Multisite Hebbian Plasticity Restores Function in Humans with Spinal Cord Injury

Hang Jin Jo; Ethan Kizziar; Sina Sangari; David Chen; Allison Kessler; Ki Kim; Alan Anschel; Allen W Heinemann; Brett D Mensh; Saria Awadalla; Richard L Lieber; Martin Oudega; Monica A Perez

doi:10.1002/ana.26622

Multisite Hebbian Plasticity Restores Function in Humans with Spinal Cord Injury

Ann Neurol. 2023 Jun;93(6):1198-1213. doi: 10.1002/ana.26622. Epub 2023 Mar 30.

Authors

Hang Jin Jo^{1

2}, Ethan Kizziar^{1

2

3}, Sina Sangari^{1

2}, David Chen^{1

2}, Allison Kessler^{1

2}, Ki Kim^{1

2}, Alan Anschel^{1

2}, Allen W Heinemann^{1

2}, Brett D Mensh⁴, Saria Awadalla⁵, Richard L Lieber^{1

2

3

6}, Martin Oudega^{1

3

6}, Monica A Perez^{1

2

3

6}

Affiliations

¹ Shirley Ryan AbilityLab, Chicago, IL, USA.
² Department of Physical Medicine and Rehabilitation, Northwestern University, Chicago, IL.
³ Department of Physical Therapy and Human Movement Sciences, Northwestern University, Chicago, IL.
⁴ Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA.
⁵ Division of Epidemiology & Biostatistics, University of Illinois at Chicago, Chicago, IL.
⁶ Research Service 151, Edward Jr. Hines VA Hospital, Chicago, IL.

PMID: 36843340
PMCID: PMC10268028 (available on 2024-06-01)
DOI: 10.1002/ana.26622

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. ANN NEUROL 2023;93:1198-1213.

Publication types

Randomized Controlled Trial
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Evoked Potentials, Motor / physiology
Humans
Motor Neurons / physiology
Muscle, Skeletal / physiology
Neuronal Plasticity / physiology
Prospective Studies
Pyramidal Tracts
Quality of Life*
Spinal Cord
Spinal Cord Injuries* / therapy

Abstract

Publication types

MeSH terms

Grants and funding