High Gamma and Beta Temporal Interference Stimulation in the Human Motor Cortex Improves Motor Functions

Background: Temporal interference (TI) stimulation is a new technique of non-invasive brain stimulation. Envelope-modulated waveforms with two high-frequency carriers can activate neurons in target brain regions without stimulating the overlying cortex, which has been validated in mouse brains. However, whether TI stimulation can work on the human brain has not been elucidated.Objective: To assess the effectiveness of the envelope-modulated waveform of TI stimulation on the human primary motor cortex (M1).Methods: Participants attended three sessions of 30-min TI stimulation during a random reaction time task (RRTT) or a serial reaction time task (SRTT). Motor cortex excitability was measured before and after TI stimulation.Results: In the RRTT experiment, only 70 Hz TI stimulation had a promoting effect on the reaction time (RT) performance and excitability of the motor cortex compared to sham stimulation. Meanwhile, compared with the sham condition, only 20 Hz TI stimulation significantly facilitated motor learning in the SRTT experiment, which was significantly positively correlated with the increase in motor evoked potential.Conclusion: These results indicate that the envelope-modulated waveform of TI stimulation has a significant promoting effect on human motor functions, experimentally suggesting the effectiveness of TI stimulation in humans for the first time and paving the way for further explorations.

BDNF polymorphism and inter hemispheric balance of motor cortex excitability: a preliminary study

Preclinical studies have demonstrated that Brain-Derived Neurotrophic Factor (BDNF) plays a crucial role in the homeostatic regulation of cortical excitability and excitation/inhibition balance. Using transcranial magnetic stimulation (TMS) techniques we investigated whether BDNF polymorphism could influence cortical excitability of the left and right primary motor cortex in healthy humans. Twenty-nine participants were recruited and genotyped for the presence of the BDNF Val66Met polymorphism, namely homozygous for the valine allele (Val/Val), heterozygotes (Val/Met), and homozygous for the methionine allele (Met/Met). Blinded to the latter, we evaluated inhibitory and facilitatory circuits of the left (LH) and right motor cortex (RH) by measuring resting (RMT) and active motor threshold (AMT), short interval intracortical inhibition (SICI) and intracortical facilitation (ICF). For each neurophysiological metric we also considered the inter-hemispheric balance expressed by the Laterality Index (LI). Val/Val participants (n= 21) exhibited an overall higher excitability of the LH compared to the RH, as probed by lower motor thresholds, lower SICI and higher ICF. Val/Val participants displayed positive LI, especially for AMT and ICF (all p< 0.05), indicating higher LH excitability and more pronounced inter-hemispheric excitability imbalance as compared to Met carriers. Our preliminary results suggest that BDNF Val66Met polymorphism might influence interhemispheric balance of motor cortex excitability.

Neurophysiological Predictors of Response to Medication in Parkinson's Disease

Background: Although dopaminergic medication has been the foundation of Parkinson's disease (PD) therapy for decades, sensitive and specific therapeutic response biomarkers that allow for better treatment optimization are lacking.Objective: We tested whether the features of Transcranial Magnetic Stimulation-based neurophysiological measures taken off-medication are associated with dopaminergic medication-induced clinical effects.Method: Motor cortex excitability [short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), and input-output (IO) curve], and plasticity [paired associative stimulation (PAS) protocol] neurophysiological measures were examined in 23 PD patients off-medication. Clinical features were quantified by the motor section of the Unified Parkinson's Disease Scale (total score and lateralized total, bradykinesia, and rigidity sub-scores), and the differences between measures off-medication and on-medication (following the usual morning dose), were determined. Total daily dopaminergic medication dose (expressed as levodopa equivalent daily dose-LEDD), was also determined.Results: SICI significantly correlated with changes in lateralized UPDRS motor and bradykinesia sub-scores, suggesting that patients with stronger basal intracortical inhibition benefit more from dopaminergic treatment than patients with weaker intracortical inhibition. Also, ICF significantly negatively correlated with LEDD, suggesting that patients with stronger intracortical facilitation require less dopaminergic medication to achieve optimal therapeutic benefit. Both associations were independent of disease severity and duration.Conclusions: The results suggest variability of (patho) physiological phenotypes related to intracortical inhibitory and facilitatory mechanisms determining clinical response to dopaminergic medication in PD. Measures of intracortical excitability may help predict patients' response to dopaminergic therapy, thus potentially providing a background for developing personalized therapy in PD.

Efficacy of Repetitive Transcranial Magnetic Stimulation for Acute Central Post-stroke Pain: A Case Study

Although rare, central post-stroke pain remains one of the most refractory forms of neuropathic pain. Repetitive transcranial magnetic stimulation (rTMS) has been reported to be effective in chronic cases. However, there are no data on the effects in the acute and subacute phases after stroke. In this study, we present a case of a patient with thalamic stroke with acute onset of pain and paresthesia who was responsive to rTMS. After a right thalamic stroke, a 32-year-old woman presented with drug-resistant pain and paresthesia on the left side of the body. There were no motor or sensory deficits, except for blunted thermal sensation and allodynia on light touch. Ten daily sessions were performed, where 10 Hz rTMS was applied to the hand area of the right primary motor cortex, 40 days after stroke. Before rTMS treatment (T0), immediately after treatment conclusion (T1), and 1 month after treatment (T2), three pain questionnaires were administered, and cortical responses to single and paired-pulse TMS were assessed. Eight healthy participants served as controls. At T0, when the patient was experiencing the worst pain, the excitability of the ipsilesional motor cortex was reduced. At T1 and T2, the pain scores and paresthesia' spread decreased. The clinical improvement was paralleled by the recovery in motor cortex excitability of the affected hemisphere, in terms of both intra- and inter-hemispheric connections. In this subacute central post-stroke pain case, rTMS treatment was associated with decreased pain and motor cortex excitability changes.

