My research program is focused on understanding the mechanisms which lead to the generation of psychotic symptoms (delusions and hallucinations) which may occur in multiple disorders. These symptoms are core features of the most common psychotic disorder, schizophrenia, but also occur in about 50% of individuals with Alzheimer Disease. We have proposed that there are common genetic risk factors and vulnerable brain circuits that act together to cause positive symptoms across these disorders. My research program has both clinical and laboratory components.

In my lab, we conduct studies of post-mortem brain tissue from subjects with schizophrenia. Structural imaging studies in subjects with schizophrenia have identified gray matter volume reductions in the auditory cortex that are present prior to treatment and are correlated with the severity of psychotic symptoms and with impaired auditory sensory processing. Our findings to date have demonstrated deficits within excitatory projections in the auditory cortex.

We are currently testing the hypothesis that schizophrenia is associated with selective impairments of auditory feedforward, but not feedback, projections. Our approach uses quantitative anatomic techniques, emphasizing the rigorous application of unbiased stereologic methods in histochemical and immunocytochemical preparations. Control studies are conducted in brain tissue from neuroleptic-treated non-human primates.

My clinical research program conducts studies to refine the definition of psychotic phenotypes and outcomes in Alzheimer disease, and relate these to underlying genetic variation. We have demonstrated that the presence of psychotic symptoms in Alzheimer disease subjects is familial, with a heritability of 60%-70%. We have hypothesized that psychosis in Alzheimer disease identifies one or more genetically homogenous subgroups, and that some of the genetic liability to psychosis in Alzheimer disease is shared with schizophrenia. We are currently testing this hypothesis in both case-control and family-based study designs. To date, we have identified novel associations of psychosis in Alzheimer disease with two putative genes for schizophrenic psychosis: neuregulin-1 and catechol-O-methyltransferase.

More information about these two programs and about our brain tissue donation program for late life depression can be found by following the links in the toolbar on the left side of this page.