Severe spinal cord injuries result in permanent paraparesis in spite of the frequent sparing of small portions of white matter. Spared fiber tracts are often incapable of maintaining and modulating the activity of lower spinal motor centers. Effects of rehabilitative training thus remain limited. Here, we activated spared descending brainstem fibers by electrical deep brain stimulation of the cuneiform nucleus of the mesencephalic locomotor region, the main control center 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 vs. n = 7 unstimulated vs. n = 7 untrained rats) and chronic (n = 14 stimulated vs. n = 9 unstimulated vs. 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.

IntroductionNeurogenic lower urinary tract dysfunction (NLUTD), including neurogenic detrusor overactivity (NDO) and detrusor sphincter dyssynergia, is one of the most frequent and devastating sequelae of spinal cord injury (SCI), as it can lead to urinary incontinence and secondary damage such as renal failure. Transcutaneous tibial nerve stimulation (TTNS) is a promising, non-invasive neuromodulatory intervention that may prevent the emergence of the C-fibre evoked bladder reflexes that are thought to cause NDO. This paper presents the protocol for TTNS in acute SCI (TASCI), which will evaluate the efficacy of TTNS in preventing NDO. Furthermore, TASCI will provide insight into the mechanisms underlying TTNS, and the course of NLUTD development after SCI.Methods and analysisTASCI is a nationwide, randomised, sham-controlled, double-blind clinical trial, conducted at all four SCI centres in Switzerland. The longitudinal design includes a baseline assessment period 5–39 days after acute SCI and follow-up assessments occurring 3, 6 and 12 months after SCI. A planned 114 participants will be randomised into verum or sham TTNS groups (1:1 ratio), stratified on study centre and lower extremity motor score. TTNS is performed for 30 min/day, 5 days/week, for 6–9 weeks starting within 40 days after SCI. The primary outcome is the occurrence of NDO jeopardising the upper urinary tract at 1 year after SCI, assessed by urodynamic investigation. Secondary outcome measures assess bladder and bowel function and symptoms, sexual function, neurological structure and function, functional independence, quality of life, as well as changes in biomarkers in the urine, blood, stool and bladder tissue. Safety of TTNS is the tertiary outcome.Ethics and disseminationTASCI is approved by the Swiss Ethics Committee for Northwest/Central Switzerland, the Swiss Ethics Committee Vaud and the Swiss Ethics Committee Zürich (#2019-00074). Findings will be disseminated through peer-reviewed publications.Trial registration numberNCT03965299.

During REM sleep, a powerful postsynaptic inhibition of spinal motoneurons induces a generalized muscle hypotonia. Despite this inhibition, it has been shown that by transcranial magnetic stimulation of the brain (TMS), muscle responses of normal amplitude can be evoked in small hand muscles of humans. Tonic innervation during sleep is different in postural vs. limb muscles, and the spinal inhibition differs during tonic vs. phasic REM episodes, Both phenomena may affect muscle responses to TMS. In this study, muscle responses of 14 healthy subjects were compared to TMS in abductor digiti minimi, lumbar erector spinae, trapezius, and diaphragm during phasic and tonic REM sleep. In all four muscles, the amplitudes of the muscle responses were extremely variable, ranging for example in trapezius from -100% to +473% as compared to wakefulness. There was no systematic difference between the muscles. Moreover, no differences were found for TMS during phasic REM events compared to tonic REM sleep. Thus, responses to TMS during REM sleep may be preserved, with a decreased or increased amplitude. As a likely explanation, the cortical excitability and/or the spinal inhibition fluctuates during REM sleep in humans.