We found bilateral reductions of ventromedial and polar PFC GM volumes in 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 ventromedial PFC (BA 11,12) GM reductions are associated with both genetic vulnerability and early disease processes in young relatives of schizophrenia patients. Compared with controls, FHR subjects had less GM volume in a ventromedial PFC area that overlaps with the medial PFC ROI found to be hyperactive in our functional MRI (fMRI) study of a subset of these FHR subjects (Whitfield-Gabrieli et al., 2009
), all of whom are included in this report. We therefore have converging anatomical and functional imaging evidence in the same sample that medial PFC abnormalities are associated with familial risk for schizophrenia in young adulthood. Ventromedial PFC volumes also correlated with self-reported anhedonia and magical ideation, subpsychotic symptoms found to predict the emergence of full-blown psychosis in certain high-risk samples (Horan et al., 2008
; Meehl, 1962
). Thus, we postulate that ventromedial PFC GM deficits may partly mediate the transition to psychosis by becoming more pronounced among FHR adolescents who convert. This would dovetail with VBM findings of the EHRP where adolescents at heightened genetic risk for schizophrenia had a medial PFC GM density intermediate between that of low-risk adolescents and first-episode schizophrenia patients (Job et al., 2003
; Lawrie et al., 2008
). In addition, Koutsouleris et al. (2009)
found more pronounced ventromedial PFC GM loss in the late versus early stage of the schizophrenia prodrome, suggesting this deficit may progress in parallel with emerging disease.
This is the first report of decreased frontal pole (BA 10, 9) GM volume in young biological relatives of schizophrenia patients. Frontal pole deficits have been found in some studies of older biological relatives (Cannon et al., 2002
; Honea et al., 2008
), including a twin study where GM declined proportionally with degree of genetic loading for schizophrenia (Cannon et al., 2002
). Their presence in both young and older adult biological relatives of patients suggests the hypothesis that frontal pole GM deficits may be stable markers of genetic risk for schizophrenia.
The ventromedial PFC and frontal pole mediate an array of behaviors that are compromised in schizophrenia. Both regions have been implicated in socioemotional and self-monitoring functions, including mentalizing (i.e., “theory of mind”) and reality monitoring. The frontal poles are involved in aspects of self/other distinctions, including the ability to distinguish information that is perceived in the environment (other-generated) from information that is imagined (self-generated) (Simons et al., 2006
). Deficits in these abilities, in turn, may underlie the genesis of psychotic symptoms (Frith, 1992
). Medial PFC involvement is the most replicated finding of functional imaging studies of mentalizing (Brunet-Gouet and Decety, 2006
). Moreover, in the only fMRI study of biological relatives of schizophrenia patients performing a mentalizing task, medial PFC activation was positively associated with both genetic risk and subpsychotic symptoms (Marjoram et al., 2006
A lack of significant familial risk group differences in lateral PFC and OFC volumes may be consistent with research linking anatomical abnormalities in these areas with transition to full-blown psychosis (Smieskova et al., 2010
; Wood et al., 2008
). In a study of prodromal youth, Pantelis and colleagues (2003)
found that subjects who developed psychosis (“converters”) had significantly less baseline right DLPFC GM, and a significant reduction of OFC GM over time compared with non-converters. In similar longitudinal studies, Borgwardt and colleagues (2007
) found more pronounced reductions of lateral and orbital PFC GM in converters relative to non-converters over time, and Sun et al (2009)
reported greater contraction of the right DLPFC in association with psychosis onset. Thus, lateral and orbital PFC GM reductions may mark transition to psychotic symptoms, more so than genetic predisposition to schizophrenia in youth. Alternatively, these reductions may appear later in the developmental course of the disorder, since the DLPFC completes maturation later than the frontal pole and ventromedial PFC (Gogtay et al., 2004
). Finally, the absence of significant volume differences in lateral and orbital PFC does not preclude functional abnormalities. In fact, abnormal DLPFC activation has been found in two previous fMRI studies of executive functioning in young FHR subjects (Keshavan et al., 2002
), including a subsample from the current study (Seidman et al., 2006b
As with all studies, this investigation has a number of limitations. Due to the labor- and time-intensive nature of ROI methods, our sample size is limited for the detection of small effects. In addition, the FHR subjects have not passed through the age of risk for onset of psychosis, such that information on clinical outcome is not available. The design of the study also precludes separation of genetic effects from shared environmental effects. Nevertheless, our findings encourage further research into PFC GM subregions as markers of risk for schizophrenia, specifically regarding the hypothesis that they may differentially mark inherited vulnerability and early symptom emergence processes in adolescence and young adulthood.