Multisite Hebbian Plasticity Restores Function in Humans with Spinal Cord Injury

Abstract

Objective: Spinal cord injury (SCI) damages synaptic connections between corticospinal axons and motoneurons of many muscles, resulting in devastating paralysis. We hypothesized that strengthening corticospinal-motoneuronal synapses at multiple spinal cord levels through Hebbian plasticity (i.e., "neurons that fire together, wire together") promotes recovery of leg and arm function. Methods: Twenty participants with chronic SCI were randomly assigned to receive 20 sessions of Hebbian or sham stimulation targeting corticospinal-motoneuronal synapses of multiple leg muscles followed by exercise. Based on the results from this study, in a follow-up prospective study, 11 more participants received 40 sessions of Hebbian stimulation targeting corticospinal-motoneuronal synapses of multiple arm and leg muscles followed by exercise. During Hebbian stimulation sessions, 180 paired pulses elicited corticospinal action potentials by magnetic (motor cortex) and/or electrical (thoracic spine) stimulation allowing volleys to arrive at the spinal cord 1-2 milliseconds before motoneurons were activated retrogradely via bilateral electrical stimulation (brachial plexus, ulnar, femoral, and common peroneal nerves) for biceps brachii, first dorsal interosseous, quadriceps femoris, and tibialis anterior muscles as needed. Results: We found in our randomized study that participants receiving Hebbian stimulation improved their walking speed and corticospinal function to a greater extent than individuals receiving sham stimulation. In agreement, prospective study participants improved their grasping and walking, corticospinal function, and quality of life metrics, exhibiting greater improvements with more sessions that persisted 9-month post-therapy. Interpretation: Our findings suggest that multisite Hebbian stimulation, informed by the physiology of the corticospinal system, represents an effective strategy to promote functional recovery following SCI.

Effects of noninvasive neuromodulation targeting the spinal cord on early learning of force control by the digits

“…Functional improvements occurred in both the intervention and sham groups, but gains in corticospinal transmission and maximum voluntary contraction were preserved 6 months after treatment only in the intervention group. In a more recent trial, a method was developed to simultaneously target multiple upper and lower limb muscles with PCMS prior to activity‐based therapy 19 . Increased walking speed and corticospinal excitability were observed in the intervention group, and a prospective cohort that underwent twice the volume of retraining (20 vs. 40 sessions) showed gains in grasping and walking ability which were accompanied by improvement on quality‐of‐life indexes.…”

“…Increased size of motor‐evoked potentials (MEPs) that are elicited at a subcortical level in absence of changes in the intrinsic excitability of spinal motor neurons is thought to be mediated by STDP‐like mechanisms in synapses connecting upper motor neurons in cortex with lower motor neurons in the spinal cord. Therapeutic enhancement of activity‐based therapy by way of this paired corticospinal‐motor neuronal stimulation (PCMS) protocol has been shown in individuals with longstanding motor impairment due to spinal cord injury (SCI) 18,19 …”

“…Therapeutic enhancement of activity-based therapy by way of this paired corticospinal-motor neuronal stimulation (PCMS) protocol has been shown in individuals with longstanding motor impairment due to spinal cord injury (SCI). 18,19 PCMS is typically administerd with the targeted muscle at rest, but individual differences in individuals with and without SCI have been observed in its aftereffects. 20,21 Administering PCMS against the background of isometric contractions upregulates corticospinal excitability in subjects who otherise do not show this effect and further enhances it in those who already show increased excitability.…”

Motor-targeted spinal stimulation promotes concurrent rebalancing of pathologic nociceptive transmission in chronic spinal cord injury

“…After all, maladaptive neural activity was allowed to develop unchecked and to chronify naturally, resulting in a 'worst case scenario' for plasticity-promoting interventions. And whereas preclinical and clinical studies have repeatedly demonstrated the ability of motor-dominant circuits below a lesion to beneficially and durably reorganize (25)(26)(27)(28)(29)(30)(31)(32), neural transmission in spinal pain pathways has been comparatively difficult to shape. Indeed, interventions explicitly designed to promote functionally-relevant neural plasticity as well as those that attempt to pharmacologically rebalance spinal excitability have been met with variable and generally nominal successespecially when initiated after establishment of the neuropathic pain state (33,34).…”

Home-based arm cycling exercise improves trunk control in persons with incomplete spinal cord injury: an observational study

“…Conversely, two previous studies reported no improvement in reaching distance after a similar exercise program involving the upper body in people with chronic SCI; one study delivered 15 sessions of group-based arm-crank exercise 17 , while the other study conducted 8 sessions of indoor wheelchair curling training 41 . This suggests the number of exercise sessions is an important consideration for trunk rehabilitation following SCI 42 . Note that prior work using supervised, task-speci c balance exercise training reported improvements in lateral reaching distance in a similar population 43 , while we did not observe changes in lateral reaching after the intervention in our participants.…”