Original Article

Relationship between frontostriatalmorphology and executive function deficits inbipolar I disorder following a first manicepisode: data from the Systematic TreatmentOptimization Program for Early Mania(STOP-EM)

Kozicky J-M, Ha TH, Torres IJ, Bond DJ, Honer WG, Lam RW,Yatham LN. Relationship between frontostriatal morphology andexecutive function deficits in bipolar I disorder following a first manicepisode: data from the Systematic Treatment Optimization Program forEarly Mania (STOP-EM).Bipolar Disord 2013: 15: 657–668. © 2013 John Wiley & Sons A/S.Published by John Wiley & Sons Ltd.

Objectives: Executive function impairments are a core feature of bipolarI disorder (BD-I), not only present during acute episodes but alsopersisting following remission of mood symptoms. Despite advances inknowledge regarding the neural basis of executive functions in healthysubjects, research into morphological abnormalities underlying thedeficits in BD-I is lacking.

Methods: Patients with BD-I within three months of sustained remissionfrom their first manic episode (n = 41) underwent neuropsychologicaltesting and a 3T magnetic resonance imaging scan and were compared tohealthy subjects matched for age, sex, and premorbid IQ (n = 30).Group dorsolateral prefrontal cortex (DLPFC; Brodmann areas 9 and46) and caudate volumes were examined and analyzed for relationshipswith the average score from three computerized tests of executivefunction: Spatial Working Memory, Stockings of Cambridge, andIntradimensional/Extradimensional Shift.

Results: Right caudate volumes were enlarged in patients (z = 3.57,p < 0.05 corrected). No differences in DLPFC volumes were found.Patients showed large deficits in executive function relative to healthysubjects (d = �0.92, p < 0.001). While in healthy subjects, a larger right(r = +0.39, p < 0.05) and left (r = +0.44, p < 0.05) caudate was associatedwith better executive function score, in patients, larger right (r = �0.36,p < 0.05) and left (r = �0.34, p < 0.05) volumes correlated with poorerperformance.

Conclusions: Although the etiology of gray matter changes is unknown,volume increases in the right caudate may be an important factorunderlying executive function impairments during remission in patientswith BD-I.

Jan-Marie Kozickya, Tae Hyon Haa,b,Ivan J Torresa,c, David J Bonda,William G Honera, Raymond W Lama

and Lakshmi N Yathama

aDepartment of Psychiatry, University of British

Columbia, Vancouver, BC, Canada,bDepartment of Psychiatry, Seoul National

University Bundang Hospital, Seongnam City,

Kyeonggi-do, South Korea, cResearch

Department, Riverview Hospital, British

Columbia Mental Health and Addictions

Services, Coquitlam, BC, Canada

doi: 10.1111/bdi.12103

Key words: basal ganglia – bipolar disorder –

CANTAB – caudate – cognition – dorsolateral

prefrontal cortex – executive function –

magnetic resonance imaging – voxel-based

morphometry

Received 8 May 2012, revised and accepted for

publication 24 February 2013

Corresponding author:

Lakshmi N. Yatham, MBBS, FRCPC, MRCPsych

(UK)

Department of Psychiatry

University of British Columbia

Room 2C7-2255 Wesbrook Mall

Vancouver, BC V6T 2A1

Canada

Fax: +1-604-822-7922

E-mail: yatham@mail.ubc.ca

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Bipolar Disorders 2013: 15: 657–668 © 2013 John Wiley & Sons A/SPublished by John Wiley & Sons Ltd.

BIPOLAR DISORDERS

Cognitive deficits, particularly in the domain ofexecutive functioning, are a core feature of bipolarI disorder (BD-I), not only present during acutemanic or depressive episodes but also persistinginto periods of remission (1, 2). These skills areimportant for many aspects of daily life, and evenmodest impairments can lead to noticeablebehavioural difficulties including problems in plan-ning, organization, abstract reasoning, problemsolving, and decision making (3, 4). Impairmentsin executive functioning may affect a patient’s abil-ity to work and attend school, function indepen-dently at home, or develop and maintainappropriate social relations. As such, it is no sur-prise that problems in executive functioning arestrongly associated with the marked psychosocialimpairment present in people with BD-I betweenmood episodes (5), a relationship even beyond theinfluence subsyndromal symptoms (6).This is acritical issue, even early in the course of illness. Inthe two years following syndromal recovery fromtheir first manic or mixed episode, less than half ofpatients return to their premorbid functional status(7). At this initial stage of diagnosis there are sig-nificant impairments in executive function, withresults from the Systematic Treatment Optimiza-tion Program for Early Mania (STOP-EM) indi-cating that, despite syndromal recovery andcontinuation of maintenance pharmacologicaltreatment, patients who have recently experiencedtheir first manic episode still show significant defi-cits in many tests of executive function (8). Simi-larly, Barrett et al. (9) found that, after controllingfor current intellectual abilities, the severity ofexecutive impairments in patients with BD-I expe-riencing their first episode of mania was similar tothat of patients with schizophrenia during theonset of psychosis.

