Probing phase- and frequency-dependent characteristics of cortical interneurons using combined transcranial alternating current stimulation and transcranial magnetic stimulation.

Paired-pulse transcranial magnetic stimulation (TMS) and peripheral stimulation combined with TMS can be used to study cortical interneuronal circuitry. By combining these procedures with concurrent transcranial alternating current stimulation (tACS), Guerra and colleagues recently showed that different cortical interneuronal populations are differentially modulated by the phase and frequency of tACS-imposed oscillations (Guerra A, Pogosyan A, Nowak M, Tan H, Ferreri F, Di Lazzaro V, Brown P. Cerebral Cortex 26: 3977-2990, 2016). This work suggests that different cortical interneuronal populations can be characterized by their phase and frequency dependency. Here we discuss how combining TMS and tACS can reveal the frequency at which cortical interneuronal populations oscillate, the neuronal origins of behaviorally relevant cortical oscillations, and how entraining cortical oscillations could potentially treat brain disorders.

Dissociable roles of preSMA in motor sequence chunking and hand switching-a TMS study.

Motor chunking, the grouping of individual movements into larger units, is crucial for sequential motor performance. The presupplementary motor area (preSMA) is involved in chunking and other related processes such as task switching, response selection, and response inhibition that are crucial for organizing sequential movements. However, previous studies have not systematically differentiated the role of preSMA in motor chunking and hand switching, thus leaving its relative contribution to each of these processes unclear. The aim of this study is to demonstrate the differential role of preSMA in motor chunking and hand switching. We designed motor sequences in which different kinds of hand switches (switching toward the right or left hand or continuing with the right hand) were counterbalanced across between- and within-chunk sequence points. Eighteen healthy, right-handed participants practiced four short subsequences (chunks) of key presses. In a subsequent task, these chunks had to be concatenated into one long sequence. We applied double-pulse transcranial magnetic stimulation (TMS) over left preSMA or left M1 areas at sequence initiation, between chunks, or within chunks. TMS over the left preSMA significantly slowed the next response when stimulation was given between chunks, but only if a hand switch toward the contralateral (right) hand was required. PreSMA stimulation within chunks did not interfere with responses. TMS over the left M1 area delayed responses with the contralateral hand, both within and between chunks. Both preSMA and M1 stimulation decreased response times at sequence initiation. These results suggest that left preSMA is not necessary for chunking per se, but rather for organizing complex movements that require chunking and hand switching simultaneously.

Inducing LTD-Like Effect in the Human Motor Cortex with Low Frequency and Very Short Duration Paired Associative Stimulation: An Exploratory Study.

Introduction. Paired associative stimulation (PAS) is an established technique to investigate synaptic plasticity in the human motor cortex (M1). Classically, to induce long-term depression- (LTD-) or long-term potentiation-like effects in the human M1, studies have used low frequency and long duration trains of PAS. In the present study, we explored an LTD-like effect using very short duration and low frequency of PAS10 ms protocols in human M1. Methods. Six protocols of low frequency PAS10 ms (ranging from 0.2 Hz to 1 Hz) were investigated with very short durations of 1 and 2 minutes stimulation. Six healthy volunteers were included in each protocol. We obtained motor-evoked potentials from right abductor pollicis brevis muscle before and after applying PAS10 ms up to 30 minutes. After we found PAS10 ms protocol which induced an LTD-like effect, we tested that protocol on additional 5 subjects. Results. One-way repeated-measures ANOVA showed that only the group of 1-minute stimulation of 0.25 Hz induced an LTD-like effect. When adding the additional subjects, the effect remained and lasted for 30 minutes. Conclusion. Low frequency and very short duration of PAS10 ms potentially induced an LTD-like effect in human M1. With further verification, this method might be useful for research relating to synaptic plasticity by reducing the duration of study and minimizing subject discomfort.

Distinct interneuronal networks influence excitability of the surround during movement initiation.

