Increased M1 Excitability Research Articles

Repetitive paired-pulse TMS increases motor cortex excitability and visuomotor skill acquisition in young and older adults.

Transcranial magnetic stimulation (TMS) over primary motor cortex (M1) recruits indirect (I) waves that can be modulated by repetitive paired-pulse TMS (rppTMS). The purpose of this study was to examine the effect of rppTMS on M1 excitability and visuomotor skill acquisition in young and older adults. A total of 37 healthy adults (22 young, 18-32yr; 15 older, 60-79yr) participated in a study that involved rppTMS at early (1.4ms) and late (4.5ms) interstimulus intervals (ISIs), followed by the performance of a visuomotor training task. M1 excitability was examined with motor-evoked potential (MEP) amplitudes and short-interval intracortical facilitation (SICF) using posterior-anterior (PA) and anterior-posterior (AP) TMS current directions. We found that rppTMS increased M1 excitability in young and old adults, with the greatest effects for PA TMS at the late ISI (4.5ms). Motor skill acquisition was improved by rppTMS at an early (1.4ms) but not late (4.5ms) ISI in young and older adults. An additional study using a non-I-wave interval (3.5ms) also showed increased M1 excitability and visuomotor skill acquisition. These findings show that rppTMS at both I-wave and non-I-wave intervals can alter M1 excitability and improve visuomotor skill acquisition in young and older adults.

Excitatory-inhibitory modulation of transcranial focus ultrasound stimulation on human motor cortex.

Transcranial focus ultrasound stimulation (tFUS) is a promising non-invasive neuromodulation technology. This study aimed to evaluate the modulatory effects of tFUS on human motor cortex (M1) excitability and explore the mechanism of neurotransmitter-related intracortical circuitry and plasticity. Single pulse transcranial magnetic stimulation (TMS)-eliciting motor-evoked potentials (MEPs) were used to assessed M1 excitability in 10 subjects. Paired-pulse TMS was used to measure the effects of tFUS on GABA- and glutamate-related intracortical excitability and 1 H-MRS was used to assess the effects of repetitive tFUS on GABA and Glx (glutamine + glutamate) neurometabolic concentrations in the targeting region in nine subjects. The etFUS significantly increased M1 excitability, decreased short interval intracortical inhibition (SICI) and long interval intracortical inhibition (LICI). The itFUS significantly suppressed M1 excitability, increased SICI, LICI, and decreased intracortical facilitation (ICF). Seven times of etFUS decreased the GABA concentration (6.32%), increased the Glx concentration (12.40%), and decreased the GABA/Glx ratio measured by MRS, while itFUS increased the GABA concentration (18.59%), decreased Glx concentration (0.35%), and significantly increased GABA/Glx ratio. The findings support that tFUS with different parameters can exert excitatory and inhibitory neuromodulatory effects on the human motor cortex. We provide novel insights that tFUS change cortical excitability and plasticity by regulating excitatory-inhibition balance related to the GABAergic and glutamatergic receptor function and neurotransmitter metabolic level.

Neurophysiological and Clinical Effects of Low-intensity Transcranial Ultrasound of the Motor Cortex in Parkinson’s Disease (P4-11.014)

