Schizophrenia Research 130 (2011) 78ndash85

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Diffusion tensor imaging of anterior commissural fibers in patientswith schizophrenia

Hongyoon Choi ab Marek Kubicki ac Thomas J Whitford ad Jorge L Alvarado a Douglas P Terry aMargaret Niznikiewicz c Robert W McCarley c Jun Soo Kwon ef Martha E Shenton acga Department of Psychiatry Psychiatry Neuroimaging Laboratory Brigham and Womens Hospital Harvard Medical School Boston Massachusetts USAb Seoul National University College of Medicine Seoul Republic of Koreac Clinical Neuroscience Division Laboratory of Neuroscience VA Boston Healthcare System Brockton Massachusetts USAd Melbourne Neuropsychiatry Centre Department of Psychiatry University of Melbourne and Melbourne Health Melbourne Australiae Department of Psychiatry Seoul National University College of Medicine Seoul Republic of Koreaf Department of Brain amp Cognitive Sciences-WCU program College of Natural Sciences Seoul National University Seoul Republic of Koreag Surgical Planning Laboratory MRI Division Department of Radiology Brigham and Womens Hospital Harvard Medical School Boston Massachusetts USA

Corresponding author at Psychiatry NeuroimaginPsychiatry Brigham and Womens Hospital Harvard MStreet Boston MA 02215 USA

E-mail address Shentonbwhharvardedu (ME Sh

0920-9964$ ndash see front matter Published by Elsevierdoi101016jschres201104016

a b s t r a c t

a r t i c l e i n f o

Article history

Received 15 November 2010Received in revised form 11 April 2011Accepted 14 April 2011Available online 10 May 2011

KeywordsSchizophreniaDiffusion tensor imagingAnterior commissureWhite matter tractographyFractional anisotropyTrace

Introduction Alterations in white matter connections in schizophrenia have been investigated using diffusiontensor imaging (DTI) There is also evidence from post-mortem studies as well as from magnetic resonanceimaging morphometry studies that the anterior commissure (AC) might be implicated in schizophrenia butno studies to date have investigated the AC using DTI or tractographyMethod DTI scans were analyzed from 25 patients and 23 controls Mean fractional anisotropy (FA) and tracewere measured from the AC tracts SANS and SAPS were used to evaluate clinical symptoms and the IowaGambling Task related to decision making was also examinedResults Results revealed a significant decrease in mean FA and a significant increase in mean trace of AC tractsin patients compared with controls In addition patients but not controls showed a negative correlationbetween age and AC integrity Statistically significant positive correlations were also found between AC FAand total positive symptom score Decision making was negatively correlated with FA in patients on the IowaGambling Task but not in controls

Conclusion This study provides quantitative evidence for a reduction of interhemispheric connectivity inschizophrenia within the AC Negative correlation between age and AC FA in the patients is consistent withthe idea that schizophrenia may be a disorder of white matter maturation Positive correlation between FAand positive symptom is discussed in the context of white matters established role in modulating neuralconduction velocity

Published by Elsevier BV

1 Introduction

The idea that connections between brain regions are disrupted inschizophrenia goes back at least as far as Kraepelin (1919) whospeculated that schizophrenia was caused by a disruption of con-nectivity between the frontal and temporal lobes The tools to in-vestigate such connections however had to await new imagingtechniques such as diffusion tensor imaging (DTI) which is a relativelynew magnetic resonance method used to investigate water diffusionwithin living tissue (Basser et al 1994) This method also provides anopportunity to investigate white matter (WM) integrity in the brainMore specifically fiber tracts restrict the motion of water especially in

g Laboratory Department ofedical School 1249 Boylston

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directions that are perpendicular to the tract so that water diffusion isanisotropic in WMwhile more isotropic in cerebral spinal fluid or graymatter Accordingly quantitative indices of water diffusivity anddiffusion anisotropy have been introduced based on the properties ofbiological tissues Trace (Tr) which characterizes the overall displace-ment of the water molecules and fractional anisotropy (FA) whichcharacterizes the degree of directionality of anisotropic water diffusionare the most commonly used indices to evaluate WM integrity (Basser1995)

White matter connections between fronto-temporal regions havebeen examined in schizophrenia including the arcuate fasciculus(Burns et al 2003 Hubl et al 2004) cingulum bundle (Kubicki et al2003 Sun et al 2003 Fujiwara et al 2007 Mori et al 2007) and thecorpus callosum (Foong et al 2000 Agartz et al 2001 Ardekani et al2003 Kanaan et al 2006 Mori et al 2007 Kubicki et al 2008)Findings here have generally supported the idea that there aredisruptions in white matter connectivity in schizophrenia although

79H Choi et al Schizophrenia Research 130 (2011) 78ndash85

there have also been negative findings (Sun et al 2003 Price et al2005) The anterior commissure (AC) is a white matter fiber tract thatconnects orbitofrontal cortex with inferior parts of the temporal lobe(Di Virgilio et al 1999 Peuskens et al 2004) andwhich has long beenthought to be implicated in schizophrenia (Shenton et al 2001) Thistract however has received little attention in schizophrenia despitethe fact that there is evidence to support an association betweenabnormal connectivity of AC and schizophrenia in post-mortemstudies (Highley et al 1999) Specifically the number of AC fibers isunchanged but the fiber density of AC is reduced in schizophrenia(Highley et al 1999)

