Regional prefrontal cortex gray matter volumes in youth at familial risk for schizophrenia from the Harvard Adolescent High Risk Study

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Abstract

Background:

Regional prefrontal cortex gray matter reductions have been identified in schizophrenia, likely reflecting a combination of genetic vulnerability and disease effects. Few morphometric studies to date have examined regional prefrontal abnormalities in non-psychotic biological relatives who have not passed through the age range of peak risk for onset of psychosis. We conducted a region-of-interest morphometric study of prefrontal subregions in adolescent and young adult relatives of schizophrenia patients.

Methods:

Twenty-seven familial high-risk (FHR) first-degree relatives of schizophrenia patients and forty-eight control subjects without a family history of psychosis (ages 13–28) underwent high-resolution magnetic resonance imaging at 1.5 Tesla. The prefrontal cortex was parcellated into polar, dorsolateral, ventrolateral, ventromedial and orbital subregions. The Chapman scales measured subpsychotic symptoms. General linear models examined associations of prefrontal subregion volumes with familial risk and subpsychotic symptoms.

Results:

FHR subjects had significantly reduced bilateral ventromedial prefrontal and frontal pole gray matter volumes compared with controls. Ventromedial volume was significantly negatively correlated with magical ideation and anhedonia scores in FHR subjects.

Conclusions:

Selective, regional prefrontal gray matter reductions may differentially mark genetic vulnerability and early symptom processes among non-psychotic young adults at familial risk for schizophrenia.

Introduction

Since schizophrenia was first posited to be a brain disorder a century ago (Bleuler, 1911, Kraepelin, 1919), a wealth of postmortem and neuroimaging evidence has provided robust confirmation (Johnstone et al., 1976, Selemon & Goldman-Rakic, 1999, Shenton et al., 2001). Among many brain regions, the prefrontal cortex (PFC) has been implicated by an impressive variety of empirical research, and figures prominently in theoretical accounts of schizophrenia (Keshavan et al., 1994, Seidman, 1983, Weinberger, 1987). Schizophrenia has been associated with reduced prefrontal cortical thickness (e.g., (Selemon et al., 1995)), and with reduced gray matter (GM) in lateral, medial, and orbital prefrontal areas (Gur et al., 2000, Kuperberg et al., 2003, Yamada et al., 2007), although the particular subregions implicated vary across studies and negative reports exist (Chemerinski et al., 2002).

Genetic predisposition accounts for approximately 80% of liability for schizophrenia, and is thought to alter brain development in ways that affect an individual's probability of developing psychosis (Keshavan & Hogarty, 1999, Tsuang, 2001). Thus, one way of parsing the heterogeneous findings on PFC morphometry is to disambiguate aspects of pathology related to genetic risk for schizophrenia from those associated with the disease process. Studies of patients' nonpsychotic first-degree relatives can identify brain alterations that mark genetic (familial) loading for schizophrenia.

Anatomical MRI studies of PFC subregions in older adult relatives, who have passed through the age of peak risk for schizophrenia (> age 30), have reported deviations in prefrontal GM integrity, although their regional specificity has varied. One voxel-based morphometry (VBM) investigation found bilateral orbitofrontal cortex (OFC) GM deficits in 36 adult siblings of schizophrenia patients compared with 37 control subjects (McDonald et al., 2004), while two similar sized studies of discordant twin pairs reported a left-sided OFC GM deficit in relation to genetic loading (Hulshoff Pol et al., 2006), or no OFC deficit (Cannon et al., 2002). The latter twin study reported liability-associated GM deficits in the frontal pole and dorsolateral PFC (DLPFC). Some subsequent investigations also found that lateral prefrontal GM was reduced in adult relatives [(McDonald et al., 2006, McIntosh et al., 2006), but see (Borgwardt et al., 2010, McIntosh et al., 2004)], or was inversely correlated with continuous measures of genetic liability (Cannon et al., 2002, McIntosh et al., 2006). However, in the largest VBM study of adult relatives, unaffected siblings showed a trend for increased lateral PFC GM density compared with controls, along with significantly decreased medial PFC and frontal pole GM densities (Honea et al., 2008).

