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

Bastijn J G van den Boom; Alfredo Elhazaz-Fernandez; Peter A Rasmussen; Enny H van Beest; Aishwarya Parthasarathy; Damiaan Denys; Ingo Willuhn

doi:10.1038/s41467-023-41026-x

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

Bastijn J G van den Boom, Alfredo Elhazaz-Fernandez, Peter A Rasmussen, Enny H van Beest, Aishwarya Parthasarathy, Damiaan Denys, Ingo Willuhn

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

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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.

Original language	English
Pages (from-to)	5385
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-41026-x
Publication status	Published - 04 Sept 2023

Keywords

Animals
Mice
Internal Capsule
Disease Models, Animal
Compulsive Behavior
Brain
Corpus Striatum

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title = "Unraveling the mechanisms of deep-brain stimulation of the internal capsule in a mouse model",

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.",

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AU - Elhazaz-Fernandez, Alfredo

AU - Rasmussen, Peter A

AU - van Beest, Enny H

AU - Parthasarathy, Aishwarya

AU - Denys, Damiaan

AU - Willuhn, Ingo

PY - 2023/9/4

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N2 - 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.

AB - 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.

KW - Animals

KW - Mice

KW - Internal Capsule

KW - Disease Models, Animal

KW - Compulsive Behavior

KW - Brain

KW - Corpus Striatum

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DO - 10.1038/s41467-023-41026-x

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SN - 2041-1723

VL - 14

SP - 5385

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

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