Alterations in asymmetry in schizophrenia are also reported inthe parahippocampal gyrus and fusiform gyrus (Highley et al1998) areas in which AC axons are known to synapse (Demeteret al 1988 1990) Because of an association between brain asym-metry and interhemispheric connectivity (Witelson and Goldsmith1991 Ringo et al 1994) these findings suggest disruptions in the AC inschizophrenia

Parahippocampal gyrus has been identified as an important brainarea in the etiology of delusional symptoms possibly due to its role inemotion and memory processing (Casanova 1997 Acioly et al2010) Furthermore AC interconnects the orbitofrontal cortices (DiVirgilio et al 1999 Peuskens et al 2004) which play an importantrole in decision making processes (Krawczyk 2002) There is alsoneuroimaging evidence of orbitofrontal cortex abnormalities in schizo-phrenia (Crespo-Facorro et al 2000 Pantelis et al 2003 Nakamuraet al 2008) These findings suggest AC could influence the delusionalsymptoms and decision making impairments that are associated withschizophrenia

Additionally the AC contains interhemispheric fibers from theauditory cortex (Bamiou et al 2007) Planum temporale in particularlocated posterior to the auditory cortex has been reported asabnormal in schizophrenic patients (eg Falkai et al 1995 Kwonet al 1999) There is also evidence to suggest an association betweenplanum temporale and AC fibers where there is an associationbetween hemispheric asymmetry of the anatomical size of theplanum temporale and the sectional area of the AC based on apostmortem study (Kopp et al 1977) It is also well known that one ofthe most common symptoms of schizophrenia is auditory hallucina-tions Findings that suggest alterations in interhemispheric connec-tivity in schizophrenia especially in the AC could therefore underlieauditory symptoms in schizophrenia

To our knowledge there are no DTI studies of the AC inschizophrenia Currently there is only one MRI study evaluating theAC in schizophrenia where white matter tracts were analyzed usingvoxel-based morphometry and a decrease in white matter densitywas found in the right AC in schizophrenic patients (Hulshoff Pol et al2004) A small number of studies have investigated the AC in otherdisorders including a finding of ACWM abnormalities using region ofinterest (ROI) approaches in Chiari II-malformation (Herweh et al2009) and in neonatal hypoxicndashischemic encephalopathy (Chan et al2009) However tractography techniques were not employed tomeasure AC in those studies In the current study AC fiber tracts wereinvestigated using novel DTI post-processing techniques to define thisWM tract This study is thus the first to use tractography to investigateand to quantify AC tract integrity Of further note fiber tractographyhas been shown to have higher sensitivity and specificity than ROIapproaches or voxel-based analyses (Jones et al 2006 Kanaan et al2006)

The purpose of this study was to identify and to evaluate ACintegrity in patients with schizophrenia compared to healthy controlsSince the AC is anatomically related to the orbitofrontal cortex and thetemporal lobes (Di Virgilio et al 1999 Peuskens et al 2004) wepredicted that specific clinical symptoms including delusionshallucinations and impairments in executive functioning would beassociated with AC WM integrity anomalies in schizophrenia

2 Methods

21 Subjects

Twenty-six male patients with chronic schizophrenia wererecruited from the VA Boston Healthcare System Brockton MAcampus Patients were diagnosed on the basis of DSM-IV criteriaTwenty-six healthy male controls were recruited through localnewspaper advertisements They were group matched to patientson age sex handedness (Oldfield 1971) parental socioeconomicstatus (Hollingshead 1965) and a measure of premorbid WRAT scorefor IQ (Jastak and Wilkinson 1993) The study was approved by theIRB at the VA Boston Healthcare System and Brigham and WomensHospital All study participants signed an informed consent form

Inclusion and exclusion criteria for all subjects were 1) agebetween 18 and 55 years 2) right-handedness 3) no history ofelectroconvulsive treatment 4) no history of neurological illnessincluding epilepsy 5) no history of alcohol or drug dependence norabuse within the last year nor long duration (N1 year) of past abuse(DSM-IV criteria) 6) no presentmedication formedical disorders thatwould have deleterious EEG neurological or cognitive functioningconsequences 7) verbal IQ above 75 8) no alcohol use in the 24 hoursprior to testing and 9) English as a first language

All patients were receiving antipsychotic medication and allmedication dosages were converted to chlorpromazine equivalents(Stoll 2001) Clinical symptoms were measured by the Scale for theAssessment of Positive Symptoms (SAPS) (Andreasen 1984) and theScale for Assessment of Negative Symptoms (SANS) (Andreasen1981) Additionally we examined the performance of subjects on theIowa Gambling Task (Bechara et al 1994) a decision making taskbelieved to be associated with the orbitofrontal cortex (Bechara et al1998) In the Iowa Gambling Task subjects are asked to select cardsfrom four decks (A B C and D) Each card is associated with either again or loss of money Decks A and B are lsquodisadvantageousrsquo in thatsubjects will in the long run incur a net loss if they routinely selectfrom them In contrast Decks C and D are lsquoadvantageousrsquo A total of100 trials were performed without informing subjects the length ofthe experiment Net gambling score was measured as the number ofadvantageous choices minus the number of disadvantageous choicesTotal amount won total amount lost and total amounted earned(calculated as total amount won minus total amount lost) were alsomeasured to evaluate the decision making process

