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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. [ABSTRACT FROM AUTHOR]

Background: The ability to manipulate the excitability of the network between the inferior parietal lobule (IPL) and primary motor cortex (M1) may have clinical value. Objective: To investigate the possibility of inducing long-lasting changes in M1 excitability by applying quadripulse transcranial magnetic stimulation (QPS) to the IPL, and to ascertain stimulus condition- and site-dependent differences in the effects. Methods: QPS was applied to M1, the primary somatosensory cortex (S1), the supramarginal gyrus (SMG) and angular gyrus (AG) IPL areas, with the inter-stimulus interval (ISI) in the train of pulses set to either 5 ms (QPS-5) or 50 ms (QPS-50). QPS was repeated at 0.2 Hz for 30 min, or not presented (sham condition). Excitability changes in the target site were examined by means of single-pulse transcranial magnetic stimulation (TMS). Results: QPS-5 and QPS-50 at M1 increased and decreased M1 excitability, respectively. QPS at S1 induced no obvious change in M1 excitability. However, QPS at the SMG induced mainly suppressive effects in M1 for at least 30 min, regardless of the ISI length. Both QPS ISIs at the AG yielded significantly different MEP compared to those at the SMG. Thus, the direction of the plastic effect of QPS differed depending on the site, even under the same stimulation conditions. Conclusions: QPS at the IPL produced long-lasting changes in M1 excitability, which differed depending on the precise stimulation site within the IPL. These results raise the possibility of noninvasive induction of functional plasticity in M1 via input from the IPL.

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. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a fatal disease that can cause severe disability. Cortical reorganization subserved the recovery of spontaneous function after SCI, although the potential molecular mechanism in this remote control is largely unknown. Therefore, using proteomics analysis, RNA interference/overexpression, and CRISPR/Cas9 in vivo and in vitro, we analyzed how the molecular network functions in neurological improvement, especially in the recovery of motor function after spinal cord transection (SCT) via the remote regulation of cerebral cortex. We discovered that the overexpression of pyridoxal kinase (PDXK) in the motor cortex enhanced neuronal growth and survival and improved locomotor function in the hindlimb. In addition, PDXK was confirmed as a target of miR-339 but not miR-124. MiR-339 knockout (KO) significantly increased the neurite outgrowth and decreased cell apoptosis in cortical neurons. Moreover, miR-339 KO rats exhibited functional recovery indicated by improved Basso, Beattie, and Bresnehan (BBB) score. Furthermore, bioinformatics prediction showed that PDXK was associated with GAP43, a crucial molecule related to neurite growth and functional improvement. The current research therefore confirmed that miR-339 targeting PDXK facilitated neurological recovery in the motor cortex of SCT rats, and the underlying mechanism was associated with regulating GAP43 in the remote cortex of rats subjected to SCT. These findings may uncover a new understanding of remoting cortex control following SCI and provide a new therapeutic strategy for the recovery of SCI in future clinical trials.

The ability to manipulate the excitability of the network between the inferior parietal lobule (IPL) and primary motor cortex (M1) may have clinical value. To investigate the possibility of inducing long-lasting changes in M1 excitability by applying quadripulse transcranial magnetic stimulation (QPS) to the IPL, and to ascertain stimulus condition- and site-dependent differences in the effects. QPS was applied to M1, the primary somatosensory cortex (S1), the supramarginal gyrus (SMG) and angular gyrus (AG) IPL areas, with the inter-stimulus interval (ISI) in the train of pulses set to either 5 ms (QPS-5) or 50 ms (QPS-50). QPS was repeated at 0.2 Hz for 30 min, or not presented (sham condition). Excitability changes in the target site were examined by means of single-pulse transcranial magnetic stimulation (TMS). QPS-5 and QPS-50 at M1 increased and decreased M1 excitability, respectively. QPS at S1 induced no obvious change in M1 excitability. However, QPS at the SMG induced mainly suppressive effects in M1 for at least 30 min, regardless of the ISI length. Both QPS ISIs at the AG yielded significantly different MEP compared to those at the SMG. Thus, the direction of the plastic effect of QPS differed depending on the site, even under the same stimulation conditions. QPS at the IPL produced long-lasting changes in M1 excitability, which differed depending on the precise stimulation site within the IPL. These results raise the possibility of noninvasive induction of functional plasticity in M1 via input from the IPL. • We tested quadripulse transcranial magnetic stimulation (QPS) of cortical sites. • We looked at effects on the primary motor cortex (M1) excitability. • QPS of the supramarginal gyrus and angular gyrus had different long-lasting effects. • The inter-stimulus interval used in QPS also strongly influenced the effects. • It was possible to induce long-lasting bidirectional plasticity in M1 noninvasively. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. Significance Application of magnetic-PAS might be relevant for motor rehabilitation. [ABSTRACT FROM AUTHOR]

