Does transcranial electrical stimulation enhance corticospinal excitability of the motor cortex in healthy individuals? A systematic review and meta‐analysis

Numerous studies have explored the effects of transcranial electrical stimulation (tES) – including anodal transcranial direct current stimulation (a‐tDCS), cathodal transcranial direct current stimulation (c‐tDCS), transcranial alternative current stimulation (tACS), transcranial random noise stimulation (tRNS) and transcranial pulsed current stimulation (tPCS) – on corticospinal excitability (CSE) in healthy populations. However, the efficacy of these techniques and their optimal parameters for producing robust results has not been studied. Thus, the aim of this systematic review was to consolidate current knowledge about the effects of various parameters of a‐tDCS, c‐tDCS, tACS, tRNS and tPCS on the CSE of the primary motor cortex (M1) in healthy people. Leading electronic databases were searched for relevant studies published between January 1990 and February 2017; 126 articles were identified, and their results were extracted and analysed using RevMan software. The meta‐analysis showed that a‐tDCS application on the dominant side significantly increases CSE (P < 0.01) and that the efficacy of a‐tDCS is dependent on current density and duration of application. Similar results were obtained for stimulation of M1 on the non‐dominant side (P = 0.003). The effects of a‐tDCS reduce significantly after 24 h (P = 0.006). Meta‐analysis also revealed significant reduction in CSE following c‐tDCS (P < 0.001) and significant increases after tRNS (P = 0.03) and tPCS (P = 0.01). However, tACS effects on CSE were only significant when the stimulation frequency was ≥140 Hz. This review provides evidence that tES has substantial effects on CSE in healthy individuals for a range of stimulus parameters.     

Paired associative stimulation increases motor cortex excitability more effectively than theta-burst stimulation

Objective

To examine the effects of theta burst stimulation (TBS) and paired associative stimulation (PAS) on excitability in the human motor cortex.

Methods

Sixteen healthy young participants received intermittent TBS (iTBS) or PAS to the primary motor cortex on two testing occasions, at least a week apart. Ten of the participants also received iTBS or PAS after conditioning with continuous TBS on two other occasions. Cortical excitability was assessed with single TMS pulses to the motor cortex. Motor evoked potentials (MEPs) were measured from the first dorsal interosseus (FDI) muscle before TBS or PAS stimulation, and every 10 min for 60 min after stimulation. Changes in excitability were compared against the potential for motor learning, assessed with the rotor pursuit task.

Results

After the PAS protocol MEP amplitudes were significantly increased. This increase was greater than after intermittent TBS, which did not change MEPs significantly. Conditioning with continuous TBS showed no significant effect. Participants’ responses were not correlated across protocols and were not correlated with rotor pursuit learning.

Conclusions

PAS was the only protocol which induced significant increases in MEP amplitude.

Significance

PAS is robust in inducing excitatory cortical change. This makes it a suitable protocol for testing plasticity in healthy and patient groups.     

Rigor and reproducibility in research with transcranial electrical stimulation: An NIMH-sponsored workshop

Background

Neuropsychiatric disorders are a leading source of disability and require novel treatments that target mechanisms of disease. As such disorders are thought to result from aberrant neuronal circuit activity, neuromodulation approaches are of increasing interest given their potential for manipulating circuits directly. Low intensity transcranial electrical stimulation (tES) with direct currents (transcranial direct current stimulation, tDCS) or alternating currents (transcranial alternating current stimulation, tACS) represent novel, safe, well-tolerated, and relatively inexpensive putative treatment modalities.

Comparative efficacy of non-invasive neurostimulation therapies for poststroke dysphagia: A systematic review and meta-analysis