22 Image acquisition

For the Structural MRI volume measures images were acquiredusing a 3T GE scanner at BWH in Boston MA The structural MRIacquisition protocol included two MRI pulse sequences The firstresulted in contiguous spoiled gradient-recalled acquisition(fastSPGR) with the following parameters TR=74 ms TE=3 msTI=600 10deg flip angle 256 cm2

field of viewmatrix=256times256 Thevoxel dimensions were 1times1times1 mm The second-XETA (eXtendedEcho Train Acquisition) produces a series of contiguous T2-weightedimages (TR=2500 ms TE=80 ms 256 cm2

field of view) Voxeldimensions were 1times1times1 mm This latter sequence was used as theadditional channel of information for brain segmentation It was alsoused tomeasure volume of total intracranial contents whichwas thenused as an independent factor in a regression procedure to account forthe effect of head size

DTI data were collected on the 3 T GE Echospeed system (GeneralElectric Medical Systems Milwaukee WI) Scans were acquired usingan echoplanar imaging (EPI) DTI Tensor sequence and a double echooption to reduce eddyndashcurrent related distortions To reduce theimpact of EPI spatial distortion an 8 Channel coil and ASSETT (ArraySpatial Sensitivity Encoding techniques GE) with a SENSE-factor(speed-up) of 2 was used Eighty-five axial slices parallel to the ACndashPC

80 H Choi et al Schizophrenia Research 130 (2011) 78ndash85

line covering whole brain were acquired in 51 diffusion directionswith b=900 In addition 8 baseline scans with b=0 were alsoacquired Scan parameters were as follows TR 17000 ms TE 78 msFOV 24 cm 144times144 encoding steps 17 mm slice thicknessproducing isotropic 17times17times17 mm voxels

23 Image processing and analysis

We utilized Slicer 3D software Version 2 (wwwslicerorg) toanalyze the images and to measure tracts Tractography from twoROIs was carried out to analyze the AC tracts We used the fiberassignment by continuous tracking (FACT)method to extract the fibertract which made fiber trajectories from seeding points (Mori et al1999) This method initiates fiber trajectories from defined ROIs andfollows the primary eigenvector the orientation of the diffusiontensor from voxel to voxel After reaching the next voxel the fibertrajectory moves along the primary eigenvector of the next voxelTractography stopping criteria was FA b015 and an angle ofcurvature N20deg per 1 mm (Jones et al 2006)

To draw the AC ROIs were manually placed on color-by-orientation maps Because AC tracts travel from right to left voxels

Fig 1 ROIs to draw the AC and Tractography (A) In the color-by-orientation images the ROI(B) Because anterior commissure fibers pass through the midline a second ROI (indicatedextracted from the two ROIs

containing the AC appear red on color-by-orientationmaps The entireAC was therefore drawn using predominantly red voxels in coronalslices However since the AC is a very thin tract through the mid-sagittal slice and is surrounded by other fibers such as the fornix andhorizontal portions of the internal capsule many extraneous fiberswere included in this seeding In order to obtain precise and accurateAC tracts an additional ROI was drawn in the midsagittal plane thatincluded the medial portion of the AC tracts Because the AC is one ofthe commissural bundles it interconnects both hemispheres andpasses through the midline Accordingly we selected for tracts thattraveled through the midline ROI (Fig 1) Only axially-traversingtracts identified on a color-by-orientation map and that passedthrough the two ROIs were selected for fiber tracking and for furtherstatistical analyses All ROIs were drawn manually blind to diagnosisAverage trace length and FA were calculated for the extracted tracts

In some cases seeding from the two ROIs resulted in short andanatomically inaccurate AC tracts These cases produced tracts with anaverage fiber length plus standard deviation that was less than onevoxel in length (17 mm) Four such scans were found (three normalcontrols and one schizophrenia patient) and excluded from furtheranalyses resulting in a final count of 48 cases

(indicated in green) was drawn on the red voxels (ie representing rightndashleft diffusion)in blue) was drawn in the midsagittal plane (C) (D) Anterior commissure fibers were

Table 1Demographic data

Variable Mean (SD)

Patients with schizophrenia(N=25)

Controls(N=23)

Age (yr) 4469 (969) 4222 (1006)Sex ( male) 100 100Level of education (yr) 1318 (184) 1479 (201)Socioeconomic status 344 (108) 226 (087)Parental socioeconomic status 261 (112) 228 (127)Handednessa 072 (024) 074 (020)WRAT 986 (1423) 1035 (1170)Age of onset 2276 (502)Medication doseb 3576 (2644)SANS sum of score 1142 (732)SAPS sum of scorec 917 (407)

Pb001a Ratio of (rightminus left)(right+left) on handedness inventoryb Chlorpromazine equivalent in 2 patients medication dose was unavailablec In 1 patient clinical symptom scores were unavailable

81H Choi et al Schizophrenia Research 130 (2011) 78ndash85

24 Statistical analysis

For statistical analyses we used the Statistical Package for SocialSciences (SPSS version 160) To test for group differences in FAwithinthe AC analysis of variance (ANOVA) was performed with age andlevel of education as covariates and group as the between-subjectfactor Post-hoc independent T-tests were carried out to finddifferences in trace and FA within the AC between patients withschizophrenia and normal controls We also performed correlationalanalyses between mean FA values and age in both groups Pearsonscorrelational analyses of FA values with duration of illness daily doseof drugs SAPS scores SANS scores and Iowa Gambling Task scoreswere also carried out

