Anodal transcranial pulsed current stimulation: A novel technique to enhance corticospinal excitability

ObjectiveWe aimed to compare the effects of anodal-transcranial pulsed current stimulation (a-tPCS) with conventional anodal transcranial direct current stimulation (a-tDCS) on corticospinal excitability (CSE) in healthy individuals.MethodsCSE of the dominant primary motor cortex of the resting right extensor carpi radialis muscle was assessed before, immediately, 10, 20 and 30 min after application of four experimental conditions: (1) a-tDCS, (2) a-tPCS with short inter-pulse interval (a-tPCS_SIPI, 50 ms), (3) a-tPCS with long inter-pulse interval (a-tPCS_LIPI., 650 ms) and (4) sham a-tPCS. The total charges were kept constant in all experimental conditions except sham condition. The outcome measure in this study was motor evoked potentials.ResultsOnly a-tDCS and a-tPCS_SIPI (P < 0.05) induced significant increases in CSE, lasted for at least 30 min. Post-hoc tests indicated that this increase was larger in a-tPCS_SIPI (P < 0.05). There were no significant changes following application of a-tPCS_LIPI and sham a-tPCS. All participants tolerated the applied currents in all experimental conditions very well.ConclusionsCompared to a-tDCS, a-tPCS_SIPI is a better technique for enhancement of CSE. There were no sham effects for application of a-tPCS. However, unlike a-tDCS which modifies neuronal excitability by tonic depolarization of the resting membrane potential, a-tPCS modifies neuronal excitability by a combination of tonic and phasic effects.Significancea-tPCS could be considered as a promising neuromodulatory tool in basic neuroscience and as a therapeutic technique in neurorehabilitation.     

Effects of beta-tACS on corticospinal excitability: A meta-analysis

Over the past decade several studies have shown that transcranial alternating current stimulation (tACS) delivered at the beta (15–25 Hz) frequency range can increase corticospinal excitability of the primary motor cortex (M1). The aim of this study was to systematically quantify the effect size of beta-tACS on corticospinal excitability in healthy volunteers, as well as to identify significant outcome predictors. A meta-analysis was performed on the results of 47 experiments reported in 21 studies. Random effects modelling of the effect sizes showed that beta-tACS significantly increases M1 excitability (Ē = 0.287, 95% CI = 0.133–0.440). Further analysis showed that tACS intensities above 1 mA peak-to-peak yield a robust increase in M1 excitability, whereas intensities of 1 mA peak-to-peak and below do not induce a reliable change. Additionally, results showed an impact of tACS montages on these effects. No difference in effect size for online compared to offline application of tACS was found. In conclusion, these findings indicate that beta-tACS can increase cortical excitability if stimulation intensity is above 1 mA, yet more research is needed to titrate the stimulation parameters that yield optimal results.     

Sensorimotor mu-alpha power is positively related to corticospinal excitability

Background

Alpha (8–14?Hz) oscillatory power is linked to cortical excitability and corresponding modulations of sensory evoked potentials and perceptual detection performance. In somatosensory cortex (S1), negative linear and inverted U-shape relationships exist, whereas its effect on the primary motor cortex (M1) is hardly known.

Systematic assessment of duration and intensity of anodal transcranial direct current stimulation on primary motor cortex excitability

