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L-dopa variably influences transcranial magnetic stimulation (TMS) parameters of motor cortex (M1) excitability and plasticity in Parkinson's disease (PD). In patients OFF dopaminergic medication, impaired M1 plasticity and defective GABA-A-ergic inhibition can be restored by boosting gamma (γ) oscillations via transcranial alternating current stimulation (tACS) during intermittent theta-burst stimulation (iTBS). However, it is unknown whether L-dopa modifies the beneficial effects of iTBS-γ-tACS on M1 in PD. In this study, a PD patients group underwent combined iTBS-γ-tACS and iTBS-sham-tACS, each performed both OFF and ON dopaminergic therapy (four sessions in total). Motor evoked potentials (MEPs) elicited by single TMS pulses and short-interval intracortical inhibition (SICI) were assessed before and after iTBS-tACS. We also evaluated possible SICI changes during γ-tACS delivered alone in OFF and ON conditions. The amplitude of MEP elicited by single TMS pulses and the degree of SICI inhibition significantly increased after iTBS-γ-tACS. The amount of change produced by iTBS-γ-tACS was similar in patients OFF and ON therapy. Finally, γ-tACS (delivered alone) modulated SICI during stimulation and this effect did not depend on the dopaminergic condition of patients. In conclusion, boosting cortical γ oscillatory activity via tACS during iTBS improved M1 plasticity and enhanced GABA-A-ergic transmission in PD patients to the same extent regardless of dopaminergic state. These results suggest a lack of interaction between L-dopa and γ-tACS effects at the M1 level. The possible neural substrate underlying iTBS-γ tACS effects, that is, γ-resonant GABA-A-ergic interneurons activity, may explain our findings.

Musculoskeletal pain is associated with altered motor control that, despite short-term benefit, is hypothesised to have long-term consequences, contributing to the development of chronic pain. However, data on how motor control is altered when pain is sustained beyond a transient event are scarce. Here, we investigated motor adaptation, and its relationship with corticomotor excitability, in the transition to sustained muscle pain. Twenty-eight healthy individuals were injected with nerve growth factor into the right extensor carpi radialis brevis muscle on days 0 and 2. Motor adaptation and corticomotor excitability were assessed on day -2, before injection on days 0 and 2, and again on days 4 and 14. Motor adaptation was quantified during a radial-ulnar movement as kinematic variability of wrist flexion-extension and pronation-supination, and as electromyographic (EMG) variability of extensor carpi radialis brevis activity. Pain, muscle soreness, and functional limitation were assessed from days 0 to 14. Pain, muscle soreness, and functional limitation were evident at days 2 and 4 (P < 0.001). Electromyographic variability reduced at days 4 and 14 (P < 0.04), with no change in kinematic variability (P = 0.9). However, data revealed variation in EMG and kinematic variability between individuals: some displayed increased motor variability, whereas others a decrease. Individuals who displayed an increase in EMG variability after 4 days of pain also displayed an increase in corticomotor excitability (r = 0.43, P = 0.034). These findings suggest individual adaptation of the motor system in the transition to sustained pain that could have implications for clinical musculoskeletal pain disorders.