ObjectiveTo explore the effect of non-invasive neurostimulation therapies on dysphagia patients after stroke.MethodsWe searched MEDLINE (Ovid), PubMed, Embase, Web of Science, ScienceDirect, and Cochrane library databases until April 22, 2020. All published and unpublished randomized controlled trials (RCT) were included. Full texts were independently reviewed. The risk of RCT bias was evaluated by two independent assessors using the Cochrane risk of bias tool. The primary outcome measure was swallowing function before and after neurostimulation therapy. The effect sizes are calculated from the extracted data and combined into a comprehensive summary statistic.ResultA total of 27 randomized controlled trials were included in this study, involving 914 stroke patients (27 intervention groups and 20 control groups). Meta-analysis showed that compared with the control group, noninvasive neurostimulation therapies (repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), surface neuromuscular electrical stimulation (sNMES) or pharyngeal electrical stimulation (PES)) had a better effect (SMD = 0.91; 95% CI: 0.54–1.27; Z = 4.84; P < 0.00001; I² = 86%). In the subgroup analysis based on type of stimulus, rTMS appeared to perform better. In the subgroup analysis based on clinical phase, stimulation applied in the acute phase may be more effective. In the subgroup analysis based on the site of injury, the brainstem injury group seemed to achieve better outcomes. In the subgroup analysis based on stroke type, the cerebral infarction group had better outcomes than the cerebral infarction/hemorrhage mixed group.ConclusionsNon-invasive neurostimulation therapies can effectively promote the recovery of dysphagia after stroke.     

Modulation of motor learning by a paired associative stimulation protocol inducing LTD-like effects

BackgroundPaired associative stimulation (PAS) induces long-term potentiation (LTP)-like effects when interstimulus intervals (ISIs) between electrical peripheral nerve stimulation and transcranial magnetic stimulation (TMS) to M1 are approximately 21–25 ms (PAS_LTP). It was previously reported that two forms of motor learning (i.e., mode-free and model-based learning) can be differentially modulated by PAS_LTP depending on the different synaptic inputs to corticospinal neurons (CSNs), which relate to posterior-to-anterior (PA) or anterior-to-posterior (AP) currents induced by TMS (PA or AP inputs, respectively). However, the effects of long-term depression (LTD)-inducing PAS with an ISI of approximately 10 ms (PAS_LTD) on motor learning and its dependency on current direction have not yet been tested.ObjectiveTo investigate whether, and how, PAS_LTD affects distinct types of motor learning.MethodsEighteen healthy volunteers participated. We adopted the standard PAS using suprathreshold TMS with the target muscle relaxed, as well as subthreshold PAS during voluntary contraction, which was suggested to selectively recruit PA or AP inputs depending on the orientation of the TMS coil. We examined the effects of suprathreshold and subthreshold PAS_LTD on the performance of model-free and model-based learning, as well as the corticospinal excitability, indexed as the amplitudes of motor evoked potentials (MEPs).ResultsPAS_LTD inhibited model-free learning and MEPs only when subthreshold AP currents were applied. The PAS_LTD protocols tested here showed no effects on model-based learning.ConclusionsPAS_LTD affected model-free learning, presumably by modulating CSN excitability changes, rather than PA inputs, which are thought to be related to model-free learning.     

Inter-individual Variability in Response to Non-invasive Brain Stimulation Paradigms

BackgroundNon-invasive Brain Stimulation (NIBS) paradigms are unique in their ability to safely modulate cortical plasticity for experimental or therapeutic applications. However, increasingly, there is concern regarding inter-individual variability in the efficacy and reliability of these paradigms.HypothesisInter-individual variability in response to NIBS paradigms would be better explained if a multimodal distribution was assumed.MethodsIn three different sessions for each subject (n = 56), we studied the Paired Associative Stimulation (PAS₂₅), Anodal transcranial DC stimulation (AtDCS) and intermittent theta burst stimulation (iTBS) protocols. We applied cluster analysis to detect distinct patterns of response between individuals. Furthermore, we tested whether baseline TMS measures (such as short intracortical inhibition (SICI), resting motor threshold (RMT)) or factors such as time of day could predict each individual's response pattern.ResultsAll three paradigms show similar efficacy over the first hour post stimulation – there is no significant effect on excitatory or inhibitory circuits for the whole sample, and AtDCS fares no better than iTBS or PAS₂₅. Cluster analysis reveals a bimodal response pattern – but only 39%, 45% and 43% of subjects responded as expected to PAS₂₅, AtDCS, and iTBS respectively. Pre-stimulation SICI accounted for 10% of the variability in response to PAS₂₅, but no other baseline measures were predictive of response. Finally, we report implications for sample size calculation and the remarkable effect of sample enrichment.ConclusionThe implications of the high rate of ‘dose-failure’ for experimental and therapeutic applications of NIBS lead us to conclude that addressing inter-individual variability is a key area of concern for the field.     