As chronic effects of BD-I on the presence orseverity of executive deficits are still minimal at thispoint in the disorder, dysfunction is likely moreclosely related to risk factors associated with illnessexpression. Indeed, poor executive function perfor-mance may be attributable to environmental fac-tors such as childhood trauma or substance abuse(10), or to genetic risk. Many of the same genesthat have been implicated in BD-I are also impor-tant for executive functions (11, 12), with unaf-fected first-degree relatives of patients alsoshowing similar, though less pronounced, impair-ments (13, 14). Dysfunctions may become progres-sively more severe throughout the course of illness(15); this may be a consequence of neurodegenera-tion caused by stress-related overload of behav-ioral and physiological regulatory systems (16), asmany neural regions implicated in executive

function are sensitive to their effects (17). Iatro-genic effects of pharmacological treatment on exec-utive abilities also cannot be ruled out;antipsychotic use in particular has been consis-tently associated with impaired executive functionin this population (18, 19), with some studies sug-gesting normal performance in those who are notreceiving these drugs (20).

Prior studies examining the morphologicalbasis for cognitive impairment in samples ofpatients with BD-I have found that the relation-ship between brain volume and executive abilitiesdiffers between patients and controls in severalsubregions including the dorsolateral prefrontalcortex (DLPFC), anterior cingulate cortex, andbasal ganglia (21–23). However, these studieswere conducted in heterogeneous patient sampleswhich included subjects with variable mood statesand illness or treatment duration, and focused onregions of interest that were based on areas impli-cated in the general pathophysiology of BD-Irather than executive function per se. Extensivestudies in human and non-human cognitive neu-roscience indicate that the DLPFC and its con-nections to the caudate nucleus of the basalganglia are essential for executive function abili-ties (24, 25). This circuit also shows relevance forthe pathophysiology of BD-I, potentially underly-ing not only cognitive deficits but also problemswith emotional regulation that define this disor-der (26–28). Although inconsistent, prior struc-tural imaging studies have found abnormalities inthese regions. Caudate enlargements have beenobserved in adolescents with BD-I (29) and theirunaffected relatives (30), as well as in more heter-ogeneous samples (reviewed in 31). Reductions inDLPFC volume have also been found, and maybe related to severity of mood symptoms (32) orillness progression (33). Due to a near absence ofwell-designed studies looking at the role of treat-ment in structural changes, it is unclear whethermedications have any effects. A recent meta-anal-ysis suggests that any impact of mood stabilizersis likely to be minimal, limited to normalizingdisease-related volume loss in medial areas, whileantipsychotics overall do not show consistenteffects (34).

Computerized tests of executive function fromthe Cambridge Neurocognitive Test AutomatedBattery (CANTAB) are sensitive to dysfunctionin and between the DLPFC and caudate (35,36). By comparing performance on these tests tovolumetric measures of these regions, this studywill examine the contribution of frontostriatalmorphology to the severity of executive functiondeficits in BD-I. Furthermore, through study of

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a sample of patients following remission of theirfirst manic episode, we will be able to minimizethe potentially confounding effects of acutemood state, illness duration, or chronic treat-ment. We hypothesized that compared to healthysubjects patients would show significant impair-ments in executive function, and at this point inthe illness caudate enlargements and DLPFCvolume reductions would be associated with theseverity of deficits.

