Caudate volume in offspring of patients with schizophrenia

Caudate nuclei are smaller in drug-naive people with schizophreniabut larger in antipsychotic-treated patients. In this magneticresonance imaging study we found volume reduction of rightand left caudate by 8.9 and 8.1% respectively in 50 offspringwithout psychosis of patients with schizophrenia compared with53 age- and gender-matched controls, providing new evidencethat caudate volume reduction may be a trait-related abnormalityin schizophrenia.

INTRODUCTION

TOP

INTRODUCTION

The caudate nucleus is a major target area for the subcorticaldopamine projection system, which is implicated in the pathophysiologyof schizophrenia. Caudate and other basal ganglia nuclei helpregulate and organise the information flow between frontallobes and the rest of the brain and play a major part in highercognitive functions and movement (Middleton & Strick, 1994).Disruptions in this system or lesions of the basal ganglia resultin movement disorders and behavioural problems similar to schizophrenia (Heckers, 1997).

Previous studies have shown enlarged caudate in patients treatedwith dopamine-blocking antipsychotics (Jernigan et al, 1991);however, a reduction has been reported among drug-naive patients(e.g. Keshavan et al, 1998) but it is not known whether thisreduction precedes the illness. At-risk studies have shownbrain abnormalities and behavioural deviances supporting neurodevelopmentalpathology prior to psychosis (Lawrie et al, 2001; Rajarethinam et al, 2004;Job et al, 2005; Keshavan et al, 2005). We predicted thatindividuals at risk would have a smaller caudate nucleus thanthose with no family history of mental illness.

METHOD

TOP

METHOD

Fifty young people (22 males and 28 females, mean age 15.4 years,s.d.=3.6) with at least one parent with schizophrenia and 53healthy comparison participants (27 males and 28 females, meanage 16.5 years, s.d.=4.4) with no family history of mentalillness participated from an ongoing study at the Universityof Pittsburgh. Other findings from this study have been reported elsewhere (Rajarethinam et al, 2004; Keshavan et al, 2005).The parental diagnosis in the high-risk group was ascertainedwith the Structured Clinical Interview for DSM–IV (SCID; Spitzer et al, 1992) and consensus clinical diagnosis. Comparisonparticipants were similar in age, gender and socio-economicand geographical background but with no family history of mentalillness. In the high-risk group 26 (57%) had Axis I psychopathologyand IQ was lower (control group, mean IQ 115, s.d.=12; high-riskgroup, mean IQ 103, s.d.=13; F=7.184, P<0.011). None ofthe participants had psychosis. Seven participants were beingtreated with stimulants and four with antidepressants, butnone with antipsychotics. The University of Pittsburgh institutionalreview board approved the study. All participants providedwritten consent; those under 18 years provided informed assentalso. Participants aged 15 years or younger were evaluated withthe Schedule for Affective Disorders and Schizophrenia for School-Age Children (K–SADS–PL version; Kaufman et al, 1999) and those over 15 were evaluated using the SCID. Anyone witha lifetime history of psychosis, significant neurological ormedical illness, current substance use disorder, or any contraindicationfor magnetic resonance imaging (MRI) was excluded from participatingin either group.

For MRI, 124 T₁-weighted 1.5 mm coronal slices, without interslicegap, were obtained using a 1.5 T GE scanner (General Electric, Milwaukee, Wisconsin, USA) with three-dimensional spoiled gradientrecall acquisition, matrix 256x256x192, field of view 24 cm,repetition time 25 ms, and time to echo 5 ms. Scans were reviewedto exclude structural abnormalities. The total brain volumewas measured by a semi-automatic method using BRAINS2 software(Magnotta et al, 2002) and manually edited for accuracy. Theinterrater reliability between the four raters ranged from0.98 to 0.99.

Caudate volumes were measured using the artificial neural network application, a semi-automated tracing method in BRAINS2, withmanual editing for accuracy by two trained raters (P.T. andM.U.). Measurement included the head and body of the caudatebut not the tail. The test–retest reliability for eachrater was established using a set of three scans: (P.T.) rightcaudate r=0.98, left caudate r=0.99; (M.U.) right caudate r=0.99,left caudate r=0.95. The interrater reliability (intraclassr=0.94 for both right and left caudate) was established usinga set of nine scans. Differences in age and intracranial volumewere examined by two-tailed unpaired t-tests. Multivariate analysisbased on the general linear model was conducted with group status (at-risk v. control) and intracranial volume as predictor variables and caudate volumes as dependent variables.

