No evidence for changes in GABA concentration, functional connectivity, or working memory following continuous theta burst stimulation over dorsolateral prefrontal cortex

Continuous theta burst stimulation (cTBS) is thought to reduce cortical excitability and modulate functional connectivity, possibly by altering cortical inhibition at the site of stimulation. However, most evidence comes from the motor cortex and it remains unclear whether similar effects occur following stimulation over other brain regions. We assessed whether cTBS over left dorsolateral prefrontal cortex altered gamma aminobutyric acid (GABA) concentration, functional connectivity and brain dynamics at rest, and brain activation and memory performance during a working memory task. Seventeen healthy individuals participated in a randomised, sham-controlled, cross-over experiment. Before and after either real or sham cTBS, magnetic resonance spectroscopy was obtained at rest to measure GABA concentrations. Functional magnetic resonance imaging (fMRI) was also recorded at rest and during an n-back working memory task to measure functional connectivity, regional brain activity (low-frequency fluctuations), and task-related patterns of brain activity. We could not find evidence for changes in GABA concentration (P = 0.66, Bayes factor [BF10] = 0.07), resting-state functional connectivity (P(FWE) > 0.05), resting-state low-frequency fluctuations (P = 0.88, BF10 = 0.04), blood-oxygen level dependent activity during the n-back task (P(FWE) > 0.05), or working memory performance (P = 0.13, BF10 = 0.05) following real or sham cTBS. Our findings add to a growing body of literature suggesting the effects of cTBS are highly variable between individuals and question the notion that cTBS is a universal ‘inhibitory’ paradigm

Crossover design in transcranial direct current stimulation studies on motor learning: potential pitfalls and difficulties in interpretation of findings

Crossover designs are used by a high proportion of studies investigating the effects of transcranial direct current stimulation (tDCS) on motor learning. These designs necessitate attention to aspects of data collection and analysis to take account of design-related confounds including order, carryover, and period effects. In this systematic review, we appraised the method sections of crossover-designed tDCS studies of motor learning and discussed the strategies adopted to address these factors. A systematic search of 10 databases was performed and 19 research papers, including 21 experimental studies, were identified. Potential risks of bias were addressed in all of the studies, however, not in a rigorous and structured manner. In the data collection phase, unclear methods of randomization, various lengths of washout period, and inconsistency in the counteracting period effect can be observed. In the analytical procedures, the stratification by sequence group was often ignored, and data were treated as if it belongs to a simple repeated-measures design. An inappropriate use of crossover design can seriously affect the findings and therefore the conclusions drawn from tDCS studies on motor learning. The results indicate a pressing need for the development of detailed guidelines for this type of studies to benefit from the advantages of a crossover design

The minimal number of TMS trials required for the reliable assessment of corticospinal excitability, short interval intracortical inhibition, and intracortical facilitation

•Averaging less than 20 consecutive TMS-evoked MEPs gives highly variable results.•More than 25 paired-pulse stimuli are required for highly reliable SICI estimates.•After 30 successive pulses, ICF measures stabilize with low inter-session reliability. Transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs) are frequently used to assess corticospinal and intercortical activities. Trial to trial variance of the potentials is commonly observed, and averages of multiple MEPs are usually reported. Multiple trials have resources implications and are not compatible with some experimental protocols. This study investigated the minimum number of MEPs required to reliably assess corticospinal excitability (CSE), short interval intracortical inhibition (SICI) and intercortical facilitation (ICF), within and between sessions. Fifteen healthy volunteers received 35 single-pulse TMS for CSE assessments and 35 paired-pulse TMS for SICI and ICF measurements. Intra- and intersession reliability were examined using intra-class correlation coefficient tests, and stability of the measures was assessed using a general equation estimation analysis. Coefficients of variation were used to probe the effects of inter-individual variability on reliability results. All analyses were carried out on cumulative averages. The optimal number of trials to ensure “excellent” intra and inter-session reliability with low inter-individual variability and the highest level of stability was found to be 20 for CSE and 26 for SICI assessments. Although 30 consecutive trials produced highly reliable ICF measures within a session, inter-session reliability was not significant across 35 trials. These findings have significant implications for improving time efficiency of TMS experiments without compromising intra- or intersession reliability

