Background It is well known that transcranial direct current stimulation (tDCS) is capable of modulating corticomotor excitability. However, a source of growing concern has been the observed inter- and intra-individual variability of tDCS-responses. Recent studies have assessed whether individuals respond in a predictable manner across repeated sessions of anodal tDCS (atDCS). The findings of these investigations have been inconsistent, and their methods have some limitations (i.e. lack of sham condition or testing only one tDCS intensity). Objective To study inter- and intra-individual variability of atDCS effects at two different intensities on primary motor cortex (M1) excitability. Methods Twelve subjects participated in a crossover study testing 7-min atDCS over M1 in three separate conditions (2mA, 1mA, sham) each repeated three times separated by 48hrs. Motor evoked potentials were recorded before and after stimulation (up to 30min). Time of testing was maintained consistent within participants. To estimate the reliability of tDCS effects across sessions, we calculated the Intra-class Correlation Coefficient (ICC). Results AtDCS at 2mA, but not 1mA, significantly increased cortical excitability at the group level in all sessions. The overall ICC revealed fair to high reliability of tDCS effects for multiple sessions. Given that the distribution of responses showed important variability in the sham condition, we established a Sham Variability-Based Threshold to classify responses and to track individual changes across sessions. Using this threshold an intra-individual consistent response pattern was then observed only for the 2mA condition. Conclusion 2mA anodal tDCS results in consistent intra- and inter-individual increases of M1 excitability.

In Parkinson’s disease, striatal dopamine depletion produces profound alterations in the neural activity of the cortico-basal ganglia motor loop, leading to dysfunctional motor output and parkinsonism. A key regulator of motor output is the balance between excitation and inhibition in the primary motor cortex, which can be assessed in humans with transcranial magnetic stimulation techniques. Despite decades of research, the functional state of cortical inhibition in Parkinson’s disease remains uncertain. Towards resolving this issue, we applied paired-pulse transcranial magnetic stimulation protocols in 166 patients with Parkinson’s disease (57 levodopa-naïve, 50 non-dyskinetic, 59 dyskinetic) and 40 healthy controls (age-matched with the levodopa-naïve group). All patients were studied OFF medication. All analyses were performed with fully automatic procedures to avoid confirmation bias, and we systematically considered and excluded several potential confounding factors such as age, gender, resting motor threshold, EMG background activity and amplitude of the motor evoked potential elicited by the single-pulse test stimuli. Our results show that short-interval intracortical inhibition is decreased in Parkinson’s disease compared to controls. This reduction of intracortical inhibition was obtained with relatively low-intensity conditioning stimuli (80% of the resting motor threshold) and was not associated with any significant increase in short-interval intracortical facilitation or intracortical facilitation with the same low-intensity conditioning stimuli, supporting the involvement of cortical inhibitory circuits. Short-interval intracortical inhibition was similarly reduced in levodopa-naïve, non-dyskinetic and dyskinetic patients. Importantly, intracortical inhibition was reduced compared to control subjects also on the less affected side (n = 145), even in de novo drug-naïve patients in whom the less affected side was minimally symptomatic (lateralized Unified Parkinson’s Disease Rating Scale part III = 0 or 1, n = 23). These results suggest that cortical disinhibition is a very early, possibly prodromal feature of Parkinson’s disease.

Motor learning consists of the ability to improve motor actions through practice playing a major role in the acquisition of skills required for high-performance sports or motor function recovery after brain lesions. During the last decades, it has been reported that transcranial direct-current stimulation (tDCS), consisting in applying weak direct current through the scalp, is able of inducing polarity-specific changes in the excitability of cortical neurons. This low-cost, painless and well-tolerated portable technique has found a wide-spread use in the motor learning domain where it has been successfully applied to enhance motor learning in healthy individuals and for motor recovery after brain lesion as well as in pathological states associated to motor deficits. The main objective of this mini-review is to offer an integrative view about the potential use of tDCS for human motor learning modulation. Furthermore, we introduce the basic mechanisms underlying immediate and long-term effects associated to tDCS along with important considerations about its limitations and progression in recent years.

Classical blink conditioning is a well known model for studying neural generation of acquired motor responses. The acquisition of this type of associative learning has been related to many cortical, subcortical, and cerebellar structures. However, until now, no one has studied the motor cortex (MC) and its possible role in classical eyeblink conditioning. We recorded in rabbits the activity of MC neurons during blink conditioning using a delay paradigm. Neurons were identified by their antidromic activation from facial nucleus (FN) or red nucleus (RN). For conditioning, we used a tone as a conditioned stimulus (CS) followed by an air puff as an unconditioned stimulus (US) that coterminated with it. Conditioned responses (CRs) were determined from the electromyographic activity of the orbicularis oculi muscle and/or from eyelid position recorded with the search coil technique. Type A neurons increased their discharge rates across conditioning sessions and reached peak firing during the CS-US interval, while type B cells presented a second peak during US presentation. Both of them project to the FN. Type C cells increased their firing acrosstheCS-USinterval,reachingpeakvaluesatthetimeofUSpresentation,andwereactivatedfromtheRN.Thesethreetypesofneuronsfired well in advance of the beginning of CRs and changed with them. Reversible inactivation of the MC during conditioning evoked a decrease in learning curves and in the amplitude of CRs, while train stimulation of the MC simulated the profile and kinematics of conditioned blinks. In conclusion, MC neurons are involved in the acquisition and expression of CRs.

