Paired stimulation plasticity for motor recovery - cervical spinal cord injury (SCI) often impairs the reach and grasp movements which are so important to independent living

The National Institute of Neurological Disorders and Stroke (part of the Department of Health and Human Services National Institutes of Health) awarded $367,075 to the University of Newcastle Upon Tyne on September 5, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853, Project Grant R01NS150256).

The award funds research into paired stimulation plasticity for motor recovery following cervical spinal cord injury, with the goal of improving reach and grasp movements. The project investigates two methods for inducing plastic changes in sub-cortical circuits: spinal paired associative stimulation, which pairs transcranial magnetic stimulation of the motor cortex with peripheral nerve stimulation, and startle protocols that pair transcranial magnetic stimulation with loud sound. The first project aim involves experiments in monkeys to determine which synapses are modified by these protocols and to validate assessment methods applicable to humans. The second aim develops approaches to enhance plastic changes through combined stimulation techniques.

Performance occurs at the University of Newcastle Upon Tyne in Great Britain, United Kingdom, with a period of performance from September 5, 2026, through August 31, 2031.

Targeted neural stimulation is a promising approach to enhance neural connections and improve function. This involves activating different parts of a neural circuit using paired stimuli. By changing the precise time between the two stimuli, IT is possible to increase or decrease connection strength. Many studies have applied this concept to cortical circuits, but comparatively little attention has been paid to the potential for sub-cortical plasticity to aid recovery. We know that reaching and grasping movements involve coordinated control by corticospinal and reticulospinal descending tracts, originating in the cortex and brainstem respectively. Thus, exploiting plasticity in sub-cortical circuits could access new avenues to improve rehabilitation. This project will focus on two promising methods for inducing plastic changes in sub-cortical circuits in monkeys with and without SCI. Spinal paired associative stimulation (spinal PAS) involves pairing transcranial magnetic stimulation (TMS) of the motor cortex with supramaximal stimulation of a peripheral nerve. Startle involves pairing TMS with a loud sound. We hypothesize that spinal PAS and startle act on corticospinal synapses and the cortico-reticulospinal system respectively. The first aim of the project is to understand the mechanism of action of these protocols. Experiments in monkeys will determine definitively which synapses are modified by these protocols, and validate common methods used in humans for assessing sub-cortical circuits. This information will permit the principled combination of the two protocols, allowing them to act synergistically to increase the extent of plastic change. The second aim of the project is to develop ways to enhance plastic changes. Studies in monkeys will assess whether combining stimulation with appropriate pharmacological pretreatment and specific tasks can increase plasticity. The output of this research will be a highly optimized stimulation protocol with strong understanding of its underlying mechanisms; this will be ready for translation into people with SCI.