Cervical Spinal Cord Associative Plasticity

Official title

Paired Non-invasive Stimulation of Hand Motor Cortex and Median Nerve to Induce Plasticity in the Cervical Spinal Cord

Overview

Associative plasticity has been used to promote functional recovery from conditions affecting movement. Prior work from the Carmel laboratory has shown that paired associative stimulation protocols timed to converge in the cervical spinal cord induce significantly larger upper limb motor responses than if timed to converge in the motor cortex. The goal of this prospective experimental study in typically developing adults is to test the effects of pairing sub-threshold hand motor cortical and median nerve stimulation targeted to induce plasticity in the cervical spinal cord, rather than in the motor cortex. Based on preliminary data, the investigators are performing a confirmatory study to test the physiological and behavioral effects of the paired brain and peripheral nerve protocol, called the SCAP-Nerve protocol. This study will first be conducted in typically developing adults to confirm the cervical spinal cord as the ideal target and verify the present stimulation parameters are sufficient to promote induction of associative plasticity of sensorimotor connections for manual dexterity. The outcomes from this study could then be translated to efficacy studies in people with spinal cord injury and cerebral palsy to promote clinically meaningful improvements in dexterity.

Detailed description

Associative plasticity has been used to promote functional recovery in patient populations, such as adults with spinal cord injuries (SCI). Using non-invasive neuromodulation approaches, pairing of motor cortical stimulation and peripheral nerve stimulation has been shown to augment motor responses and promote plasticity, primarily through the convergence of sensory afferent stimuli and descending cortical stimuli in the motor cortex.

However, prior work from the Carmel laboratory has shown that paired associative stimulation timed to converge in the cervical spinal cord induces significantly larger upper limb motor responses than if timed to converge in the motor cortex. While paired associative stimulation has shown promise for strengthening motor responses, it is unclear if plasticity from convergence of non-invasive stimuli in the spinal cord (termed spinal cord associative plasticity or SCAP) instead of the motor cortex can produce greater motor effects, and potentially greater promotion of movement recovery.

The goal of this present study is to test the effects of pairing sub-threshold hand motor cortical and median nerve stimulation targeted to induce plasticity in the cervical spinal cord, rather than in the motor cortex. The investigators aim to fill a knowledge gap regarding the ideal target of non-invasive stimulation to maximize associative plasticity for upper limb movement recovery. The study hypothesis is that pairing low-intensity stimulation of the hand motor cortex with low-intensity median nerve stimulation will produce associative plasticity in the cervical spinal cord measured through augmentation of motor responses in upper limb muscles.

Based on preliminary data, the investigators are performing a confirmatory study to test the physiological and behavioral effects of the paired brain and peripheral nerve protocol, called the SCAP-Nerve protocol. This protocol uses a specific set of TMS (transcranial magnetic stimulation) and PNS (peripheral nerve stimulation) parameters: targeting hand motor cortex at 90% resting motor threshold and targeting median nerve sensory afferents (with a nerve stimulus pulse duration of 1000 microseconds) at 90% resting motor threshold, precisely timed to converge in the cervical spinal cord.

This study will first be conducted with a single session of 90 trials of pairing in typically developing adults to confirm the cervical spinal cord as the ideal target and verify the present stimulation parameters as sufficient to promote induction of associative plasticity of sensorimotor connections for manual dexterity. Prior work from the Carmel laboratory has shown that the magnitude and duration of lasting effects of paired motor cortex and afferent stimulation is similar in rodents with and without neural injury.

This then drives the premise for this study that the identification of the cervical spinal cord as an ideal target for associative plasticity involving cortical and sensory afferents would inform translation to people suffering from neurological injuries such as spinal cord injury and cerebral palsy. The outcomes from this study could be translated to efficacy studies in these patient populations to determine if this plasticity is present in those populations as well. This could then lead to the investigation of whether pairing brain and afferent-targeted nerve stimulation for convergence in the cervical spinal cord can lead to clinically meaningful improvements in manual dexterity.

Interventions

• Other SCAP
  This utilizes pairing of repetitive transcranial magnetic stimulation (rTMS) and peripheral nerve stimulation (rPNS) timed to converge in the cervical spinal cord.
• Device MagPro X100
  This stimulator will be use to provide repetitive transcranial magnetic stimulation (rTMS).
• Device Digitimer DS8R
  This stimulator will be used to provide repetitive peripheral nerve stimulation (rPNS).
• Other Paired non-associative stimulation
  This utilizes pairing of repetitive transcranial magnetic stimulation (rTMS) and peripheral nerve stimulation (rPNS) timed to arrive at a pairing interval of 40 msec.