Introduction:This review will first discuss evidence of motor and sensory abnormalities as yielded by neurophysiological techniques in patients with PD. It will then go on to describe the effects of L-dopa replacement on motor and sensory abnormalities in PD as assessed by neurophysiological studies. Areas covered:We analyzed papers in English using Pubmed with the following keywords: L-dopa, dopamine, bradykinesia, basal ganglia, kinematic analysis, TMS, motor cortex plasticity, motor cortex excitability, somatosensory discrimination threshold, pain Expert commentary:L-dopa improves the amplitude and speed of upper limb voluntary movements, but it does not restore abnormalities in the sequence effect or voluntary facial movements. L-dopa only partially normalizes changes in motor cortex excitability and plasticity and has also contrasting effects on the sensory system and on sensory-motor integration. The neurophysiological studies reviewed here show that PD is more than a hypo-dopaminergic disease, and non-dopaminergic mechanisms should also be considered. [ABSTRACT FROM PUBLISHER]

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 minutes post-exercise) for BFR-C and remained elevated for 60 minutes 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.

Fourteen healthy children (13.8±2.2 years, range 10 to 16; M:F=5:9) received 30 Hz intermittent theta burst transcranial magnetic stimulation (iTBS) with a stimulation intensity of 70% of resting motor threshold (RMT) with a total of 300 (iTBS300) pulses. All volunteers were free of neurologic, psychiatric and serious medical illnesses, not taking any neuropsychiatric medications, and did not have any contraindications to Transcranial Magnetic Stimulation. Changes in the mean amplitudes of motor-evoked potentials from baseline following iTBS were expressed as a ratio and assessed from 1 to 10 minutes (BLOCK1) and 1 to 30 minutes (BLOCK2) using repeated-measures analysis of variance. All 14 subjects completed iTBS300 over the dominant primary motor cortex (M1) without any clinically reported adverse events. ITBS300 produced significant M1 facilitation (F5,65=3.165, p=0.01) at BLOCK1 and trend level M1 facilitation at BLOCK2 (F10,129=1.69, p=0.089). Although iTBS300 (stimulation duration of 92 seconds at 70% RMT) delivered over M1 in typically developed children was well-tolerated and produced on average significant facilitatory changes in cortical excitability, the post-iTBS300 neurophysiologic response was variable in our small sample. ITBS300-induced changes may represent a potential neuroplastic biomarker in healthy children and those with neuro-genetic or neuro-psychiatric disorders. However, a larger sample size is needed to address safety and concerns of response variability.