Plasticity induced by non-invasive transcranial brain stimulation: A position paper

Several techniques and protocols of non-invasive transcranial brain stimulation (NIBS), including transcranial magnetic and electrical stimuli, have been developed in the past decades. Non-invasive transcranial brain stimulation may modulate cortical excitability outlasting the period of non-invasive transcranial brain stimulation itself from several minutes to more than one hour. Quite a few lines of evidence, including pharmacological, physiological and behavioral studies in humans and animals, suggest that the effects of non-invasive transcranial brain stimulation are produced through effects on synaptic plasticity. However, there is still a need for more direct and conclusive evidence. The fragility and variability of the effects are the major challenges that non-invasive transcranial brain stimulation currently faces. A variety of factors, including biological variation, measurement reproducibility and the neuronal state of the stimulated area, which can be affected by factors such as past and present physical activity, may influence the response to non-invasive transcranial brain stimulation. Work is ongoing to test whether the reliability and consistency of non-invasive transcranial brain stimulation can be improved by controlling or monitoring neuronal state and by optimizing the protocol and timing of stimulation.     

Intermittent theta burst stimulation over primary motor cortex enhances movement-related beta synchronisation

Objective

The objective of this study is to investigate how transcranial magnetic intermittent theta burst stimulation (iTBS) with a prolonged protocol affects human cortical excitability and movement-related oscillations.

Methods

Using motor-evoked potentials (MEPs) and movement-related magnetoencephalography (MEG), we assessed the changes of corticospinal excitability and cortical oscillations after iTBS with double the conventional stimulation time (1200 pulses, iTBS1200) over the primary motor cortex (M1) in 10 healthy subjects. Continuous TBS (cTBS1200) and sham stimulation served as controls.

Results

iTBS1200 facilitated MEPs evoked from the conditioned M1, while inhibiting MEPs from the contralateral M1 for 30 min. By contrast, cTBS1200 inhibited MEPs from the conditioned M1. Importantly, empirical mode decomposition-based MEG analysis showed that the amplitude of post-movement beta synchronisation (16–26 Hz) was significantly increased by iTBS1200 at the conditioned M1, but was suppressed at the nonconditioned M1. Alpha (8–13 Hz) and low gamma-ranged (35–45 Hz) rhythms were not notably affected. Movement kinetics remained consistent throughout.

Conclusions

TBS1200 modulated corticospinal excitability in parallel with the direction of conventional paradigms with modestly prolonged efficacy. Moreover, iTBS1200 increased post-movement beta synchronisation of the stimulated M1, and decreased that of the contralateral M1, probably through interhemispheric interaction.

Significance

Our results provide insight into the underlying mechanism of TBS and reinforce the connection between movement-related beta synchronisation and corticospinal output.     

Target specific effects of direct current stimulation in schizo-obsessive disorder: A case report

Transcranial direct current stimulation (tDCS) is a type of non-invasive brain stimulation technique that is explored as an add-on treatment for the alleviation of symptoms across the diverse symptom domains in neuropsychiatric disorders. In psychiatry, data is emerging on the effects of tDCS as an add-on treatment in schizophrenia as well as obsessive-compulsive disorder (OCD). But despite high prevalence, the effectiveness of tDCS in co-morbid schizophrenia and OCD is lacking. This case report for the first time examines the clinical utility with target-specific effects of the add-on tDCS in a patient diagnosed with schizo-obsessive disorder.     

Repetitive transcranial magnetic stimulation (rTMS) versus transcranial direct current stimulation (tDCS) in the management of patients with fibromyalgia: A randomized controlled trial

ObjectivesThe aim of this study was to compare the effects of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) on pain and quality of life in patients with fibromyalgia.MethodsThirty participants were randomized into two groups of 15 patients, to receive 3 sessions of either high-frequency (10 Hz) rTMS or 2 mA, 20 min anodal transcranial direct current stimulation over the left dorsolateral prefrontal cortex (DLPFC) over 1 week. Pain was assessed using a Visual Analog Scale (VAS) before treatment, immediately after treatment, 6 and 12 weeks later. Quality of life was evaluated using the Revised Fibromyalgia Impact Questionnaire (FIQR) and psychiatric symptoms were measured using the Depression Anxiety Stress Scale-21 Item (DASS-21) before treatment, and 6 and 12 weeks after treatment.ResultsFor the VAS there was a significant time-group interaction, showing that the behavior of two groups differed regarding changes of VAS in favor of the RTMS group (df = 1.73, F = 4.80, p = <0.016). Time-group interaction effect on DASS-21 and FIQR was not significant. 66.6% of patients in rTMS group and 26.6% of patients in tDCS group experienced at least a 30% reduction of VAS from baseline to last follow-up (p = 0.028).DiscussionWith the methodology used in this study, both rTMS and tDCS were safe modalities and three sessions of rTMS over DLPFC had greater and longer lasting analgesic effects compared to tDCS in patients with FM. However, considering the limitations of this study, further studies are needed to explore the most effective modality.     

