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High-resolution functional imaging of the habenula in healthy and depressed individuals [electronic resource]

Neuroscientists have recently identified a role for the habenula, a phylogenetically primitive and conserved component of the vertebrate epithalamus, in predicting, and responding to, the occurrence of negative events. In monkeys, habenula circuitry has been found to operate in parallel and opposition to the dopaminergic reward response system: whereas midbrain dopamine release has been linked to the anticipation and receipt of reward, and to the initiation of motor behaviors required to attain reward, the habenula is posited to respond both to cues predicting future punishment or reward omission and to unexpected negative outcomes. Further, activation of the habenula inhibits the release of midbrain dopamine, thereby suppressing behavior in the face of negative feedback or the anticipation of future failure. Very few studies, however, have examined habenula function in humans, likely due to the difficulty in resolving this small structure with conventional neuroimaging methods. Consequently, we have an incomplete picture of whether the human habenula, like the homologous structure in non-human primates, encodes the prediction of future suboptimal outcomes and whether its activation in response to negative outcomes varies with the extent to which they were expected. Further, we do not know how variation in habenula activity is related to individual differences in cognitive and affective responses to negative occurrences. Indeed, investigators have speculated that perturbations in habenula activity contribute to the pathophysiology of Major Depressive Disorder (MDD), a psychiatric illness characterized by abnormalities in behavioral, cognitive, and affective responding to negative feedback and by marked pessimism in evaluating the likelihood of future events. Although accumulating evidence of structural and metabolic anomalies in depressed humans and in animal models of depression supports this hypothesis, no work to date has examined the extent to which depressed individuals exhibit abnormal activation of the habenula during the prediction or receipt of negative feedback. The current study was designed to characterize habenula response to, and anticipation of, negative outcomes in both neurotypical and depressed individuals using a combination of high-resolution functional magnetic resonance imaging (fMRI) and manual segmentation methods. The results suggest that, in healthy adults, the habenula encodes the probability of a negative outcome, influences behavioral responding, and signals the degree of discrepancy between initial predictions and actual outcomes. In contrast, in depressed individuals, the habenula does not accurately track the likelihood of a negative event, influence behavioral responding, or exhibit the normal pattern of activation in response to the receipt of negative feedback. While additional work is needed to determine the downstream behavioral, affective, and cognitive consequences of abnormal habenula function in MDD, the observed results suggest that depressed individuals are characterized by dysfunction in a neural system involved in the generation of expectations about the future and in the comparison of negative expectations and reality.