Clinical Trial Designs for Neuromodulation in Chronic Spinal Cord Injury Using Epidural Stimulation

Boakye, Maxwell; Ugiliweneza, Beatrice; Mesbah, Samineh; Ovechkin, Alexander V.; Angeli, Cláudia A.; Bloom, Ona; Wecht, Jill W.; Ditterline, Bonnie Legg; Harel, Noam Y.; Kirshblum, Steven; Forrest, Gail; Wu, Samuel S.; Harkema, Susan J.; Guest, James D.

doi:10.1111/ner.13381

Cited by 5 publications

(4 citation statements)

References 92 publications

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“…These models have their own advantages and disadvantages, and the choice of model often depends on the specific research question being addressed ( 33 ). Moreover, this study only examined the effects of Ccl2 depletion in microglia, and other cells in the spine may also contribute to chronic spinal compression/SCI-associated pain ( 34 ). Future studies could investigate the effects of Ccl2 depletion in other cells in the spine and in other cell types in the nervous system, specifically focusing on the crosstalk among different cell types in the microenvironment using Ccl2 as a mediator ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Suppression of microglial Ccl2 reduces neuropathic pain associated with chronic spinal compression

Yang

Wang

et al. 2023

Front. Immunol.

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IntroductionChronic spinal compression is a common complication of spinal cord injury (SCI), which can lead to spinal stenosis or herniated discs. The ensuing neuropathic pain is often associated with the activation of microglia. In this investigation, our objective was to explore whether modifying the levels of chemokine (C-C motif) ligand 2 (Ccl2) in microglia could alleviate neuropathic pain resulting from chronic spinal compression.MethodsWe used a public database to look for major altered gene associated in a SCI model established in rats. We then employed adeno-associated virus (AAV) vectors, expressing siRNA for the identified significantly altered gene under a microglia-specific TMEM119 promoter. We also tested the impact of this treatment in microglia in vivo on the severity of chronic spinal compression and associated pain using a ttw mouse model for progressive spinal compression.ResultsWe identified chemokine (C-C motif) ligand 2 (Ccl2) as the primary gene altered in microglia within a rat SCI model, utilizing a public database. Microglial Ccl2 levels were then found to be significantly elevated in disc specimens from SCI patients diagnosed with chronic spinal compression and strongly correlated with the Thompson classification of the degeneration level and pain score. Depletion of Ccl2 in microglia-specific TMEM119 promoter were developed to transfect mouse microglia in vitro, resulting in a proinflammatory to anti-inflammatory phenotypic adaption. In vivo depletion of Ccl2 in microglia mitigated the severity of chronic spinal compression and related pain in ttw mice, likely due to significant changes in pain-associated cytokines and factors.ConclusionDisc microglia expressing high levels of Ccl2 may contribute to chronic spinal compression and SCI-associated pain. Therapeutically targeting Ccl2 in microglia could offer a potential avenue for treating chronic spinal compression and SCI-associated pain.

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Section: Discussionmentioning

confidence: 99%

Suppression of microglial Ccl2 reduces neuropathic pain associated with chronic spinal compression

Yang

Wang

et al. 2023

Front. Immunol.

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“…Additionally, many new clinical trials are studying different stimulation parameters as well as concurrent pharmacologic treatments. To move towards further clinical translation, further clinical trials should adopt more robust research designs to reduce bias, such as including control groups, incorporating randomization before implantation, and adding further blinding to patients and assessors, as well as developing the framework for multicenter studies in an effort to include more patients and make data accessible for external analysis [ 125 ].…”

Section: Discussionmentioning

confidence: 99%

“…To move towards further clinical translation, further clinical trials should adopt more robust research designs to reduce bias, such as including control groups, incorporating randomization before implantation, and adding further blinding to patients and assessors, as well as developing the framework for multicenter studies in an effort to include more patients and make data accessible for external analysis. 125 The use of SCS to induce functional recovery after SCI is still a fairly new technique-the data gathered across the studies listed in this paper are mostly from case or case-series studies with no appropriate control groups to assess if SCS is a better treatment than placebo or the current standard of care. The patients in the reviewed studies were mostly male (n = 257), indiwww.e-neurospine.org 729 cating a gender bias-though males are more commonly injured, these results suggest that more females should be included in SCS studies to identify potential gender differences.…”