Surround inhibition (SI) is a feature of motor control in which activation of task-related muscles is associated with inhibition of neighboring, nonprotagonist muscles, allowing selective motor control. The physiological basis for SI still remains unknown. In all previous studies, SI in the motor system was measured during movement initiation by using transcranial magnetic stimulation (TMS) to deliver a posteroanterior current at a single suprathreshold intensity. To expand our understanding of SI, we explored this phenomenon at a wide range of intensities and by stimulating motor cortex with currents along anteroposterior and lateromedial directions. Fifteen healthy volunteers performed a brief isometric index finger flexion on hearing a tone. Electromyography was recorded from the synergist and surround finger muscles. Single-pulse TMS was applied to stimulate the surround muscle at different intensities at rest or movement initiation. The motor evoked potential (MEP) amplitudes were then plotted against stimulation intensities to obtain the MEP recruitment curves for the rest and movement initiation conditions and for the three current directions for every subject. From the recruitment curves, we found that surround inhibition could be elicited only by the posteroanterior current. Hence, we postulate that surround inhibition is mediated by intracortical circuits in the motor cortex. Also, for the first time, we observed surround facilitation when the motor cortex was stimulated with anteroposterior current. Further studies are needed to investigate the mechanisms underlying both these phenomena individually in healthy subjects and patients with dystonia and other movement disorders.

Essential Tremor and Essential Tremor Plus Are Essentially Similar Electrophysiologically.

BACKGROUND: The merits of classifying the heterogeneous group of essential tremors into essential tremor (ET) and essential tremor plus (ETP) are debated. OBJECTIVES: We studied the electrophysiological and spiral characteristics of tremor in ET and ETP. METHODS: We reviewed standardized videos from a tremor database and clinically classified patients into ET, ETP, or dystonic tremor (DT). The following variables were derived from combined tri-axial accelerometry-surface electromyography (EMG)-peak frequency, total power, peak power, full width half maximum, tremor stability index and EMG-coherence. We analyzed hand-drawn spirals to derive mean deviation, tremor variability, inter-, and intra-loop widths. We compared these variables among the groups. RESULTS: We recruited 72 participants (81.9% male) with mean age 47.7 ± 16.1 years and Fahn-Tolosa-Marin Tremor Rating Scale total score 31.1 ± 14.1. Patients with ET were younger (P = 0.014) and had less severe tremor (P = 0.020) compared to ETP and DT. In ETP group, 48.6% had subtle dystonia. Peak frequency was greater in ETP (7.3 ± 0.3 Hz) compared to DT (6.1 ± 0.4 Hz; P = 0.024). Peak power was greater in ETP and DT for postural tremor. Rest tremor was recordable on accelerometry in 26.7% of ET. Other variables were similar among the groups. CONCLUSION: Electrophysiological evaluation revealed postural tremor of frequency 6 to 7 Hz in ET, ETP, and DT with subtle differences more severe tremor in ETP and DT, and higher frequency in ETP compared to DT. Our findings suggest a similar tremor oscillator in these conditions, supporting the view that these entities are part of a spectrum of tremor disorders, rather than distinct etiological entities.

Neuroplasticity in cigarette smokers is altered under withdrawal and partially restituted by nicotine exposition.

Nicotine improves cognitive functions by modulating neuroplasticity and cortical excitability in nonsmoking subjects. As shown recently, the positive effect of nicotine on cognition might at least partially be caused by a focusing effect of nicotine on neuroplasticity in these subjects. Concordant to this, smokers under nicotine withdrawal show reduced cognitive abilities, which are at least partially restituted by nicotine consumption. We aimed to explore the neurophysiological foundation of these effects by exploring nonfocal and focal plasticity-inducing protocols in human smokers under nicotine withdrawal and exposition. Focal, synapse-specific plasticity was induced by paired associative stimulation (PAS), while nonfocal plasticity was induced by transcranial direct current stimulation (tDCS). Each subject (12) received placebo and nicotine patches combined with one of the stimulation protocols to the primary motor cortex. Corticospinal excitability was monitored by transcranial magnetic stimulation-induced motor-evoked potential amplitudes. In smokers during nicotine withdrawal, facilitatory plasticity induced by tDCS and PAS was abolished, but restituted by nicotine. In contrast, excitability-diminishing plasticity was not affected by nicotine withdrawal. Under nicotine, the inhibitory aftereffects of PAS were delayed and prolonged, while the tDCS-generated excitability reduction was abolished. Thus, absent facilitatory plasticity in smokers during nicotine withdrawal is restituted by nicotine, favoring the deficit-compensating hypothesis of nicotine consumption. These results might shed further light on the proposed mechanism of nicotine on cognition and attention, which might be connected to nicotine addiction and probability of relapse in smokers.