Maladaptive cortical plasticity has been described in individuals with heroin and methamphetamine addiction and may mediate other substance abuse disorders. It is unknown whether cannabis dependence in humans alters the capacity for induction of cortical plasticity. The aim of this study was to non‐invasively investigate cortical plasticity with transcranial magnetic stimulation in young adults who meet DSM‐5 criteria for cannabis use disorder (CUD). Thirty men (ages 20– 30) who used cannabis daily over the previous 6 months (15 diagnosed of CUD) and 15 demographically matched non‐users were enrolled in this study. All participants underwent two sessions of theta burst stimulation (TBS) in which either continuous TBS (cTBS; 600 pulses, 80% active motor threshold) or intermittent TBS (iTBS; 2‐s train of cTBS repeated every 10 s for a total of 190 s, 600 pulses) was applied over the primary motor cortex. The effects of these protocols were assessed by analysing the contralateral motor evoked potentials (MEPs). The relationships between cortical plasticity and problematic cannabis use, degree of dependence, and nicotine addiction were also investigated. Significant MEP inhibition after cTBS was observed in both cannabis users without CUD and non‐users, while this inhibition was not seen in cannabis users with CUD. Strikingly, less motor cortical plasticity was observed in subjects with severe problematic cannabis use. No significant differences between users and non‐users were found in the iTBS‐induced cortical plasticity measures. Our study provides the first evidence of maladaptive cortical plasticity associated with cannabis use disorder and problematic cannabis use in humans., This work was supported by the Instituto de Salud Carlos III‐Fondo Europeo de Desarrollo Regional (ISCIII‐FEDER) (PI14/01823, PI16/01575), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía (CVI‐02526, CTS‐7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI‐0437‐2012, PI‐0471/2013), the Fundación Progreso y Salud (FPS 2014 PI‐0055‐2014), the Sociedad Andaluza de Neurología, the Fundación Alicia Koplowitz and the Fundación Mutua Madrileña. J.F.M.‐R. was supported by the “Sara Borrell” Programme from the Instituto de Salud Carlos III and the VI PPIT‐US from the University of Seville; P.A.d.T. was supported by the FPU programme of the Ministry of Education, Culture and Sport of Spain; and M.R.‐V. was supported by Grant BAE 09/90088.

Aberrant motor cortex plasticity is hypothesized to contribute to chronic musculoskeletal pain, but evidence is limited. Critically, studies have not considered individual differences in motor plasticity or how this relates to pain susceptibility. Here we examined the relationship between corticomotor excitability and an individual's susceptibility to pain as pain developed, was sustained and resolved over 21 days. Nerve growth factor was injected into the right extensor carpi radialis brevis muscle of 20 healthy individuals on day 0, 2, and 4. Corticomotor excitability, pressure pain thresholds and performance on a cognitive conflict task were examined longitudinally (day 0, 2, 4, 6, and 14). Pain and disability were assessed on each alternate day (1,3…21). Two patterns of motor plasticity were observed in response to pain––corticomotor depression or corticomotor facilitation (P = .009). Individuals who displayed corticomotor depression experienced greater pain (P = .027), and had worse cognitive task performance (P = .038), than those who displayed facilitation. Pressure pain thresholds were reduced to a similar magnitude in both groups. Corticomotor depression in the early stage of pain could indicate a higher susceptibility to pain. Further work is required to determine whether corticomotor depression is a marker of pain susceptibility in musculoskeletal conditions. Perspective This article explores individual differences in motor plasticity in the transition to sustained pain. Individuals who developed corticomotor depression experienced higher pain and worse cognitive task performance than those who developed corticomotor facilitation. Corticomotor depression in the early stage of pain could indicate a higher susceptibility to pain.

Objective: Repetitive application of peripheral electrical stimuli paired with transcranial magnetic stimulation (rTMS) of M1 cortex at low frequency, known as paired associative stimulation (PAS), is an effective method to induce motor cortex plasticity in humans. Here we investigated the effects of repetitive peripheral magnetic stimulation (rPMS) combined with low frequency rTMS ('magnetic-PAS') on intracortical and corticospinal excitability and whether those changes were widespread or circumscribed to the cortical area controlling the stimulated muscle.& para;& para;Methods: Eleven healthy subjects underwent three 10 min stimulation sessions: 10 Hz rPMS alone, applied in trains of 5 stimuli every 10 s (60 trains) on the extensor carpi radialis (ECR) muscle; rTMS alone at an intensity 120% of ECR threshold, applied over motor cortex of ECR and at a frequency of 0.1 Hz (60 stimuli) and magnetic PAS, i.e., paired rPMS and rTMS. We recorded motor evoked potentials (MEPs) from ECR and first dorsal interosseous (FDI) muscles. We measured resting motor threshold, motor evoked potentials (MEP) amplitude at 120% of RMT, short intracortical inhibition (SICI) at interstimulus interval (ISI) of 2 ms and intracortical facilitation (ICF) at an ISI of 15 ms before and immediately after each intervention.& para;& para;Results: Magnetic-PAS but not rTMS or rPMS applied separately, increased MEP amplitude and reduced short intracortical inhibition in ECR but not in FDI muscle.& para;& para;Conclusion: Magnetic-PAS can increase corticospinal excitability and reduce intracortical inhibition. The effects may be specific for the area of cortical representation of the stimulated muscle.& para;& para;Significance: Application of magnetic-PAS might be relevant for motor rehabilitation. (C) 2017 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

