Improving the Early Detection of Schizophrenia and Outcomes with a Novel Method of Precisely Measuring Substansia Nigra Activity

Jong Yoon, M.D.

Stanford University School of Medicine

Funded in September, 2013: $200000 for 3 years


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Imaging may be a key to understanding and treating the neural basis of schizophrenia

This study will examine whether high dopamine levels, as measured by high resolution fMRI, correlates with the onset of psychosis in schizophrenia and can serve as a diagnostic and therapeutic biomarker. The prognosis for schizophrenia is poor. No treatments currently prevent or reverse its course and available therapies only help in managing some symptoms. It may well be that the disease is at a late stage when the definitive diagnosis of psychosis (marked by hallucinations and delusions) is evident, usually in the late teens or early twenties. By that time the brain changes already may be irreversible. Starting treatment earlier is not feasible because the early symptoms that start in childhood--social awkwardness and gaze aversion—are common to several mental conditions. In fact, only a small percent of children with these problems go on to develop schizophrenia in later years. Accordingly, clinicians do not prescribe powerful antipsychotics to the children since the medications have such serious side effects. Instead, the safest and most effective opportunity for intervention may be when the brain signs associated with the development of psychosis first appear. This rationale is based on two findings: 1) there is progressive brain atrophy for at least a decade after the onset of psychosis; and 2) the longer psychosis goes untreated, the worse the outcomes. Animal model studies suggest that the neural basis for psychosis involves excessive amounts of the neurotransmitter dopamine, which is produced and regulated in the “substania nigra.” Excess dopamine may induce neural network changes, and prolonged excess dopamine exposure may permanently change the networks or render treatments ineffective. The investigators hypothesize that development of schizophrenia is therefore associated with higher activity in the substantia nigra. They will measure activity there using high-resolution fMRI in 60 high-risk young adults. The imaging method does not require use of ionizing radiation and has sufficient resolution to precisely measure activity in this tiny structure deep in the brain. They anticipate that 20 percent of participants will convert to schizophrenia within a two year period and will have higher dopamine activity compared to those who do not become schizophrenic. Significance: If preliminary results correlate schizophrenia onset with excess dopamine, and these results are confirmed in larger-scale studies, the research would lead to fundamentally new approaches to preventing schizophrenia by blocking receptors on cells that utilize dopamine.