Section: Safety Of Scsmentioning

confidence: 99%

A Review of Functional Restoration From Spinal Cord Stimulation in Patients With Spinal Cord Injury

et al. 2022

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Traumatic spinal cord injury often leads to loss of sensory, motor, and autonomic function below the level of injury. Recent advancements in spinal cord electrical stimulation (SCS) for spinal cord injury have provided potential avenues for restoration of neurologic function in affected patients. This review aims to assess the efficacy of spinal cord stimulation, both epidural (eSCS) and transcutaneous (tSCS), on the return of function in individuals with chronic spinal cord injury. The current literature on human clinical eSCS and tSCS for spinal cord injury was reviewed. Seventy-one relevant studies were included for review, specifically examining changes in volitional movement, changes in muscle activity or spasticity, or return of cardiovascular pulmonary, or genitourinary autonomic function. The total participant sample comprised of 327 patients with spinal cord injury, each evaluated using different stimulation protocols, some for sensorimotor function and others for various autonomic functions. One hundred eight of 127 patients saw improvement in sensorimotor function, 51 of 70 patients saw improvement in autonomic genitourinary function, 32 of 32 patients saw improvement in autonomic pulmonary function, and 32 of 36 patients saw improvement in autonomic cardiovascular function. Although this review highlights SCS as a promising therapeutic neuromodulatory technique to improve rehabilitation in patients with SCI, further mechanistic studies and stimulus parameter optimization are necessary before clinical translation.

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“…Future, larger studies based on this one may be able to confirm efficacy in improving gait dysfunction associated with conditions such as PD, spinal cord injury, or stroke. Interestingly, our subject is able to reliably detect when stimulation is turned on, stating that his legs feel like they “want to go.” This unfortunately makes it difficult to blind the subject to DBS during gait testing to control for potential placebo effects, a known challenge in designing effective neuromodulation studies ( Boakye et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

MR Tractography-Based Targeting and Physiological Identification of the Cuneiform Nucleus for Directional DBS in a Parkinson’s Disease Patient With Levodopa-Resistant Freezing of Gait

Chang

Cajigas

Guest

et al. 2021

Front. Hum. Neurosci.

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BackgroundFreezing of gait (FOG) is a debilitating motor deficit in a subset of Parkinson’s Disease (PD) patients that is poorly responsive to levodopa or deep brain stimulation (DBS) of established PD targets. The proposal of a DBS target in the midbrain, known as the pedunculopontine nucleus (PPN), to address FOG was based on its observed neuropathology in PD and its hypothesized involvement in locomotor control as a part of the mesencephalic locomotor region (MLR). Initial reports of PPN DBS were met with enthusiasm; however, subsequent studies reported mixed results. A closer review of the MLR basic science literature, suggests that the closely related cuneiform nucleus (CnF), dorsal to the PPN, may be a superior site to promote gait. Although suspected to have a conserved role in the control of gait in humans, deliberate stimulation of a homolog to the CnF in humans using directional DBS electrodes has not been attempted.MethodsAs part of an open-label Phase 1 clinical study, one PD patient with predominantly axial symptoms and severe FOG refractory to levodopa therapy was implanted with directional DBS electrodes (Boston Science Vercise CartesiaTM) targeting the CnF bilaterally. Since the CnF is a poorly defined reticular nucleus, targeting was guided both by diffusion tensor imaging (DTI) tractography and anatomical landmarks. Intraoperative stimulation and microelectrode recordings were performed near the targets with leg EMG surface recordings in the subject.ResultsPost-operative imaging revealed accurate targeting of both leads to the designated CnF. Intraoperative stimulation near the target at low thresholds in the awake patient evoked involuntary electromyography (EMG) oscillations in the legs with a peak power at the stimulation frequency, similar to observations with CnF DBS in animals. Oscillopsia was the primary side effect evoked at higher currents, especially when directed posterolaterally. Directional DBS could mitigate oscillopsia.ConclusionDTI-based targeting and intraoperative stimulation to evoke limb EMG activity may be useful methods to help target the CnF accurately and safely in patients. Long term follow-up and detailed gait testing of patients undergoing CnF stimulation will be necessary to confirm the effects on FOG.Clinical Trial RegistrationClinicaltrials.gov identifier: NCT04218526.

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Clinical Trial Designs for Neuromodulation in Chronic Spinal Cord Injury Using Epidural Stimulation

Cited by 5 publications

References 92 publications

Suppression of microglial Ccl2 reduces neuropathic pain associated with chronic spinal compression

Suppression of microglial Ccl2 reduces neuropathic pain associated with chronic spinal compression

A Review of Functional Restoration From Spinal Cord Stimulation in Patients With Spinal Cord Injury

MR Tractography-Based Targeting and Physiological Identification of the Cuneiform Nucleus for Directional DBS in a Parkinson’s Disease Patient With Levodopa-Resistant Freezing of Gait

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