Substantia Nigra Hyperactivity in Schizophrenia

Abstract

Mapping the clinical features of schizophrenia to circuits in the brain is a major goal for schizophrenia researchers. The prefrontal cortex (PFC), the ventral midbrain, and the striatum are among the brain areas of primary interest. The PFC has been linked to cognitive deficits, especially impairment of working memory. The dopaminergic cells of the substantia nigra (SN) and ventral tegmental area have been studied intensely to better understand the mechanism of antipsychotic drugs. The striatum was initially implicated in catatonia, then as a site of action of antipsychotic drugs, and more recently as part of a corticostriatal circuit governing emotion and cognition. Abnormal connections between the cortex and basal ganglia (BG) have been proposed as substrates for psychosis and impaired cognition in schizophrenia (1). One prominent model postulates that PFC dysfunction leads to increased subcortical dopamine release, which in turn leads to psychosis (2). Yoon et al. (3) designed an experiment to test this hypothesis. Eighteen patients with schizophrenia/schizoaffective disorder and 19 healthy control subjects completed a delayed-response face working memory paradigm (3). The subject was presented with the image of a face for 1 second (encoding phase). After a delay of 15 seconds (maintenance phase), the subject indicated whether a second face, presented for 1 second, matched the first face (response phase). This slow-event related design allowed for the analysis of brain activity (inferred via the blood oxygen level–dependent signal [BOLD]) during the encoding, maintenance, and response phase of working memory. The experiment included 50 trials, only half of which were matches. To be included in the study, a subject had to achieve at least 60% accuracy on the match trials, which translates into 15 correct responses used for the analysis. On average, 18.75 trials were used for subjects with schizophrenia/schizoaffective disorder and 21.5 for control subjects. In addition to brain activity, the investigators measured connectivity among cortex, ventral midbrain, and striatum during the response phase of the working memory experiment. What did the investigators find? First, patients were slower and less accurate, which was to be expected. Second, PFC activity was decreased in patients during the response phase, a result in line with previous studies. Third, patients exhibited striatal hypoactivity and nigral hyperactivity during the response phase (Figure 1A). Fourth, SN–PFC and caudate–PFC connectivity was decreased in patients (Figure 1B). Finally, Yoon et al. tested whether the abnormal connectivity pattern was related to the clinical features of the patients. They found SN–caudate connectivity to be highly correlated with psychosis (delusion and hallucinations) but not with negative symptoms or disorganization (Figure 1B).