Background: Pairing peripheral electrical stimulation (ES) and transcranial magnetic stimulation (TMS) increases corticospinal excitability when applied with a specific temporal pattern. When the two stimulation techniques are applied separately, motor imagery (MI)-related oscillatory modulation amplifies both ES-related cortical effects--sensorimotor event-related desynchronization (ERD), and TMS-induced peripheral responses--motor-evoked potentials (MEP). However, the influence of brain self-regulation on the associative pairing of these stimulation techniques is still unclear. Objective: The aim of this pilot study was to investigate the effects of MI-related ERD during associative ES and TMS on subsequent corticospinal excitability. Method: The paired application of functional electrical stimulation (FES) of the extensor digitorum communis (EDC) muscle and subsequent single-pulse TMS (110% resting motor threshold (RMT)) of the contralateral primary motor cortex (M1) was controlled by beta-band (16-22 Hz) ERD during MI of finger extension and applied within a brainmachine interface environment in six healthy subjects. Neural correlates were probed by acquiring the stimulus-response curve (SRC) of both MEP peak-to-peak amplitude and area under the curve (AUC) before and after the intervention. Result: The application of approximately 150 pairs of associative FES and TMS resulted in a significant increase of MEP amplitudes and AUC, indicating that the induced increase of corticospinal excitability was mediated by the recruitment of additional neuronal pools. MEP increases were brain state-dependent and correlated with beta-band ERD, but not with the background EDC muscle activity; this finding was independent of the FES intensity applied. Conclusion: These results could be relevant for developing closed-loop therapeutic approaches such as the application of brain state-dependent, paired associative stimulation (PAS) in the context of neurorehabilitation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Normal motor behavior involves the creation of appropriate activity patterns across motor networks, enabling firing synchrony, synaptic integration and normal functioning of these net works. Strong topography-specific connections among the basal ganglia, cerebellum and their projections to overlapping areas in the motor cortices suggest that these networks could influence each other’s plastic responses and functions. The defective striatal signaling in Parkinson’s disease (PD) could therefore lead to abnormal oscillatory activity and aberrant plasticity at multiple levels within the interlinked motor networks. Normal striatal dopaminergic signaling and cerebellar sensory processing functions influence the scaling and topographic specificity of M1 plasticity. Both these functions are abnormal in PD and appear to contribute to the abnormal M1 plasticity. Defective motor map plasticity and topographic specificity within M1 could lead to incorrect muscle synergies, which could manifest as abnormal or undesired movements, and as abnormal motor learning in PD. We propose that the loss of M1 plasticity in PD reflects a loss of co-ordination among the basal ganglia, cerebellar and cortical inputs which translates to an abnormal plasticity of motor maps within M1 and eventually to some of the motor signs of PD. The initial benefits of dopamine replacement therapy on M1 plasticity and motor signs are lost during the progressive course of disease. Levodopa-induced dyskinesias in patients with advanced PD is linked to a loss of M1 sensorimotor plasticity and the attenuation of dyskinesias by cerebellar inhibitory stimulation is associated with restoration of M1 plasticity. Complimentary interventions should target reestablishing physiological communication between the striatal and cerebellar circuits, and within striato-cerebellar loop. This may facilitate correct motor synergies and reduce abnormal movements in PD.

Background Plasticity of the primary motor cortex (M1) has a critical role in motor control and learning. The cerebellum facilitates these functions using sensory feedback. Objective We investigated how cerebellar degeneration influences the plasticity of the M1 by using PAS (paired associative stimulation) technique. PAS involves repeated pairs of electrical stimuli to the median nerve and transcranial magnetic stimulation (TMS) of the motor cortex. If the interval between peripheral and TMS stimulation is around 21–25 ms, corticospinal excitability is increased via a long term potentiation (LTP)-like effect within M1. Our aims were: (i) to explore the presence of a time-specific influence of cerebellar degeneration on human associative plasticity; (ii) to evaluate the role played by somatosensory pathway on cerebellar modulation of sensory-motor plasticity. Methods We studied 10 patients with pure cerebellar atrophy and 10 age-matched healthy subjects. Motor-evoked-potentials amplitudes, short-afferent inhibition (SAI), motor thresholds, I/O curves, somatosensory-evoked-potential (SEP) were measured before, just after and 30 min after PAS at ISIs (interstimulus intervals) of 21.5 and 25 ms. Results Cerebellar patients show a selective lack of LTP-like effect induced by PAS25 ms, but not at 21.5 ms. SAI was overall not truly modulated by PAS but clearly differed between cerebellar patients and healthy subjects for ISIs around 25 ms (+6 ms and +8 ms) ( P < 0.01). SEPs showed the amplitude of P25 wave was markedly reduced in patients with a more severe clinical and radiological impairment of cerebellum. Conclusions Cerebellar patients have an altered capability of cerebellar filtering or processing of time-specific incoming sensory volleys, influencing the plasticity of M1. [ABSTRACT FROM AUTHOR]