The PFC undergoes maturational alterations in gray matter through the third decade of life, and pathological deviations of these processes may occur in association with both inherited risk and emerging psychosis (Cannon, 2005). Yet, there are few morphometric studies of PFC GM abnormalities in relatives younger than 30, who have not passed through the age of peak risk for psychosis onset (Seidman et al., 2006a, Seidman et al., 2006b). In the only region-of-interest (ROI) study of the PFC in young relatives, Lawrie et al. (2001) found no significant difference in total PFC GM volumes between FHR and control adolescents of the Edinburgh High Risk Project (EHRP); however, within FHR subjects, total PFC volume did correlate with a quantitative estimate of genetic liability. In subsequent VBM studies, medial PFC GM density emerged as significantly lower in FHR adolescents than controls, and significantly higher in FHR adolescents than first-episode schizophrenia patients (Job et al., 2003, Lawrie et al., 2008). In a different cohort, Diwadkar et al. (2006) found reduced regional GM densities of the ventral- and dorsal-lateral PFC in FHR adolescents compared with controls; moreover, DLPFC GM deficits were more pronounced among FHR adolescents with subpsychotic symptoms. In combination, these structural MRI studies in young relatives point to a dual association of medial and DLPFC GM with risk and early disease processes.

We report on an ROI morphometry study of PFC subregions in young relatives of schizophrenia patients. Hand-traced ROI-based morphometry, though labor-intensive and time-consuming, is still considered the gold standard for validating the more exploratory findings of automated VBM studies (Giuliani et al., 2005, Honea et al., 2005, Kubicki et al., 2002). This cross-sectional study tested the hypothesis that FHR subjects would show regional reductions in ventromedial and DLPFC GM volumes compared with controls, and that GM volumes of these subregions would be inversely correlated with subpsychotic symptoms in FHR subjects (i.e., smaller volumes, more symptoms).

Section snippets

Subjects

Subjects were 27 antipsychotic-naïve FHR children and siblings of persons with DSM-IV (APA, 2000) schizophrenia or schizoaffective disorder, depressed type, and 48 children of healthy adults with no family history of psychosis, selected to be comparable on age (13–28 years) and other demographic variables (Table 1). They were recruited as part of the Harvard Adolescent Genetic Risk Study, previously described in detail (Glatt et al., 2006, Seidman et al., 2006a, Seidman et al., 2006b).

Results

Demographic data are presented in Table 1 Groups were comparable except for a significantly lower parental SES in the FHR group.

Discussion

We found bilateral reductions of ventromedial and polar PFC GM volumes in non-psychotic adolescent and young adult relatives of schizophrenia patients. Neither deficit was explained by differences in total brain size, SES or IQ. As hypothesized, ventromedial PFC GM was also negatively correlated with subpsychotic symptoms in FHR subjects. Contrary to our expectations, DLPFC GM was not related to familial risk for schizophrenia or subpsychotic symptoms.

Our pattern of findings suggests that

Role of Funding Source

Funding for this study was provided by the Mental Illness and Neuroscience Discovery (MIND) Institute; National Association of Research in Schizophrenia and Depression Stone Award (LJS); National Institute of Mental Health (NIMH) R18 MH 43518 and R01 MH 65562 (MTT, LJS), R01 MH 63951, P50 MH80272 and U01 MH81928 (LJS), R25 MH 60485 (to HWT, Training PI: MTT), K01 MH 06987 (IMR); Commonwealth Research Center, Massachusetts Department of Mental Health (LJS). This work was also supported in part

Contributors

Drs. Seidman, Faraone and Tsuang designed the study and wrote the protocol. Drs. Thermenos and Brown collected the neuroimaging data and performed the interviews at the imaging session. Mr. Hodge supervised data management and performed some statistical analyses. Drs. Makris, Caviness, and Kennedy developed the parcellation methods and provided expert neuroanatomical consultation. Dr. Rosso performed the cortical parcellations and statistical analyses, and wrote the first draft of the

Conflict of Interest

All authors declare that they have no conflict of interest.

Acknowledgements

We thank the patients with schizophrenia and their family members, control families, and project staff for their generous contributions to the study. Staff included Lisa Gabel, Anthony Giuliano, Stephen Glatt, Jennifer Koch, Marc Korczykowski, Erica Lee, Virna Merino, Elon Mesholam, Raquelle Mesholam-Gately, Caroline Patterson, Nicole Peace, William Stone, Rosemary Toomey, and Sharon White.

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