3 Results

There were no group differences in mean age parental socioeco-nomic status handedness WRAT score or gender (all males) Level ofeducation and social economic status showed significant differencesbetween two groups (t=minus276 df=42 p=001 for level ofeducation and t=387 df=42 pb001 for social economic status)(Table 1)

There was a group effect for AC FA (F=980 pb001) and for Trace(F=859 pb001) Mean trace was significantly increased and meanFA was significantly decreased in AC tracts in the schizophrenia group

Fig 2 Results of FA and

compared with normal controls (t=304 df=289 pb001 for traceand t=minus314 df=46 pb001 for FA) (Fig 2) (Table 2)

A significant negative correlation was found between mean FA andage in schizophrenics but not in controls (r=minus0484 p=001 forschizophrenics and r=minus019 p=040 for controls) (Fig 3) Patientswith schizophrenia showed a trend for a positive correlation betweenTrace and age but this trend was not significant (r=039 p=006 forschizophrenics and r=035 p=010 for controls) Schizophrenicsshowed a trend towards decreased FAwith increased duration of illness(r=minus039 p=009) No significant correlations of mean FA in the ACwere found with socioeconomic status antipsychotic medication doseor duration of medication (r=minus012 p=058 for socioeconomicstatus r=minus030 p=0168 for medication dose r=minus010 p=0681for duration of medication)

Correlation analyses between clinical symptoms examined usingSANS and SAPS in schizophrenics and mean FA were also performedMean FAwas significantly positively correlatedwith positive symptoms(r=044 p=003 for global SAPS) but not with negative symptoms(r=012 p=057 for global SANS) Trace was not significantlycorrelated with global SAPS (r=minus024 p=026) or SANS (r=0151p=0472) scores (Table 3)

For the Iowa Gambling Task there were no significant differencesbetween groups in net gambling score (p=083) total amount won(p=091) total amount lost (p=034) or total amount earned(p=017) We examined correlations between the Iowa GamblingTask and mean FA in subjects FA was significantly negativelycorrelated with net gambling score [(C+D)minus(A+B)] (r=minus046p=004) and total amount earned (r=minus050 p=002) in schizo-phrenics but not in normal controls (r=minus021 p=056 for netgambling score r=minus043 p=022 for total amount earned) Therewere no significant correlation between Trace and Iowa GamblingTask scores (r=024 p=020 for net gambling score r=24 p=020for total amount earned) (Fig 4)

4 Discussion

Our main finding is that patients with schizophrenia reveal asignificant decrease in FA and an increase in trace in the AC comparedwithhealthy controls To the extent that FA is related to axonal integritydensity caliber andmyelination (Beaulieu andAllen 1994) ourfindingsof subnormal levels of FA in the AC suggest the presence ofmicrostructural abnormalities in this fasciculus in patients withschizophrenia Our results are consistent with those of Highley et al(1999) who reported reduced fiber density in the AC in schizophreniapatients postmortem With respect to our finding of higher trace in theschizophrenia patients compared with controls several previous DTI

Trace comparison

Table 2Mean fractional anisotropy and trace in the anterior commissure

Variable Mean (SD) P-value

Patients with schizophrenia(N=25)

Controls(N=23)

FA 0303 (0061) 0358 (0061) b001Tracea 359 (048) 329 (015) b001

a times103 mm2s

Table 3Correlation between FA Trace in anterior commissure and clinical symptoms inschizophrenia

Clinical measure Number of subjects Pearsons correlationcoefficients

P-value

FASum of global SAPS score 24 0444 0030

Sum of global SANS score 25 0121 0565Trace

Sum of global SAPS score 24 -0238 0260Sum of global SANS score 25 0151 0472

Pb005

82 H Choi et al Schizophrenia Research 130 (2011) 78ndash85

studies have suggested that increased trace is associated withimmaturity of the brain (Neil et al 1998) and structural brain disorderssuch as cerebral ischemia (Kim et al 2005) or hydrocephalus(Gideonet al 1994) The changes in trace and FA in our study thus suggest thatthere are structural abnormalities in the AC in schizophrenia

Our correlational findings between age and integrity of the AC inschizophrenia are similar to results of previous investigations withcingulum uncinate fasciculus (Mandl et al 2010 Rosenberger et al2008) and whole brain WM (Jones et al 2006 Mori et al 2007) Ourfinding and that of others that suggest negative correlations betweenage and white matter integrity support the hypothesis that thepathophysiology of schizophrenia may reflect progressive neurode-generation (DeLisi 1997 de Haan and Bakker 2004) However weobserved no significant correlations between duration of illness andFA suggesting that it is likely age rather than duration of illness that isrelevant to the observed correlations Longitudinal studies arehowever needed to clarify further whether or not white matterintegrity reduction reflects disease progression The latter is partic-ularly important given that findings of a correlation between age andFA have been reported in normal controls (Sullivan and Pfefferbaum2006 Kubicki et al 2008) Thus more research needs to be done thatcan tease apart what is age related effects that are seen in both normalcontrols and patients with schizophrenia and to address the questionof whether or not the age effects observed are different inschizophrenia and suggest disease progression Furthermore addi-tional studies will be needed to clarify whether medication or diseaseprogression affect the altered integrity of AC Longitudinal and first-episode studies of AC integrity will help to clarify these issues

