Psychiatry Research: Neuroimaging 122 (2003) 153–167 Searching for a structural endophenotype in psychosis using computational morphometry Machteld Marcelisa , John Suckling b,c,fd , Peter Woodruff e , Paul Hofman f , Ed Bullmore , Jim van Osa,g, * aDepartment of Psychiatry and Neuropsychology, European Graduate School of Neuroscience, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands bClinical Age Research Unit, Department of Health Care of the Elderly, Guy’s King’s and St. Thomas’ Medical School, London, UK cDepartment of Biostatistics and Computing, Institute of Psychiatry, London, UK dUniversity of Sheffield, Sheffield, UK eDepartment of Radiology, University Hospital Maastricht, Maastricht, The Netherlands fDepartment of Psychiatry, University of Cambridge, UK gDivision of Psychological Medicine, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK Received 26 November 2001; received in revised form 17 September 2002; accepted 14 November 2002 Abstract Structural cerebral abnormalities are frequently observed in schizophrenia. These abnormalities may indicate vulnerability for the disorder, as evidenced by reports of familial clustering of measures identified through region-of- interest analyses using manual outlining procedures. We used computational morphometry to detect structural differences within the entire brain to further examine possible structural endophenotypes. Magnetic resonance imaging scans were obtained in 31 psychotic patients, 32 non-psychotic first-degree relatives of psychotic patients and 27 healthy controls. The images were processed using an automated procedure, yielding global grey matter, white matter, CSF and total brain volume. The relative distribution ofgrey matter was compared between groups on a clustered- voxel basis. Global grey matter and total brain volume did not differ between the groups. White matter volume was significantly higher and CSF volume significantly lower in relatives compared to both cases and controls. The clustered-voxel based group comparison yielded evidence for significant grey matter deficits in fronto-thalamic- cerebellar regions, in psychotic patients, whereas the most prominent deficits in relatives involved the cerebellum. Patients with psychosis and first-degree healthy relatives of patients with psychosis show cerebellar abnormalities, which may constitute a marker ofgenetic transmission. ᮊ 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Schizophrenia; Structural magnetic resonance imaging; Voxel-based; Cerebellum; Marker; Family study; Brain *Corresponding author. Tel.: q31-43-3299-773; fax: q31-20-877-9249. E-mail address: [email protected] (J. van Os). 0925-4927/03/$ - see front matter ᮊ 2002 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0925-4927(02)00125-7 154 M. Marcelis et al. / Psychiatry Research: Neuroimaging 122 (2003) 153–167 1. Introduction which we hypothesised that structural abnormali- ties would be present in psychotic patients, and Many questions remain regarding the origins of not necessarily in the same regions given the the structural cerebral abnormalities associated possible effects of the illness and its treatment, in with schizophrenia. The structural alterations have non-psychotic first-degree relatives of patients with been directly related to the clinical phenotype, but psychosis. have also been found to be indicators of (genetic) liability for the disorder (endophenotypic markers 2. Methods ofliability ). In addition, certain structural brain alterations may be the result ofmedication and the 2.1. Study sample illness itself, thus not reflecting a possible cause but rather a consequence ofthe disorder. MRI scans were acquired from 31 patients with Studies of first-degree relatives are useful in the psychosis, 32 non-psychotic first-degree relatives search for endophenotypes. In addition to evidence ofpatients with psychosis and 27 healthy controls. for familial aggregation of ventricular enlargement The present subsample is part ofa larger study, typically derived from computed tomography scan- the Maastricht Psychosis Study (Krabbendam et ning (reviewed in Cannon and Marco, 1994), al., 2001). recent magnetic resonance imaging (MRI) studies Patients with a lifetime history of clinical psy- show more diverse patterns ofcortical and yor chosis (ofat least 2 weeks ) according to the subcortical alterations in both patients with schiz- Rearch Diagnostic Criteria (RDC)(Spitzer et al., ophrenia and their first-degree relatives (Seidman 1978), who were not in need ofin-patient treat- et al., 1997; Sharma et al., 1997; Cannon et al., ment, were recruited at the community mental 1998; Staal et al., 1998; Seidman et al., 1999; health centre in Maastricht, the Netherlands. Non- Staal