Unraveling the mechanisms of deep-brain stimulation of the internal capsule in a mouse model

Bastijn J. G. Boom (), Alfredo Elhazaz-Fernandez, Peter A. Rasmussen, Enny H. Beest, Aishwarya Parthasarathy, Damiaan Denys and Ingo Willuhn ()
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Bastijn J. G. Boom: Royal Netherlands Academy of Arts and Sciences
Alfredo Elhazaz-Fernandez: Royal Netherlands Academy of Arts and Sciences
Peter A. Rasmussen: Royal Netherlands Academy of Arts and Sciences
Enny H. Beest: Royal Netherlands Academy of Arts and Sciences
Aishwarya Parthasarathy: Royal Netherlands Academy of Arts and Sciences
Damiaan Denys: University of Amsterdam
Ingo Willuhn: Royal Netherlands Academy of Arts and Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Deep-brain stimulation (DBS) is an effective treatment for patients suffering from otherwise therapy-resistant psychiatric disorders, including obsessive-compulsive disorder. Modulation of cortico-striatal circuits has been suggested as a mechanism of action. To gain mechanistic insight, we monitored neuronal activity in cortico-striatal regions in a mouse model for compulsive behavior, while systematically varying clinically-relevant parameters of internal-capsule DBS. DBS showed dose-dependent effects on both brain and behavior: An increasing, yet balanced, number of excited and inhibited neurons was recruited, scattered throughout cortico-striatal regions, while excessive grooming decreased. Such neuronal recruitment did not alter basic brain function such as resting-state activity, and only occurred in awake animals, indicating a dependency on network activity. In addition to these widespread effects, we observed specific involvement of the medial orbitofrontal cortex in therapeutic outcomes, which was corroborated by optogenetic stimulation. Together, our findings provide mechanistic insight into how DBS exerts its therapeutic effects on compulsive behaviors.

Date: 2023
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DOI: 10.1038/s41467-023-41026-x

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