ABSTRACT
Among the 800,000 individuals who sustain a stroke annually in the United States, up to 65% continue to experience mod-
erate-to-severe impairments in one hand six months or more, limiting their ability to perform daily tasks. These impairments,
often characterized by the limited functional wrist and finger extension (< 20º), prevent the use of the paretic hand in func-
tional tasks. Functional electrical stimulation (FES), commonly used to promote repeated use of the paretic hand in func-
tional tasks, shows modest and transient effects in this population. Several non-invasive approaches of neuromodulation
[e.g., repeated transcranial magnetic stimulation (rTMS), transcranial direct current stimulation, or paired associative stim-
ulation] have also been applied to cortical motor areas, in either the same hemisphere as the stroke or contralaterally, to
augment the effects of FES-facilitated task-specific practice. However, there is limited evidence supporting the effectiveness
of these approaches. Thus, it is critical to examine alternative approaches to improving hand function and functional inde-
pendence in this more impaired population. Our long-term goal is to develop mechanistic and theory-driven rehabili-
tation interventions to improve hand function and functional independence in individuals with severe stroke. The
strength of the synaptic connections between corticospinal axons and spinal motor neurons—which is severely affected
after stroke—is essential to produce functionally relevant voluntary movements. Emerging evidence points to the potential
for the reorganization of residual corticospinal inputs on spinal motor neuron pools to support recovery after stroke. Paired
corticospinal-motor neuronal stimulation (PCMS) has been shown to strengthen the synapse between surviving corticospi-
nal axons and spinal motor neurons. In PCMS, TMS is paired with peripheral nerve stimulation (PNS) such that the TMS-
evoked corticospinal volleys arrive at corticospinal-motor neuronal synapses ~1-2 ms before the antidromic activation of
spinal motor neurons via PNS. Previous research in individuals with incomplete spinal cord injury indicates that PCMS
delivered during voluntary contraction elicits greater gains in corticospinal transmission (i.e., the size of motor evoked
potentials [MEPs]) than at rest. These improvements in corticospinal transmission were also associated with improvements
in hand function, indicating that voluntary contraction during PCMS strengthens residual synaptic connections and enhances
motor performance. However, the behavioral effects of PCMS after moderate-to-severe stroke, particularly when combined
with a functional task, are not known. Therefore, a critical step in understanding the potential of PCMS in stroke reha-
bilitation is to employ PCMS during a functional task to augment task-specific practice in more impaired individuals
after stroke. Thus, our central hypothesis is that delivering PCMS during functionally relevant voluntary movements
(or task-specific PCMS) will improve corticospinal transmission and hand function after moderate-to-severe stroke.
To this end, using a within-subjects repeated measures design, we will test each participant on three conditions (task-specific
PCMS, task-specific sham-PCMS, and PCMS-rest) in a randomized order. The proposed proof of concept study will eval-
uate the short-term neurophysiological and behavioral effects of task-specific PCMS after moderate-to-severe stroke.