Since the initial demonstration of linear effects of stimulation duration and intensity on the strength of after‐effects associated with transcranial direct current stimulation (tDCS), few studies have systematically assessed how varying these parameters modulates corticospinal excitability. Therefore, the objective of this study was to systematically evaluate the effects of anodal tDCS on corticospinal excitability at two stimulation intensities (1 mA, 2 mA) and durations (10 min, 20 min), and determine the value of several variables in predicting response. Two groups of 20 individuals received, in two separate sessions, 1 and 2 mA anodal tDCS (left primary motor cortex (M1)‐right supra‐orbital montage) for either 10‐ or 20‐min. Transcranial magnetic stimulation was delivered over left M1 and motor evoked potentials (MEPs) of the contralateral hand were recorded prior to tDCS and every 5 min for 20‐min post‐tDCS. The following predictive variables were evaluated: I‐wave recruitment, stimulation intensity, baseline M1 excitability and inter‐trial MEP variability. Results show that anodal tDCS failed to significantly modulate corticospinal excitability in all conditions. Furthermore, low response rates were identified across all parameter combinations. No baseline measure was significantly correlated with increases in MEP amplitude. However, a decrease in inter‐trial MEP variability was linked to response to anodal tDCS. In conclusion, the present findings are consistent with recent reports showing high levels of inter‐subject variability in the neurophysiological response to tDCS, which may partly explain inconsistent group results. Furthermore, the level of variability in the neurophysiological outcome measure, i.e. MEPs, appears to be related to response.     

tDCS changes in motor excitability are specific to orientation of current flow

Background

Measurements and models of current flow in the brain during transcranial Direct Current Stimulation (tDCS) indicate stimulation of regions in-between electrodes. Moreover, the folded cortex results in local fluctuations in current flow intensity and direction, and animal studies suggest current flow direction relative to cortical columns determines response to tDCS.

Corticospinal excitability during walking in humans with absent and partial body weight support

Objective

To establish changes in corticospinal excitability with absent and partial body weight support (BWS), and determine test–retest reliability of motor evoked potentials (MEPs) recordings during stepping in healthy humans.

Methods

The tibialis anterior (TA) and soleus MEPs during stepping at 0 and at 25 BWS were recorded in two experimental sessions in the same subjects. Transcranial magnetic stimulation was delivered randomly across the step cycle at 1.2 × TA MEP resting threshold. The non-stimulated associated electromyogram (EMG) was subtracted from the TA and soleus MEPs at identical time windows and bins of the step cycle, and the resultant values were normalized to the maximal homologous EMG activity during stepping. The relationship between MEPs and background EMG activity was determined for each BWS level and session tested.

Results

The TA MEPs were facilitated at heel contact, progressively decreased during the stance phase, and facilitated throughout the swing phase of the step cycle. In contrast, the soleus MEPs were progressively increased at early-stance, depressed at the stance-to-swing transition, and remained depressed throughout the swing phase. The TA and soleus MEPs were modulated in a similar pattern across sessions at 0 and at 25 BWS, and were linearly related to the associated background EMG activity.

Conclusions

These results provide evidence that reduced body weight loading does not alter the strength of corticospinal excitability, and that MEPs can be reliably recorded at different sessions during stepping in healthy humans.

Significance

A rehabilitation strategy to restore gait in neurological disorders utilizes BWS during stepping on a motorized treadmill. Based on our findings, the strength of corticospinal drive will not be affected negatively during stepping under conditions of partial body loading.     

Transcranial magnetic stimulation modulation of corticospinal excitability by targeting cortical I-waves with biphasic paired-pulses

Background

Transcranial magnetic stimulation (TMS) induced I-wave behavior can be demonstrated at neuronal population level using paired-pulses and by observing short-interval cortical facilitation (SICF). Advancements in stimulator technology have made it possible to apply biphasic paired-pulses to induce SICF.

Within-session repeated a-tDCS: The effects of repetition rate and inter-stimulus interval on corticospinal excitability and motor performance

ObjectiveThis study investigated the effect of rate and stimulation interval of anodal transcranial direct current stimulation (a-tDCS) on CSE and motor performance.MethodsTwelve healthy individuals participated in this study. CSE was assessed before and after five experimental conditions of one, two or three applications of 10 min of a-tDCS with an interval of 5 or 25 min. a-tDCS was applied with a constant current density of 0.016 mA/cm². Purdue pegboard-test was selected for motor performance assessment.ResultsCompared to single 10 min stimulation, the magnitude of the within-session repeated a-tDCS induced excitability was enhanced significantly after the second stimulation was performed with an interval of 25 min, but not 5 min. However, by increasing the number of a-tDCS to three repetitions the CSE was significantly increased and lasted for 2 h with both 5 and 25 min intervals. Furthermore, CSE enhancement remained significant for up to 24 h for within session a-tDCS repetitions with 25 min intervals. Likewise, significant improvement was seen in motor performance following three times repetition with 25 min inter-stimulus intervals.ConclusionsThe results suggest that within session repeated a-tDCS with longer intervals within the lasting effects of the previous stimulations are preferable for increasing induced excitability changes with longer lasting effects. Significance: It is of particular importance to increase the a-tDCS lasting effects to consolidate the neuroplastic CSE changes.     