Behavioral Validation of Individualized Low-Intensity Transcranial Electrical Stimulation (tES) Protocols.

Large interindividual variability in the effects of low-intensity transcranial electrical stimulation (tES) considerably limits its potential for clinical applications. It has been recently proposed that individualizing stimulation dose by accounting for interindividual anatomic differences would reduce the variability in electric fields (E-fields) over the targeted cortical site and therefore produce more consistent behavioral outcomes. However, improvement in behavioral outcomes following individualized dose tES has never been compared with that of conventional fixed dose tES. In this study, we aimed to empirically evaluate the effect of individualized dose tES on behavior and further compare it with the effects of sham and fixed dose stimulations. We conducted a single-blinded, sham-controlled, repeated-measures study to examine the impact of transcranial direct current stimulation on motor learning and that of transcranial alternating current stimulation on the working memory of 42 healthy adult individuals. Each participant underwent three sessions of tES, receiving fixed dose, individualized dose, or sham stimulation over the targeted brain region for the entire behavioral task. Our results showed that the individualized dose reduced the variability in E-fields at the targeted cortical surfaces. However, there was no significant effect of tES on behavioral outcomes. We argue that although the stimulation dose and E-field intensity at the targeted cortical site are linearly correlated, the effect of E-fields on behavior seems to be more complex. Effective optimization of tES protocols warrants further research considering both neuroanatomical and functional aspects of behavior.

Dose-dependent nonlinear effect of L-DOPA on paired associative stimulation-induced neuroplasticity in humans.

Dopamine is one of the major neuromodulators in the CNS, which is involved in learning and memory processes. A nonlinear, inverted U-shaped dose-response curve of its effects on cognition has been observed in animal studies. The basis for this nonlinear effect might be a similar effect of dopamine on neuroplasticity. Whereas it has been shown that dopamine affects paired associative stimulation (PAS)-induced plasticity, which might reflect learning-related processes to a larger degree than other noninvasive plasticity induction protocols in the human motor cortex in principle, its dose-dependency has not been explored previously. We studied the effect of different dosages of the dopamine precursor L-DOPA on motor cortex plasticity induced by facilitatory and inhibitory PAS of the motor cortex in 12 healthy humans. They received 25, 100, or 200 mg of L-DOPA or placebo medication combined with either excitability-enhancing or -diminishing PAS. Cortical excitability level was monitored before and for up to 2 d after plasticity induction by assessment of transcranial magnetic stimulation-induced motor-evoked potentials. Low-dose L-DOPA abolished the aftereffects of PAS and medium-dose L-DOPA prolonged facilitatory plasticity. High-dose L-DOPA reversed the excitability enhancement accomplished by facilitatory PAS to diminution. Thus, the results show a clear nonlinear effect of L-DOPA dosage on associative plasticity, different from that on nonfocal plasticity. This might help to explain dopaminergic effect on cognition and could be relevant for understanding the pathophysiology and treatment of neuropsychiatric diseases accompanied by alterations of the dopaminergic system.

Evaluating interhemispheric connectivity during midline object recognition using EEG.

