Brain Research Institute, University of Zurich, 8057 Zurich, Switzerland.
Institute for Regenerative Medicine, University of Zurich, 8952 Schlieren, Switzerland.
Brain. 2022 Oct 21;145(10):3681-3697. doi: 10.1093/brain/awac184.
Severe spinal cord injuries result in permanent paraparesis in spite of the frequent sparing of small portions of white matter. Spared fibre tracts are often incapable of maintaining and modulating the activity of lower spinal motor centres. Effects of rehabilitative training thus remain limited. Here, we activated spared descending brainstem fibres by electrical deep brain stimulation of the cuneiform nucleus of the mesencephalic locomotor region, the main control centre for locomotion in the brainstem, in adult female Lewis rats. We show that deep brain stimulation of the cuneiform nucleus enhances the weak remaining motor drive in highly paraparetic rats with severe, incomplete spinal cord injuries and enables high-intensity locomotor training. Stimulation of the cuneiform nucleus during rehabilitative aquatraining after subchronic (n = 8 stimulated versus n = 7 unstimulated versus n = 7 untrained rats) and chronic (n = 14 stimulated versus n = 9 unstimulated versus n = 9 untrained rats) spinal cord injury re-established substantial locomotion and improved long-term recovery of motor function. We additionally identified a safety window of stimulation parameters ensuring context-specific locomotor control in intact rats (n = 18) and illustrate the importance of timing of treatment initiation after spinal cord injury (n = 14). This study highlights stimulation of the cuneiform nucleus as a highly promising therapeutic strategy to enhance motor recovery after subchronic and chronic incomplete spinal cord injury with direct clinical applicability.
严重的脊髓损伤导致永久性截瘫，尽管白质的小部分经常幸免。幸免的纤维束通常无法维持和调节较低脊髓运动中枢的活动。因此，康复训练的效果仍然有限。在这里，我们通过电刺激中脑运动区楔形核对成年雌性 Lewis 大鼠进行深部脑刺激，激活幸免的下行脑干纤维。我们表明，楔形核深部脑刺激增强了严重不完全性脊髓损伤高度截瘫大鼠微弱的剩余运动驱动力，并使高强度运动训练成为可能。在亚慢性（n = 8 刺激组与 n = 7 未刺激组与 n = 7 未训练组）和慢性（n = 14 刺激组与 n = 9 未刺激组与 n = 9 未训练组）脊髓损伤后的康复水疗中，刺激楔形核恢复了大量的运动，并改善了运动功能的长期恢复。我们还确定了刺激参数的安全窗口，以确保在完整大鼠中实现特定于情境的运动控制（n = 18），并说明了在脊髓损伤后开始治疗的时机的重要性（n = 14）。这项研究强调了刺激楔形核作为一种很有前途的治疗策略，可增强亚慢性和慢性不完全性脊髓损伤后的运动恢复，具有直接的临床适用性。