We used transcranial magnetic stimulation (TMS) to investigate whether an acute bout of resistance exercise with blood flow restriction (BFR) stimulated changes in corticomotor excitability (motor evoked potential, MEP) and short-interval intracortical inhibition (SICI), and compared the responses to two traditional resistance exercise methods. Ten males completed four unilateral elbow flexion exercise trials in a balanced, randomized crossover design: (1) heavy-load (HL: 80% one-repetition maximum [1-RM]); (2) light-load (LL; 20% 1-RM) and two other light-load trials with BFR applied; (3) continuously at 80% resting systolic blood pressure (BFR-C); or (4) intermittently at 130% resting systolic blood pressure (BFR-I). MEP amplitude and SICI were measured using TMS at baseline, and at four time-points over a 60 min post-exercise period. MEP amplitude increased rapidly (within 5 min post-exercise) for BFR-C and remained elevated for 60 min post-exercise compared with all other trials. MEP amplitudes increased for up to 20 and 40 min for LL and BFR-I, respectively. These findings provide evidence that BFR resistance exercise can modulate corticomotor excitability, possibly due to altered sensory feedback via group III and IV afferents. This response may be an acute indication of neuromuscular adaptations that underpin changes in muscle strength following a BFR resistance training programme.

Background Desynchronization of sensorimotor rhythmic activity increases instantaneous corticospinal excitability, as indexed by amplitudes of motor-evoked potentials (MEP) elicited by transcranial magnetic stimulation (TMS). The accumulative effect of cortical stimulation in conjunction with sensorimotor desynchronization is, however, unclear. Objective The aim of this study was to investigate the effects of repetitive pairing event-related desynchronization (ERD) with TMS of the precentral gyrus on corticospinal excitability. Methods Closed-loop single-pulse TMS was controlled by beta-band (16–22 Hz) ERD during motor-imagery of finger extension and applied within a brain–computer interface environment in eleven healthy subjects. The same number and pattern of stimuli were applied in a control group of eleven subjects during rest, i.e. independent of ERD. To probe for plasticity resistant to depotentiation, stimulation protocols were followed by a depotentiation task. Results Brain state-dependent application of approximately 300 TMS pulses during beta-ERD resulted in a significant increase of corticospinal excitability. By contrast, the identical stimulation pattern applied independent of beta-ERD in the control experiment resulted in a decrease of corticospinal excitability. These effects persisted beyond the period of stimulation and the depotentiation task. Conclusion These results could be instrumental in developing new therapeutic approaches such as the application of closed-loop stimulation in the context of neurorehabilitation.

