symmetrical perform-ance between extremities. Functional assessment scoresfor each participant are listed in Table 1.MR data acquisitionMR acquisition was conducted at the UBC MRI Re-search Centre on a Philips Achieva 3.0 T whole bodyMRI scanner (Phillips Healthcare, Andover, MD) usingBorich et al. BMC Neuroscience 2012, 13:107 Page 6 of 11http://www.biomedcentral.com/1471-2202/13/107Table 1 Demographic informationStroke participantsSubjectIDAge(y)Gender LesionlocationDominantHandPSD(mo)MMSE FM WMFTAffectedWMFTUnaffectedWMFTAsymGripAffectedGripUnaffectedGripAsymBBTAffectedBBTUnaffectedBBTAsymCC FA PLIC FAMotor Sensory Contra IpsiS01 65 M R R 20 28 51 3.24 1.15 0.48 16 39.5 0.42 30 56 0.30 0.75 0.71 0.62 0.56S02 72 M R R 169 29 32 3.9 1.41 0.47 12 38 0.52 9 45 0.67 0.72 0.69 0.58 0.47S03 59 F R R 42 30 61 1.09 1.03 0.03 19 18 -0.03 69 72 0.02 0.68 0.70 0.63 0.65S04 72 M R R 101 27 52 5.28 1.19 0.63 NT NT NT 12 57 0.65 0.63 0.49 0.63 0.45S05 74 M R R 65 29 36 4 1.2 0.54 8 42 0.68 12 42 0.56 0.66 0.67 0.60 0.59S06 55 F R R 19 30 51 1.47 0.97 0.20 10 22 0.38 37 59 0.23 0.64 0.72 0.61 0.57S07 59 M L R 38 28 62 1.71 0.94 0.29 37 46 0.11 34 59 0.27 0.67 0.60 0.65 0.57S08 55 M L R 101 30 51 2.5 1.1 0.39 23 37 0.23 25 50 0.32 0.59 0.57 0.65 0.26S09 64 M R R 29 30 66 0.66 0.64 0.02 26 30 0.07 49 70 0.18 0.75 0.73 0.63 0.52S10 65 F R R 90 29 60 4.16 0.72 0.23 18 26 0.18 32 59 0.30 0.62 0.57 0.61 0.35S11 68 F R R 136 30 26 4.5 0.81 0.84 6 20 0.54 0 63 1.00 0.68 0.62 0.60 0.47S12 58 M R R 17 30 66 1.28 0.81 0.22 27.33 37.33 0.15 45 46 0.01 0.70 0.65 0.63 0.67S13 63 M R R 28 29 66 1 0.9 0.05 25 30 0.09 51 63 0.11 0.62 0.57 0.63 0.54Mean ± SD:63.76 ± 6.4268.08 ±50.9929.15 ±0.9952.31 ±13.442.45 ±1.562.45 ±1.560.99 ±0.2218.94 ±9.1732.15 ±9.170.28 ±0.2231.15 ±19.6157 ±19.610.35 ±0.290.67 ±0.050.64 ±0.070.62 ±0.020.52 ±0.12Healthy participantsSubjectIDAge(y)Gender DominantHandBBTNon-dominantBBTDominantBBTAsymCC FA PLIC FAMotor Sensor Contra IpsiS101 64 F R 55 63 0.07 0.67 0.75 0.58 0.60S102 72 F R 68 58 −0.08 0.70 0.75 0.64 0.63S103 67 F R 68 77 0.06 0.63 0.66 0.68 0.66S104 63 M R 77 74 −0.02 0.67 0.72 0.61 0.60S105 60 F R 56 61 0.04 0.67 0.75 0.67 0.67S106 51 M R 82 75 −0.04 0.72 0.71 0.64 0.64S107 68 M R 67 63 −0.03 0.68 0.76 0.65 0.63S108 69 M R 68 72 0.03 0.62 0.64 0.62 0.64S109 48 F R 77 77 0.00 0.70 0.73 0.63 0.65S110 67 F R 52 54 0.02 0.73 0.76 0.63 0.64Borichetal.BMCNeuroscience2012,13:107Page7of11http://www.biomedcentral.com/1471-2202/13/107Table 1 Demographic information (Continued)S111 55 F R NT NT NT 0.75 0.80 0.68 0.68S112 68 F R 53 65 0.10 0.72 0.73 0.68 0.67S113 66 M R 47 55 0.08 0.72 0.74 0.69 0.67Mean± SD:62.92 ± 7.36 64.17 ±11.3566.17 ±8.500.02 ±0.050.69 ±0.040.73 ±0.040.65 ±0.030.64 ±0.02PSD: Post-stroke duration, MMSE: Mini-Mental Status Exam, BBT: Box and Blocks test, FM: Fugl-Meyer, WMFT: Wolf motor function test, Asym: Asymmetry, Contra: Contralesional, Ispi: Ipsilesional, M: Male, F: Female, L:Left, R: Right, SD: Standard deviation, y: years, mo: months, NT: not tested.Borichetal.BMCNeuroscience2012,13:107Page8of11http://www.biomedcentral.com/1471-2202/13/107an eight-channel sensitivity encoding head coil (SENSEfactor = 2.4) and parallel imaging. A high-resolution ana-tomical scan (TR= 12.4 ms, TE = 5.4 ms, flip angle θ= 8°,FOV= 256 mm, 170 slices, 1 mm thickness) was col-lected. A diffusion weighted scan was conducted witha single shot echo-planar imaging (EPI) sequence(TR=7465 ms, TE= 75 ms, FOV=212× 212 mm, 60slices, 2.2 mm slice thickness, voxel dimension =2.23 mm).Diffusion weighting was applied across 15 independentnon-collinear orientations (b = 1000 s/mm2) along with anon-weighted diffusion weighted image acquired (b = 0).A gradient table was used for subsequent data analysis,computed using parameters of the diffusion-weightedimages [35].MR data processingPrior to tensor calculation, the quality of the raw imageswere visually inspected for excessive motion artifact orinstrumental noise using a slice-by-slice procedure; if animage was deemed corrupt, it was removed prior to finaltensor calculation [36]. Less than 1% of images wereremoved across all subjects. After tensor calculation, FAmaps were produced based on the magnitude of diffusiv-ity in three defined orientations and the