Human postmortem brain studies are critical for elucidating the pathophysiology and etiology of schizophrenia and other major mental illnesses. The traditional approach compares patients and controls, but is potentially confounded by a number of artifacts including medication, substance misuse and other secondary effects of illness. Now, genetic advances make possible a novel approach that focuses on how allelic variation in risk-associated genes impacts on expression and function of transcripts and proteins. These questions can be addressed in normal brain, overcoming to some extent the confounding effects of studying brains from subjects with schizophrenia; equally, extension of the studies to include cases also has advantages. Conceptually, the approach may be seen as the neuropathologic counterpart of genetic neuroimaging, representing a potentially powerful intermediate phenotype. For several schizophrenia susceptibility genes, the data show that risk-associated polymorphisms do affect gene expression or the function of the encoded protein; in some instances expression of downstream or interacting partners of the gene are also altered. A further striking finding is that the implicated transcripts often appear to be enriched in, or specific to, human brain. Some also show enhanced expression in fetal brain. These considerations give a unique importance to postmortem human brain tissue in elucidating the genetic mechanisms underlying schizophrenia, and probably other neurodevelopmental disorders too. Studies of this kind can provide clues as to the biologic mechanisms of genetic association, especially when carried out in conjunction with experimental studies. Moreover, the data, interpreted judiciously, can strengthen the plausibility of the association itself.

Introduction The study of postmortem human brain tissue is central to the advancement of the neurobiological studies of psychiatric illness, particularly for the study of brain-specific isoforms and molecules. Methods The state-of-the-art methods and recommendations for maintaining a successful brain bank for psychiatric disorders are discussed, using the convergence of viewpoints from three brain collections, the National Institute of Mental Health Brain Collection (NIMH), the Harvard Brain Tissue Resource Center (HBTRC), and the Mt. Sinai School of Medicine Brain Bank (MSSM-BB), with diverse research interests and divergent approaches to tissue acquisition. Results While the NIMH obtains donations from medical examiners for its collection, and places particular emphasis on clinical diagnosis, toxicology, and building lifespan control cohorts, the HBTRC is uniquely designed as a repository whose sole purpose is to collect large-volume, high quality brain tissue from community-based donors based on relationships across an expansive nationwide network, and places emphasis on the accessibility of its bank in disseminating tissue and related data to research groups worldwide. The MSSM-BB collection has shown that, with dedication, prospective recruitment is a successful approach to tissue donation, and places particular emphasis on rigorous clinical diagnosis through antemortem contact with donors. The MSSM-BB places great importance on stereological tissue sampling methods for neuroanatomical studies, and frozen tissue sampling approaches that enable multiple assessments (RNA, DNA, protein, enzyme activity, binding, etc.) of the same tissue block. Promising scientific approaches for elucidating the molecular and cellular pathways in brain that may contribute to schizophrenia and/or bipolar disorder, such as cell culture techniques and microarray-based gene expression and genotyping studies are briefly discussed. Conclusions Despite unique perspectives from three established brain collections, there is a consensus that (1) diverse strategies for tissue acquisition, (2) rigor in tissue and diagnostic characterization, (3) the importance of sample accessibility, and (4) continual application of innovative scientific approaches to the study of brain tissue are all integral to the success and future of psychiatric brain banking. The future of neuropsychiatric research depends upon in the availability of high quality brain specimens from large numbers of subjects, including non-psychiatric controls.

First episode psychosis (FEP), and subsequent diagnosis of schizophrenia or schizoaffective disorder, predominantly occurs during late adolescence, is accompanied by a significant decline in function and represents a traumatic experience for patients and families alike. Prior to first episode psychosis, most patients experience a prodromal period of 1–2 years, during which symptoms first appear and then progress. During that time period, subjects are referred to as being at Clinical High Risk (CHR), as a prodromal period can only be designated in hindsight in those who convert. The clinical high-risk period represents a critical window during which interventions may be targeted to slow or prevent conversion to psychosis. However, only one third of subjects at clinical high risk will convert to psychosis and receive a formal diagnosis of a primary psychotic disorder. Therefore, in order for targeted interventions to be developed and applied, predicting who among this population will convert is of critical importance. To date, a variety of neuroimaging modalities have identified numerous differences between CHR subjects and healthy controls. However, complicating attempts at predicting conversion are increasingly recognized co-morbidities, such as major depressive disorder, in a significant number of CHR subjects. The result of this is that phenotypes discovered between CHR subjects and healthy controls are likely non-specific to psychosis and generalized for major mental illness. In this paper, we selectively review evidence for neuroimaging phenotypes in CHR subjects who later converted to psychosis. We then evaluate the recent landscape of machine learning as it relates to neuroimaging phenotypes in predicting conversion to psychosis.