Acute effects of lithium on excitability of human motor cortex

ObjectiveLithium has been widely used to treat bipolar affective disorder for over 60 years. Still, its acute effects in human cerebral cortex are poorly understood. This study aimed at investigating the acute effects of lithium on motor cortex excitability as measured by transcranial magnetic stimulation (TMS).MethodsTen healthy young adults participated in a double-blind placebo-controlled randomized crossover study with four sessions, where a single oral dose of lithium carbonate (450 mg, 900 mg, or 1350 mg) or placebo was tested. Focal TMS of the hand area of left motor cortex was used to test resting and active motor thresholds, motor evoked potential input–output curve (MEP IO-curve), slope of the MEP IO-curve and paired-pulse measures of intracortical inhibition and facilitation before, and two and four hours after drug administration.ResultsTwo hours post drug administration, 450 mg of lithium carbonate increased the slope of the MEP IO-curve while 1350 mg tended to decrease it. Lithium had no effect on motor thresholds, or intracortical inhibition or facilitation.ConclusionsThe acute effects of lithium on MEP IO-curve, a marker of corticospinal excitability, are consistent with an inverted U-shaped dose–response relationship.SignificanceFindings are important for our understanding of the therapeutic and toxic effects of lithium on the human central nervous system.     

Increased Transcranial Direct Current Stimulation After Effects During Concurrent Peripheral Electrical Nerve Stimulation

In this study we tested the hypothesis whether a lasting change in the excitability of cortical output circuits can be obtained in healthy humans by combining a peripheral nerve stimulation during a concomitant depolarization and/or hyperpolarization of motor cortex. To reach this aim we combined two different neurophysiological techniques each of them able to induce a lasting increase of cortical excitability by them self: namely median nerve repetitive electrical stimulation (rEPNS) and transcranial direct current stimulation (tDCS). Ten normal young volunteers were enrolled in the present study. All subjects underwent five different protocols of stimulation: (1, 2) tDCS alone (anodal or cathodal); (3) Sham tDCS plus rEPNS; (4, 5) anodal or cathodal tDCS plus rEPNS. The baseline MEP amplitude from abductor pollicis brevis (APB) and flexor carpi radialis (FCR) muscle, the FCR H-reflex were compared with that obtained immediately after and 10, 20, 30, 60 min after the stimulation protocol. Anodal tDCS alone induced a significant transient increase of MEP amplitude immediately after the end of stimulation while anodal tDCS + rEPNS determined MEP changes which persisted for up 60 min. Cathodal tDCS alone induced a significant reduction of MEP amplitude immediately after the end of stimulation while cathodal tDCS + rEPNS prolonged the effects for up to 60 min. Sham tDCS + rEPNS did not induce significant changes in corticospinal excitability. Anodal or cathodal tDCS + rEPNS and sham tDCS + rEPNS caused a lasting facilitation of H-reflex. These findings suggest that by providing afferent input to the motor cortex while its excitability level is increased or decreased by tDCS may be a highly effective means for inducing an enduring bi-directional plasticity. The mechanism of this protocol may be complex, involving either cortical and spinal after effects.     