Functional integration between two hemispheres is crucial for perceptual binding to occur when visual stimuli are presented in the midline of the visual field. Mima and colleagues (2001) showed using EEG that midline object recognition was associated with task-related decrease in alpha band power (alpha desynchronisation) and a transient increase in interhemispheric coherence. Our objective in the current study was to replicate the results of Mima et al. and to further evaluate interhemispheric effective connectivity during midline object recognition in source space. We recruited 11 healthy adult volunteers and recorded EEG from 64 channels while they performed a midline object recognition task. Task-related power and coherence were estimated in sensor and source spaces. Further, effective connectivity was evaluated using Granger causality. While we were able to replicate the alpha desynchronisation associated with midline object recognition, we could not replicate the coherence results of Mima et al. The data-driven approach that we employed in our study localised the source of alpha desynchronisation over the left occipito-temporal region. In the alpha band, we further observed significant increase in imaginary part of coherency between bilateral occipito-temporal regions during object recognition. Finally, Granger causality analysis between the left and right occipito-temporal regions provided an insight that even though there is bidirectional interaction, the left occipito-temporal region may be crucial for integrating the information necessary for object recognition. The significance of the current study lies in using high-density EEG and applying more appropriate and robust measures of connectivity as well as statistical analysis to validate and enhance our current knowledge on the neural basis of midline object recognition.

Inter-Individual Variability in Motor Output Is Driven by Recruitment Gain in the Corticospinal Tract Rather Than Motor Threshold.

Variability in the response of individuals to various non-invasive brain stimulation protocols is a major problem that limits their potential for clinical applications. Baseline motor-evoked potential (MEP) amplitude is the key predictor of an individual's response to transcranial magnetic stimulation protocols. However, the factors that predict MEP amplitude and its variability remain unclear. In this study, we aimed to identify the input-output curve (IOC) parameters that best predict MEP amplitude and its variability. We analysed IOC data from 75 subjects and built a general linear model (GLM) using the IOC parameters as regressors and MEP amplitude at 120% resting motor threshold (RMT) as the response variable. We bootstrapped the data to estimate variability of IOC parameters and included them in a GLM to identify the significant predictors of MEP amplitude variability. Peak slope, motor threshold, and maximum MEP amplitude of the IOC were significant predictors of MEP amplitude at 120% RMT and its variability was primarily driven by the variability of peak slope and maximum MEP amplitude. Recruitment gain and maximum corticospinal excitability are the key predictors of MEP amplitude and its variability. Inter-individual variability in motor output may be reduced by achieving a uniform IOC slope.

Tapping the Potential of Multimodal Non-invasive Brain Stimulation to Elucidate the Pathophysiology of Movement Disorders.

This mini-review provides a detailed outline of studies that have used multimodal approaches in non-invasive brain stimulation to investigate the pathophysiology of the three common movement disorders, namely, essential tremor, Parkinson's disease, and dystonia. Using specific search terms and filters in the PubMed® database, we finally shortlisted 27 studies in total that were relevant to this review. While two-thirds (Brittain et al., 2013) of these studies were performed on Parkinson's disease patients, we could find only three studies that were conducted in patients with essential tremor. We clearly show that although multimodal non-invasive brain stimulation holds immense potential in unraveling the physiological mechanisms that are disrupted in movement disorders, the technical challenges and pitfalls of combining these methods may hinder their widespread application by movement disorder specialists. A multidisciplinary team with clinical and technical expertise may be crucial in reaping the fullest benefits from such novel multimodal approaches.

Dose-dependent inverted U-shaped effect of dopamine (D2-like) receptor activation on focal and nonfocal plasticity in humans.

The neuromodulator dopamine (DA) has multiple modes of action on neuroplasticity induction and modulation, depending on subreceptor specificity, concentration level, and the kind of stimulation-induced plasticity. To determine the dosage-dependent effects of D(2)-like receptor activation on nonfocal and focal neuroplasticity in the human motor cortex, different doses of ropinirole (0.125, 0.25, 0.5, and 1.0 mg), a D(2)/D(3) dopamine agonist, or placebo medication were combined with anodal and cathodal transcranial direct current stimulation (tDCS) protocols, which induce nonfocal plasticity, or paired associative stimulation (PAS, ISI of 10 or 25 ms), which generates focal plasticity, in healthy volunteers. D(2)-like receptor activation produced an inverted "U"-shaped dose-response curve on plasticity for facilitatory tDCS and PAS and for inhibitory tDCS. Here, high or low dosages of ropinirole impaired plasticity. However, no dose-dependent response effect of D(2)-like receptor activation was evident for focal inhibitory plasticity. In general, our study supports the assumption that modulation of D(2)-like receptor activity exerts dose-dependent inhibitory or facilitatory effects on neuroplasticity in the human motor cortex depending on the topographic specificity of plasticity.