mean diffusivityof each within a given tensor [37]. Color-coded orienta-tion maps were used to visualize the principal fiberorientation within each pixel (red: right-left, blue: super-ior-inferior, green: anterior-posterior).The ROIEditor software program (www.MriStudio.org)was used to perform manual quantification of the integ-rity of the segments of the CC comprised of motor andsensory fibers [19] and the PLIC [8]. The cross-sectionalregions of interest (ROIs) were delineated consulting theFA and color maps produced and standard white matteratlas [38]. ROIs for the CC were delineated in the mid-sagittal plane and in the adjacent five slices to the rightand to the left using the scheme proposed by Hofer andFrahm [19]. A geometric baseline for the CC wasdefined by connecting the most anterior and posteriorpoints of the CC. ROIs were then delineated over theregions comprising fibers projecting to motor and sen-sory cortices. The motor region was defined as the pos-terior half minus the posterior third of the callosum andthe sensory region as the posterior one-third minus theposterior one fourth of the callosum [19] (Figure 3A).No lesions penetrated the callosum. The PLIC was deli-neated bilaterally, beginning at the level of the anteriorcommissure and terminating at the inferior border ofthe corona radiata [8] (Figure 3B). Lesions penetratingthe PLIC were not excluded from the drawing proced-ure. Complete disruption of the affected PLIC was notobserved for any participant. Mean FA values for eachregion (CC motor, CC sensory, ipsilesional PLIC, andcontralesional PLIC) were then computed removingpixels with zero or negative FA values and the mean FAfrom the remaining voxels within the manually definedROI mask were used for statistical analyses.Figure 3 DTI-derived color and FA maps depicting region of interest drawings from a representative subject in the stroke group. A.Sagittal view of CC motor (yellow) and sensory (blue) regions as identified using Hofer and Frahm’s modified scheme [18]. B. Coronal view ofright (pink) and left (orange) PLIC ROIs. C. Axial view of PLIC ROIs at level of the anterior commissure.Borich et al. BMC Neuroscience 2012, 13:107 Page 9 of 11http://www.biomedcentral.com/1471-2202/13/107Statistical analysesA between-groups multivariate analysis of variance(MANOVA) assessed differences in white matter integ-rity between healthy individuals and individuals withstroke. The dependent variables were FA obtained fromthe various ROIs drawn: CC motor region, CC sensoryregion, ipsi- and contralesional PLIC. For participants inthe healthy group, FA of “ipsi- and contralesional” PLICwere quantified from the non-dominant and dominanthemisphere, respectively. Additionally, an independentsamples t-test was conducted to evaluate differences be-tween groups in BBT asymmetry.After assessing between-group differences in motorfunction and white matter integrity, the groups wereevaluated individually to study the relationships betweenwhite matter integrity and baseline measures of motorfunction. Simple bivariate parametric correlation ana-lyses between measures of age and post-stroke duration,measures of motor function, and white matter integritywere conducted. For each statistical test, significancelevel was: uncorrected p < 0.05. All statistical procedureswere conducted using SPSS software (SPSS 19.0).Authors’ contributionsLAB conceived and participated in the design of the study. MRB performeddata processing, statistical analysis and drafted the manuscript. CMparticipated in data processing and analysis and helped draft the manuscript.All authors contributed to interpretation of results. All authors read andapproved the final manuscript.AcknowledgementsThis work was supported by the National Institutes of Health [NS051714 to L.A.B.] and the Canadian Institutes of Health Research [MOP-106651 to L.A.B.].Support was also provided to LAB by the Canada Research Chairs and theMichael Smith Foundation for Health Research. The Natural Sciences andEngineering Research Council of Canada provided support to CM and theHeart and Stroke Foundation of Canada supported MRB.Received: 13 July 2012 Accepted: 22 August 2012Published: 29 August 2012References1. 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