Concurrent excitation of the opposite motor cortex during transcranial magnetic stimulation to activate the abdominal muscles

The study investigated the potential for stimulation of both motor cortices during transcranial magnetic stimulation (TMS) to evoke abdominal muscle responses. Electromyographic activity (EMG) of transversus abdominis (TrA) was recorded bilaterally in eleven healthy volunteers using fine-wire electrodes. TMS at 120% motor threshold (MT) was delivered at rest and during 10% activation at 1 cm intervals from the midline to 5 cm lateral, along a line 2 cm anterior to the vertex. The optimal site to evoke responses in TrA is located 2 cm lateral to the vertex. When bilateral abdominal responses were evoked at or lateral to this site, onset of ipsilateral motor evoked potentials (MEPs) were 3–4 ms longer than contralateral MEPs. The difference between latencies is consistent with activation of faster crossed-, and slower uncrossed-corticospinal pathways from one hemisphere. However, latencies of MEPs were similar between sides when stimulation was applied more medially and were consistent with concurrent activation of crossed corticospinal tracts on both sides. The findings suggest that stimulation of both motor cortices is possible when TMS is delivered less than 2 cm from midline. Concurrent stimulation of both motor cortices can be minimised if TMS is delivered at least 2 cm lateral to midline.     

Confounding effects of caffeine on neuroplasticity induced by transcranial alternating current stimulation and paired associative stimulation

ObjectiveWe examined the effects of caffeine, time of day, and alertness fluctuation on plasticity effects after transcranial alternating current stimulation (tACS) or 25 ms paired associative stimulation (PAS25) in caffeine-naïve and caffeine-adapted subjects.MethodsIn two randomised, double-blinded, cross-over or placebo-controlled (caffeine) studies, we measured sixty subjects in eight sessions (n = 30, Male: Female = 1:1 in each study).ResultsWe found caffeine increased motor cortex excitability in caffeine naïve subjects. The aftereffects in caffeine naïve subjects were enhanced and prolonged when combined with PAS 25. Caffeine also increased alertness and the motor evoked potentials (MEPs) were reduced under light deprivation in caffeine consumers both with and without caffeine. In caffeine consumers, the time of day had no effect on tACS-induced plasticity.ConclusionsWe conclude that caffeine should be avoided or controlled as confounding factor for brain stimulation protocols. It is also important to keep the brightness constant in all sessions and study groups should not be mixed with caffeine-naïve and caffeine consuming participants.SignificanceCaffeine is one of the confounding factors in the plasticity induction studies and it induces different excitability effects in caffeine-naïve and caffeine-adapted subjects.This study was registered in the ClinicalTrials.gov with these registration IDs:1) NCT03720665 https://clinicaltrials.gov/ct2/results?cond=NCT03720665&term=&cntry=&state=&city=&dist=2) NCT04011670 https://clinicaltrials.gov/ct2/results?cond=&term=NCT04011670&cntry=&state=&city=&dist=     

¿Desempeña un papel decisivo la excitabilidad corticoespinal ipsilateral en el efecto cruzado provocado por el entrenamiento de fuerza unilateral? Una revisión sistemática

IntroductionUnilateral resistance training has been shown to improve muscle strength in both the trained and the untrained limb. One of the most widely accepted theories is that this improved performance is due to nervous system adaptations, specifically in the primary motor cortex. According to this hypothesis, increased corticospinal excitability (CSE), measured with transcranial magnetic stimulation, is one of the main adaptations observed following prolonged periods of training. The principal aim of this review is to determine the degree of adaptation of CSE and its possible functional association with increased strength in the untrained limb.DevelopmentWe performed a systematic literature review of studies published between January 1970 and December 2016, extracted from Medline (via PubMed), Ovid, Web of Science, and Science Direct online databases. The search terms were as follows: (transcranial magnetic stimulation OR excitability) AND (strength training OR resistance training OR force) AND (cross transfer OR contralateral limb OR cross education). A total of 10 articles were found.ConclusionResults regarding increased CSE were inconsistent. Although the possibility that the methodology had a role in this inconsistency cannot be ruled out, the results appear to suggest that there may not be a functional association between increases in muscle strength and in CSE.     

