Title: Hippocampal Subfield Alterations Across the Psychotic Disease Spectrum
Description: Psychiatry stands at a pivotal point of development. With the advent of brain imaging modalities, descriptive diagnostic criteria have been called into question. Psychotic disorders, historically dichotomized into “schizophrenia” and “bipolar disorder,” and the intermediate “schizoaffective disorder,” have been shown to overlap in clinical symptomatology, familial inheritance, and genetic association studies. Scientific investigation of disease pathogenesis provides an opportunity to develop biological diagnostic criteria from the ground upwards – correlating anatomy, pathophysiology, genetics, and symptomatology. In this context, structural MRI studies have the capacity to shed light on structural abnormalities underlying psychotic disorders (schizophrenia, schizoaffective disorder, and psychotic bipolar disorder) and contribute to the development of a comprehensive mechanistic model of disease. Neuropathological and in vivo neuroimaging studies have identified the temporal lobe as a key area of alteration in schizophrenia, but large-scale studies examining the hippocampal volumes of patients across the psychotic spectrum have not yet been performed. Further, until recently, the manual labor and error involved in parcellating hippocampal subfield volumes made the task unfeasible. New automatic parcellation techniques enable the analysis of hippocampal subfield volumes among patients with schizophrenia, schizoaffective disorder, and bipolar disorder.

The objectives of our study were to: (1) investigate using magnetic resonance imaging hippocampal volume in addition to entorhinal cortex volume, parahippocampal gyrus volume, and hippocampal subfield volumes in patients with schizophrenia, schizoaffective disorder, and bipolar disorder; and, to (2) correlate volumetric alterations with clinical metrics of psychosis and cognition. We utilized a case-control cross- sectional design to collect data from patients with schizophrenia (n=219), patients with schizoaffective disorder (n=142), patients with psychotic bipolar disorder (n=188), and healthy controls (n=337). Freesurfer image analysis software was utilized to automatically parcellate and quantify hippocampal, hippocampal subfield, entorhinal cortex, and parahippocampal gyrus volumes. Clinical ratings and neuropsychological tests were administered as well to assess positive symptoms and cognition. Bilateral hippocampal volume alterations were noted among patients with all three psychotic disorders, while alterations in the surrounding medial temporal lobe regions were noted only in schizoaffective disorder and schizophrenia, but not in patients with bipolar disorder. While widespread hippocampal subfield volume alterations were noted in schizophrenia and schizoaffective disorder, only the cornu ammonis 2/3, dentate gyrus, and subicular regions were noted to be altered across all three psychotic disorders. The most prominent alterations were noted in the cornu ammonis 2/3. Hippocampal volumes were negatively correlated with psychosis and positively correlated with measures of declarative memory. Findings suggest that alterations in the hippocampus are present across psychotic disorders and may contribute to the pathogenesis of psychosis. In particular, alterations in the cornu ammonis, an area which supports memory pattern completion, and in the dentate gyrus, an area which supports memory separation may play a role in the pathophysiology of psychosis.