Crossover design in transcranial direct current stimulation studies on motor learning: potential pitfalls and difficulties in interpretation of findings

Crossover designs are used by a high proportion of studies investigating the effects of transcranial direct current stimulation (tDCS) on motor learning. These designs necessitate attention to aspects of data collection and analysis to take account of design-related confounds including order, carryover, and period effects. In this systematic review, we appraised the method sections of crossover-designed tDCS studies of motor learning and discussed the strategies adopted to address these factors. A systematic search of 10 databases was performed and 19 research papers, including 21 experimental studies, were identified. Potential risks of bias were addressed in all of the studies, however, not in a rigorous and structured manner. In the data collection phase, unclear methods of randomization, various lengths of washout period, and inconsistency in the counteracting period effect can be observed. In the analytical procedures, the stratification by sequence group was often ignored, and data were treated as if it belongs to a simple repeated-measures design. An inappropriate use of crossover design can seriously affect the findings and therefore the conclusions drawn from tDCS studies on motor learning. The results indicate a pressing need for the development of detailed guidelines for this type of studies to benefit from the advantages of a crossover design

The effects of transcranial direct current stimulation on short-interval intracortical inhibition and intracortical facilitation: a systematic review and meta-analysis

Transcranial direct current stimulation (tDCS) is increasingly being used to affect the neurological conditions with deficient intracortical synaptic activities (i.e. Parkinson's disease and epilepsy). In addition, it is suggested that the lasting effects of tDCS on corticospinal excitability (CSE) have intracortical origin. This systematic review and meta-analysis aimed to examine whether tDCS has any effect on intracortical circuits. Eleven electronic databases were searched for the studies investigating intracortical changes induced by anodal (a) and cathodal (c) tDCS, in healthy individuals, using two paired-pulse transcranial magnetic stimulation (TMS) paradigms: short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). Additionally, motor-evoked potential (MEP) size alterations, assessed by single-pulse TMS, were extracted from these studies to investigate the probable intracortical origin of tDCS effects on CSE. The methodological quality of included studies was examined using Physiotherapy Evidence Database (PEDro) and Downs and Black's (D&B) assessment tools. Thirteen research papers, including 24 experiments, were included in this study scoring good and medium quality in PEDro and D&B scales, respectively. Immediately following anodal tDCS (a-tDCS) applications, we found significant decreases in SICI, but increases in ICF and MEP size. However, ICF and MEP size significantly decreased, and SICI increased immediately following cathodal tDCS (c-tDCS). The results of this systematic review and meta-analysis reveal that a-tDCS changes intracortical activities (SICI and ICF) toward facilitation, whereas c-tDCS alters them toward inhibition. It can also be concluded that increases and decreases in CSE after tDCS application are associated with corresponding changes in intracortical activities. The results suggest that tDCS can be clinically useful to modulate intracortical circuits

The effects of transcranial direct current stimulation on short-interval intracortical inhibition and intracortical facilitation: a systematic review and meta-analysis

Transcranial direct current stimulation (tDCS) is increasingly being used to affect the neurological conditions with deficient intracortical synaptic activities (i.e. Parkinson's disease and epilepsy). In addition, it is suggested that the lasting effects of tDCS on corticospinal excitability (CSE) have intracortical origin. This systematic review and meta-analysis aimed to examine whether tDCS has any effect on intracortical circuits. Eleven electronic databases were searched for the studies investigating intracortical changes induced by anodal (a) and cathodal (c) tDCS, in healthy individuals, using two paired-pulse transcranial magnetic stimulation (TMS) paradigms: short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). Additionally, motor-evoked potential (MEP) size alterations, assessed by single-pulse TMS, were extracted from these studies to investigate the probable intracortical origin of tDCS effects on CSE. The methodological quality of included studies was examined using Physiotherapy Evidence Database (PEDro) and Downs and Black's (D&B) assessment tools. Thirteen research papers, including 24 experiments, were included in this study scoring good and medium quality in PEDro and D&B scales, respectively. Immediately following anodal tDCS (a-tDCS) applications, we found significant decreases in SICI, but increases in ICF and MEP size. However, ICF and MEP size significantly decreased, and SICI increased immediately following cathodal tDCS (c-tDCS). The results of this systematic review and meta-analysis reveal that a-tDCS changes intracortical activities (SICI and ICF) toward facilitation, whereas c-tDCS alters them toward inhibition. It can also be concluded that increases and decreases in CSE after tDCS application are associated with corresponding changes in intracortical activities. The results suggest that tDCS can be clinically useful to modulate intracortical circuits