Background Motor cortex excitability was found to be changed after repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex highlighting the occurrence of cross-modal plasticity in non-invasive brain stimulation. Here, we investigated the effects of temporal low-frequency rTMS on motor cortex plasticity in a large sample of tinnitus patients. In 116 patients with chronic tinnitus different parameters of cortical excitability were assessed before and after ten rTMS treatment sessions. Patients received one of three different protocols all including 1 Hz rTMS over the left temporal cortex. Treatment response was defined as improvement by at least five points in the tinnitus questionnaire (TQ). Variables of interest were resting motor threshold (RMT), short-interval intra-cortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP). Results After rTMS treatment RMT was decreased by about 1% of stimulator output nearsignificantly in the whole group of patients. SICI was associated with significant changes with respect to treatment response. The group of treatment responders showed a decrease of SICI over the course of treatment, the group of non-responders the reverse pattern. Conclusions Minor RMT changes during rTMS treatment do not necessarily suggest the need for systematic re-examination of the RMT for safety and efficacy issues. Treatment response to rTMS was shown to be related to changes in SICI that might reflect modulation of GABAergic mechanisms directly or indirectly related to rTMS treatment effects. [ABSTRACT FROM AUTHOR]

Normal motor behavior involves the creation of appropriate activity patterns across motor networks, enabling firing synchrony, synaptic integration, and normal functioning of these networks. Strong topography-specific connections among the basal ganglia, cerebellum, and their projections to overlapping areas in the motor cortices suggest that these networks could influence each other's plastic responses and functions. The defective striatal signaling in Parkinson's disease (PD) could therefore lead to abnormal oscillatory activity and aberrant plasticity at multiple levels within the interlinked motor networks. Normal striatal dopaminergic signaling and cerebellar sensory processing functions influence the scaling and topographic specificity of M1 plasticity. Both these functions are abnormal in PD and appear to contribute to the abnormal M1 plasticity. Defective motor map plasticity and topographic specificity within M1 could lead to incorrect muscle synergies, which could manifest as abnormal or undesired movements, and as abnormal motor learning in PD. We propose that the loss of M1 plasticity in PD reflects a loss of co-ordination among the basal ganglia, cerebellar, and cortical inputs which translates to an abnormal plasticity of motor maps within M1 and eventually to some of the motor signs of PD. The initial benefits of dopamine replacement therapy on M1 plasticity and motor signs are lost during the progressive course of disease. Levodopa-induced dyskinesias in patients with advanced PD is linked to a loss of M1 sensorimotor plasticity and the attenuation of dyskinesias by cerebellar inhibitory stimulation is associated with restoration of M1 plasticity. Complimentary interventions should target reestablishing physiological communication between the striatal and cerebellar circuits, and within striato-cerebellar loop. This may facilitate correct motor synergies and reduce abnormal movements in PD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Animal studies using polarising currents have shown that induction of synaptic long-term potentiation (LTP) and long-term depression (LTD) by bursts of patterned stimulation is affected by the membrane potential of the postsynaptic neurone. The aim of the present experiments was to test whether it is possible to observe similar phenomena in humans with the aim of improving present protocols of inducing synaptic plasticity for therapeutic purposes. We tested whether the LTP/LTD-like after effects of transcranial theta-burst stimulation (TBS) of human motor cortex, an analogue of patterned electrical stimulation in animals, were affected by simultaneous transcranial direct-current stimulation (tDCS), a non-invasive method of polarising cortical neurones in humans. Nine healthy volunteers were investigated in a single-blind, balanced cross-over study; continuous TBS (cTBS) was used to introduce LTD-like after effects, whereas intermittent TBS (iTBS) produced LTP-like effects. Each pattern was coupled with concurrent application of tDCS (<200 s, anodal, cathodal, sham). Cathodal tDCS increased the response to iTBS and abolished the effects of cTBS. Anodal tDCS changed the effects of cTBS towards facilitation, but had no impact on iTBS. Cortical motor thresholds and intracortical inhibitory/facilitatory networks were not altered by any of the stimulation protocols. We conclude that the after effects of TBS can be modulated by concurrent tDCS. We hypothesise that tDCS changes the membrane potential of the apical dendrites of cortical pyramidal neurones and that this changes the response to patterned synaptic input evoked by TBS. The data show that it may be possible to enhance LTP-like plasticity after TBS in the human cortex. [ABSTRACT FROM AUTHOR]

