Dose duration effect of concurrent and synchronized motor cortex theta burst stimulation and upper-limb neuromuscular electrical stimulation

Intermittent theta burst stimulation (iTBS) can induce rapid cortical facilitation, while neuromuscular electrical stimulation (NMES) can activate sensorimotor networks to excite the central nervous system. Application of iTBS and NMES delivered concurrently at a synchronized 50 Hz frequency was recently shown to elicit greater but transient corticospinal facilitation compared to each intervention. Our current study aimed to investigate the dose-duration neuromodulation effects of concurrent and synchronized associative stimulation using iTBS-NMES. A single dose consisted of 600 pulses of iTBS applied simultaneously with 50 Hz NMES for 2 s ON/8s OFF over 192 s. Four interventions were tested on separate days in eleven able-bodied individuals: iTBS600-NMES (one dose), iTBS1200-NMES (two doses), iTBS1800-NMES (three doses), and iTBS1800 (control intervention consisting of three iTBS-alone doses without NMES). Single-pulse transcranial magnetic stimulation (TMS) of motor cortex was used to evaluate corticospinal excitability through motor evoked potentials (MEP). Paired-pulse TMS short-interval intracortical inhibition (SICI) was used to evaluate intracortical inhibition, and maximum motor responses (M_max) were elicited by radial nerve stimulation to monitor fatigue. Assessments were completed before, immediately after, and every 10 min for total 30 min after each intervention. Our results showed significant MEP facilitation for at least 30 min only after iTBS1800-NMES intervention, while the iTBS1800 control intervention was ineffective. SICI and M_max responses were not affected by any intervention. Our findings demonstrate that increased iTBS-NMES dose-duration extends corticospinal facilitation that likely involved the cumulative effect to overcome the homeostatic threshold with repetitive synchronized activation of cortical and peripheral inputs at the subcortical level.