Methods

Participants

Clinically stable patients meeting DSM-IV-TR cri-teria for BD-I were identified as part of the ongo-ing STOP-EM study at the University of BritishColumbia (UBC) Hospital and affiliated sites, aswell as through community and hospital referralsfrom physicians and psychiatrists. A more com-plete description of the study protocol can befound elsewhere (37). Briefly, all patients werediagnosed and identified for inclusion based on acomprehensive clinical interview by an academicresearch psychiatrist and confirmed by the Mini-International Neuropsychiatric Interview (38).Participants were required to be 17–35 years ofage, and to be within three months of remissionfrom their first manic/mixed episode, where remis-sion was defined as no longer meeting DSM-IVcriteria for a manic/mixed episode for two consecu-tive weeks. Those who had experienced psychoticsymptoms during a mood episode or any pre/com-orbidities were not excluded as long as the primarydiagnosis was BD-I. Patients received ongoingnaturalistic treatment from psychiatrists withexpertise in the management of mood disordersaccording to current clinical practice guidelines(39). Of the first 75 patients enrolled in the pro-gram, 41 completed the baseline cognitive assess-ment while meeting criteria for continuedremission [Hamilton Depression Rating Scale(HAM-D) and Young Mania Rating Scale(YMRS) ≤ 12 at the time closest to testing (moodscores were obtained on the same day as cognitiveassessment for 39% of the patients, within twoweeks for 83%, within one month for 90%, andwithin two months for all patients)], and also had amagnetic resonance imaging (MRI) scan (neuroi-maging and cognitive testing were performed onthe same day for 29% of patients, within twoweeks for 63% and within one month for 79%,and all subjects had both visits completed within10 weeks of each other). Healthy subjects, free of apersonal or family history of psychiatric illness in

their first- or second-degree relatives were recruitedfrom the community through advertising. A totalof 38 healthy subjects underwent neurocognitivetesting and of those 30 also underwent an MRIscan (cognitive testing and neuroimaging wereperformed on the same day for 23% of healthysubjects, within two weeks for 60% and within onemonth for 80%, and all had the two visits com-pleted within 12 weeks of each other). Ethicsapproval was granted by the UBC ClinicalResearch Ethics Board, and written informedconsent was obtained from all patients andhealthy subjects prior to performing any studyprocedures.

Clinical assessment

Sociodemographic and clinical variables werecollected as per the STOP-EM protocol. TheHAM-D, YMRS, Positive and Negative Syn-drome Scale, and Brief Psychiatric Rating Scaleswere administered to assess subthreshold symp-toms. Additional variables recorded includedpremorbid and current occupational functioning,the number of prior depressive episodes, anyhistory of psychotic symptoms during a moodepisode, time since remission of manic symp-toms, age of onset of illness, and lifetime sub-stance abuse or dependence, as well as dose andduration of current psychotropic treatment. Tofacilitate statistical comparison, antipsychoticdoses were standardized according to relativedopamine D2 receptor (D2R) potency by theempirically grounded method proposed byBaitz et al. (40), whereby 1 mg of loxapine isequivalent to 0.08 mg of risperidone, 5.73 mg ofolanzapine, or 8.72 mg of quetiapine.

Assessment of executive function

All executive functioning tests were administeredin a quiet testing room following standard pro-cedures as part of a 2–3-hour cognitive battery.Three measures from the CANTAB were chosento represent executive function abilities (35):Spatial Working Memory between errors(SWM), Stockings of Cambridge problemssolved within the minimum number of moves(SOC), and Intradimensional/ExtradimensionalShift extradimensional shift errors (IED/EDS).The North American Adult Reading Test full-scale intelligence quotient (IQ) was used tomeasure premorbid intellectual function (41),and the Kaufman Brief Intelligence Test full-scale IQ was used to assess current intellectualability (42).

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Acquisition and preprocessing of T1 magnetic

resonance (MR) images

T1-weighted MR images were acquired on a Phi-lips Achieva 3.0 Tesla scanner (Amsterdam, TheNetherlands) using a three-dimensional axial inver-sion recovery-weighted spoiled gradient recalledsequence with the following parameters: field ofview = 25.6 cm, matrix = 256 9 256, isotropicvoxels (1 9 1 9 1 mm3), autoshim, repetitiontime/echo time = autoset shortest, T/R head coil,flip angle = 8°, and 1-mm-thick contiguous 180slices of the whole brain.

