Low-frequency rTMS to ventral medial frontal cortex induces depression-like behavioral and physiological state in monkeys

Abstract

The medial frontal cortex (MFC), including the anterior cingulate cortex (ACC), has long been implicated in emotional, motivational and social behavior. And the abnormal functioning of rostroventral regions of the ACC, the pregenual and subgenual ACCs, has been repeatedly reported in patients with mood disorders. In this study, we aimed to causally examine how the MFC is involved in the regulation of mood and affective state in monkeys by using repetitive transcranial magnetic stimulation (rTMS) as a tool to manipulate local cortical activity. Low-frequency (1 Hz) 1200-pulse rTMS was delivered to the monkey MFC through two types of the TMS coil. The dorsal and ventral regions of the anterior part of the MFC (d+vMFC) was stimulated with a 70-mm double-cone coil, which can stimulate deep brain regions. The same location was also stimulated with a 70-mm figure-of-eight coil to stimulate only the dorsal region of the anterior MFC. The within-cage spontaneous activity, motivational level, sociability, and plasma cortisol level were examined as indices of mood and affective state. As a result, we found significant decrease in the within-cage spontaneous activity, motivational level, and sociability, and a significant increase in the evening plasma cortisol level when the d+vMFC was stimulated. We also found that the reduction of within-cage spontaneous activity and the increase in evening plasma cortisol level induced by the d+vMFC stimulation returned to the baseline level by the administration of ketamine, which recently has been considered as a fast-reacting antidepressant. These results indicate that the ventral MFC including the rostroventral region of the ACC is critically involved in the regulation of mood and affect in monkeys, and the inhibition of its activity can be regarded as a model of major depression.