Significant positive correlations were observed between patientsFA in the AC and severity of positive symptoms as measured by totalscores on SAPS This is not the first time that positive correlations havebeen observed between FA and positive symptom severity inschizophrenia patients On the contrary significant positive correla-tions have been reported in the corpus callosum (Hubl et al 2004Rotarska-Jagiela et al 2008) cingulum bundle (Hubl et al 2004)superior longitudinal fasciculus (Seok et al 2007 Shergill et al2007) arcuate fasciculus (Hubl et al 2004) and inferior fronto-occipital fasciculus (Szeszko et al 2008) However the present studyis the first (to our knowledge) to report a significant positive

20 30 40 50 6000

01

02

03

04

05

Normal Controls

Schizophrenia

Age

mea

n F

A v

alu

e

Fig 3 A scatter plot between mean FA and age Blue dots represent patients withschizophrenia and green dots represent normal controls Blue line indicates aregression line for schizophrenia (r=0484 pb001) and the green line indicates aregression line for normal controls (r=019 p=040)

correlation between positive symptom severity and FA in the AC inschizophrenia patients With regard to the cause of this seeminglyparadoxical yet consistently reported correlation Whitford et al(2010) have suggested that the answer may lie in the extent of theconduction delays that would be expected to arise from mild asopposed to severe white matter damage Specifically Whitford et al(2010) suggest thatmild conduction delays (such as might be expectedfrom mild FA reductions) could result in the aberrant neuralsynchronization (Andreasen et al 1999) that has been proposed tounderlie the symptoms of schizophrenia (Andreasen et al 1999Bartzokis 2002) In contrast severe conduction delays (such as mightbe expected from more severe FA reductions) could result in neuralsignals that are sufficiently disjointed so as to be unincorporable into acoherent phenomenological framework such as necessary for acoherent systematized delusion for example Our results showedsevere positive symptoms were related to minimally dysfunctionalFA However we found negative symptoms were not related to FAthough AC FA reduction predicted higher negative symptom score aswe predicted Nonetheless we needmore functional studies about therelationship between specific symptoms of schizophrenia and whitematter tracts Testing this speculation may provide a worthwhileavenue for future research

Since it has been reported that the orbitofrontal cortex plays animportant role in decision making processes (Krawczyk 2002) weinvestigated the relationship between FA in the AC which in-terconnects the orbitofrontal cortices (Di Virgilio et al 1999Peuskens et al 2004) and its abnormalities in schizophrenia andthe Iowa Gambling Task Our results indicate that such a relationshipindeed exists suggesting the notion that changes in interconnectivityof the AC affect decision making processes in schizophrenia It ispossible that altered interconnectivity of the AC may be related to thesame pathology producing orbitofrontal cortex volume reductionwhich has been shown to be associated with thought disorder inschizophrenia (Nakamura et al 2008) It is unclear why FA is higherin patients with severe decision making impairment however asimilar result was found in an impulsivity study of schizophrenia(Hoptman et al 2004) where FA was positively correlated withimpulsivity in the left postcentral gyrus right superiormiddletemporal gyrus and bilateral fusiform gyrus which might compro-mise a fronto-temporal-limbic circuit Additionally patients withschizophrenia showed a pattern of compromised decision makingthat is somewhat different from orbitofrontal cortex lesion patients(Shurman et al 2005) We therefore suspect that the AC plays a rolein the patterns of decision making impairment in schizophrenia Offurther note equivocal results have been found in terms of differencesin Iowa Gambling Task performance between SZ and NC with somestudies showing significant differences (Ritter et al 2004 Kesteret al 2006) but others not (Cavallaro et al 2003 Evans et al 2005Rodriacuteguez-Saacutenchez et al 2005) Regarding our study we observedthat patients with a large FA reduction had minimal decision makingimpairments which could potentially account for the minimal IowaGambling Task differences between patients and controls

-50 0 5000

01

02

03

04

05

Normal Controlsr=-021p=056

Schizophreniar=-046p=004

Net Gambling Score

FA

-4000 -2000 0 2000 400000

01

02

03

04

05

Normal Controlsr=-043p=022

Schizophreniar=-050p=002

Total Amount Earned

FA

Fig 4 Correlation analyses between Iowa Gambling Tasks and FA of AC In schizophrenia group (blue circles) FAwas significantly correlatedwith net gambling score [(C+D)minus(A+B)](r=minus046 p=004) total amountwon (r=051 p=002) total amount lost (r=052 p=002) and total amount earned (r=minus050 p=002) Innormal controls (green squares) FAwas not significantly correlated with all parameters

83H Choi et al Schizophrenia Research 130 (2011) 78ndash85

While AC FA was associated with decision making and positivesymptoms in our study it is unclear whether schizophrenia symptomsand decision making are related Some studies suggest decision makingimpairment of schizophrenia and negative symptoms are associated(Shurman et al 2005) while some studies do not (Evans et al 2005)Another study suggests that some negative symptoms are associatedwith frontal medial cortex dysfunction as measured with a Theory ofMind test but that there was not a significant correlation between theIowaGambling Task and negative symptom scores (Martino et al 2007)To our knowledge there is no evidence to suggest a relationship betweendecision making and positive symptom scores However regardless ofwhether decisionmaking and clinical symptoms are related AC integrityseems to be related to multiple symptoms in schizophrenia