Data were processed and examined using theStatistical Parametric Mapping (SPM8) software(43), where we applied voxel-based morphometry(VBM) implemented in the VBM8 toolbox (44). T1images were bias corrected, segmented into graymatter, white matter, and cerebrospinal fluid, andapplied via affine transformation to MontrealNeurological Institute (MNI) standardized space.The affine registered gray and white mattersegments were used to create a customized Diffeo-morphic Anatomical Registration Through Expo-nential Lie Algebra (DARTEL) template fornon-linear warping. Then, each subject’s originalimages were normalized using the high-dimen-sional DARTEL algorithm to MNI space. Nor-malized segmented gray matter images weremultiplied by the non-linear components derivedfrom the normalization matrix in order to preserveactual gray matter values locally (modulation)(45). This allows comparison of the absolutevolumes of tissue corrected for individual brainsizes. The modulated normalized gray matterimages with a voxel size of 1.5 9 1.5 9 1.5 mm3

were smoothed with an 8-mm full-width at half-maximum Gaussian kernel.

Statistical analysis

All data are reported as means and standard devia-tions (SDs). Correlations, regressions, and groupcomparisons for clinical and cognitive variableswere conducted using SPSS 19.0 (SPSS Inc., Chi-cago, IL, USA). We conducted group comparisonsof clinical variables using chi-square for categoricalvariables and the independent samples t-test forcontinuous variables.

All executive raw scores were first adjusted forage, sex, and premorbid intelligence based onCANTAB normative data. Summary executivescores for each subject were calculated using theaverage adjusted score of the three tests. Standard-ized z-scores were then calculated using the meanand SD of the summary executive score from the

larger group of healthy subjects who underwentneurocognitive testing but may have not had anMRI scan. This enhanced normalization of the dis-tribution of the executive summary score, andfacilitated comparison between groups; which wasperformed using the independent samples t-test.

Bilateral masks for the DLPFC (Brodmannareas 9 and 46) and caudate [head/body; the tailwas excluded due to its role in sensorimotor ratherthan executive control (46)] were generated usingthe WFU PickAtlas toolbox (47). Group gray mat-ter volume contrasts with small volume correction(SVC) were confined to these regions of interest(ROIs), using voxel-based analysis covarying forage, gender, and total gray matter. We report coor-dinates that meet a threshold of p < 0.05 family-wise error-corrected at voxel and cluster level.

Separate Pearson correlations for patients andhealthy subjects were used to examine the relation-ship between executive scores and morphologicaland demographic/clinical variables. For this analy-sis, gray matter volumes from the four ROIs wereextracted from smoothed normalized gray matterimages of all subjects using the MarsBar toolbox(48). Volumetric or clinical measures that showedat least trend correlation (p < 0.1) with the sum-mary executive score were included as predictors ina hierarchical multiple regression.

Results

Demographic and clinical variables

The patient population (n = 41) was young [meanage 22.8 (SD = 4.6) years], educated [mean time ineducation 13.4 (SD = 2.4) years], and displayedaverage to high average premorbid IQ [mean 107.0(SD = 7.2)]. Patients and the healthy subjects werecomparable in regard to age, sex, and premorbidand current intellectual functioning (Table 1),although the patient group had a significantlylower level of educational attainment (t = �2.39,df = 1, 69, p < 0.05). Patients had been in remis-sion from their first manic episode for a mean 48(SD = 31) days. Overall functioning was only min-imally impaired, with the average Global Assess-ment of Functioning score = 70.0 (SD = 14). Ofthe 37 patients who were employed or in schoolprior to onset of the manic episode, 59.5%returned to work or school, 29.7% were on sickleave or disability benefits, and the remaining10.8% were unemployed. All but two healthysubjects were employed or in school; one was onlong-term disability benefits, and the other wasunemployed. The proportion of individuals unem-ployed or on sick leave/disability benefits was

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higher in patients than in healthy subjects(v2 = 10.44, p < 0.001).

Patients were early in their course of illness, hav-ing experienced an average of 1.1 (SD = 1.7) priordepressive episodes. Subthreshold symptomatol-ogy was low; mean YMRS = 0.9 (SD = 2.0) andmean HAM-D score = 3.8 (SD = 4.2). A total of73% patients experienced psychotic symptomsduring their first manic episode. Five patients hada prior history of anxiety (n = 4) or attention-deficit hyperactivity disorder (n = 1).

No patients had any exposure to mood-stabiliz-ing or antipsychotic treatment prior to their firstmanic episode; seven had previously been treatedwith antidepressant(s). At the time of assessment,90.2% of patients were taking pharmacologicaltreatments: 70.7% were receiving combinationtreatment with an antipsychotic and a mood stabi-lizer, 12.2% mood stabilizer monotherapy, and7.3% antipsychotic monotherapy. One patient wasbeing treated with an antidepressant. The averageduration of current antipsychotic/mood-stabilizingtreatment was 6.4 (SD = 4.1) weeks. The averageantipsychotic dose was 17.0 (SD = 19.6) mg loxa-pine equivalents. The average dose of lithium was

909 (SD = 154) mg and that of valproate was967 (SD = 362) mg.

