Hypothalamic deep brain stimulation augments walking after spinal cord injury
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<sup>Vglut2</sup>) 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<sup>LH</sup>) 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<sup>LH</sup> immediately improved walking in two participants with incomplete SCI and, in conjunction with rehabilitation, mediated functional recovery that persisted when DBS<sup>LH</sup> was turned off. There were no serious adverse events related to DBS<sup>LH</sup>. 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<sup>LH</sup>, including potential changes in body weight, psychological status, hormonal profiles and autonomic functions.
Authors
- Bogdan Draganski (ORCID: https://orcid.org/0000-0002-5159-5919)
- Matthieu Gautier (ORCID: https://orcid.org/0000-0003-4910-8576)
- Inssia Dewany (ORCID: https://orcid.org/0000-0001-9544-4285)
- Stefano Carda (ORCID: https://orcid.org/0000-0001-7849-1290)
- Jocelyne Bloch (ORCID: https://orcid.org/0000-0002-6405-1590)
- Kristina Sveistyte
- Robin Demesmaeker (ORCID: https://orcid.org/0000-0003-0856-0929)
- Viviana Aureli (ORCID: https://orcid.org/0000-0002-7416-621X)
- Grégoire Courtine (ORCID: https://orcid.org/0000-0002-5744-4142)
- Nicolas Hankov (ORCID: https://orcid.org/0000-0001-7112-0091)
- Jordan W. Squair (ORCID: https://orcid.org/0000-0003-0551-859X)
- Léa Bole-Feysot
- Quentin Barraud (ORCID: https://orcid.org/0000-0003-0894-1959)
- Anne Watrin
- Thomas H. Hutson (ORCID: https://orcid.org/0000-0001-6795-2688)
- Newton Cho (ORCID: https://orcid.org/0000-0001-8715-611X)
- Claudia Kathe (ORCID: https://orcid.org/0000-0001-6441-1755)
- Michael A. Skinnider (ORCID: https://orcid.org/0000-0002-2168-1621)
- Laura Batti (ORCID: https://orcid.org/0000-0003-3717-8470)
- Jimmy Ravier
- Maged Goubran (ORCID: https://orcid.org/0000-0001-5880-0818)
- Camille Varescon
- Stéphane Pagès (ORCID: https://orcid.org/0000-0003-0618-777X)
- Achilleas Laskaratos (ORCID: https://orcid.org/0000-0002-2456-5781)
- Mark A. Anderson (ORCID: https://orcid.org/0000-0003-1855-6106)
- Léonie Asboth (ORCID: https://orcid.org/0000-0003-2414-9574)
- Kay Bartholdi
- Anna Leonhartsberger
- Laetitia Baud (ORCID: https://orcid.org/0000-0001-7531-0036)
- Nadia Bérard (ORCID: https://orcid.org/0000-0002-2082-4221)
- Nadine Intering (ORCID: https://orcid.org/0000-0003-1741-2178)
- Nicholas D. James (ORCID: https://orcid.org/0000-0001-5233-8677)
- Katia Galan (ORCID: https://orcid.org/0009-0000-5240-7388)
- Léa Duguet
- Frédéric Merlos
Institutions
- University of Toronto (CA)
- Princeton University (US)
- Centre Hospitalier Universitaire Vaudois (CH)
- Hôpital Orthopédique de la Suisse Romande (CH)
- Ludwig Cancer Research (US)
- Wyss Center for Bio and Neuroengineering (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Lausanne (CH)
Publication Details
- Journal
- Nature Medicine
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1038/s41591-024-03306-x
- Citations
- 41
- Primary Topic
- Neurological disorders and treatments
- Type
- article
- Field-Weighted Citation Impact
- 15.13