Background and Objectives:Unilateral Magnetic Resonance-guided Focused Ultrasound subthalamotomy (FUS-STN) has been shown to improve the cardinal motor features of Parkinson’s disease (PD). Whether this effect is sustained is not known. This study aims to report the long-term outcome of PD patients treated with unilateral FUS-STN.Methods:We conducted a prospective, open-label study of asymmetrical PD patients who underwent unilateral FUS-STN. All patients were evaluated up to 36 months after treatment. The primary outcome was the difference from baseline to 36 months after FUS-STN in the score of the Movement Disorders Society-Unified Rating scale (MDS-UPDRS) motor part (III) for the treated hemibody in the off-medication state. The safety outcome included all adverse events occurring during follow-up. Secondary outcomes were the change in the MDS-UPDRS III score on-medication; sub-scores of rigidity, bradykinesia, tremor, and axial features; total MDS-UPDRS III; and the MDS-UPDRS part IV. Functional disability and quality of life were assessed using the MDS-UPDRS II and the PDQ39, respectively. Patient impression of change and satisfaction with the treatment were self-assessed. The Wilcoxon signed-rank test with subsequent Bonferroni’s correction was used for data analysis.Results:Thirty-two PD patients were evaluated 36 months after treatment. The mean (±SD) age at baseline was 56.0±10.1 years, with a mean disease duration of 6.8±2.8 years. The MDS-UPDRS III score for the treated hemibody off-medication was improved by 52.3% from baseline to 3 years (score reduction from 19.0±3.2 to 8.9±3.3, 95% confidence interval [95CI] 8.7 to 11.6,P<0.001), and all specific motor features were improved from baseline. No disabling or delayed adverse events were reported. The total MDS-UPDRS III off-medication score was 22.9% lower at 3 years than before treatment (36.8±7.4 vs 27.4±6.2, 95CI 6.0 to 11.5,P<0.001). The MDS-UPDRS II, IV, and PDQ39 scores and levodopa dose were equivalent to those at baseline.Discussion:The benefit of unilateral FUS-STN on PD motor features is sustained in the long term. FUS-STN contributes to better clinical control over several years of evolution.NCT02912871/03454425.Classification of Evidence:This study provides Class IV evidence on the utility of focused ultrasound unilateral subthalamotomy in the treatment of people with Parkinson's disease.

The use of brain-derived signals for controlling external devices has long attracted the attention from neuroscientists and engineers during last decades. Although much effort has been dedicated to establishing effective brain-to-computer communication, computer-to-brain communication feedback for “closing the loop” is now becoming a major research theme. While intracortical microstimulation of the sensory cortex has already been successfully used for this purpose, its future application in humans partly relies on the use of non-invasive brain stimulation technologies. In the present study, we explore the potential use of transcranial alternating-current stimulation (tACS) for synthetic tactile perception in alert behaving animals. More specifically, we determined the effects of tACS on sensory local field potentials (LFPs) and motor output and tested its capability for inducing tactile perception using classical eyeblink conditioning in the behaving animal. We demonstrated that tACS of the primary somatosensory cortex vibrissa area could indeed substitute natural stimuli during training in the associative learning paradigm.

The amplitude of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) is a common yet highly variable measure of corticospinal excitability. The tradeoff between maximizing the number of trials and minimizing experimental time remains a hurdle. It is therefore important to establish how many trials should be used. The aim of this study is not to provide rule-of-thumb answers that may be valid only in specific experimental conditions, but to offer a more general framework to inform the decision about how many trials to use under different experimental conditions. Specifically, we present a set of equations that show how the number of trials affects single-subject MEP amplitude, population MEP amplitude, hypothesis testing and test–retest reliability, depending on the variability within and between subjects. The equations are derived analytically, validated with Monte Carlo simulations, and representatively applied to experimental data. Our findings show that the minimum number of trials for estimating single-subject MEP amplitude largely depends on the experimental conditions and on the error considered acceptable by the experimenter. Conversely, estimating population MEP amplitude and hypothesis testing are markedly more dependent on the number of subjects than on the number of trials. These tools and results help to clarify the impact of the number of trials in the design and reproducibility of past and future experiments.

Purkinje cells (PC) control deep cerebellar nuclei (DCN), which in turn inhibit inferior olive nucleus, closing a positive feedback loop via climbing fibers. PC highly express potassium BK channels but their contribution to the olivo-cerebellar loop is not clear. Using multiple-unit recordings in alert mice we found in that selective deletion of BK channels in PC induces a decrease in their simple spike firing with a beta-range bursting pattern and fast intraburst frequency (~200 Hz). To determine the impact of this abnormal rhythm on the olivo-cerebellar loop we analyzed simultaneous rhythmicity in different cerebellar structures. We found that this abnormal PC rhythmicity is transmitted to DCN neurons with no effect on their mean firing frequency. Long term depression at the parallel-PC synapses was altered and the intra-burst complex spike spikelets frequency was increased without modification of the mean complex spike frequency in BK-PC−/− mice. We argue that the ataxia present in these conditional knockout mice could be explained by rhythmic disruptions transmitted from mutant PC to DCN but not by rate code modification only. This suggests a neuronal mechanism for ataxia with possible implications for human disease.