Comparison of executive function scores between

groups

The distribution of the summary executive score ofthe two groups is shown in Figure 1. Table 2reveals that patients had a significantly lower exec-utive function summary score when compared tohealthy subjects (t = �4.02, df = 1, 69, p < 0.001).These results were maintained after covarying foreducation. Significant (p < 0.05) impairments inthe patient group were also seen in all of the threeindividual measures of executive function. Theseresults were maintained after using the Mann–Whitney U-test for non-parametric data.

Volumetric differences between groups

Patients had increased gray matter volume in theright caudate (cluster size = 169 voxels, p < 0.05corrected; peak voxel MNI coordinates: 18, 17, 15;t = 3.77, p < 0.05 corrected) (Fig. 2). This wasmaintained after covarying for age, gender, and

Table 1. Demographic and clinical variables among patients with bipolar I disorder and healthy subjects

Patients with bipolarI disorder (n = 41)

Healthy subjects(n = 30) t-test

Mean (SD) Mean (SD) t (df = 1, 69)

Age (years) 22.8 (4.6) 22.9 (4.7) �0.08, NSEducation (years) 13.4 (2.4) 14.7 (2.2) �2.39, p < 0.05Premorbid intellectual function (IQ) 107.0 (7.2) 107.2 (7.9) �0.3, NSCurrent intellectual function (IQ) 105.7 (11.1) 109.3 (9.2) �1.44, NSAge of onset (years)a 20.4 (5.0)No. of prior depressive episodes 1.1 (1.7)HAM-D score 3.8 (4.2)YMRS score 0.9 (2.0)BPRS score 21.4 (5.4)PANSS score 7.4 (1.0)GAF score 70.0 (14.3)Weeks in remission from mania 6.9 (4.4)Weeks on medication 6.4 (4.1)Antipsychotic dose (mg loxapine) 17.0 (19.6)

% (n) % (n) v2

Sex, male 58.5 (24) 40.0 (12.0) 2.38, NSMood stabilizer 82.9 (34)Lithium 39.0 (16)Divalproex 41.4 (17)Antipsychotic 78.0 (32)Olanzapine 17.1 (7)Quetiapine 24.4 (10)Risperidone 36.6 (15)History of psychosis 78.0 (32)History of drug abuse 43.9 (18)

BPRS = Brief Psychiatric Rating Scale; GAF = Global Assessment of Functioning; HAM-D = Hamilton Depression Rating Scale;NS = non-significant (p > 0.05); PANSS = Positive and Negative Syndrome Scale; YMRS = Young Mania Rating Scale.aAge of first self-reported hypo/manic or depressive episode.

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total gray matter volume (p < 0.05 corrected).There were no significant gray matter volume dif-ferences in the left caudate or right or left DLPFC.

Correlations between executive function scores and

clinical and morphometric variables

In patients, there was a significant negative rela-tionship between summary executive score andboth right (r = �0.39, p < 0.05) and left(r = �0.34, p < 0.05) caudate volumes such thatsmaller caudate volume was associated with higherexecutive functioning (Fig. 3). Executive score didnot correlate with right or left DLPFC volume(p > 0.15).

Higher executive scores in patients showed a sig-nificant relationship with current intellectual func-tioning (r = 0.38, p < 0.05), and trend associationswith higher premorbid intellectual functioning(r = 0.26, p = 0.10) and education (r = 0.26,p = 0.10). No correlations were seen betweenexecutive scores and age, or any illness variablesincluding age of onset, current symptom scores,time since remission or medication dose or dura-tion (all p > 0.10).

Because of the potentially confounding effects ofsubsyndromal mood symptoms on the relationshipbetween cognitive performance and frontostriatalvolume, we next specifically examined correlates ofexecutive function in the subgroup of patients(n = 28) who met strict criteria for euthymia(HAM-D, YMRS ≤ 7). In this group, a strongrelationship with medication emerged, withincreased duration of pharmacological treatment(r = �0.59, p < 0.001) and dose of antipsychotic(r = �0.42, p = 0.05) associated with impairedexecutive function. In these subjects, the correla-tion between right caudate volume and executivescore was reduced to trend significance (r = �0.34,p = 0.08), and the relationship with left caudatevolume was non-significant (r = �0.26, p = 0.18).There were no significant relationships betweenantipsychotic dose and caudate volume (p > 0.4).