Use of theta-burst stimulation in changing excitability of motor cortex: A systematic review and meta-analysis

Noninvasive brain stimulation has been demonstrated to modulate cortical activity in humans. In particular, theta burst stimulation (TBS) has gained notable attention due to its ability to induce lasting physiological changes after short stimulation durations. The present study aimed to provide a comprehensive meta-analytic review of the efficacy of two TBS paradigms; intermittent (iTBS) and continuous (cTBS), on corticospinal excitability in healthy individuals. Literature searches yielded a total of 87 studies adhering to the inclusion criteria. iTBS yielded moderately large MEP increases lasting up to 30 min with a pooled SMD of 0.71 (p < 0.00001). cTBS produced a reduction in MEP amplitudes lasting up to 60 min, with the largest effect size seen at 5 min post stimulation (SMD = −0.9, P < 0.00001). The collected studies were of heterogeneous nature, and a series of tests conducted indicated a degree of publication bias. No significant change in SICI and ICF was observed, with exception to decrease in SICI with cTBS at the early time point (SMD = 0.42, P = 0.00036). The results also highlight several factors contributing to TBS efficacy, including the number of pulses, frequency of stimulation and BDNF polymorphisms. Further research investigating optimal TBS stimulation parameters, particularly for iTBS, is needed in order for these paradigms to be successfully translated into clinical settings.     

Effects of Hesel-coil deep transcranial magnetic stimulation for depression – a systematic review

Background: One third of the depressed patients are not improved by antidepressant drugs and psychological treatments, and there is a need for additional treatments. Repetitive transcranial magnetic stimulation (rTMS) is being developed towards an alternative in treatment-resistant depression. Deep transcranial stimulation (dTMS) with the Hesel-coil (H-coil) is a further development of rTMS aiming to enhance the effect by getting the magnetic pulses to penetrate deeper into the brain.

Aims: This report aims to assess the evidence-base for dTMS for depression. The report also includes an assessment of the ethical and economic aspects involved.

Methods: A systematic review of the effects of H-coil dTMS on depression was conducted and the scientific support was evaluated using GRADE (Grading of Recommendations Assessment, Development and Evaluation).

Results: Only one controlled study was identified. In the sham-controlled randomized study, 212 participants with major depression that had not responded to antidepressant medication were enrolled. A two-point superiority in Hamilton Depression Rating Scale was observed in the dTMS arm vs the sham-arm at 4 weeks, but the difference was not statistically significant. No serious adverse events were reported apart from rare cases of epileptic seizures.

Conclusions: The existing scientific support for H-coil dTMS therapy for depression is insufficient. The clinical implication is that the use of dTMS in depression should be restricted to the framework of clinical trials pending further studies. Fortunately, additional studies are underway and the evidence base should presumably improve over the next several years.     

Concurrent conventional & high-definition transcranial direct current stimulation for treatment of schizophrenia with co-morbid obsessive-compulsive disorder: A case report

Non-invasive brain stimulation techniques such as conventional transcranial direct current stimulation (tDCS) and high definition tDCS (HD-tDCS) are increasingly being used as add-on treatment options in schizophrenia and obsessive-compulsive disorder (OCD). This is reporting of the use of a novel accelerated, symptom-specific, add-on tDCS (combining conventional and high definition) protocol in a patient with both schizophrenia and OCD. The intervention showed clinical utility by reducing both schizophrenia and OCD symptoms.     

Non-invasive brain stimulation in Parkinson’s disease: Exploiting crossroads of cognition and mood

Cognitive impairments and depression are common non-motor manifestations in Parkinson’s disease (PD). Recent evidence suggests that both partially arise via the same frontostriatal network, opening the opportunity for concomitant treatment with non-invasive brain stimulation (NIBS) techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS).In this systematic review, we evaluate the effects of NIBS on cognition and/or mood in 19 placebo-controlled studies involving 561 PD patients. Outcomes depended on the area stimulated and the technique used. rTMS over the dorsolateral-prefrontal cortex (DLPFC) resulted in significant reductions in scores of depressive symptoms with moderate to large effect sizes along with increased performance in several tests of cognitive functions. tDCS over the DLPFC improved performance in several cognitive measures, including executive functions with large effect sizes. Additional effects of tDCS on mood were not detectable; however, only non-depressed patients were assessed. Further confirmatory research is needed to clarify the contribution that NIBS could make in the care of PD patients.     