20 Hz Transcranial Alternating Current Stimulation Inhibits Observation-Execution-Related Motor Cortex Excitability

The present study aimed to investigate the effect of transcranial alternating current stimulation (tACS) on the primary motor cortex (M1) during action observation, and subsequent action execution, on motor cortex excitability. The participants received tACS at 10 Hz or 20 Hz, or a sham stimulation over the left M1 for 10 min while they observed a video displaying a repeated button-tapping task using the right hand, and then performed an identical task with their right hand. Motor-evoked potential (MEP) amplitudes were measured before (T0) and after the action observation paired with tACS or a sham stimulation (T1), and after the performance of the action (T2). The results showed that MEPs were significantly reduced at time point T1 (p = 0.042, Cohen’s d = 0.611) and T2 (p = 0.0003, Cohen’s d = 0.852) in the 20 Hz tACS condition, in contrast with the sham stimulation. There was a significantly smaller MEP amplitude at time point T2 in the 20 Hz tACS condition, as compared to the 10 Hz tACS condition (p = 0.01, Cohen’s d = 0.622), but the MEP amplitude did not significantly change at time point T1 between the 20 Hz and 10 Hz tACS conditions (p = 0.136, Cohen’s d = 0.536). There were no significant differences at time point T1 and T2 between the 10 Hz tACS condition and the sham stimulation. We conclude that 20 Hz tACS during action observation inhibited motor cortex excitability and subsequently inhibited execution-related motor cortex excitability. The effects of tACS on task-related motor cortex excitability are frequency-dependent.

Motor Cortical Network Flexibility is Associated With Biomechanical Walking Impairment in Chronic Stroke

Background: The inability to flexibly modulate motor behavior with changes in task demand or environmental context is a pervasive feature of motor impairment and dysfunctional mobility after stroke. Objective: The purpose of this study was to test the reactive and modulatory capacity of lower-limb primary motor cortical (M1) networks using electroencephalography (EEG) measures of cortical activity evoked by transcranial magnetic stimulation (TMS) and to evaluate their associations with clinical and biomechanical measures of walking function in chronic stroke. Methods: TMS assessments of motor cortex excitability were performed during rest and active ipsilateral plantarflexion in chronic stroke and age-matched controls. TMS-evoked motor cortical network interactions were quantified with simultaneous EEG as the post-TMS (0–300 ms) beta (15–30 Hz) coherence between electrodes overlying M1 bilaterally. We compared TMS-evoked coherence between groups during rest and active conditions and tested associations with poststroke motor impairment, paretic propulsive gait deficits, and the presence of paretic leg motor evoked potentials (MEPs). Results: Stroke ( n = 14, 66 ± 9 years, F = 4) showed lower TMS-evoked cortical coherence and activity-dependent modulation compared to controls ( n = 9, 68 ± 6 years, F = 3). Blunted reactivity and atypical modulation of TMS-evoked coherence were associated with lower paretic ankle moments for propulsive force generation during walking and absent paretic MEPs. Conclusions: Impaired flexibility of motor cortical networks to react to TMS and modulate during motor activity is distinctly associated with paretic limb biomechanical walking impairment, and may provide useful insight into the neuromechanistic underpinnings of chronic post-stroke mobility deficits.

Therapeutic Use of Cerebellar Intermittent Theta Burst Stimulation (iTBS) in a Sardinian Family Affected by Spinocerebellar Ataxia 38 (SCA 38)

Spinocerebellar ataxia 38 (SCA 38) is an autosomal dominant disorder caused by conventional mutations in the ELOVL5 gene which encodes an enzyme involved in the synthesis of very long fatty acids, with a specific expression in cerebellar Purkinje cells. Three Italian families carrying the mutation, one of which is of Sardinian descent, have been identified and characterized. One session of cerebellar intermittent theta burst stimulation (iTBS) was applied to 6 affected members of the Sardinian family to probe motor cortex excitability measured by motor-evoked potentials (MEPs). Afterwards, patients were exposed to ten sessions of cerebellar real and sham iTBS in a cross-over study and clinical symptoms were evaluated before and after treatment by Modified International Cooperative Ataxia Rating Scale (MICARS). Moreover, serum BDNF levels were evaluated before and after real and sham cerebellar iTBS and the role of BDNF Val66Met polymorphism in influencing iTBS effect was explored. Present data show that one session of cerebellar iTBS was able to increase MEPs in all tested patients, suggesting an enhancement of the cerebello-thalamo-cortical pathway in SCA 38. MICARS scores were reduced after ten sessions of real cerebellar iTBS showing an improvement in clinical symptoms. Finally, although serum BDNF levels were not affected by cerebellar iTBS when considering all samples, segregating for genotype a difference was found between Val66Val and Val66Met carriers. These preliminary data suggest a potential therapeutic use of cerebellar iTBS in improving motor symptoms of SCA38.