In healthy subjects, executive function positivelycorrelated with the right (r = 0.44, p < 0.05) andleft (r = 0.39, p < 0.05) caudate volumes; incontrast to patients with BD-I, the direction of thisrelationship was such that larger caudate volumewas associated with better executive functioning.Executive score did not correlate with age, educa-

Table 2. Executive function z-scores in patients with bipolar I disorder and healthy subjects

Patients with bipolarI disorder (n = 41)

Healthy subjects(n = 30) t-test

Effectsize

Summary executive score �1.06 (1.59) 0.14 (0.92) �4.02 (p < 0.001) 0.92SOC problems solved in minimum moves �0.24 (1.18) 0.63 (0.87) �3.42 (p < 0.001) 0.84ID/EDS EDS errorsa �0.49 (1.42) 0.31 (0.80) �3.02 (p < 0.01) 0.69SWM between search errors �0.37 (1.35) 0.33 (1.06) �2.44 (p < 0.05) 0.58

ID/EDS EDS = Intradimensional/Extradimensional Shift Extradimensional Shift Errors; SOC = Stockings of Cambridge; SWM = SpatialWorking Memory.aIn cases where the EDS stage was not reached, 25 errors was substituted (35).

0

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Bipolar I disorderHealthy subjects

Fig. 1. Distribution of summary executive z-scores in patients with bipolar I disorder and healthy subjects.

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tion, intellectual functioning, or DLPFC volume(all p > 0.1).

Regression models predicting executive function in

patients

For the first step of a hierarchical regressionmodel, current IQ (b = 0.43, p < 0.01) and educa-tion (b = 0.08, non-significant) predicted theexecutive summary score in patients (r2 = 0.22,

F = 4.78, p < 0.05). Addition of right caudatevolume (b = �0.30, p < 0.05), duration ofpharmacological treatment (b = �0.30, p < 0.05),and dose of antipsychotic medication (b = �0.25,p = 0.07) significantly improved the model(DF = 4.02, p < 0.05); with the predictive value ofcurrent intellectual function (b = 0.42, p < 0.01)and education (b = 0.05, non-significant) main-tained. Together these variables accounted for42.9% of the variance in executive function.

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X rBDI= –0.39 p<0.05rHS= +0.39, p<0.05

X rBDI= –0.43, p<0.05rHS= +0.44, p<0.05

Fig. 3. Correlation between summary executive score and caudate gray matter volume in patients with bipolar I disorder and healthysubjects. BD-I = bipolar I disorder; HS = healthy subjects.

Fig. 2. Coronal, parasagittal, and axial sections of grey matter increase in the caudate in bipolar I disorder. Gray bar indicates peakvoxel t-values.

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In the subgroup of patients who met strict crite-ria for euthymia for the first step of the hierarchicalregression model, intellectual function (b = 0.39,p < 0.05) and education (b = 0.07, non-significant)predicted executive function ability at trend levelsignificance (r2 = 0.17, F = 2.52, p = 0.10). Addi-tion of right caudate volume (b = �0.29,p < 0.05), weeks on medication (b = �0.45,p < 0.01), and antipsychotic dose (b = �0.36,p < 0.05) significantly improved the model(DF = 10.64, p < 0.001), and the predictive valueof current intellectual function (b = 0.42, p < 0.01)and education (b = 0.12, non-significant).Together, these variables accounted for 66.0% ofthe variance in executive function.

Discussion

Results from this study indicate that patients withBD-I who have recently recovered from their firstmanic episode demonstrate significant impairmentsin executive function when compared to healthysubjects, deficits that may be partially attributableto an enlargement of the caudate nucleus. Theseresults are in strong accordance with those of Hart-berg et al. (23) who found that the volume of theright putamen, which shows much functionalhomology with the caudate (49), was inverselyrelated to the severity of executive (verbal fluency)deficits in a large sample of patients with bipolarspectrum disorder and schizophrenia.