<h3>Objective:</h3> Evaluate the neurophysiological and clinical effects of transcranial ultrasound stimulation (TUS) of motor cortex (M1) in PD patients. <h3>Background:</h3> Low-intensity TUS is a non-invasive brain stimulation technique that can reduce cortical excitability during sonication (online effect). TUS in a theta burst (tb) mode (tbTUS) can increase cortical excitability (offline or plasticity effect). PD have altered cortical excitability, and benefit from non-invasive stimulation of M1. <h3>Design/Methods:</h3> Eleven PD patients (2F, age 60.7±7.7 [mean±SD] years) were evaluated in ON and OFF dopaminergic medication states, and 16 controls (6F, age 65.6±10 years). The online protocol consisted of M1 TUS of 20W (active) and 0W (sham), with simultaneous transcranial magnetic stimulation measures of motor-evoked potential (MEP) amplitude. The offline protocol was 80 seconds of M1 tbTUS at 20W contralateral to the more affected side. MEP was recorded at baseline (before tbTUS), at 5-minutes (T5), T30, and T60 after tbTUS. Motor (m)UPDRS was evaluated in PD at baseline and at T60. <h3>Results:</h3> Online TUS did not reduced MEP amplitudes. For offline effects, a linear mixed model on MEP amplitudes showed a significant effect of time (F=2.8, p=0.046) and trend for time x group interaction (F=2.23, p=0.092) comparing PD-OFF and controls. There was a significant effect of time (F=4.17; p=0.009) but not group comparing PD-ON and controls. There was a trend for an effect of group (F=3.47; p=0.069) comparing MEP ratios for PD-ON and PD-OFF. The mUPDRS was significantly reduced at T60 (ON 24.1 ± 2.1; OFF 29.3 ± 1.7 [mean ± SE]) compared to baseline (ON 29.5 ± 2.3; OFF 30.8 ± 62.0 (paired t-test, ON p=0.004, OFF p=0.064) in PD-ON group. <h3>Conclusions:</h3> Increased M1 excitability following tbTUS also occurs in older controls and PD-ON, but not in PD-OFF. The mUPDRS reduction indicate a possible clinical effect in PD-ON. The study is ongoing, and more subjects are being recruited. <b>Disclosure:</b> Dr. Grippe has nothing to disclose. Mr. Shamli Oghli has nothing to disclose. Dr. SARICA has nothing to disclose. Miss Rinchon has nothing to disclose. Dr. Nankoo has nothing to disclose. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merz. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Paladin Labs. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ipsen. Dr. Chen has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Canadian Journal of Neurological Sciences. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Movement Disorders. The institution of Dr. Chen has received research support from Canadian Institutes of Health Research. The institution of Dr. Chen has received research support from NIH. The institution of Dr. Chen has received research support from Natural Science and Engineering Research Council of Canada. Dr. Chen has received research support from Parkinson Foundation. The institution of Dr. Chen has received research support from National Organization for Rare Disease. The institution of Dr. Chen has received research support from Merz.

Neural noise and cortical inhibition in schizophrenia

BackgroundNeural information processing is subject to noise and this leads to variability in neural firing and behavior. Schizophrenia has been associated with both more variable motor control and impaired cortical inhibition, which is crucial for excitatory/inhibitory balance in neural commands. HypothesisIn this study, we hypothesized that impaired intracortical inhibition in motor cortex would contribute to task-related motor noise in schizophrenia. MethodsWe measured variability of force and of electromyographic (EMG) activity in upper limb and hand muscles during a visuomotor grip force-tracking paradigm in patients with schizophrenia (N = 25), in unaffected siblings (N = 17) and in healthy control participants (N = 25). Task-dependent primary motor cortex (M1) excitability and inhibition were assessed using transcranial magnetic stimulation (TMS). ResultsDuring force maintenance patients with schizophrenia showed increased variability in force and EMG, despite similar mean force and EMG magnitudes. Compared to healthy controls, patients with schizophrenia also showed increased M1 excitability and reduced cortical inhibition during grip-force tracking. EMG variability and force variability correlated negatively to cortical inhibition in patients with schizophrenia. EMG variability also correlated positively to negative symptoms. Siblings had similar variability and cortical inhibition compared to controls. Increased EMG and force variability indicate enhanced motor noise in schizophrenia, which relates to reduced motor cortex inhibition. ConclusionThe findings suggest that excessive motor noise in schizophrenia may arise from an imbalance of M1 excitation/inhibition of GABAergic origin. Thus, higher motor noise may provide a useful marker of impaired cortical inhibition in schizophrenia.

The Response of the Primary Motor Cortex to Neuromodulation is Altered in Chronic Low Back Pain: A Preliminary Study

