Hypothalamic deep brain stimulation augments walking after spinal cord injury

IF 58.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Nature Medicine Pub Date : 2024-12-02 DOI:10.1038/s41591-024-03306-x

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

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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 (LHVglut2) 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 (DBSLH) 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 DBSLH immediately improved walking in two participants with incomplete SCI and, in conjunction with rehabilitation, mediated functional recovery that persisted when DBSLH was turned off. There were no serious adverse events related to DBSLH. 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 DBSLH, including potential changes in body weight, psychological status, hormonal profiles and autonomic functions. Whole-brain anatomical and activity surveys identify the lateral hypothalamus as a key driver of recovery from spinal cord injury, leading to a deep brain stimulation therapy that augments the recovery of walking in humans.

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下丘脑深部脑刺激增强脊髓损伤后的行走能力

脊髓损伤（SCI）破坏了从大脑到产生行走的脊髓区域的神经元投射，导致不同程度的瘫痪。在这里，我们的目标是确定引导不完全性脊髓损伤后行走恢复的大脑区域，并有针对性地增强这种恢复。为了揭示这些区域，我们构建了一个时空脑范围的转录活跃和脊髓投射神经元图谱，这些神经元是不完全性脊髓损伤后行走恢复的基础。出乎意料的是，对这个图谱的询问指定了外侧下丘脑（LH）。我们证明位于LH （LHVglut2）的谷氨酸能神经元有助于不完全性脊髓损伤后行走的恢复，并且增加它们的活动可以改善行走。我们将这一发现转化为LH深部脑刺激疗法（DBSLH），该疗法立即增强了脊髓损伤小鼠和大鼠的行走能力，并通过重组脑干神经元残留的腰末梢投射持久地提高了恢复能力。一项试点临床研究表明，DBSLH立即改善了两名不完全性脊髓损伤患者的行走，并与康复治疗相结合，介导了功能恢复，当DBSLH关闭时，功能恢复持续存在。无与DBSLH相关的严重不良事件。这些结果强调了靶向特定脑区在脊髓损伤后神经功能恢复中最大限度地参与脊髓投射神经元的潜力。进一步的试验必须确定DBSLH的安全性和有效性，包括体重、心理状态、激素水平和自主神经功能的潜在变化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Medicine 医学-生化与分子生物学

CiteScore

100.90

自引率

0.70%

发文量

525

审稿时长

1 months

期刊介绍： Nature Medicine is a monthly journal publishing original peer-reviewed research in all areas of medicine. The publication focuses on originality, timeliness, interdisciplinary interest, and the impact on improving human health. In addition to research articles, Nature Medicine also publishes commissioned content such as News, Reviews, and Perspectives. This content aims to provide context for the latest advances in translational and clinical research, reaching a wide audience of M.D. and Ph.D. readers. All editorial decisions for the journal are made by a team of full-time professional editors. Nature Medicine consider all types of clinical research, including: -Case-reports and small case series -Clinical trials, whether phase 1, 2, 3 or 4 -Observational studies -Meta-analyses -Biomarker studies -Public and global health studies Nature Medicine is also committed to facilitating communication between translational and clinical researchers. As such, we consider “hybrid” studies with preclinical and translational findings reported alongside data from clinical studies.