Factors influencing the magnitude and reproducibility of corticomotor excitability changes induced by paired associative stimulation

Several paired-associative stimulation (PAS) protocols induce neuroplastic changes in human motor cortex (M1). To understand better the inherent variability of responses to PAS, we investigated the effectiveness and reproducibility of two PAS paradigms, and neurophysiological and experimental variables that may influence this. Motor evoked potentials (MEPs) were elicited by transcranial magnetic stimulation (TMS) of right M1, and recorded from surface EMG of left abductor pollicis brevis (APB) and first dorsal interosseous before and after PAS. PAS consisted of electrical stimulation of left median nerve paired with TMS over right M1 25 ms later. Twenty subjects were given one of two PAS protocols: short (132 paired stimuli at 0.2 Hz) or long (90 paired stimuli at 0.05 Hz), and were re-tested with the same protocol on 3 separate occasions, with 11 subjects tested in the morning and 9 in the afternoon. Neurophysiological variables assessed included MEP amplitude, resting and active motor threshold, short-interval intracortical inhibition, intracortical facilitation and cortical silent period duration. The short PAS protocol produced greater APB MEP facilitation (51%) than the long protocol (11%), and this did not differ between sessions. The neurophysiological variables did not consistently predict responses to PAS. Both PAS protocols induced more APB MEP facilitation, and greater reproducibility between sessions, in experiments conducted in the afternoon. The mechanism for this is unclear, but circadian rhythms in hormones and neuromodulators known to influence neuroplasticity warrant investigation. Future studies involving PAS should be conducted at a fixed time of day, preferably in the afternoon, to maximise neuroplasticity and reduce variability.