Dysfunction in the caudate and other basal gan-glia structures has been implicated in the patho-physiology of BD-I for the last two decades (25,50). As part of the striatum—the main input struc-ture of the basal ganglia—the caudate plays a pri-mary role in the funneling and integration of higherorder sensory, emotional and cognitive inputs fromthroughout the brain. Along with the rest of thebasal nuclei, it is crucial for selectively gating whatinformation gets updated in the DLPFC where itcan be further integrated, maintained and/ormanipulated and used to bias processing in poster-ior regions (24, 25, 51, 52). Functional MRI studiesconsistently report hyperactivity of the caudateduring both emotional and cognitive tasks in thispopulation (53–56), and connectivity between thecaudate nucleus and prefrontal cortex is altered inpatients with bipolar disorder when compared tohealthy controls (57–59).

Morphometric studies of the caudate indicatethat, despite minimal differences in volumebetween patients with bipolar disorder and healthysubjects, abnormalities may still have biologicalsignificance. While there are several reports ofincreased caudate volume in patients with bipolar

disorder, most studies have yielded negative results(reviewed in 26, 60). There is evidence to supportthe hypothesis that caudate abnormalities may pre-cede onset of bipolar disorder; in a study of off-spring of patients with bipolar disorder, Hajeket al. (61) found a similar magnitude of caudateenlargement as in the present analysis. In bothunaffected and affected offspring, the maximaleffect was found in the anterior portion of the cau-date head, an area linked to neuropsychologicaldysfunction in treatment-na€ıve patients withschizophrenia (62). Research in healthy subjectsindicates caudate volumes are highly heritable, andrelated to variants in dopamine-related functioning(63–65). These genes are also related to executivefunction performance in healthy subjects (66, 67)and patients with schizophrenia (68), as well asimplicated in risk for bipolar disorder (69, 70).

In a subset of patients who met strict criteria foreuthymia, weeks spent on antipsychotic medica-tion also contributed to the extent of executivefunction impairments, an effect stronger than thatof caudate changes. Several post hoc analyses haveindicated a strong negative effect of antipsychoticson executive performance in BD-I (10, 18–20), withindication from a different subset of this samplethat there may be differences between agents—spe-cifically, an association between treatment with ris-peridone and poorer executive performancerelative to quetiapine use (71). This result has alsobeen reported in a more heterogeneous group (72).Iatrogenic effects of antipsychotic treatment oncaudate volume also cannot be ruled out. While wedid not detect any differences in volume betweenpatients who were receiving antipsychotics andthose who were not, this is likely due to the largevariety of treatment combinations and short dura-tions used in this first-episode naturalistic design.The only available study of caudate morphology inrelation to medication use was carried out byHwang et al. (73), who found that shape altera-tions compared to healthy controls were present inthe right posterior dorsal and anterior ventral cau-date in unmedicated patients but not in patientsbeing treated with lithium, valproate, or atypicalantipsychotics. There have been several studiesinvestigating the effect of atypical antipsychoticson basal ganglia volumes in first-episode schizo-phrenia, most of which have found no effect ofthese agents on the caudate (74–77). However,Massana et al. (78) found that treatment with ahigh dose of risperidone was associated with anincrease in caudate volume in initially treatment-na€ıve patients with schizophrenia, a finding thatwas attributed to the similarity in pharmacody-namic profiles between risperidone and typical

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antipsychotics, which do increase caudate volume(79). In contrast, quetiapine, which does not sharethe same similarity with risperidone and typicalantipsychotics, may decrease caudate volume in adose-dependent manner (80). Although there is sig-nificant overlap in pathophysiology and treatmentbetween bipolar disorder and schizophrenia, stud-ies in patients with BD-I are needed to elucidatethe effects of individual antipsychotic agents onbasal ganglia shape, structure, and function.

In contrast to findings by Haldane et al. (22)who investigated the relationship between responseinhibition and brain volumes in a sample ofpatients with chronic BD-I, we did not find anycontribution of DLPFC volumes to executiveimpairments in this sample. We also did not findany differences in volume in this area betweenpatients and healthy subjects; consistent with otherfirst-episode studies from this (81) and otherresearch sites (82). DLPFC volume (35), like exec-utive function performance (15), has shown a nega-tive correlation with number of previous manicepisodes, indicating that abnormalities may emergeas a consequence of disease progression as a mech-anism by which impairments in executive functioncould be induced or exacerbated throughout thecourse of illness (83). Specifically, chronic, mal-adaptive overload of behavioral and physiologicalregulatory systems within and between mood epi-sodes (reviewed in 16) can lead to architecturalchanges in the prefrontal cortex, including reduceddendritic length, branching, and spine density;changes which are associated with reduced cogni-tive functioning in animal models of stressresponse (17). Further longitudinal studies areneeded to explore the rate and cognitive correlatesof neurodegeneration in this area, and the impactof both genetic predisposition and pharmacologi-cal intervention on a patient’s sensitivity to itseffects.

