Hypothalamic deep brain stimulation augments walking after spinal cord injury

Newton Cho; Jordan W Squair; Viviana Aureli; Nicholas D James; Léa Bole-Feysot; Inssia Dewany; Nicolas Hankov; Laetitia Baud; Anna Leonhartsberger; Kristina Sveistyte; Michael A Skinnider; Matthieu Gautier; Achilleas Laskaratos; Katia Galan; Maged Goubran; Jimmy Ravier; Frederic Merlos; Laura Batti; Stéphane Pages; Nadia Berard; Nadine Intering; Camille Varescon; Anne Watrin; Léa Duguet; Stefano Carda; Kay A Bartholdi; Thomas H Hutson; Claudia Kathe; Michael Hodara; Mark A Anderson; Bogdan Draganski; Robin Demesmaeker; Leonie Asboth; Quentin Barraud; Jocelyne Bloch; Grégoire Courtine

doi:10.1038/s41591-024-03306-x

Hypothalamic deep brain stimulation augments walking after spinal cord injury

Nat Med. 2024 Dec 2. doi: 10.1038/s41591-024-03306-x. Online ahead of print.

Authors

Newton Cho^#^{1

2}, Jordan W Squair^#^{1

2

3

4}, Viviana Aureli^{1

2

3

4}, Nicholas D James^{1

2}, Léa Bole-Feysot^{1

2}, Inssia Dewany^{1

2}, Nicolas Hankov^{1

2}, Laetitia Baud^{1

2}, Anna Leonhartsberger^{1

2}, Kristina Sveistyte^{1

2}, Michael A Skinnider⁵, Matthieu Gautier^{1

2}, Achilleas Laskaratos^{1

2}, Katia Galan^{1

2}, Maged Goubran⁶, Jimmy Ravier^{1

2}, Frederic Merlos^{1

2}, Laura Batti⁷, Stéphane Pages⁷, Nadia Berard^{1

4}, Nadine Intering^{1

4}, Camille Varescon^{1

4}, Anne Watrin⁸, Léa Duguet⁸, Stefano Carda⁴, Kay A Bartholdi^{1

2}, Thomas H Hutson^{1

2

7}, Claudia Kathe^{1

2}, Michael Hodara^{1

2}, Mark A Anderson^{1

2

7}, Bogdan Draganski⁴, Robin Demesmaeker^{1

2}, Leonie Asboth^{1

2}, Quentin Barraud^{1

2}, Jocelyne Bloch^{9

10

11

12}, Grégoire Courtine^{13

14

15

16}

Affiliations

¹ Defitech Center for Interventional Neurotherapies (.NeuroRestore), CHUV/UNIL/EPFL, Lausanne, Switzerland.
² NeuroX Institute, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
³ Department of Neurosurgery, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland.
⁴ Department of Clinical Neuroscience, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland.
⁵ Lewis-Sigler Institute of Integrative Genomics and Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA.
⁶ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
⁷ Wyss Center for Bio and Neuroengineering, Geneva, Switzerland.
⁸ ONWARD Medical, Lausanne, Switzerland.
⁹ Defitech Center for Interventional Neurotherapies (.NeuroRestore), CHUV/UNIL/EPFL, Lausanne, Switzerland. jocelyne.bloch@chuv.ch.
¹⁰ NeuroX Institute, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland. jocelyne.bloch@chuv.ch.
¹¹ Department of Neurosurgery, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland. jocelyne.bloch@chuv.ch.
¹² Department of Clinical Neuroscience, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland. jocelyne.bloch@chuv.ch.
¹³ Defitech Center for Interventional Neurotherapies (.NeuroRestore), CHUV/UNIL/EPFL, Lausanne, Switzerland. gregoire.courtine@epfl.ch.
¹⁴ NeuroX Institute, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland. gregoire.courtine@epfl.ch.
¹⁵ Department of Neurosurgery, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland. gregoire.courtine@epfl.ch.
¹⁶ Department of Clinical Neuroscience, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland. gregoire.courtine@epfl.ch.

^# Contributed equally.

PMID: 39623087
DOI: 10.1038/s41591-024-03306-x

Abstract

A spinal cord injury (SCI) disrupts the neuronal projections from the brain to the region of the spinal cord that produces walking, leading to various degrees of paralysis. Here, we aimed to identify brain regions that steer the recovery of walking after incomplete SCI and that could be targeted to augment this recovery. To uncover these regions, we constructed a space-time brain-wide atlas of transcriptionally active and spinal cord-projecting neurons underlying the recovery of walking after incomplete SCI. Unexpectedly, interrogation of this atlas nominated the lateral hypothalamus (LH). We demonstrate that glutamatergic neurons located in the LH (LH^Vglut2) contribute to the recovery of walking after incomplete SCI and that augmenting their activity improves walking. We translated this discovery into a deep brain stimulation therapy of the LH (DBS^LH) that immediately augmented walking in mice and rats with SCI and durably increased recovery through the reorganization of residual lumbar-terminating projections from brainstem neurons. A pilot clinical study showed that DBS^LH immediately improved walking in two participants with incomplete SCI and, in conjunction with rehabilitation, mediated functional recovery that persisted when DBS^LH was turned off. There were no serious adverse events related to DBS^LH. These results highlight the potential of targeting specific brain regions to maximize the engagement of spinal cord-projecting neurons in the recovery of neurological functions after SCI. Further trials must establish the safety and efficacy profile of DBS^LH, including potential changes in body weight, psychological status, hormonal profiles and autonomic functions.

Abstract

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