Deep TMS add-on treatment for intractable Tourette syndrome: A feasibility study

Objectives. In a considerable minority of patients who suffer from Tourette syndrome (TS) the disorder persists into adulthood and is associated with severe symptoms and limited therapeutic options. Repetitive transcranial magnetic stimulation (rTMS) to the supplementary motor area (SMA) has shown promising therapeutic results. Deep rTMS is a novel technology that enables deeper non-invasive cortical stimulation. This open-label pilot study is the first to examine the possible role of deep rTMS as add-on treatment for intractable TS. Methods. Twelve patients were recruited in order to examine bilateral SMA inhibition via deep TMS using the HBDL coil, as a possible treatment for adult TS treatment-resistant patients. Two patients did not complete the 20-day study protocol. Results. There were no significant side effects. While tics did not improve among the group as a whole, the subgroup of six patients with combined TS and OCD (obsessive compulsive syndrome) showed significant improvement in tic severity (P = 0.037). Conclusions. These findings support the safety of deep rTMS for treating TS. The results also highlight the importance of studying the different TS syndromes separately (e.g., with or without OCD comorbidity) when evaluating deep rTMS protocols for TS patients.     

The intensity of continuous theta burst stimulation,but not the waveform used to elicit motor evoked potentials,influences its outcome in the human motor cortex

Background

Responses to continuous theta burst stimulation (cTBS) applied to the human primary motor cortex are highly variable between individuals. However, little is known about how to improve the after-effects of cTBS by adjusting the protocol characteristics.

Deep brain stimulation, vagal nerve stimulation and transcranial stimulation: An overview of stimulation parameters and neurotransmitter release

Neurological disorders are among the most challenging medical problems faced by science today. To treat these disorders more effectively, new technologies are being developed by reviving old ideas such as brain stimulation. This review aims to compile stimulation techniques that are currently in use to explore or treat neurological disorders. Transcranial magnetic stimulation is a non-invasive method of modulating neuronal activity with induced electric currents. Other more invasive methods, such as deep brain stimulation and vagal nerve stimulation, use implanted probes to introduce brain activity alterations. Scientific and clinical applications have largely preceded the development of extensive animal models, presenting a challenge for researchers. This has left researchers with information on alleviating symptoms in humans but without solid research as to the mechanisms and neurobiological effects of the devices. This review combines stimulation parameters developed in animal models and stimulation techniques used in human treatment; thus, resulting in a greater understanding of the mechanisms and neurobiological effects of neuromodulation devices.     

Transcutaneous electrical acupoint stimulation as an adjunct therapy for obsessive-compulsive disorder: A randomized controlled study

BackgroundTranscutaneous electrical acupoint stimulation (TEAS) is thought to have potential to treat obsessive-compulsive disorder (OCD).ObjectiveThe purpose of this study was to determine whether adding TEAS to cognitive behavioral therapy (CBT) and clomipramine would improve the efficacy of these conventional treatments in OCD.MethodsIn this randomized controlled trial, 360 OCD patients were assigned to receive TEAS combined with CBT plus clomipramine (Group A, n = 120), TEAS combined with CBT plus placebo (Group B, n = 120), and simulated (placebo) TEAS combined with CBT plus clomipramine (Group C, n = 120) for 12 weeks. The primary outcome was measured using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS).ResultsOCD symptoms in all patients reduced over time, however Groups A and B had a significantly greater reduction in Y-BOCS total score and the subscale for obsession and compulsion between week 2 and week 12 compared to Group C. Groups A and B had similar scores on these measures. Both groups had significantly higher rates of clinical response than Group C (88.3% and 81.7% vs. 67.5%, respectively, p < 0.001); and higher rates of remission (30.0% and 22.5% vs. 9.2%, respectively, p < 0.001). Group B experienced fewer adverse events than the other two groups.ConclusionsTEAS enhances the efficacy of conventional OCD interventions and avoids the adverse effects associated with conventional pharmacological treatment. It can be considered as an effective adjunct intervention for OCD.