There are several limitations that need to benoted in the interpretation of these results. Thepatients who were examined were all early in theircourse of illness. As mentioned above, emergingliterature on the neurobiology of BD-I indicatesthat many of the morphometric and cognitiveabnormalities found at illness onset may progressover time and the relationships between them arealso likely to evolve. Patients were treated natural-istically and thus received combinations of phar-macological treatments, making any conclusionson their effects tentative and in need of replication.Although a large proportion of subjects wereeuthymic, many patients did have mild subsyndro-mal mood symptoms. Although we did not find anobvious relationship between mood and structural

or executive changes, we cannot eliminate any con-tributing effects. Caution also must be exercised ingeneralizing findings from these measures to execu-tive abilities overall, as tests were chosen based ontheir sensitivity for frontostriatal dysfunction (36).Furthermore, we only examined the relationshipbetween test scores and DLPFC and caudate vol-umes, eliminating the opportunity to detect contri-butions from abnormalities in other brain areas orbroader circuits which also could underlie execu-tive functions. These results are consistent withprior findings from this sample: when comparingvolumes of the entire prefrontal cortex, anteriorcingulate cortex, and striatum using voxel-basedmorphometry, patients who demonstrated impair-ments on paper and pencil tests of executive func-tion showed a trend toward increased rightcaudate volume when compared to healthy sub-jects, a result not shared with patients who hadnormal executive functioning (84).

In summary, we found that enlargements of theright caudate are a significant predictor of execu-tive function deficits in patients with BD-I. Abnor-malities in the caudate may reflect vulnerability toBD-I, as findings in first-episode patients excludemuch of the impact of chronic illness; howeverstudies combining cognitive and morphologicalmeasurements in high-risk samples are needed tofurther explore this possibility. As antipsychotics,and in particular conventional antipsychotics mayalso increase caudate volumes and impact cogni-tive functioning, studies specifically designed toexamine treatment effects, or those restricted topatients who are unmedicated, will also be impor-tant to clarify these relationships. Longitudinalprospective studies in the current sample shouldprove valuable in further elucidating the contribu-tion of illness recurrence and chronic antipsychotictreatment to the relationship between frontostria-tal morphology and executive function in BD-I.

Acknowledgements

The data for this study were generated from the SystematicTreatment Optimization Program for Early Mania (STOP-EM) which was supported by unrestricted grant funding fromAstraZeneca, Canada.

Disclosures

DJB has been an investigator in clinical trials sponsored by Sa-nofi-Aventis, GlaxoSmithKline, and Servier; has receivedgrant/research support from Pfizer, the Canadian Institutes ofHealth Research, and the Coast Capital Depression ResearchFund/UBC Institute of Mental Health; and has received hono-raria from AstraZeneca, Janssen-Ortho, Lundbeck, Sunovion,Bristol-Myers Squibb, the Canadian Psychiatric Association,

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and the Canadian Network for Mood and Anxiety Treatments.WGH has received grants from the Canadian Institutes ofHealth Research (CIHR); has received consulting fees or hasparticipated in paid advisory boards for MDH Consulting, InSilico, Novartis, Lundbeck and Roche; and has received hono-raria from Rush University, the Korean Society for Schizo-phrenia Research, the Centre for Addiction and Mental Health(Toronto), the BC Schizophrenia Society, The Fraser, Vancou-ver Coastal, and the Providence Health Authorities, and theCanadian Agency for Drugs and Technology in Health. RWLhas received research support or honoraria from Aquaceutica,AstraZeneca, Biovail, Bristol-Myers Squibb, Canadian Insti-tutes of Health Research, Canadian Network for Mood andAnxiety Treatments, Canadian Psychiatric Association Foun-dation, Eli Lilly & Co., Litebook Co., Lundbeck, LundbeckInstitute, Mochida, Pfizer, Servier, St. Jude Medical, Takeda,and UBC Institute of Mental Health/Coast Capital Savings.LNY has received research grants from, has been a member ofadvisory boards for, and has been a speaker for AstraZeneca,Janssen, Eli Lilly & Co., GlaxoSmithKline, Bristol-MyersSquibb, Novartis, Servier, and Pfizer. JK, THH, and IJT haveno conflicts of interest to report.

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