There is a considerable overlap between the participant sample inthe current paper and the sample presented in the Whitford et alpaper Specifically 16 (615) of SZ patients and 11 (423) of the HCparticipants were also investigated in theWhitford et al paper Thereis some evidence from the literature that the CC and AC are closelyrelated in terms of their structural integrity In a previous study aboutcallosal agenesis (Fischer et al 1992) there was hypertrophy of AC inpatients with callosal agenesis suggesting that AC may compensatefor damage to the CC Regarding the relationship between AC and CCin the present study we correlated the AC Fractional Anisotropyresults with the CC1 (genu) Fractional Anisotropy results from theWhitford et al paper and observed a non-significant trend for apositive correlation (r=032 p=010) across both groups

Our study is the first to measure AC integrity using tractography inschizophrenia Tractography has shown higher sensitivity andspecificity compared to ROI or voxel-based morphometry analysis(Kanaan et al 2006) Though the AC plays an important role ininterconnection of the two hemispheres there are few studies thatinvestigate its changes in schizophrenia By using tractography toanalyze AC fibers wewere able to define extract and directlymeasureAC integrity and its relationship with clinical symptoms and age Wenote however that a diffusion tensor model is not always adequateespecially in voxels containing complex crossing tracts from differ-ently oriented fibers (Alexander et al 2002 Tuch et al 2002)Nonetheless DTI is the most popular approach to tractography andfiber crossings are not such an issue with AC Further studies shouldinclude a multi-tensor approach that may provide more informationabout AC tract and integrity Since some studies have found thatchanges in FA might be related to medication dosage (Minami et al2003 Okugawa et al 2004) and our schizophrenia subjects are allchronically medicated and additional studies are needed to clarifywhether the relationship between age and FA is due to a medicationeffect Sex differences in fiber numbers or cross sectional areas in theAC have also been reported (Allen and Gorski 1991 Highley et al1999) In the current study however we only investigated changes inmale subjects We therefore need a larger mixed-sex cohort to obtaina full interpretation of AC pathology in schizophrenia

Conclusions

Reduced connectivity within the anterior commissure in schizo-phrenia was found in our study using high resolution DTI and atractography approach Our study found that age affected the reducedinterhemispheric connectivity in schizophrenia and interconnectivityof the AC was positively correlated with positive symptoms as well asdecision making impairment These results can help us understandthe functional anatomy of the brain by understanding further therelationship between symptoms and interconnectivity of the AC in thepathophysiology of schizophrenia

Supplementarymaterials related to this article can be found onlineat doi101016jschres201104016

Role of funding sourceAll of the study sponsors had no further role in study design in the collection

analysis and interpretation of data in the writing of the report and in the decision tosubmit the paper for publication

ContributorsHongyoon Choi Marek Kubicki ThomasWhitford andMartha E Shenton designed

the study and wrote the protocol Hongyoon Choi also wrote the first draft of themanuscript Jorge L Alvarado and Douglas P Terry collected some data and undertookthe statistical analysis Margaret Niznikiewicz and Robert W McCarley managed therecruitment and collected clinical information of participants Martha E ShentonMarek Kubicki Thomas Whitford and Jun Soo Kwon supervised the statistical analysesand edited multiple iterations of the manuscript All authors contributed to and haveimproved the final manuscript

Conflict of interestAll authors declare that they have no competing financial interests

AcknowledgementsThis study was supported in part by grants from the National Institute of Health

(K05MH070047 and R01MH 50740 toMES R01MH 40799 to RWM P50MH 080272mdash

CIDAR awardmdash to RWM MES) the Department of Veterans Affairs Merit Awards (MESRWM) and the VA Schizophrenia Center Grant (RWMMES) This work was alsosupported in part by the National Alliance for Medical Image Computing (NA-MIC)the latter a grant supported through the National Institutes of Health Roadmap forMedical Research Grant U54 EB005149 (MK) and by an Overseas-Based BiomedicalTraining Fellowship from the National Health andMedical Council of Australia (NHMRC520627) through the University of Melbourne (TW)

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Bartzokis G 2002 Schizophrenia breakdown in the well-regulated lifelong process ofbrain development and maturation Neuropsychopharmacology 27 672ndash683

Basser PJ 1995 Inferring microstructural features and the physiological state oftissues from diffusion-weighted images NMR Biomed 8 333ndash344

Basser PJ Mattiello J LeBihan D 1994 MR diffusion tensor spectroscopy andimaging Biophys J 66 259ndash267

Beaulieu C Allen P 1994 Determinants of anisotropic water diffusion in nerves MRM31 394ndash400

Bechara A Damasio AR Damasio H Anderson SW 1994 Insensitivity to futureconsequences following damage to human prefrontal cortex Cognition 50 7ndash15

Bechara A Damasio H Tranel D Anderson SW 1998 Dissociation of workingmemory from decision making within the human prefrontal cortex J Neurosci 18428ndash437

Burns J Job D Bastin ME Whalley H Macgillivray T Johnstone EC Lawrie SM2003 Structural disconnectivity in schizophrenia a diffusion tensor magneticresonance imaging study Br J Psychiatry 182 439ndash443

