The clinical use of mirror visual feedback (MVF) was initially introduced to alleviate phantom pain, and has since been applied to the improvement of hemiparesis following stroke. However, it is not known whether MVF can restore motor function by producing plastic changes in the human primary motor cortex (M1). Here, we used transcranial magnetic stimulation to test whether M1 plasticity is a physiological substrate of MVF-induced motor behavioral improvement. MVF intervention in normal volunteers using a mirror box improved motor behavior and enhanced excitatory functions of the M1. Moreover, behavioral and physiological measures of MVFinduced changes were positively correlated with each other. Improved motor performance occurred after observation of a simple action, but not after repetitive motor training of the nontarget hand without MVF, suggesting the crucial importance of visual feedback. The beneficial effects of MVF were disrupted by continuous theta burst stimulation (cTBS) over the M1, but not the control site in the occipital cortex. However, MVF following cTBS could further improve the motor functions. Our findings indicate that M1 plasticity, especially in its excitatory connections, is an essential component of MVF-based therapies.

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Repeated paired associative stimulation combining peripheral nerve stimulation and transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) can produce human motor plasticity. However, previous studies used paired artificial stimuli, so that it is not known whether repetitive natural M1 activity associated with TMS can induce plasticity or not. To test this hypothesis, we developed a movement-related cortical stimulation (MRCS) protocol, in which the left M1 was stimulated by TMS at specific timing with respect to the mean expected reaction time (RT) of voluntary movement during a simple reaction time task using the right abductor pollicis brevis (APB) muscle. Seventeen normal volunteers were subjected to repeated MRCS intervention (0.2 Hz, 240 pairs). Motor function was assessed before and after MRCS. When TMS was given 50 ms before the RT of movement [MRCS(Ϫ50)], motor-evoked potential (MEP) amplitude of the right APB, but not other muscles, increased for up to 15 min post-MRCS. The RT of the right APB was also shortened. However, spinal excitability measured by F-wave did not change. When TMS was given 100 ms after the RT [MRCS(ϩ100)], MEP amplitude was decreased. These findings show that this new MRCS protocol can produce timing-dependent motor associative plasticity, which may be clinically useful.

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Patients with chronic stroke often show increased flexor hypertonia in their affected upper limbs. Although an intervention strategy targeting the extensors of the affected upper limb might thus be expected to have benefits for functional recovery, conventional repetitive motor training has limited clinical utility. Recent studies have shown that repetitive transcranial magnetic stimulation could induce motor recovery. The present study tested whether 5 Hz repetitive transcranial magnetic stimulation of the upper-limb area of the primary motor cortex, combined with extensor motor training, had a greater effect on motor recovery than either intervention alone in stroke hemiparesis. Nine patients with chronic subcortical stroke and nine age-matched healthy subjects completed the crossover study. In separate sessions, we examined the single intervention effect of repetitive wrist and finger extension exercises aided by neuromuscular stimulation, the single intervention effect of 5 Hz repetitive transcranial magnetic stimulation and the combined effect of the two interventions. The motor functions were evaluated behaviourally in patients (Experiment 1) and electrophysiologically in healthy subjects (Experiment 2), both before and after the intervention. In addition, we tested the long-term effect by repeating the combined interventions 12 times in patients (Experiment 3). The motor functions were measured again 2 weeks after the end of the repetitive intervention period. In Experiment 1, the combined intervention, but neither of the single interventions, resulted in an improvement of extensor movement (P < 0.0001) and grip power (P < 0.05), along with a reduction of flexor hypertonia (P < 0.01), in their paretic upper limbs. In Experiment 2, only the combined intervention resulted in selective plastic changes of cortico-spinal excitability (P < 0.01), motor threshold (P < 0.001) and silent period (P < 0.01) for the extensors. In Experiment 3, we also confirmed long-term beneficial effects of the combined intervention in patients. These findings indicate that combining motor training with repetitive transcranial magnetic stimulation can facilitate use-dependent plasticity and achieve functional recovery of motor impairments that cannot be attained by either intervention alone. This method could be a powerful rehabilitative approach for patients with hemiparetic stroke.

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Paired associative stimulation (PAS) is an effective non-invasive method to induce human motor plasticity by the repetitive pairing of peripheral nerve stimulation and transcranial magnetic stimulation (TMS) at the primary motor cortex (M1) with a specific time interval. Although the repetitive pairing of two types of afferent stimulation might be a biological basis of neural plasticity and memory, other types of paired stimulation of the human brain have rarely been studied. We hypothesized that the repetitive pairing of TMS and interhemispheric cortico-cortical projection or paired bihemispheric stimulation (PBS), in which the right and left M1 were serially stimulated with a time interval of 15 ms, would produce an associative long-term potentiation (LTP)-like effect. In this study, 23 right-handed healthy volunteers were subjected to a 0.1 Hz repetition of 180 pairings of bihemispheric TMS, and physiological and behavioural measures of the motor system were compared before, immediately after, 20 min after and 40 min after PBS intervention. The amplitude of the motor evoked potential (MEP) induced by the left M1 stimulation and its input-output function increased for up to ∼20 min post-PBS. Fine finger movements were also facilitated by PBS. Spinal excitability measured by the H-reflex was insensitive to PBS, suggesting a cortical mechanism. The associative LTP-like effect induced by PBS was timing dependent, occurring only when the interstimulus interval was 5-25 ms. These findings demonstrate that using PBS in PAS can induce motor cortical plasticity, and this approach might be applicable to the rehabilitation of patients with motor disorders.

Background and Purpose— Gait disturbance is one of serious impairments lowering activity of daily life in poststroke patients. The patients often show reduced hip and knee joint flexion and ankle dorsiflexion of the lower limbs during the swing phase of gait, which is partly controlled by the primary motor cortex (M1). In the present study, we investigated whether gait-synchronized rhythmic brain stimulation targeting swing phase-related M1 activity can improve gait function in poststroke patients. Methods— Eleven poststroke patients in the chronic phase participated in this single-blind crossover study. Each patient received oscillatory transcranial direct current stimulation over the affected M1 foot area and sham stimulation during treadmill gait. The brain stimulation was synchronized with individual gait rhythm, and the electrical current peaks reached immediately before initiation of the swing phase of the paretic lower limb. Ankle dorsiflexion was assisted by electrical neuromuscular stimulation in both real and sham conditions. Results— Regarding the effects of a single intervention, the speed of self-paced gait was significantly increased after oscillatory transcranial direct current stimulation, but not after sham stimulation (paired t test, P =0.009). After we administered the intervention repeatedly, self- and maximally paced gait speed and timed up and go test performance were significantly improved (self-paced: F (1,21) =8.91, P =0.007, maximally paced: F (1,21) =7.09, P =0.015 and timed up and go test: F (1,21) =12.27, P =0.002), along with improved balance function and increased joint flexion of the paretic limbs during gait. Conclusions— These findings suggest that rhythmic brain stimulation synchronized with gait rhythm might be a promising approach to induce gait recovery in poststroke patients. Clinical Trial Registration— URL: https://www.umin.ac.jp/ctr/ . Unique identifier: UMIN000013676.