Contribution of the premotor cortex to consolidation of motor sequence learning in humans during sleep.

Motor learning and memory consolidation require the contribution of different cortices. For motor sequence learning, the primary motor cortex is involved primarily in its acquisition. Premotor areas might be important for consolidation. In accordance, modulation of cortical excitability via transcranial DC stimulation (tDCS) during learning affects performance when applied to the primary motor cortex, but not premotor cortex. We aimed to explore whether premotor tDCS influences task performance during motor memory consolidation. The impact of excitability-enhancing, -diminishing, or placebo premotor tDCS during rapid eye movement (REM) sleep on recall in the serial reaction time task (SRTT) was explored in healthy humans. The motor task was learned in the evening. Recall was performed immediately after tDCS or the following morning. In two separate control experiments, excitability-enhancing premotor tDCS was performed 4 h after task learning during daytime or immediately before conduction of a simple reaction time task. Excitability-enhancing tDCS performed during REM sleep increased recall of the learned movement sequences, when tested immediately after stimulation. REM density was enhanced by excitability-increasing tDCS and reduced by inhibitory tDCS, but did not correlate with task performance. In the control experiments, tDCS did not improve performance. We conclude that the premotor cortex is involved in motor memory consolidation during REM sleep.

Task-specific interhemispheric hypoconnectivity in writer's cramp - An EEG study.

OBJECTIVE: Writer's cramp (WC) is a focal task-specific dystonia characterized by abnormal posturing of the hand muscles during handwriting, but not during other tasks that involve the same set of muscles and objects such as sharpening a pencil. Our objective was to investigate the pathophysiology underlying the task specificity of this disorder using EEG. We hypothesized that premotor-parietal connectivity will be lower in WC patients specifically during handwriting and motor imagery of handwriting. METHODS: We recruited 15 WC patients and 15 healthy controls. EEG was recorded while participants performed 4 tasks - writing with a pencil, sharpening a pencil, imagining writing and imagining sharpening. We determined the connectivity changes between relevant brain regions during these tasks. RESULTS: We found reduced interhemispheric alpha coherence in the sensorimotor areas in WC patients exclusively during handwriting. WC patients also showed less reduction of task-related beta spectral power and a trend for reduced premotor-parietal coherence during motor tasks. CONCLUSION: We could not confirm an abnormality in premotor-parietal connectivity specific to handwriting by this method. However, there was a task-specific reduction in interhemispheric alpha connectivity in WC patients, whose behavioral correlate remains unknown. SIGNIFICANCE: Interhemispheric alpha connectivity can be a potential interventional target in WC.

Parietal conditioning enhances motor surround inhibition.

BACKGROUND: Motor surround inhibition (mSI) is a phenomenon supportive for executing selective finger movements, wherein synergist muscles are selectively facilitated while surround muscles are inhibited. Previous studies of conditioning inputs to several intracortical and cortico-cortical inhibitory networks did not show an influence on mSI. The inhibitory posterior parietal-motor network, which is crucial for executing fine movements, however, has not been studied. OBJECTIVE/HYPOTHESIS: To investigate the role of inhibitory posterior parietal-motor network in mSI. We hypothesized that conditioning this inhibitory network would enhance mSI. METHODS: 11 healthy adults completed study. mSI was elicited by applying a TMS pulse over the motor cortex coupled with or without a conditioning input to an inhibitory spot in the posterior parietal cortex at 2 or 4 ms interval. RESULTS: Conditioning input to the posterior parietal cortex increased mSI by ∼20% CONCLUSION: The inhibitory posterior parietal-motor network appears to contribute to the genesis of mSI.