Casanova MF 1997 The temporolimbic system theory of paranoid schizophreniaSchizophr Bull 23 513ndash515

Cavallaro R Cavedini P Mistretta P Bassi T Angelone SM Ubbiali A Bellodi L2003 Basalndashcorticofrontal circuits in schizophrenia and obsessivendashcompulsivedisorder a controlled double dissociation study Biol Psychiatry 54 437ndash443

Chan KC Khong PL Lau HF Cheung PT Wu EX 2009 Late measures ofmicrostructural alterations in severe neonatal hypoxicndashischemic encephalopathyby MR diffusion tensor imaging Int J Dev Neurosci 27 607ndash615

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de Haan L Bakker JM 2004 Overview of neuropathological theories of schizophreniafrom degeneration to progressive developmental disorder Psychopathology 37 1ndash7

DeLisi LE 1997 Is schizophrenia a lifetime disorder of brain plasticity growth andaging Schizophr Res 23 119ndash129

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Di Virgilio G Clarke S Pizzolato G Schaffner T 1999 Cortical regions contributingto the anterior commissure in man Exp Brain Res 124 1ndash7

Evans CE Bowman CH Turnbull OH 2005 Subjective awareness on the IowaGambling Task the key role of emotional experience in schizophrenia J Clin ExpNeuropsychol 27 656ndash664

Falkai P Bogerts B Schneider T Greve B Pfeiffer U Pilz K Gonsiorzcyk CMajtenyi C Ovary I 1995 Disturbed planum temporale asymmetry inschizophrenia A quantitative post-mortem study Schizophr Res 14 161ndash176

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Foong J Maier M Clark CA Barker GJ Miller DH RonMA 2000 Neuropathologicalabnormalities of the corpus callosum in schizophrenia a diffusion tensor imagingstudy J Neurol Neurosurg Psychiatry 68 242ndash244

Fujiwara H Namiki C Hirao K Miyata J Shimizu M Fukuyama H Sawamoto NHayashi T Murai T 2007 Anterior and posterior cingulum abnormalities andtheir association with psychopathology in schizophrenia a diffusion tensorimaging study Schizophr Res 95 215ndash222

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Herweh C Akbar M Wengenroth M Blatow M Mair-Walther J Rehbein NNennig E Schenk JP Heiland S Stippich C 2009 DTI of commissural fibers inpatients with Chiari II-malformation Neuroimage 44 306ndash311

Highley JR Esiri MM McDonald B Cortina-Borja M Cooper SJ Herron BMCrow TJ 1998 Anomalies of cerebral asymmetry in schizophrenia interact withgender and age of onset a post-mortem study Schizophr Res 34 13ndash25

Highley JR Esiri MM McDonald B Roberts HC Walker MA Crow TJ 1999 Thesize and fiber composition of the anterior commissure with respect to gender andschizophrenia Biol Psychiatry 45 1120ndash1127

Hollingshead AB 1965 Two Factor Index of Social Position Yale University Press NewHaven CT

Hoptman MJ Ardekani BA Butler PD Nierenberg J Javitt DC Lim KO 2004 DTIand impulsivity in schizophrenia a first voxelwise correlational analysisNeuroreport 15 2467ndash2470

Hubl D Koenig T Strik W Federspiel A Kreis R Boesch C Maier SE Schroth GLovblad K Dierks T 2004 Pathways that make voices white matter changes inauditory hallucinations Arch Gen Psychiatry 61 658ndash668

Hulshoff Pol HE Schnack HG Mandl RC Cahn W Collins DL Evans AC Kahn RS2004 Focal white matter density changes in schizophrenia reduced inter-hemispheric connectivity Neuroimage 21 27ndash35

Jastak S Wilkinson G 1993 The Wide Range Achievement Testmdash (WRAT-III) 3rd edJastek Wilmington

Jones DK Catani M Pierpaoli C Reeves SJ Shergill SS OSullivan MGolesworthy P McGuire P Horsfield MA Simmons A Williams SC HowardRJ 2006 Age effects on diffusion tensor magnetic resonance imaging tractographymeasures of frontal cortex connections in schizophrenia Hum Brain Mapp 27230ndash238

Kanaan RA Shergill SS Barker GJ Catani M Ng VW Howard R McGuire PKJones DK 2006 Tract-specific anisotropy measurements in diffusion tensorimaging Psychiatry Res 146 73ndash82

Kester HM Sevy S Yechiam E Burdick KE Cervellione KL Kumra S 2006Decision-making impairments in adolescents with early-onset schizophreniaSchizophr Res 85 113ndash123

Kim HJ Choi CG Lee DH Lee JH Kim SJ Suh DC 2005 High-b-value diffusion-weightedMR imaging of hyperacute ischemic stroke at 15 T AJNR Am JNeuroradiol26 208ndash215

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human decision making Neurosci Biobehav Rev 26 631ndash664Kubicki M Westin CF Nestor PG Wible CG Frumin M Maier SE Kikinis R

Jolesz FA McCarley RW Shenton ME 2003 Cingulate fasciculus integritydisruption in schizophrenia a magnetic resonance diffusion tensor imaging studyBiol Psychiatry 54 1171ndash1180

KubickiM StynerM Bouix S GerigGMarkant D Smith K Kikinis RMcCarley RWShenton ME 2008 Reduced interhemispheric connectivity in schizophrenia-tractography based segmentation of the corpus callosum Schizophr Res 106125ndash131

