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Deep brain stimulation of the “medial forebrain bundle”: a strategy to modulate the reward system and manage treatment-resistant depression

Abstract

The medial forebrain bundle—a white matter pathway projecting from the ventral tegmental area—is a structure that has been under a lot of scrutinies recently due to its implications in the modulation of certain affective disorders such as major depression. In the following, we will discuss major depression in the context of being a disorder dependent on multiple relevant networks, the pathological performance of which is responsible for the manifestation of various symptoms of the disease which extend into emotional, motivational, physiological, and also cognitive domains of daily living. We will focus on the reward system, an evolutionarily conserved pathway whose underperformance leads to anhedonia and lack of motivation, which are key traits in depression. In the field of deep brain stimulation (DBS), different “hypothesis-driven” targets have been chosen as the subject of clinical trials on efficacy in the treatment-resistant depressed patient. The “medial forebrain bundle” is one such target for DBS, and has had remarkably rapid success in alleviating depressive symptoms, improving anhedonia and motivation. We will review what we have learned from pre-clinical animal studies on defining this white matter tract, its connectivity, and the complex molecular (i.e., neurotransmitter) mechanisms by which its modulation exerts its effects. Imaging studies in the form of tractographic depictions have elucidated its presence in the human brain. Such has led to ongoing clinical trials of DBS targeting this pathway to assess efficacy, which is promising yet still lack in sufficient numbers. Ultimately, one must confirm the mechanism of action and validate proof of antidepressant effect in order to have such treatment become mainstream, to promote widespread improvement in the quality of life of suffering patients.

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Fig. 1: Targets used in DBS for TRD.
Fig. 2: VTA-NAc reward circuit.
Fig. 3: Illustration of the slMFB/VTApp.

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Acknowledgements

The Center of Excellence on Mood Disorders is funded by the Pat Rutherford Jr. Chair in Psychiatry, John S. Dunn Foundation, and Anne and Don Fizer Foundation Endowment for Depression Research.

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JQ reported no biomedical financial interests or potential conflicts of interest. AJF serves as a consultant for Medtronic, Inc. JCS receives grant/research support from Bristol-Meyers Squibb, Forest Laboratories, Merck and Elan Pharmaceuticals, and serves as a consultant for Pfizer, Abbot, and Astellas Pharma, Inc.

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Fenoy, A.J., Quevedo, J. & Soares, J.C. Deep brain stimulation of the “medial forebrain bundle”: a strategy to modulate the reward system and manage treatment-resistant depression. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01100-6

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