Schizophrenia in translation: the presence of absence: habenular regulation of dopamine neurons and the encoding of negative outcomes

Abstract

Many patients with schizophrenia have pronounced deficits in the use of negative feedback to guide problem solving and learning, as seen on tasks like the Wisconsin Card Sorting Test. There is now a compelling body of evidence from nonhuman primates that suggests transient decreases in dopamine cell activity may reflect the occurrence of unexpected negative outcomes, such as the absence of an expected reward, and, generalizing to the human, the occurrence of negative feedback or the absence of expected reward. We present preliminary evidence that habenula projections to the midbrain are capable of producing a transient, but nearly complete, inhibition of dopamine neurons at a population level similar to that observed in behaving primates following an unexpected negative outcome. Human functional imaging studies offer further evidence that the habenula is activated following receipt of unexpected negative feedback or the absence of expected positive feedback. We present initial evidence that patients with schizophrenia lack appropriate modulation of habenula activity in response to feedback. Collectively, these data suggest that the habenula may play a critical role in mediating the feedback-processing deficits of schizophrenia.

Fig. 1

Informative Feedback Differentially Modulates Neural Activity in Normal Volunteers and Schizophrenic Patients. Panels A and C represent fMRI data obtained from 5 healthy volunteers (relevant regions are circled). Panels B and D are derived from fMRI data taken from 5 medicated schizophrenic volunteers (relevant regions have arrows). Fixed effect analyses were applied to echoplanar, event-related fMRI data acquired from a 3 Tesla Philips magnet that employed Sensor coil. Panels A and B illustrate Blood Oxygen Level Dependent (BOLD) signals that covaried with correct trials. Positive feedback was provided. Panels C and D illustrate BOLD signals that covaried with error trials. Negative feedback was provided. Healthy volunteers, Panel A, show that the caudate (right image, circled in white) is active during correct trials associated with positive feedback; this pattern is absent in schizophrenic volunteers (see Panel B). Healthy volunteers (Panel C) exhibit marked midbrain (left image) and habenula (right image) activity during error trials associated with negative feedback. Note that this pattern is also absent in schizophrenic volunteers (see respective images in Panel D).