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Mandl RC Schnack HG Luigjes J van den Heuvel MP Cahn W Kahn RSHulshoff Pol HE 2010 Tract-based analysis of magnetization transfer ratio anddiffusion tensor imaging of the frontal and frontotemporal connections inschizophrenia Schizophr Bull 36 778ndash787

Martino DJ Bucay D Butman JT Allegri RF 2007 Neuropsychological frontalimpairments and negative symptoms in schizophrenia Psychiatry Res 152121ndash128

Minami T Nobuhara K Okugawa G Takase K Yoshida T Sawada S Ha-Kawa SIkeda K Kinoshita T 2003 Diffusion tensor magnetic resonance imaging ofdisruption of regional white matter in schizophrenia Neuropsychobiology 47141ndash145

Mori S Crain BJ Chacko VP van Zijl PC 1999 Three-dimensional tracking ofaxonal projections in the brain by magnetic resonance imaging Ann Neurol 45265ndash269

Mori T Ohnishi T Hashimoto R Nemoto K Moriguchi Y Noguchi H NakabayashiT Hori H Harada S Saitoh O Matsuda H Kunugi H 2007 Progressive changesof white matter integrity in schizophrenia revealed by diffusion tensor imagingPsychiatry Res 154 133ndash145

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Okugawa G Nobuhara K Minami T Tamagaki C Takase K Sugimoto T Sawada SKinoshita T 2004 Subtle disruption of the middle cerebellar peduncles in patientswith schizophrenia Neuropsychobiology 50 119ndash123

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Pantelis C Velakoulis D McGorry PD Wood SJ Suckling J Phillips LJ Yung ARBullmore ET Brewer W Soulsby B Desmond P McGuire PK 2003Neuroanatomical abnormalities before and after onset of psychosis a cross-sectional and longitudinal MRI comparison Lancet 361 281ndash288

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Price G Bagary MS Cercignani M Altmann DR Ron MA 2005 The corpuscallosum in first episode schizophrenia a diffusion tensor imaging study J NeurolNeurosurg Psychiatry 76 585ndash587

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Rodriacuteguez-Saacutenchez JM Crespo-Facorro B Perez-Iglesias R Gonzaacutelez-Blanch CAlvarez-Jimenez M Llorca J Vaacutezquez-Barquero JL 2005 Prefrontal cognitivefunctions in stabilized first-episode patients with schizophrenia spectrumdisorders a dissociation between dorsolateral and orbitofrontal functioningSchizophr Res 77 279ndash288

Rosenberger G Kubicki M Nestor PG Connor E Bushell GB Markant DNiznikiewicz M Westin CF Kikinis R Saykin AJ McCarley RW Shenton ME2008 Age-related deficits in fronto-temporal connections in schizophrenia adiffusion tensor imaging study Schizophr Res 102 181ndash188

85H Choi et al Schizophrenia Research 130 (2011) 78ndash85

Rotarska-Jagiela A Schonmeyer R Oertel V Haenschel C Vogeley K Linden DE2008 The corpus callosum in schizophrenia-volume and connectivity changesaffect specific regions Neuroimage 39 1522ndash1532

Seok JH Park HJ Chun JW Lee SK Cho HS Kwon JS Kim JJ 2007 Whitematter abnormalities associated with auditory hallucinations in schizophrenia acombined study of voxel-based analyses of diffusion tensor imaging and structuralmagnetic resonance imaging Psychiatry Res 156 93ndash104

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Shergill SS Kanaan RA Chitnis XA ODaly O Jones DK Frangou S Williams SCHoward RJ Barker GJ Murray RM McGuire P 2007 A diffusion tensorimaging study of fasciculi in schizophrenia Am J Psychiatry 164 467ndash473

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Stoll 2001 The Psychopharmacology References Card Antipsychotic Treatment GuideMcLean Hospital Belmont MA

Sullivan EV Pfefferbaum A 2006 Diffusion tensor imaging and aging NeurosciBiobehav Rev 30 749ndash761

Sun Z Wang F Cui L Breeze J Du X Wang X Cong Z Zhang H Li B Hong NZhang D 2003 Abnormal anterior cingulum in patients with schizophrenia adiffusion tensor imaging study Neuroreport 14 1833ndash1836

Szeszko PR Robinson DG Ashtari M Vogel J Betensky J Sevy S Ardekani BALencz T Malhotra AK McCormack J Miller R Lim KO Gunduz-Bruce HKane JM Bilder RM 2008 Clinical and neuropsychological correlates of whitematter abnormalities in recent onset schizophrenia Neuropsychopharmacology33 976ndash984

Tuch DS Reese TG Wiegell MR Makris N Belliveau JW Wedeen VJ 2002 Highangular resolution diffusion imaging reveals intravoxel white matter fiberheterogeneity Magn Reson Med 48 577ndash582

Whitford TJ Kubicki M Schneiderman JS ODonnell L King R Alvarado JL KhanU Markant D Nestor PG Niznikiewica M McCarley RWWestin CF ShentonME 2010 Corpus callosum abnormalities and their association with psychoticsymptoms in patients with schizophrenia Biol Psychiatry 68 70ndash77

Witelson SF Goldsmith CH 1991 The relationship of hand preference to anatomy ofthe corpus callosum in men Brain Res 545 175ndash182