Neuromodulation is increasingly investigated for the treatment of low back pain (LBP). However, the neurophysiological effects of common neuromodulatory techniques (anodal transcranial direct current stimulation [tDCS] and peripheral electrical stimulation [PES]) have not been investigated in people with chronic LBP. Here we aimed to compare the effect of three neuromodulatory protocols (anodal tDCS, high intensity PES, and a priming protocol of combined tDCS/PES) on primary motor cortex (M1) excitability in people with and without chronic LBP. Cross-sectional. University laboratory. Ten individuals with chronic LBP and 10 pain-free controls. Participants received four interventions in random order across separate sessions: 1) anodal tDCS to M1 + PES to the back muscles; 2)tDCS + sham PES; 3) sham tDCS + PES; or 4) sham tDCS + sham PES. Motor cortical excitability (map volume, discrete map peaks, and cortical silent period [CSP]) was measured before and after each intervention. Anodal tDCS increased M1 excitability (increased map volume and reduced CSP) in controls but had no effect in the LBP group. PES reduced M1 excitability in both groups. The combined tDCS + PES treatment increased M1 excitability in the LBP group but had no effect in controls. The neurophysiological response to common neuromodulatory treatments differs between people with and without LBP. This has relevance for the design and tailoring of neuromodulation in pain. Further, if the goal of treatment is to increase M1 excitability, a priming protocol (e.g., combined tDCS + PES) may be more effective than tDCS alone.

The Mirror Illusion Increases Motor Cortex Excitability in Children With and Without Hemiparesis

Background. Mirror therapy provides a visual illusion of a normal moving limb by using the mirror reflection of the unaffected arm instead of viewing the paretic limb and is used in rehabilitation to improve hand function. Little is known about the mechanism underlying its effect in children with hemiparesis. Objective. To investigate the effect of the mirror illusion (MI) on the excitability of the primary motor cortex (M1) in children and adolescents. Methods. Twelve patients with hemiparesis (10-20 years) and 8 typically developing subjects (8-17 years) participated. Corticospinal reorganization was classified as contralateral (projection from contralateral hemisphere to affected hand) or ipsilateral (projection from ipsilateral hemisphere to affected hand). M1 excitability of the hemisphere projecting to the affected (nondominant in typically developing subjects) hand was obtained during 2 different conditions using single-pulse transcranial magnetic stimulation (TMS). Each condition (without/with mirror) consisted of a unimanual and a bimanual task. Motor-evoked potentials (MEPs) were recorded from the abductor pollicis brevis and flexor digitorum superficialis muscles. Results. MEP amplitudes were significantly increased during the mirror condition (P = .005) in typically developing subjects and in patients with contralateral reorganization. No significant effect of MI was found in subjects with ipsilateral reorganization. MI increased M1 excitability during active movements only. This increase was not correlated to hand function. Conclusion. MI increases the excitability of M1 in hemiparetic patients with contralateral corticospinal organization and in typically developing subjects. This finding provides neurophysiological evidence supporting the application of mirror therapy in selected children and adolescents with hemiparesis.

The side of chronic low back pain matters: evidence from the primary motor cortex excitability and the postural adjustments of multifidi muscles.

Hemispheric lateralization of pain processing was reported with overactivation of the right frontal lobe. Specifically in chronic low back pain (CLBP), functional changes in the left primary motor cortex (M1) with impaired anticipatory postural activation (APA) of trunk muscles have been observed. Given the connections between frontal and M1 areas for motor planning, it is hypothesized that the pain side could differently influence M1 function and APA of paravertebral multifidus (MF) muscles. This study aimed at testing whether people with right- versus left-sided CLBP showed different M1 excitability and APA. Thirty-five individuals with lateralized CLBP (19 right-sided and 16 left-sided) and 13 pain-free subjects (normative values) were tested for the excitability of MF M1 area (active motor threshold-AMT) with transcranial magnetic stimulation and for the latency of MF APA during bilateral shoulder flexion and during unilateral hip extension in prone lying. In the right-sided CLBP group, the AMT of both M1 areas was lower than in the left-sided group and the pain-free subjects; the latency of MF APA was shorter in bilateral shoulder flexion and in the left hip extension tasks as compared to the left-sided group. In CLBP, an earlier MF APA was correlated with lower AMT in both tasks. People with right-sided CLBP presented with increased M1 excitability in both hemispheres and earlier MF APA. These results likely rely on cortical motor adaptation related to the tasks and axial muscles tested. Future studies should investigate whether CLBP side-related differences have a clinical impact, e.g. in diagnosis and intervention.

Phase and Frequency-Dependent Effects of Transcranial Alternating Current Stimulation on Motor Cortical Excitability.