Dual-hemispheric transcranial direct current stimulation (tDCS) over primary motor cortex does not affect movement selection.

Volition and sense of agency are two primary components of a voluntary or internally generated movement. It has been shown that movement selection cannot be altered without interfering with the sense of volition using single pulse transcranial magnetic stimulation over the primary motor cortex. In the current study, we aimed at examining whether modulating the cortical excitability of the final effector in the voluntary motor pathway-the primary motor cortex, using transcranial direct current stimulation (tDCS) would alter movement selection. Our hypothesis was that anodal tDCS would increase motor cortical excitability and thereby decrease the threshold for movement execution, which could favor selection of the contralateral hand. We recruited 13 healthy adults to perform a movement selection task involving free-choice and externally-cued trials while applying real/sham tDCS in a C3-C4 dual-hemispheric electrode montage. Contrary to our hypothesis, we did not observe any effect of tDCS on movement selection either at the individual or group level. However, our data confirms the strong preference of right-handed individuals for the dominant right hand. We also found higher reaction time for internally generated movement compared to externally triggered movement. We therefore conclude that movement selection cannot be influenced at the level of primary motor cortex and that brain areas upstream of the primary motor cortex in the voluntary motor pathway may be possible targets for influencing movement selection.

Intracortical Inhibition and Surround Inhibition in the Motor Cortex: A TMS-EEG Study.

BACKGROUND: Short-latency intracortical inhibition (SICI) and motor surround inhibition (mSI) are cortical phenomena that have been investigated with transcranial magnetic stimulation (TMS). mSI is believed to be necessary for the execution of fine finger movements, SICI may participate in mSI genesis, and however, the mechanisms underlying both mSI and SICI are not entirely clear. OBJECTIVE: We explored the cortical physiology of SICI and mSI in healthy subjects by TMS-evoked cortical potentials (TEPs). METHODS: Single (sp) and paired-pulse (pp) TMS were delivered on the ADM muscle cortical hotspot while recording EEG and EMG. Three conditions were tested: spTMS and ppTMS at rest, and spTMS at the onset of an index finger movement. SICI and mSI were calculated on the ADM motor evoked potential (MEP) and two groups were defined based on the presence of mSI. Average TEPs were calculated for each condition and for five regions of interest. RESULTS: At movement onset we observed a widespread reduction of the inhibitory late component N100 suggesting cortical facilitation associated with motor performance. At motor cortex level, SICI and mSI are associated with similar modulation of TEPs consisting in a reduction of P30 and an increase of N45 amplitude. CONCLUSION: Our findings suggest that SICI and mSI modulate cortical excitability with shared inhibitory mechanisms.

Enhancing language performance with non-invasive brain stimulation--a transcranial direct current stimulation study in healthy humans.

In humans, transcranial direct current stimulation (tDCS) can be used to induce, depending on polarity, increases or decreases of cortical excitability by polarization of the underlying brain tissue. Cognitive enhancement as a result of tDCS has been reported. The purpose of this study was to test whether weak tDCS (current density, 57 microA/cm(2)) can be used to modify language processing. Fifteen healthy subjects performed a visual picture naming task before, during and after tDCS applied over the posterior perisylvian region (PPR), i.e. an area which includes Wernicke's area [BA 22]. Four different sessions were carried out: (1) anodal and (2) cathodal stimulation of left PPR and, for control, (3) anodal stimulation of the homologous region of the right hemisphere and (4) sham stimulation. We found that subjects responded significantly faster following anodal tDCS to the left PPR (p<0.01). No decreases in performance were detected. Our finding of a transient improvement in a language task following the application of tDCS together with previous studies which investigated the modulation of picture naming latency by transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS) suggest that tDCS applied to the left PPR (including Wernicke's area [BA 22]) can be used to enhance language processing in healthy subjects. Whether this safe, low cost, and easy to use brain stimulation technique can be used to ameliorate deficits of picture naming in aphasic patients needs further investigations.