et al., 2000; Wright et al., 2000). Traditional psychotic first-degree relatives were recruited MRI studies have been based on a priori defined through the participating patients, as well as regions ofinterest (ROI) and manual outlining through a local relative association. Relatives had procedures to assess volumetric measurements. to be free from a lifetime history of psychosis. This method, however, may preclude the observa- Unrelated healthy controls were sampled from the tion of significant but unexpected findings, and general population, using a mailing procedure to may have contributed to inconsistencies in the randomly selected households in the local catch- literature and publication bias (Wolkin et al., ment area. Controls were excluded whenever they 1998). The availability ofcomputational mor- had a personal or family history of psychosis or phometric techniques that permit the detection of other psychiatric disorder requiring hospital structural differences within the entire brain admission. (Andreasen et al., 1994a; Collins et al., 1994; The present sample included 78 families, of Wright et al., 1995; Wolkin et al., 1998; Bullmore which 11 families contributed one patient and one et al., 1999) may possibly lead to more consistent discordant sibling, and one family contributed two results regarding the origins ofcerebral abnormal- non-psychotic relatives (parent and sib). From the ities in schizophrenia and their possible role in the remaining 66 families, 20 independent patients, 19 pathophysiology. In addition, these techniques are independent first-degree relatives, and 27 controls generally more automated and faster than tradition- were included. al ROI methods ofanalysis, providing the oppor- Other inclusion criteria for all participants (cas- tunity to investigate larger samples. In the present es, relatives and controls) were being in the age family study, such a computational morphometric range of18–55 years and being in good health as technique was used, which comprised both global determined by a physical examination, electrocar- and regional (clustered-voxel) comparisons ofthe diography and routine laboratory investigations. relative distributions ofthe separate brain tissues. Individuals with a history ofsevere head trauma The present article focuses on grey matter, for with loss ofconsciousness, neurological disorders M. Marcelis et al. / Psychiatry Research: Neuroimaging 122 (2003) 153–167 155 andyor other medical disorders that might have receiving antipsychotic medication (14 patients significantly affected brain function or structure received atypical, 13 received typical and one were excluded, as well as individuals who used patient received a combination ofatypical and alcohol in excess offivestandard units per day or typical antipsychotic medication). The groups did illicit drugs on a weekly basis. not differ on mean alcohol intake (in units per week) over the last year wpatients: 9.6 (S.D.s 2.2. Clinical and diagnostic procedures 12.5), relatives: 5.0 (S.D.s8.0), controls: 5.5 (S.D.s5.8), Fs2.29, d.f.s2, 87, Ps0.11). There Patients, relatives and controls were interviewed were four patients and one relative who had used with the BriefPsychiatric Rating Scale (Overall drugs within the past year (two patients and one and Gorham, 1962; Lukoff et al., 1986) and the relative had used cannabis, one patient had used Positive and Negative Syndrome Scale (Kay et al., both cannabis and a stimulant drug, and one patient 1987). They were additionally screened for symp- had used cocaine). All ofthem stopped using toms listed in the OCCPI (McGuffin et al., 1991). drugs at least 1 month prior to study participation. Where necessary, additional information was All the subjects gave written informed consent derived from case notes and interviews with the after the procedures had been fully explained in responsible medical officer. Using the combined conformity with the local ethics committee information, the computerised program OPCRIT guidelines. (McGuffin et al., 1991) yielded the following RDC diagnoses in the cases: schizophrenia (ns25) and 2.3. Image acquisition schizo-affective disorder (ns6). Among the first- degree relatives, there were four lifetime diagnoses MRI scans were obtained at the Department of and in four first-degree relatives a (life-time) of Radiology, University Hospital Maastricht, The major depression. No other psychiatric disorders Netherlands, with a Gyroscan NT T-I1 (Philips were detected in the relatives, nor were any ofthe Medical Systems) operating at 1.5 Tesla. Inter- controls diagnosed with psychiatric illness. Hand- leaved two-dimensional dual-echo fast spin-echo edness was assessed using the Annett Handedness images (60 slices, 3-mm