The motor cortex and spinal cord possess the remarkable ability to alter structure and function in response to differential motor training. Here we review the evidence that the corticospinal system is not only plastic but that the nature and locus of this plasticity is dictated by the specifics of the motor experience. Skill training induces synaptogenesis, synaptic potentiation, and reorganization of movement representations within motor cortex. Endurance training induces angiogenesis in motor cortex, but it does not alter motor map organization or synapse number. Strength training alters spinal motoneuron excitability and induces synaptogenesis within spinal cord, but it does not alter motor map organization. All three training experiences induce changes in spinal reflexes that are dependent on the specific behavioral demands of the task. These results demonstrate that the acquisition of skilled movement induces a reorganization of neural circuitry within motor cortex that supports the production and refinement of skilled movement sequences. We present data that suggest increases in strength may be mediated by an increased capacity for activation and/or recruitment of spinal motoneurons while the increased metabolic demands associated with endurance training induce cortical angiogenesis. Together these results show the robust pattern of anatomic and physiological plasticity that occurs within the corticospinal system in response to differential motor experience. The consequences of such distributed, experience-specific plasticity for the encoding of motor experience by the motor system are discussed. [ABSTRACT FROM AUTHOR]

It is generally accepted that functional properties of the motor cortex in adult humans can be altered through behavioral or pharmacological manipulations, as well as in some pathological conditions. The ability and capacity of adult human cortex to undergo any adaptive or reorganizational changes is referred to as plasticity. Much of the evidence concerning motor cortical plasticity have been derived from studies using the non-invasive technique of transcranial magnetic stimulation (TMS). TMS has proven to be a suitable tool to explore representational plasticity and to interact with neuronal activity in settings of induction protocols either alone or coupled with altered sensory inputs. Furthermore, plastic changes induced by motor learning protocols have attracted particular interest because of their relevance in functional recovery. Recent studies support the view that learning in human motor cortex occurs through long-term potentiation (LTP)-like mechanisms. Purposeful modulation of motor cortical plastic changes by manipulative TMS protocols may offer useful rehabilitative strategies in patients with chronic motor deficits. [ABSTRACT FROM AUTHOR]

The present study investigates the time course and pattern of movement representation recovery in the motor cortex during the recovery after a peripheral paralysis. To this end a transitory flaccid paralysis of the vibrissae muscle was induced in adult rats that underwent two unilateral injections of 8 U of botulinum toxin (BTX) into a vibrissal pad, at a duration of 12 days from one another. The compound muscle action potential (MAP) of the vibrissae muscle began to reappear 4 weeks after the first BTX injection. Intracortical microstimulation (ICMS) was used to map rat motor cortices 4, 5, 6, 7 and 8 weeks after the first BTX injection. Findings demonstrated that: (i) contralateral vibrissae movement reappears in the medial part of its normal cortical territory when the MAP is almost 10% of the control value; in the remaining part, ICMS elicits eye, ipsilateral vibrissae, neck and forelimb movements; (ii) the contralateral vibrissae movement reappears in sites where ipsilateral vibrissae and/or neck movement are co-represented; (iii) as MAP recovers, the vibrissae representation expands until it recovers the 90.8% of its territory after 7 weeks, when the MAP was almost 43.4% of the control value; (iv) from 4 to 7 weeks, the ICMS-evoked contralateral vibrissae movement shows a significantly higher electrical threshold vs. the control group; (v) recovery of the baseline excitability uniformly involves the vibrissae representation 1 week later, after its cortical territory has recovered 93.1% of the control value and the MAP has returned to 78.8% of the baseline value. [ABSTRACT FROM AUTHOR]