Primary outcome measures

• Size of muscle response to brain stimulation after SCAP (percentage) [Time frame: 30 minutes after SCAP]

Secondary outcome measures (6)

• Size of muscle response to nerve stimulation during combined brain and nerve stimulation after SCAP (percentage) [Time frame: Immediately after intervention, up to 1 minute]
• Size of muscle response to nerve stimulation during combined brain and nerve stimulation (percentage) [Time frame: Immediately after intervention, up to 1 minute]
• Size of muscle response to nerve stimulation during combined brain and nerve stimulation after SCAP (percentage) [Time frame: 30 minutes after SCAP]
• Duration of effect of SCAP on subsequent responses to brain stimulation [Time frame: 30 minutes after SCAP]
• Pinch force variability [Time frame: 30 minutes after SCAP]
• Pinch force speed [Time frame: 30 minutes after SCAP]

Eligibility criteria

Inclusion criteria

• Willingness to participate in up to 4 sessions
• Maintenance of caffeine and exercise levels at time of sessions
• Ability to provide informed consent
• No known central or peripheral neurological disease or injury
• No known musculoskeletal injury of the tested arm or hand

Exclusion criteria

• Personal or family history of seizures
• Use of medications that lower seizure threshold
• History of implanted equipment including stimulators/pacemakers

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Crossover

Masking

Open label

Primary purpose

Basic science

Study locations

United States · 1 center

• Columbia University Irving Medical Center — New York

Publications

• Ling YT, Alam M, Zheng YP. Spinal Cord Injury: Lessons about Neuroplasticity from Paired Associative Stimulation. Neuroscientist. 2020 Jun;26(3):266-277. doi: 10.1177/1073858419895461. Epub 2019 Dec 31. PMID 31889474
• Shulga A, Lioumis P, Zubareva A, Brandstack N, Kuusela L, Kirveskari E, Savolainen S, Ylinen A, Makela JP. Long-term paired associative stimulation can restore voluntary control over paralyzed muscles in incomplete chronic spinal cord injury patients. Spinal Cord Ser Cases. 2016 Jul 14;2:16016. doi: 10.1038/scsandc.2016.16. eCollection 2016. PMID 28053760
• Delvendahl I, Jung NH, Kuhnke NG, Ziemann U, Mall V. Plasticity of motor threshold and motor-evoked potential amplitude--a model of intrinsic and synaptic plasticity in human motor cortex? Brain Stimul. 2012 Oct;5(4):586-93. doi: 10.1016/j.brs.2011.11.005. Epub 2012 Feb 28. PMID 22445536
• Stefan K, Kunesch E, Cohen LG, Benecke R, Classen J. Induction of plasticity in the human motor cortex by paired associative stimulation. Brain. 2000 Mar;123 Pt 3:572-84. doi: 10.1093/brain/123.3.572. PMID 10686179
• Murray LM, McIntosh JR, Goldsmith JA, Wu YK, Liu M, Sanford SP, Joiner EF, Mandigo C, Virk MS, Tyagi V, Carmel JB, Harel NY. Timing-dependent synergies between noninvasive motor cortex and spinal cord stimulation in chronic cervical spinal cord injury. medRxiv [Preprint]. 2025 Apr 27:2025.04.17.25326011. doi: 10.1101/2025.04.17.25326011. PMID 40313296
• Murray LM, McIntosh JR, Goldsmith JA, Wu YK, Liu M, Sanford SP, Joiner EF, Mandigo C, Tyagi V, Virk MS, Carmel JB, Harel NY. Timing-dependent synergies between noninvasive motor cortex and spinal cord stimulation in chronic cervical spinal cord injury. Clin Neurophysiol. 2025 Dec;180:2111372. doi: 10.1016/j.clinph.2025.2111372. Epub 2025 Oct 10. PMID 41106070
• Pal A, Park H, Ramamurthy A, Asan AS, Bethea T, Johnkutty M, Carmel JB. Spinal cord associative plasticity improves forelimb sensorimotor function after cervical injury. Brain. 2022 Dec 19;145(12):4531-4544. doi: 10.1093/brain/awac235. PMID 36063483

Identifiers

NCT: NCT07539025 · AAAV2760-TD

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