Transcranial alternating current stimulation (tACS) can entrain ongoing brain oscillations and modulate the motor system in a frequency-dependent manner. Recent animal studies have demonstrated that the phase of a sinusoidal current also has an important role in modulation of neuronal activity. However, the phase effects of tACS on the human motor system are largely unknown. Here, we systematically investigated the effects of tACS phase and frequency on the primary motor cortex (M1) by using motor evoked potentials (MEPs) with transcranial magnetic stimulation (TMS). First, we compared the phase effects (90°, 180°, 270° or 360°) of 10 and 20 Hz tACS on MEPs. The 20 Hz tACS significantly increased M1 excitability compared with the 10 Hz tACS at 90° phase only. Second, we studied the 90° phase effect on MEPs at different tACS frequencies (5, 10, 20 or 40 Hz). The 20 vs. 10 Hz difference was again observed, but the 90° phase in 5 and 40 Hz tACS did not influence M1 excitability. Third, the 90° phase effects of 10 and 20 Hz tACS were compared with sham stimulation. The 90° phase of 20 Hz tACS enhanced MEP amplitudes compared with sham stimulation, but there was no significant effect of 10 Hz tACS. Taken together, we assume that the differential 90° phase effects on 20 Hz and 10 Hz tACS can be attributed to the neural synchronization modulated by tACS. Our results further underline that phase and frequency are the important factors in the effects of tACS on M1 excitability.

Commentary: Cumulative effects of anodal and priming cathodal tDCS on pegboard test performance and motor cortical excitability.

Commentary: Cumulative effects of anodal and priming cathodal tDCS on pegboard test performance and motor cortical excitability.

Cortical Plasticity Induction by Pairing Subthalamic Nucleus Deep-Brain Stimulation and Primary Motor Cortical Transcranial Magnetic Stimulation in Parkinson's Disease.

We introduced a new experimental paradigm to test the hypothesis that pairing subthalamic nucleus deep-brain stimulation (STN-DBS) with motor cortical transcranial magnetic stimulation (M1-TMS) at specific times can induce cortical plasticity in patients with Parkinson's disease (PD). We found that repeated pairing of STN-DBS with TMS at short (∼ 3 ms) and medium (∼ 23 ms) intervals increased cortical excitability that lasted for up to 45 min, whereas the control condition (fixed latency of 167 ms) had no effects on cortical excitability. This is the first demonstration of associative plasticity in the STN-M1 circuits in PD patients using this novel technique. The potential therapeutic effects of combining DBS and noninvasive cortical stimulation should be investigated further.

Promoting Motor Cortical Plasticity with Acute Aerobic Exercise: A Role for Cerebellar Circuits.

Acute aerobic exercise facilitated long-term potentiation-like plasticity in the human primary motor cortex (M1). Here, we investigated the effect of acute aerobic exercise on cerebellar circuits, and their potential contribution to altered M1 plasticity in healthy individuals (age: 24.8 ± 4.1 years). In Experiment 1, acute aerobic exercise reduced cerebellar inhibition (CBI) (n = 10, p = 0.01), elicited by dual-coil paired-pulse transcranial magnetic stimulation. In Experiment 2, we evaluated the facilitatory effects of aerobic exercise on responses to paired associative stimulation, delivered with a 25 ms (PAS25) or 21 ms (PAS21) interstimulus interval (n = 16 per group). Increased M1 excitability evoked by PAS25, but not PAS21, relies on trans-cerebellar sensory pathways. The magnitude of the aerobic exercise effect on PAS response was not significantly different between PAS protocols (interaction effect: p = 0.30); however, planned comparisons indicated that, relative to a period of rest, acute aerobic exercise enhanced the excitatory response to PAS25 (p = 0.02), but not PAS21 (p = 0.30). Thus, the results of these planned comparisons indirectly provide modest evidence that modulation of cerebellar circuits may contribute to exercise-induced increases in M1 plasticity. The findings have implications for developing aerobic exercise strategies to “prime” M1 plasticity for enhanced motor skill learning in applied settings.