Source-based artifact-rejection techniques available in TESA, an open-source TMS–EEG toolbox

Peer reviewe

The effects of repetitive paired pulse and quadripulse transcranial magnetic stimulation on corticospinal excitability: A systematic review and meta-analysis

Abstract Background: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive form of brain stimulation that induces a change in corticospinal excitability that lasts beyond the stimulation period, known as neural plasticity. Patterned rTMS protocols like paired pulse TMS (PPS) and quadripulse TMS (QPS) utilise bursts of two or four pulses at different ISIs to induce plasticity. While these paradigms have existed for over 15 years, there is currently only 1 review which has systematically assessed the efficacy of the PPS paradigm and none assessing QPS’s capacity to alter corticospinal excitability. Subsequently, it is paramount that a quantitative review is conducted to empirically determine the degree of both PPS and QPS efficacy to induce change in corticospinal excitability. This will be accomplished by conducting a meta-analysis. Objective: To provide a protocol for a systematic review and meta-analysis on the effects of PPS and QPS on corticospinal excitability, as indexed by changes in motor evoked potential (MEP) amplitude. Methods: The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) will be used as a guideline for this protocol. Results: The systematic review will commence after registration of this protocol on Open Science Framework, where it will be locked and date stamped. Conclusions: rTMS paradigms such as PPS and QPS are considered promising protocols for inducing plasticity in the human motor cortex. The proposed systematic review and meta-analysis is being conducted to quantitatively determine the efficacy of these protocols for inducing plasticity and to assess how variability in protocol parameters effect plasticity outcome. Consequently, this review will provide a comprehensive overview of the magnitude of change in corticospinal excitability with PPS and QPS

The minimal number of TMS trials required for the reliable assessment of corticospinal excitability, short interval intracortical inhibition, and intracortical facilitation

•Averaging less than 20 consecutive TMS-evoked MEPs gives highly variable results.•More than 25 paired-pulse stimuli are required for highly reliable SICI estimates.•After 30 successive pulses, ICF measures stabilize with low inter-session reliability. Transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs) are frequently used to assess corticospinal and intercortical activities. Trial to trial variance of the potentials is commonly observed, and averages of multiple MEPs are usually reported. Multiple trials have resources implications and are not compatible with some experimental protocols. This study investigated the minimum number of MEPs required to reliably assess corticospinal excitability (CSE), short interval intracortical inhibition (SICI) and intercortical facilitation (ICF), within and between sessions. Fifteen healthy volunteers received 35 single-pulse TMS for CSE assessments and 35 paired-pulse TMS for SICI and ICF measurements. Intra- and intersession reliability were examined using intra-class correlation coefficient tests, and stability of the measures was assessed using a general equation estimation analysis. Coefficients of variation were used to probe the effects of inter-individual variability on reliability results. All analyses were carried out on cumulative averages. The optimal number of trials to ensure “excellent” intra and inter-session reliability with low inter-individual variability and the highest level of stability was found to be 20 for CSE and 26 for SICI assessments. Although 30 consecutive trials produced highly reliable ICF measures within a session, inter-session reliability was not significant across 35 trials. These findings have significant implications for improving time efficiency of TMS experiments without compromising intra- or intersession reliability

Reproducibility in TMS-EEG studies: A call for data sharing, standard procedures and effective experimental control.

Peer reviewe