Analgesia induced by anodal tDCS and high-frequency tRNS over the motor cortex: Immediate and sustained effects on pain perception

BackgroundMany studies have shown effects of anodal transcranial direct current stimulation (a-tDCS) and high-frequency transcranial random noise stimulation (tRNS) on elevating cortical excitability. Moreover, tRNS with a direct current (DC)-offset is more likely to lead to increases in cortical excitability than solely tRNS. While a-tDCS over primary motor cortex (M1) has been shown to attenuate pain perception, tRNS + DC-offset may prove as an effective means for pain relief.ObjectiveThis study aimed to examine effects of a-tDCS and high-frequency tRNS + DC-offset over M1 on pain expectation and perception, and assess whether these effects could be influenced by the certainty of pain expectation.MethodsUsing a double-blinded and sham-controlled design, 150 healthy participants were recruited to receive a single-session a-tDCS, high-frequency tRNS + DC-offset, or sham stimulation over M1. The expectation and perception of electrical stimulation in certain and uncertain contexts were assessed at baseline, immediately after, and 30 min after stimulation.ResultsCompared with sham stimulation, a-tDCS induced immediate analgesic effects that were greater when the stimulation outcome was expected with uncertainty; tRNS induced immediate and sustained analgesic effects that were mediated by decreasing pain expectation. Nevertheless, we found no strong evidence for tRNS being more effective for attenuating pain than a-tDCS.ConclusionsThe analgesic effects of a-tDCS and tRNS showed different temporal courses, which could be related to the more sustained effectiveness of high-frequency tRNS + DC-offset in elevating cortical excitability. Moreover, expectations of pain intensity should be taken into consideration to maximize the benefits of neuromodulation.     

Suppression of human cortico-motoneuronal excitability during the Stop-signal task

ObjectiveTo investigate whether motor suppression is an active process, and to clarify its somatotopic organization, we investigated cortico-motoneuronal excitability using transcranial magnetic stimulation (TMS) during the Stop-signal task.MethodsSubjects were asked to press a button following a Go cue; a Stop-signal followed the Go cue by a certain time delay in 25% of trials, indicating to subjects that they were not to press the button. TMS was given to the primary motor area of the left or right-hand or leg at variable time delays. Motor evoked potentials (MEPs) were recorded from the hand and leg muscles bilaterally.ResultsWhen TMS was delivered 400 ms after the Go cue, there was significant suppression of the MEPs of the bilateral hand and leg muscles during successful Stop trials, but not during failed Stop trials.ConclusionsThe voluntary stopping of movement in the Stop-signal task is an active process, which likely suppresses not only the cortico-motoneuronal excitability of the task-performing hand, but also causes the widespread suppression of the motor system.SignificanceStudies in the normal physiology of response inhibition would be of help in understanding the pathophysiology of neuro-psychiatric disorders associated with deficits in motor suppression.     

Modulation of motor cortex excitability by different levels of whole-hand afferent electrical stimulation

Objective

In a previous transcranial magnetic stimulation (TMS) study we demonstrated that suprathreshold mesh-glove (MG) whole-hand stimulation elicits lasting changes in motor cortical excitability. Currently, there is no consensus with regard to the optimal parameters for the induction of sensorimotor cortical plasticity using peripheral electrical stimulation. Thus, in the present study we explore the modulatory effects of MG stimulation at different stimulus intensities and different frequencies in order to identify an optimal stimulation protocol.

Methods

MG stimulation was performed on 12 healthy subjects in separate sessions at different stimulation levels: sub-sensory at 50 Hz, sensory at 50 Hz and motor at 2 Hz. To verify if stimulation at lower frequencies is less effective, an additional experiment at sensory level with 2 Hz was performed. TMS was used to assess motor threshold (MT), motor evoked potentials (MEPs) recruitment curve (RC), short latency intracortical inhibition (SICI) and intracortical facilitation (ICF) to paired-pulse TMS at baseline (T0), immediately after (T1) and 1 h (T2) after 30 min of MG stimulation. F-wave studies were performed to assess spinal motoneuron excitability.