Observing and perceiving: A combined approach to induce plasticity in human motor cortex

ObjectiveTo test whether action observation combined with peripheral nerve electrical stimulation was able to evoke plasticity in the primary motor cortex (M1). MethodsThe stimulation protocol consisted in the observation of a video showing repetitive thumb-index tapping movements (AO) combined with peripheral electrical nerve stimulation (PNS) delivered on the median nerve (AO–PNS). M1 excitability, measured by means of transcranial magnetic stimulation, was compared with that assessed after AO and PNS alone. ResultsM1 excitability increased after AO–PNS, whilst no modifications occurred after AO and PNS alone. The increased M1 excitability after AO–PNS was long-lasting (45min) and specific for the stimulated muscle. ConclusionsThis study described an innovative stimulation paradigm that exploited the mirror neuron system to induce plasticity in M1. However, this occurred only when action observation was combined with afferent signals coming from periphery. SignificanceThis study supports the literature proposing the mirror neuron system as neural substrate for rehabilitation and opens a debate on the rehabilitative treatments that employ AO to improve patients’ motor functions. Indeed, these results suggest that AO has to be combined with afferent inputs from periphery to evoke plasticity in the human motor system.

An unavoidable modulation? Sensory attention and human primary motor cortex excitability.

The link between basic physiology and its modulation by cognitive states, such as attention, is poorly understood. A significant association becomes apparent when patients with movement disorders describe experiences with changing their attention focus and the fundamental effect that this has on their motor symptoms. Moreover, frequently used mental strategies for treating such patients, e.g. with task-specific dystonia, widely lack laboratory-based knowledge about physiological mechanisms. In this largely unexplored field, we looked at how the locus of attention, when it changed between internal (locus hand) and external (visual target), influenced excitability in the primary motor cortex (M1) in healthy humans. Intriguingly, both internal and external attention had the capacity to change M1 excitability. Both led to a reduced stimulation-induced GABA-related inhibition and a change in motor evoked potential size, i.e. an overall increased M1 excitability. These previously unreported findings indicated: (i) that cognitive state differentially interacted with M1 physiology, (ii) that our view of distraction (attention locus shifted towards external or distant location), which is used as a prevention or management strategy for use-dependent motor disorders, is too simple and currently unsupported for clinical application, and (iii) the physiological state reached through attention modulation represents an alternative explanation for frequently reported electrophysiology findings in neuropsychiatric disorders, such as an aberrant inhibition.

Cerebellar continuous theta‐burst stimulation affects motor learning of voluntary arm movements in humans

In this study we investigated in healthy subjects whether continuous theta-burst stimulation (cTBS) over the lateral cerebellum alters motor practice and retention phases during ipsilateral index finger and arm reaching movements. In 12 healthy subjects we delivered cTBS before repeated index finger abductions or arm reaching movements differing in complexity (reaching-to-grasp and reaching-to-point). We evaluated kinematic variables for index finger and arm reaching movements and changes in primary motor cortex (M1) activity tested with transcranial magnetic stimulation. Peak acceleration increased during motor practice for index finger abductions and reaching-to-grasp movements and persisted during motor retention. Peak acceleration decreased during motor practice for reaching-to-point movements and the decrease remained during motor retention. Cerebellar cTBS left the changes in peak acceleration during motor practice for index finger abductions and reaching-to-grasp arm movements unchanged but reduced peak acceleration at motor retention. Cerebellar cTBS prevented the decrease in peak acceleration for reaching-to-point movements during motor practice and at motor retention. Index finger abductions and arm reaching movements increased M1 excitability. Cerebellar cTBS decreased the motor evoked potential (MEP) facilitation induced by index finger movements, but increased the MEP facilitation after reaching-to-grasp and reaching-to-point movements. Cerebellar stimulation prevents motor retention for index finger abductions, reaching-to-grasp and reaching-to-point movements and degrades motor practice only for reaching-to-point movements. Cerebellar cTBS alters practice-related changes in M1 excitability depending on how intensely the cerebellum contributes to the task. Changes in M1 excitability reflect mechanisms of homeostatic plasticity elicited by the interaction of an 'exogenous' (cTBS-induced) and an 'endogenous' (motor practice-induced) plasticity-inducing protocol.