RESULTS

TOP

RESULTS

Age and gender distribution were not significantly differentbetween the groups. The mean total brain volume of the high-riskgroup (1311.25 cm³, s.d.=130.7) was significantly smaller thanthat of the comparison group (1391.21 cm³, s.d.=136.3, F=9.223, P>0.003). Analysis of covariance using brain volume as acovariate revealed that the right caudate was significantlysmaller in the high-risk group (F=4.014, P<0.05) and theleft caudate showed a trend for reduction (F= 2.92, P=0.091) (Fig. 1). The right and left caudate nuclei were smaller inthe high-risk group by 8.9 and 8.1% respectively (right caudate:control mean volume 3.58 cm³, s.d.=0.51; high-risk mean volume3.26 cm³, s.d.=0.45; left caudate: control mean volume 3.57cm³, s.d.=0.51, high-risk mean volume 3.28 cm³, s.d.=0.49).Psychopathology or medication status did not have any significanteffect on caudate volumes.

View larger version (17K):
[in this window]
[in a new window]
[as a PowerPoint slide]
Fig. 1 Covarying for the total intracranial volume, the right caudate volume was significantly smaller in the high-risk group (HR) than in the healthy control group (HC) (F=4.014, P<0.05), and the left caudate showed a trend for reduction (F=2.92, P=0.091).

DISCUSSION

TOP

DISCUSSION

Our findings indicate that abnormalities in the caudate nucleusmay be seen in young relatives of patients with schizophrenia.Individuals at risk for schizophrenia exhibit behavioural problemsand brain abnormalities, suggesting that some form of the pathologicalprocess may begin before the onset of symptoms (Keshavan et al, 2005).However, not all of these at-risk individuals would develop schizophrenia; therefore, the observed neuroanatomical alterationsmay reflect a measure of familial risk or susceptibility. Theconversion to psychosis may result from an interaction betweensuch susceptibility factors and unknown environmental influencesor developmental/maturational changes that may involve thissystem.

Our observations are consistent with studies of basal gangliafunction in individuals at risk for schizophrenia. Adult first-degreerelatives of schizophrenia patients made more errors on anantisaccade task than a comparison group, suggesting a dysfunctionof dorsolateral prefrontal cortex, caudate nucleus, or both(Clementz et al, 1994). Similarly, functional MRI studies haveshown decreased activation of the caudate with antisaccadetasks in unaffected relatives (Raemaekers et al, 2006). Thesefindings suggest that an alteration of the structural and functionalintegrity of corticostriatal neural networks may represent familialor premorbid risk of schizophrenia. It is conceivable that this network may have a role in other neurocognitive deficits suchas attentional impairments found in at-risk individuals (Keshavan et al, 2005).In addition, in the context of conflicting research regardingthe increase and decrease in caudate volume in relation to treatment or drug-naive status, our data clearly support the hypothesisthat volume reduction rather than enlargement of the caudatenucleus is associated with the pathophysiology of schizophrenia.In contrast, Lawrie et al (2001) reported no difference inthe caudate volumes in at-risk relatives (not offspring), someof whom were symptomatic.

To our knowledge, few studies have examined basal ganglia inasymptomatic, untreated, adolescent offspring who are at geneticrisk of schizophrenia. High-risk studies enable investigationof neuropathology without the confounds of state-related illnessmanifestations and medication effects. The neuroanatomicalspecificity of the observed findings is unclear, but caudate volume reductions might be part of an abnormal corticostriatalnetwork; we and others have found prefrontal and temporal corticalvolume deficits in this population (Rajarethinam et al, 2004;Job et al, 2005). The precise mechanisms underlying caudatevolume reduction are unclear, and may involve either a failureof normal development or an excessive pruning (Keshavan et al, 2005).

These findings are intriguing, but must be considered preliminary,need replication and may not be generalisable to non-familialforms of schizophrenia. Although the difference was modest,type I errors are unlikely as the sample was large. Our findingssupport the notion that smaller caudate is a marker of geneticsusceptibility, but it is not known whether this abnormalityis present at birth or becomes evident during childhood and adolescence. Prospective studies in high-risk individuals suggestthat about 10–15% develop schizophrenia, although upto 40% develop schizophrenia-spectrum psychopathology (Erlenmeyer-Kimling et al, 1997).Follow-up of these individuals will help elucidate the role of the caudate in premorbid vulnerability to and later progressioninto schizophrenia.

ACKNOWLEDGMENTS

TOP

ACKNOWLEDGMENTS

Support from National Institute of Mental Health grants MH 64023,01180 (M.S.K.), NARSAD independent Investigator award (M.S.K.)and GCRC grant M01 RR00056. We thank Diana Dworakowski, MS,and Debra Montrose, PhD, for help with recruitment and assessment,and Jeffrey Nutche, BS, for image processing.

REFERENCES

TOP