Results

MG stimulation at sub-sensory/50 Hz and sensory/2 Hz level determines no significant cortical excitability changes; at sensory/50 Hz level and at motor/2 Hz level we found decreased MT, increased MEP RC as well as reduced SICI and increased ICF at T1 and T2.

Conclusions

MG stimulation at sensory/50 Hz and motor/2 Hz level induces similar long-lasting modulatory effects on motor cortical excitability. Both the strength of the corticospinal projections and the intracortical networks are influenced to the same extend.

Significance

The study provides further evidence that stimulation intensity and frequency can independently modulate motor cortical plasticity. The selection of optimal stimulation parameters has potentially important implications for the neurorehabilitation of patients after brain damage (e.g. stroke, traumatic brain injury) with hand motor deficits.     

Differential modulation of corticospinal excitability during observation, mental imagery and imitation of hand actions

In this study, we attempted to better delineate the changes in corticospinal excitability that accompany perceptual to motor transformations when people are asked to observe, image or imitate actions. Motor evoked potentials (MEP) from transcranial magnetic stimulation were recorded in the first dorsal interosseous (FDI) muscle of the dominant hand (15 right, 4 left) in five different conditions: (1) passive observation; (2) observation to imitate; (3) imagery; (4) imitation; and (5) counting backwards mentally. MEPs were also recorded at rest at the beginning and at the end of the session to establish baseline (BL) values. For the observation conditions, participants (n=19, 18-38 years) watched video sequences (5s) of hand actions performed by a model with the right arm (passive observation: scissors; observation to imitate: OK sign). Active imitation produced the greatest MEP facilitation compared to baseline, followed by the two observation conditions and the imagery conditions, which all produced similar levels of facilitation (post hoc comparisons). Mental counting produced some facilitation, but this effect was inconsistent. Baseline MEPs remained stable at the end of the session. A further comparison between right-handers (n=15) and left-handers (n=4) revealed no difference in the pattern of modulation across conditions. The similarity found between observation and imagery of hand actions in terms of corticospinal facilitation is interpreted in the light of the motor-simulation theory of Jeannerod [Neuroimage 14 (2001)], which proposes that perceiving actions involves neural simulation of the same action by the observer, thereby explaining the parallel between actions observed and actions imaged at the representational level.     

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.     

Variability in Response to Transcranial Direct Current Stimulation of the Motor Cortex

BackgroundResponses to a number of different plasticity-inducing brain stimulation protocols are highly variable. However there is little data available on the variability of response to transcranial direct current stimulation (TDCS).ObjectiveWe tested the effects of TDCS over the motor cortex on corticospinal excitability. We also examined whether an individual's response could be predicted from measurements of onset latency of motor evoked potential (MEP) following stimulation with different orientations of monophasic transcranial magnetic stimulation (TMS).MethodsFifty-three healthy subjects participated in a crossover-design. Baseline latency measurements with different coil orientations and MEPs were recorded from the first dorsal interosseous muscle prior to the application of 10 min of 2 mA TDCS (0.057 mA/cm²). Thirty MEPs were measured every 5 min for up to half an hour after the intervention to assess after-effects on corticospinal excitability.ResultsAnodal TDCS at 2 mA facilitated MEPs whereas there was no significant effect of 2 mA cathodal TDCS. A two-step cluster analysis suggested that approximately 50% individuals had only a minor, or no response to TDCS whereas the remainder had a facilitatory effect to both forms of stimulation. There was a significant correlation between the latency difference of MEPs (anterior–posterior stimulation minus latero-medial stimulation) and the response to anodal, but not cathodal TDCS.ConclusionsThe large variability in response to these TDCS protocols is in line with similar studies using other forms of non-invasive brain stimulation. The effects highlight the need to develop more robust protocols, and understand the individual factors that determine responsiveness.