Cho Newton, Squair Jordan W, Aureli Viviana, James Nicholas D, Bole-Feysot Léa, Dewany Inssia, Hankov Nicolas, Baud Laetitia, Leonhartsberger Anna, Sveistyte Kristina, Skinnider Michael A, Gautier Matthieu, Laskaratos Achilleas, Galan Katia, Goubran Maged, Ravier Jimmy, Merlos Frederic, Batti Laura, Pages Stéphane, Berard Nadia, Intering Nadine, Varescon Camille, Watrin Anne, Duguet Léa, Carda Stefano, Bartholdi Kay A, Hutson Thomas H, Kathe Claudia, Hodara Michael, Anderson Mark A, Draganski Bogdan, Demesmaeker Robin, Asboth Leonie, Barraud Quentin, Bloch Jocelyne, Courtine Grégoire
Defitech Center for Interventional Neurotherapies (.NeuroRestore), CHUV/UNIL/EPFL, Lausanne, Switzerland.
NeuroX Institute, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
Nat Med. 2024 Dec;30(12):3676-3686. doi: 10.1038/s41591-024-03306-x. Epub 2024 Dec 2.
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) 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) 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 immediately improved walking in two participants with incomplete SCI and, in conjunction with rehabilitation, mediated functional recovery that persisted when DBS was turned off. There were no serious adverse events related to DBS. 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, including potential changes in body weight, psychological status, hormonal profiles and autonomic functions.
脊髓损伤（SCI）会破坏从大脑到脊髓产生行走功能区域的神经元投射，导致不同程度的瘫痪。在此，我们旨在确定在不完全性脊髓损伤后引导行走功能恢复且可作为增强这种恢复的靶向目标的脑区。为了揭示这些区域，我们构建了一个时空全脑图谱，该图谱描绘了不完全性脊髓损伤后行走功能恢复过程中转录活跃且投射至脊髓的神经元。出乎意料的是，对该图谱的研究确定了外侧下丘脑（LH）。我们证明，位于外侧下丘脑（LH）的谷氨酸能神经元有助于不完全性脊髓损伤后行走功能的恢复，增强它们的活性可改善行走能力。我们将这一发现转化为对外侧下丘脑（LH）的深部脑刺激疗法（DBS），该疗法立即改善了脊髓损伤小鼠和大鼠的行走能力，并通过重组来自脑干神经元的残余腰段终末投射持久地促进了恢复。一项初步临床研究表明，深部脑刺激疗法（DBS）立即改善了两名不完全性脊髓损伤参与者的行走能力，并且与康复治疗相结合，介导了在深部脑刺激疗法（DBS）关闭后仍持续存在的功能恢复。没有与深部脑刺激疗法（DBS）相关的严重不良事件。这些结果突出了靶向特定脑区以最大限度地促进脊髓投射神经元参与脊髓损伤后神经功能恢复的潜力。进一步的试验必须确定深部脑刺激疗法（DBS）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。