P 178. Reversal of motor learning-related effects in humans

The induction of long-term potentiation (LTP) like plasticity in the human primary motor cortex (M1) using repetitive Transcranial Magnetic Stimulation can be reversed (depotentiated) if another intervention, by itself ineffective in inducing plastic changes (for example a short form of continuous theta burst stimulation-cTBS150) is delivered immediately after an experimentally inducing plasticity protocol. We here investigated if it is also possible to depotentiate the LTP-like after-effects of motor learning in the M1 and the behavioural outcome of learning (i.e. motor learning retention) using the cTBS150 as a depotentiation protocol. We used a well-characterized motor training task in which behavioural improvement is known to be associated with LTP-like plasticity changes of M1, as measured by increased M1 excitability after motor training. Eleven healthy participants were given 15 learning blocks (15 movements each) to maximize the initial acceleration of ballistic finger movements. Participants improved their motor performance during the training task and, as expected, this behavioural improvement was associated with increased M1 excitability. We found that the motor learning-related LTP-like effects were reversed if cTBS150 was given immediately after the end of the training. A control experiment confirmed that cTBS150 alone did not modify the M1 excitability. The analysis of the behavioural data showed that cTBS150 did not modify the motor-learning related behavioural outcome, supporting the hypothesis that M1 is not involved in motor retention. The present study demonstrate that is possible to reverse, i.e. depotentiate, motor learning-related LTP-like effects in the human M1 but this effect does not have a behavioural counterpart. A similar approach could be adopted to investigate if it is also possible to reverse LTP-like effect of more complex forms of motor learning, or to reverse abnormal cortical excitability associated with inappropriate motor learning in pathological conditions.

Age related differences in the neural substrates of motor sequence learning after interleaved and repetitive practice

Practice of tasks in an interleaved order generally induces superior retention compared to practicing in a repetitive order. Younger and older adults practiced serial reaction time tasks that were arranged in a repeated or an interleaved order on 2 successive days. Retention was tested on Day 5. For both groups, reaction times in the interleaved condition were slower than the repetitive condition during practice, but the reverse was true during retention on Day 5. After interleaved practice, changes in M1 excitability measured by paired-pulse TMS were greater than after repetitive practice, and this effect was more pronounced in older adults. Moreover, the increased M1 excitability correlated with the benefit of interleaved practice. BOLD signal was also increased for interleaved compared to repetitive practice in both groups. However, the pattern of correlations between increased BOLD during practice and subsequent benefit of the interleaved condition differed by group. In younger adults, dorsolateral-prefrontal activity during practice was related to this benefit, while in older adults, activation in sensorimotor regions and rostral prefrontal cortex during practice correlated with the benefit of interleaving on retention. Older adults may engage compensatory mechanisms during interleaved practice such as increasing sensorimotor recruitment which in turn benefits learning.

Boosting brain excitability by transcranial high frequency stimulation in the ripple range

Alleviating the symptoms of neurological diseases by increasing cortical excitability through transcranial stimulation is an ongoing scientific challenge. Here, we tackle this issue by interfering with high frequency oscillations (80–250 Hz) via external application of transcranial alternating current stimulation (tACS) over the human motor cortex (M1). Twenty-one subjects participated in three different experimental studies and they received on separate days tACS at three frequencies (80 Hz, 140 Hz and 250 Hz) and sham stimulation in a randomized order. tACS with 140 Hz frequency increased M1 excitability as measured by transcranial magnetic stimulation-generated motor evoked potentials (MEPs) during and for up to 1 h after stimulation. Control experiments with sham and 80 Hz stimulation were without any effect, and 250 Hz stimulation was less efficient with a delayed excitability induction and reduced duration. After-effects elicited by 140 Hz stimulation were robust against inversion of test MEP amplitudes seen normally under activation. Stimulation at 140 Hz reduced short interval intracortical inhibition, but left intracortical facilitation, long interval cortical inhibition and cortical silent period unchanged. Implicit motor learning was not facilitated by 140 Hz stimulation. High frequency stimulation in the ripple range is a new promising non-invasive brain stimulation protocol to increase human cortical excitability during and after the end of stimulation.

