Deep brain stimulation for locomotion in incomplete human spinal cord injury (DBS-SCI): protocol of a prospective one-armed multi-centre study

Abstract

IntroductionSpinal cord injury (SCI) is a devastating condition with immediate impact on the individual’s health and quality of life. Major functional recovery reaches a plateau 3–4 months after injury despite intensive rehabilitative training. To enhance training efficacy and improve long-term outcomes, the combination of rehabilitation with electrical modulation of the spinal cord and brain has recently aroused scientific interest with encouraging results. The mesencephalic locomotor region (MLR), an evolutionarily conserved brainstem locomotor command and control centre, is considered a promising target for deep brain stimulation (DBS) in patients with SCI. Experiments showed that MLR-DBS can induce locomotion in rats with spinal white matter destructions of >85%.Methods and analysisIn this prospective one-armed multi-centre study, we investigate the safety, feasibility, and therapeutic efficacy of MLR-DBS to enable and enhance locomotor training in severely affected, subchronic and chronic American Spinal Injury Association Impairment Scale C patients in order to improve functional recovery. Patients undergo an intensive training programme with MLR-DBS while being regularly followed up until 6 months post-implantation. The acquired data of each timepoint are compared with baseline while the primary endpoint is performance in the 6-minute walking test. The clinical trial protocol was written in accordance with the Standard Protocol Items: Recommendations for Interventional Trials checklist.Ethics and disseminationThis first in-man study investigates the therapeutic potential of MLR-DBS in SCI patients. One patient has already been implanted with electrodes and underwent MLR stimulation during locomotion. Based on the preliminary results which promise safety and feasibility, recruitment of further patients is currently ongoing. Ethical approval has been obtained from the Ethical Committee of the Canton of Zurich (case number BASEC 2016-01104) and Swissmedic (10000316). Results will be published in peer-reviewed journals and presented at conferences.Trial registration numberNCT03053791.

Stimulation of the cuneiform nucleus enables training and boosts recovery after spinal cord injury

“…Treatment initiation in the early, subchronic phase after injury is more efficacious than in the fully chronic phase, and high-intensity training is crucial for long-term motor improvements that persist beyond the discontinuation of training. The effect of CNF-DBS depends on spared reticulospinal fibres and thus patients need to be selected accordingly in ongoing 43 and future clinical trials.…”

“… 42 The potential of CNF-DBS to improve gait in non-ambulatory, chronic SCI patients is currently being investigated in a first in-man proof-of-concept trial ( https://clinicaltrials.gov , DBS-SCI, Identifier: NCT03053791). 43 In the present study, we first identified the safety window of stimulation parameters for CNF-DBS preserving controlled locomotor behaviour adapted to context in intact rats. We then show that the therapeutic effects of CNF-DBS on motor recovery appear progressively in the subchronic and chronic post-injury phases.…”

Functional contribution of mesencephalic locomotor region nuclei to locomotor recovery after spinal cord injury

“…With a current clinical trial assessing MLR DBS in patients with incomplete SCI, 21 , 73 our findings reveal that the CnF offers a better and more reliable neurological target in comparison with the PPN for promoting recovery of motor and locomotor functions, strengthening the importance of evaluating the role of the CnF and especially glutamatergic neurons of the CnF in patients suffering from SCI. Our results also highlight the importance of continuing genetic dissection of functional microcircuits within the PPN in biomedical research.…”

“… 10 , 11 Although deep brain stimulation (DBS) in the PPN 7 or the CnF 8 can improve locomotor recovery in animal models of SCI, there are still questions about which neuronal population is the most efficient. With ongoing clinical trials aiming to assess DBS in the vicinity of the MLR of patients with incomplete SCI, 21 it is now urgent to gain a better understanding of how these distinct neuronal populations of the midbrain can contribute to and promote functional locomotor recovery after SCI.…”

Mesencephalic locomotor region stimulation—cuneiform or pedunculopontine?

“…But what does this mean for stimulation strategies to promote recovery from spinal cord injury? In the context of a current clinical trial that aims to use MLS-DBS following spinal cord injury, 8 this is important to define. Indeed, in rats, both CnF stimulation 9 and PPN stimulation 10 have been proposed to promote recovery, the latter when combined with local lumbar epidural stimulation.…”