Background: Spasticity arises from hyperexcitability of the neural stretch reflex arc secondary to injury of the corticospinal tract. In response to injury, the density of glutamatergic inputs from afferent 1A fibers to motor neurons increases dramatically and adaptive changes occur in the morphology of microglia cells in the spinal cord. Summary: Involvement of the endocannabinoid system in pathophysiological mechanisms responsible for spasticity has been demonstrated in animal models of MS. Stimulation of cannabinoid (CB)1 receptors reduces the hyperglutamatergic drive from sensory afferents to spinal cord motor neurons and blocks the synaptic effects of activated microglia and pro-inflammatory mediators (e.g. TNF-α) on glutamatergic transmission. Enhancing corticospinal tract excitability through intermittent theta burst stimulation inhibits the stretch reflex and spasticity by promoting long-term potentiation, a form of synaptic plasticity that requires stimulation of CB1 receptors. Evidence indicates that the antispasticity effects of THC:CBD oromucosal spray (Sativex®) are associated with enhanced cortical long-term potentiation. Key Messages: Glutamatergic and GABAergic pathways are involved in the regulation of muscle tone. CB1 receptors, which are associated with movement, postural control, and pain and sensory perception, influence glutamatergic pathways. THC:CBD oromucosal spray was shown to reverse motor cortex plasticity from long-term depression through long-term potentiation of synaptic transmission, thereby restoring, at least in part, effective corticospinal inputs to spinal circuits. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a fatal disease that can cause severe disability. Cortical reorganization subserved the recovery of spontaneous function after SCI, although the potential molecular mechanism in this remote control is largely unknown. Therefore, using proteomics analysis, RNA interference/overexpression, and CRISPR/Cas9 in vivo and in vitro , we analyzed how the molecular network functions in neurological improvement, especially in the recovery of motor function after spinal cord transection (SCT) via the remote regulation of cerebral cortex. We discovered that the overexpression of pyridoxal kinase (PDXK) in the motor cortex enhanced neuronal growth and survival and improved locomotor function in the hindlimb. In addition, PDXK was confirmed as a target of miR-339 but not miR-124. MiR-339 knockout (KO) significantly increased the neurite outgrowth and decreased cell apoptosis in cortical neurons. Moreover, miR-339 KO rats exhibited functional recovery indicated by improved Basso, Beattie, and Bresnehan (BBB) score. Furthermore, bioinformatics prediction showed that PDXK was associated with GAP43, a crucial molecule related to neurite growth and functional improvement. The current research therefore confirmed that miR-339 targeting PDXK facilitated neurological recovery in the motor cortex of SCT rats, and the underlying mechanism was associated with regulating GAP43 in the remote cortex of rats subjected to SCT. These findings may uncover a new understanding of remoting cortex control following SCI and provide a new therapeutic strategy for the recovery of SCI in future clinical trials., (Copyright © 2020 Xiong, Qin, Xiao, Jin, Al-Hawwas, Ma, Wang, Belegu, Zhou, Xue, Du, Liu, Bai and Wang.)

Using paired pulse transcranial magnetic stimulation (TMS) paradigms, we studied cortical excitability in a patient with spinal cord lesion. During posterior tibial nerve stimulation, the contextual flexion of hand fingers contralateral to the stimulated lower limb had suggested a change in motor cortex excitability. Results showed a decrease in the activity of motor cortex inhibitory circuits. This could suggest that in spinal cord injury, just as in stroke and peripheral deafferentation, a disinhibition of latent synapses within the motor cortex and the rewriting of a new motor map can occur. [ABSTRACT FROM AUTHOR]

The plasticity of primary motor cortex (M1) in patients with Parkinson's disease (PD) and levodopa-induced dyskinesias (LIDs) is severely impaired. We recently reported in young healthy subjects that inhibitory cerebellar stimulation enhanced the sensorimotor plasticity of M1 that was induced by paired associative stimulation (PAS). This study demonstrates that the deficient sensorimotor M1 plasticity in 16 patients with LIDs could be reinstated by a single session of real inhibitory cerebellar stimulation but not sham stimulation. This was evident only when a sensory component was involved in the induction of plasticity, indicating that cerebellar sensory processing function is involved in the resurgence of M1 plasticity. The benefit of inhibitory cerebellar stimulation on LIDs is known. To explore whether this benefit is linked to the restoration of sensorimotor plasticity of M1, we conducted an additional study looking at changes in LIDs and PAS-induced plasticity after 10 sessions of either bilateral, real inhibitory cerebellar stimulation or sham stimulation. Only real and not sham stimulation had an antidyskinetic effect and it was paralleled by a resurgence in the sensorimotor plasticity of M1. These results suggest that alterations in cerebellar sensory processing function, occurring secondary to abnormal basal ganglia signals reaching it, may be an important element contributing to the maladaptive sensorimotor plasticity of M1 and the emergence of abnormal involuntary movements., (© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)