Boosting brain excitability by transcranial high frequency stimulation in the ripple range

Alleviating the symptoms of neurological diseases by increasing cortical excitability through transcranial stimulation is an ongoing scientific challenge. Here, we tackle this issue by interfering with high frequency oscillations (80–250 Hz) via external application of transcranial alternating current stimulation (tACS) over the human motor cortex (M1). Twenty-one subjects participated in three different experimental studies and they received on separate days tACS at three frequencies (80 Hz, 140 Hz and 250 Hz) and sham stimulation in a randomized order. tACS with 140 Hz frequency increased M1 excitability as measured by transcranial magnetic stimulation-generated motor evoked potentials (MEPs) during and for up to 1 h after stimulation. Control experiments with sham and 80 Hz stimulation were without any effect, and 250 Hz stimulation was less efficient with a delayed excitability induction and reduced duration. After-effects elicited by 140 Hz stimulation were robust against inversion of test MEP amplitudes seen normally under activation. Stimulation at 140 Hz reduced short interval intracortical inhibition, but left intracortical facilitation, long interval cortical inhibition and cortical silent period unchanged. Implicit motor learning was not facilitated by 140 Hz stimulation. High frequency stimulation in the ripple range is a new promising non-invasive brain stimulation protocol to increase human cortical excitability during and after the end of stimulation.

Modulation of preparatory volitional motor cortical activity by paired associative transcranial magnetic stimulation

Paired associative transcranial magnetic stimulation (PAS) has been shown to induce long-term potentiation (LTP)-like or long-term depression (LTD)-like change in excitability of human primary motor cortex (M1), as probed by motor evoked potential (MEP) amplitude. In contrast, little is known about PAS effects on volitional motor cortical activity. In 10 healthy subjects, movement related cortical potentials (MRCP) were recorded to index volitional motor cortical activity during preparation of simple thumb abduction (prime mover: abductor pollicis brevis, APB) or wrist extension movements (prime mover: extensor carpi radialis, ECR). PAS(LTP) increased, PAS(LTD) decreased, and PAS(control) did not change MEP(APB), while MEP(ECR), not targeted by PAS, remained unchanged in all PAS conditions. PAS(LTP) decreased MRCP negativity during the late Bereitschaftspotential (-500 to 0 ms before movement onset), only in the APB task, and predominantly over central scalp electrodes contralateral to the thumb movements. This effect correlated negatively with the PAS(LTP) induced increase in MEP(APB). PAS(LTD) and PAS(control) did not affect MRCP amplitude. Findings indicate a specific interference of PAS with preparatory volitional motor cortical activity, suggestive of a net result caused by increased M1 excitability and disrupted effective connectivity between premotor areas and M1.

Safety study of 50 Hz repetitive transcranial magnetic stimulation in patients with Parkinson’s disease

Repetitive transcranial magnetic stimulation (rTMS) has shown promising results in treating Parkinson's disease (PD), but the best values for rTMS parameters are not established. Fifty Hertz rTMS may be superior to 25 Hz rTMS investigated so far. The objective of this study was to determine if 50 Hz rTMS could be delivered safely in PD patients since current safety limits are exceeded. Fifty Hertz rTMS was applied with a circular coil on the primary motor cortex (M1). Stimulation intensity was first tested at 60% rest motor threshold [RMT] and 0.5 s train duration and then increased in 0.5 s steps to 2 s, and by 10% steps to 90% RMT. Multi-channel electromyography (EMG) was recorded to control for signs of increasing time-locked EMG activity including correlates of the spread of excitation and after-discharges, or an increase of M1 excitability. Pre- and post-50 Hz rTMS assessments included EEG, Unified Parkinson Disease Rating Scale (UPDRS), Grooved Pegboard Test, Serial Reaction Time Task (SRTT), Folstein Mini-Mental Status Examination (MMSE) and Verbal Fluency to control for motor and cognitive side effects. Ten PD patients were investigated. Multi-channel EMG showed no signs of increased time-locked EMG activity including correlates of the spread of excitation and after-discharges, or increased M1 excitability in 9 patients. A PD patient with bi-temporal spikes in the pre-testing EEG had clinical and EMG correlates of spread of excitation at 90% RMT, but no seizure activity. Pre- and post-50 Hz assessment showed no changes. No adverse events were observed. Fifty Hertz rTMS was well tolerated except by 1 patient who wished to terminate the study due to facial muscle stimulation. Fifty Hertz rTMS at an intensity of 90% RMT for 2 s appears safe in patients with PD, but caution should be taken for patients with paroxysmal EEG activity. For this reason, comprehensive screening should include EEG before higher-frequency rTMS is applied. This is the first study to investigate safety of 50 Hz rTMS in humans.