Spinal cord injury (SCI) often results in deficits in voluntary control of muscles due to injury induced necrosis and partial or complete loss of conduction in neural pathways. The most common neurological classification of SCI is tetraplegia, which results from injury to the cervical spinal cord and is characterized by deficits in upper and lower limb function (1, 2). Upper limb function is the most important resource for individuals with tetraplegia and is rated to be the most desired ability to regain after cervical SCI before bowel, bladder, sexual function, or walking ability (3). Thus, improving upper limb function is a crucial part of rehabilitation to enhance an individual’s independence and quality of life. One approach to improve voluntary control of upper limb muscles is to strengthen the connection of spared corticospinal tracts through repetitive transcranial magnetic stimulation (rTMS) (4–6). High frequency (i.e., > 5 Hz) rTMS can increase corticospinal and primary motor cortex (M1) excitability (7). Several studies have applied rTMS over the arm and leg motor representations in the M1 in nonimpaired individuals and in patients with motor impairments to increase corticospinal and M1 excitability, voluntary motor control, and motor learning processes (8–11). Although the effectiveness using different forms of rTMS in nonimpaired individuals and patients with motor impairments are variable (5, 8, 12, 13), rTMS may represent a useful technique to improve upper limb function after SCI, particularly when paired with other therapies.
A greater understanding of the utility of rTMS to improve upper limb function after SCI is needed. High-frequency rTMS protocols have been tested in individuals with tetraplegia to improve upper limb motor and sensory function in five studies to date, all of which targeted stimulation to hand representations in the M1 (4, 9, 14–16). Five sessions of rTMS alone (i.e., without adjunct therapy) improved hand motor and sensory function in one study (14). However, in a larger study involving five sessions of rTMS, results showed only modest improvement in hand motor and sensory function, which was not statistically different from sham effects, and there was no change in clinical neurological assessment (4). In another study, addition of rTMS to repetitive task practice training over three sessions demonstrated a greater effect size for improvement in grasp strength and hand function relative to repetitive task practice alone (15). Only two studies have evaluated a more specific pattern of rTMS known as intermittent theta-burst stimulation (iTBS) targeting the upper limb in individuals with tetraplegia (9); these studies demonstrated safety and feasibility (16), and modifiability of corticomotor excitability (9). Commonly, iTBS involves 2 seconds of TBS trains repeated every 10 seconds for a total of 20 cycles (600 pulses) delivered over a 190 second period (17–19). iTBS has gained much interest, arguably due to its efficacy, short stimulation period, and effects lasting up to 60 minutes post-stimulation (20), making iTBS well suited as a neural priming adjunct to motor training exercises.
Further research is needed to investigate the potential for iTBS to increase the excitability of the corticospinal motor system (hereafter referred to as corticomotor excitability) in individuals with tetraplegia. Effects of iTBS have been demonstrated primarily in nonimpaired humans with stimulation applied to hand representations in the M1 and motor-evoked potentials (MEPs) recorded from the first dorsal interosseous (17, 19, 20). A meta-analysis of studies in nonimpaired participants found that iTBS applied for 190 s significantly increases corticomotor excitability, as measured by MEPs, lasting up to 60 min with a mean maximum potentiation of 35.54 ± 3.32% (20). The mechanisms of these effects are believed to be due to changes in neural circuits in the cortex, perhaps involving long-term potentiation of cortical synapses (21, 22). Evidence from SCI studies in rats suggests that iTBS is able to facilitate MEPs and improve forelimb motor function after injury (23, 24), consistent with the mechanistic understanding of iTBS (21, 22). However, Fassett et al. (25) investigated the effects of iTBS on corticomotor excitability of the flexor carpi radialis in humans with cervical SCI and found corticomotor excitability (i.e., MEPs) to be reduced in the majority of instances after a single session of active M1 stimulation. While the results of Fassett et al. contradict previous findings in nonimpaired subjects and animal models of SCI, the results indicate that iTBS is able to modify corticomotor excitability in humans with tetraplegia, which warrants further investigation.
Depending on the specific injury and needs of an individual with tetraplegia, the biceps brachii may be responsive to iTBS and a functionally relevant target for rehabilitation. The biceps may be particularly responsive to iTBS in individuals with tetraplegia because: the biceps typically remains with some spared motor pathways and function after injury at or below C6 as the biceps is primarily innervated at the C5 and C6 levels (26), and biceps motoneurons receive more corticospinal monosynaptic facilitation relative to its antagonist (27, 28). Additionally, the biceps is relevant for upper limb rehabilitation in tetraplegia as the biceps can be transferred to restore elbow extension for some individuals with tetraplegia (29, 30). After tendon transfer surgery, an individual with tetraplegia undergoes rehabilitation to promote motor re-education of the transferred biceps to extend the elbow. In our previous work, we found a positive relationship between the corticomotor excitability of the transferred biceps and elbow extension strength, suggesting that increased biceps corticomotor excitability may improve the outcomes of tendon transfer surgery (31).
We present a sham-controlled pilot study to provide the first characterization of iTBS-induced effects targeting the biceps brachii in individuals with tetraplegia. The purpose of this study was to determine the effect of iTBS on corticomotor excitability of the biceps in individuals with tetraplegia and nonimpaired subjects. The nonimpaired control group is included to provide a context for the potential effects of iTBS in individuals with SCI. We hypothesized that biceps corticomotor excitability, as measured by MEPs, would be increased relative to baseline following active iTBS relative to sham iTBS in both subject groups. This hypothesis was based on the expectation that iTBS promotes long-term potentiation within cortical neurons. Since the effects of iTBS can be variable across sessions (8, 13, 32), we tested participants across three sessions to evaluate the reproducibility of iTBS aftereffects.