Background Transcranial direct current stimulation (tDCS) is a non-invasive technique that modulates the excitability of neurons within the primary motor cortex (M1). Research shows that anodal-tDCS applied over the non-dominant M1 (i.e. unilateral stimulation) improves motor function of the non-dominant hand. Similarly, previous studies also show that applying cathodal tDCS over the dominant M1 improves motor function of the non-dominant hand, presumably by reducing interhemispheric inhibition. In the present study, one condition involved anodal-tDCS over the non-dominant M1 (unilateral stimulation) whilst a second condition involved applying cathodal-tDCS over the dominant M1 and anodal-tDCS over non-dominant M1 (bilateral stimulation) to determine if unilateral or bilateral stimulation differentially modulates motor function of the non-dominant hand. Using a randomized, cross-over design, 11 right-handed participants underwent three stimulation conditions: 1) unilateral stimulation, that involved anodal-tDCS applied over the non-dominant M1, 2) bilateral stimulation, whereby anodal-tDCS was applied over the non-dominant M1, and cathodal-tDCS over the dominant M1, and 3) sham stimulation. Transcranial magnetic stimulation (TMS) was performed before, immediately after, 30 and 60 minutes after stimulation to elucidate the neural mechanisms underlying any potential after-effects on motor performance. Motor function was evaluated by the Purdue pegboard test. Results There were significant improvements in motor function following unilateral and bilateral stimulation when compared to sham stimulation at all-time points (all P < 0.05); however there was no difference across time points between unilateral and bilateral stimulation. There was also a similar significant increase in corticomotor excitability with both unilateral and bilateral stimulation immediately post, 30 minutes and 60 minutes compared to sham stimulation (all P < 0.05). Unilateral and bilateral stimulation reduced short-interval intracortical inhibition (SICI) immediately post and at 30 minutes (all P < 0.05), but returned to baseline in both conditions at 60 minutes. There was no difference between unilateral and bilateral stimulation for SICI (P > 0.05). Furthermore, changes in corticomotor plasticity were not related to changes in motor performance. Conclusion These results indicate that tDCS induced behavioural changes in the non-dominant hand as a consequence of mechanisms associated with use-dependant cortical plasticity that is independent of the electrode arrangement.

Background Primary motor cortex (M1) is relatively spared in the early stages of Alzheimer’s disease (AD). Objective Aim of the present study was to investigate whether abnormal M1 synaptic plasticity is present at an early stage of AD. We employed an electrophysiological protocol, named rapid paired associative stimulation (rPAS), involving repetitive transcranial magnetic stimulation (rTMS) paired with electrical stimulation of the contralateral median nerve, that modifies corticospinal excitability and short latency afferent inhibition (SAI). Methods We studied 10 patients with a diagnosis of probable mild AD according to the Mini Mental State Examination score (minimum 21) and 14 age-matched control subjects. Motor evoked potentials (MEP) amplitudes and short-afferent inhibition (SAI) were measured at baseline before and for up to 60 min after 5Hz-rPAS in abductor pollicis brevis (APB). rPAS consisted of 600 pairs of transcranial magnetic stimuli, at a rate of 5 Hz for 2 min, coupled with electrical median nerve stimulation preceding TMS over the contralateral M1 at an inter-stimulus interval of 25 ms. Results Baseline SAI was significantly reduced in AD patients. In the control subjects rPAS induced a significant increase in MEP amplitudes and a decrease of SAI in the APB muscle persistently for up to 1 h. Conversely 5Hz-rPAS did not induce any significant changes in MEP amplitudes and SAI in mild AD patients. Conclusions Sensory-motor plasticity is impaired in the motor cortex of AD at an early stage of the disease.

Stimulation-induced plasticity represents an experimental model of motor cortex reorganization. It can be produced in awaked humans by combining the non-invasive electrical stimulation of somatosensory afferents via mixed peripheral nerves with the transcranial magnetic stimulation (TMS) of the motor cortex. Animal experiments indicate that an application of two converging inputs from various sources in a tightly coupled manner, following the so called Hebbian rule of learning, leads to an increase in motor cortical excitability. The aim of our study was to compare the effects of two plasticity-inducing protocols by quantifying the motor cortex changes using TMS. Plasticity was induced by combining peripheral nerve stimulation with TMS (paired associative stimulation - PAS) and by peripheral motor point stimulation of two adjacent hand muscles (dual associative stimulation - DAS). The protocols were randomly applied in 12 right-handed healthy volunteers. The amplitudes of TMS-induced motor-evoked potentials (MEPs) in the right abductor pollicis brevis muscle were recorded before, immediately after PAS or DAS stimulation, and 10, 20 and 30 min later. Both protocols led to significant and lasting changes in MEP amplitudes, however, a significantly larger increase in MEPs was observed after PAS than DAS. The results indicate that afferent input can differently affect cortical motor circuits and produce variable motor output. Thus, the efficacy of LTP-like mechanisms, presumably involved in Hebbian-like plasticity in humans, varies with the types/origin of the converging inputs. Our findings may be relevant when designing therapeutic interventions for improving motor function after neurological injury or disease.