Pharmacologic modulation of hippocampal activity in psychosis

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PROJECT SUMMARY/ABSTRACT The development of better treatments for schizophrenia requires that we identify novel treatment targets. A recently proposed target is hippocampal hyperactivity, demonstrated with neuroimaging methods. Emerging evidence suggests that increased hippocampal activity in schizophrenia patients limits the ability to recruit the hippocampus during cognitive task performance. However, the neural basis underlying hippocampal dysfunction (i.e., hyperactivity and impaired recruitment) in schizophrenia is poorly understood. In order to better understand the neural mechanisms of this potential treatment target, I propose to a) measure hippocampal activity with two complementary, non-invasive neuroimaging techniques and b) use pharmacologic intervention in a 2-way crossover, randomized, double-blind, placebo-controlled design to test the hypothesis that hyperactivity leading to impaired recruitment is a consequence of an excitation-inhibition imbalance in the hippocampus. This work will demonstrate that the pathologic neural processes underlying hippocampal hyperactivity can be modulated through perturbation of hippocampal micro-circuitry with a pharmacologic intervention, levetiracetam (LEV). I hypothesize that a LEV intervention will normalize hippocampal activity in schizophrenia patients. First, arterial spin labeling (ASL) will be used to quantify anterior hippocampal cerebral blood flow, a measure of resting state activity, after placebo and oral, low-dose LEV administration in schizophrenia patients and controls. Serum levels of LEV will be measured to assess the relationship of LEV concentration with the change in hippocampal resting state activity. This study is a proof of concept to show that LEV reduces anterior hippocampal resting state activity and can be quantified using ASL. Second, the BOLD signal will be used to measure anterior hippocampal recruitment after placebo and oral, low-dose LEV administration in schizophrenia patients and controls. This will reveal whether a pharmacologic intervention can normalize hippocampal recruitment in schizophrenia patients. Third, the relationship between anterior hippocampus resting state activity and recruitment will be assessed. This will demonstrate whether resting state activity can be used to predict recruitment. Additionally, we will investigate whether LEV intervention is able to normalize the relationship of resting state activity and recruitment in the schizophrenia cohort. Normalization of hippocampal activity will provide novel evidence of a treatment target in schizophrenia. This project, when combined with rigorous clinical and scientific training, will provide an opportunity for interdisciplinary collaboration with experts and mastery of multiple techniques in neuroimaging and interventional study design, well-equipping me to become a psychiatrist-scientist leader in neuroscience.