We mapped regional changes in cortical thickness and intensity-based cortical gray matter concentration in first episode schizophrenia. High-resolution magnetic resonance images were obtained from 72 (51 male, 21 female) first episode patients and 78 (37 male, 41 female) healthy subjects similar in age. Cortical pattern matching methods allowed comparisons of cortical thickness and gray matter concentration at thousands of homologous cortical locations between subjects in three dimensions. Principal components analyses reduced measures obtained across the cortex to identify global differences in cortical thickness/gray matter concentration. First principal component factor scores showed significant effects of diagnosis, sex and age for both cortical measures. Diagnosis and age effects remained significant after brain size correction. Cortical thickness and gray matter concentration values were highly correlated. Statistical maps showed significant regional gray matter thinning in frontal, temporal and parietal heteromodal association cortices bilaterally in first episode patients. Regional reductions in cortical gray matter concentration were similar but pronounced in the superior temporal lobe. Regional reductions in cortical thickness and gray matter concentration are present at disease onset in brain regions linked with functional disturbances in schizophrenia. Cortical thickness and gray matter concentration mapping produce similar results, although the concentration metric may be influenced by diagnostic differences in extra-cortical cerebrospinal fluid and surface curvature/complexity.

Magnetic resonance (MR) imaging studies have identified hippocampal structural alterations in the pathogenesis of schizophrenia. Brain-derived neurotrophic factor (BDNF) is one of the neurotrophins that is widely expressed in the hippocampal formation and has been implicated in the neurobiology of schizophrenia. Polymorphisms in the BDNF gene may therefore confer risk for schizophrenia through hippocampal pathogenesis and/or making the hippocampus more susceptible to environmental insults. In this study, we investigated whether val66met, a functional and abundant missense polymorphism in the coding region of the BDNF gene, was associated with the volume of the hippocampal formation in 19 patients with first-episode schizophrenia and 25 healthy volunteers. A total of 124 contiguous T1-weighted coronal MR images (slice thickness ¼ 1.5 mm) were acquired through the whole head using a 3D Fast SPGR IR Prep sequence on a 1.5 T GE imaging system. Volumes of the right and left hippocampal formation were measured manually by an operator blind to group status and genotype. All participants were genotyped for the BDNF val66met locus. Mixed model analyses revealed a main effect of BDNF val66met genotype such that in the combined sample of patients and healthy volunteers, val/val homozygotes (N ¼ 27) had larger volumes of the hippocampal formation compared to val/met heterozygotes (N ¼ 17). In separate analyses by group, however, val66met genotype accounted for a greater proportion of the variance in the volume of the hippocampal formation in patients compared to healthy volunteers. These findings implicate genetic involvement of BDNF in variation of human hippocampal volume and suggest that this effect may be greater among patients compared to healthy volunteers. Molecular Psychiatry (2005) 10, 631-636.

Research and treatment of schizophrenia have been impeded by its heterogeneity and the lack of well-standardized methods for a comprehensive assessment of symptoms, including positive and negative dimensions. To study symptom profiles, therefore, we standardized and administered a well-operationalized 30-item psychiatric symptom scale to 240 schizophrenic inpatients. Principal component analysis suggested a pyramidlike triangular model of uncorrelated but nonexclusive syndromes that encompassed the spectrum of psychopathology. Negative, positive, and depressive features constituted divergent points of a triangular base, and excitement made up a separate vertical axis. Paired syndromes could account for symptoms of the paranoid (positive-depressive), disorganized (positive-negative), and catatonic (negative-depressive) diagnostic subtypes. The transversal positions in this model suggested polarized dimensions in schizophrenia, including a prognostic axis (depression-cognitive dysfunction). The findings imply that (1) negative and positive syndromes show factorial validity and distinction from depression but, alone, are insufficient to accommodate the full diversity of symptoms; (2) schizophrenic subtypes derive from a hybrid between unrelated but co-occurring dimensions that may define the fundamental elements of psychopathology; and (3) the pyramidical model is of heuristic value. The results help to clarify the heterogeneity of schizophrenia and to illuminate the path toward syndrome-specific treatments.