Mitchell R. Goldsworthy

The application of spaced theta burst protocols induces long-lasting neuroplastic changes in the human motor cortex.

There is some limited evidence suggesting that the spaced application of repetitive transcranial magnetic stimulation (rTMS) protocols may extend the duration of induced neuroplastic changes. However, this has yet to be demonstrated in the human primary motor cortex (M1). We evaluated whether the paired application of an inhibitory rTMS protocol [continuous theta burst stimulation (cTBS)] at 10‐min intervals prolonged the duration of induced M1 plasticity. Motor evoked potentials (MEPs) were recorded from the right first dorsal interosseous muscle before and following single and paired cTBS protocols applied with two intensities: 80% of active motor threshold (AMT80) and 70% of resting motor threshold (RMT70). Single cTBS protocols did not significantly influence MEP amplitudes. Whereas paired trains applied at AMT80 had no effect on MEP amplitudes, paired cTBS trains at RMT70 significantly reduced them. MEP amplitudes remained suppressed for at least 2 h following the second train. Control experiments suggested that the contraction used to establish active motor threshold prior to cTBS application may be responsible for blocking the effect of paired cTBS trains at AMT80. The results suggest that the spaced application of cTBS protocols may be an effective approach for establishing long‐lasting M1 neuroplasticity only in the absence of prior voluntary motor activation. These findings may have important implications for the therapeutic application of rTMS.

Minimum number of trials required for within- and between-session reliability of TMS measures of corticospinal excitability.

Transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs) exhibit considerable trial-to-trial variability, potentially reducing the sensitivity and reproducibility of this measure. While increasing the number of trials will improve accuracy, prolonged recording blocks are not always feasible. In this study, we investigated the minimum number of trials required to provide a measure of human corticospinal excitability that is stable both within and between sessions. Single-pulse TMS was applied to the left primary motor cortex, and MEPs were recorded from the right first dorsal interosseous muscle. Approximately 20-30 trials were required to provide a stable measure of MEP amplitude with high within- and between-session reliability. Extending the number of trials beyond 30 provided no additional benefit. Collecting 30 trials may be optimal for reliably estimating corticospinal excitability using TMS. These findings may have significant implications for using TMS to measure corticospinal excitability in both basic and clinical research settings.

Inter- and intra-subject variability of motor cortex plasticity following continuous theta-burst stimulation

BACKGROUND The potential of non-invasive brain stimulation (NIBS) for studying, and inducing, functionally relevant neuroplasticity is dependent on protocols that can induce lasting, robust and reliable effects. A current limiting factor is the large inter- and intra-subject variability in NIBS-induced neuroplastic responses. There has been some study of inter-subject response variability and factors that contribute to it; however, intra-subject response variability has, so far, received little investigation. OBJECTIVES By testing participants on multiple occasions we aimed to (1) compare inter- and intra-subject variability of neuroplastic responses induced by continuous theta-burst stimulation (cTBS); (2) determine whether the transcranial magnetic stimulation (TMS) intensity used to measure cTBS-induced neuroplastic responses contributes to response variability; (3) determine whether assessment of factors known to influence response variability can be used to explain some of the variability in cTBS-induced neuroplastic responses across experimental sessions. METHODS In three separate experimental sessions, motor-evoked potential (MEP) input-output (IO) curves were obtained before and after cTBS, and questionnaire-based assessments of physical activity and perceived stress were obtained. RESULTS cTBS-induced MEP suppression was greatest at the upper end of the IO curve (150-180% resting motor threshold; RMT) and most consistent across subjects and across experimental sessions when assessed with a TMS intensity of 150% RMT. The magnitude of cTBS-induced MEP suppression evoked at 150% RMT correlated with self-reported perceived stress, but not with self-reported physical activity. CONCLUSIONS The most reliable TMS intensity to probe cTBS-induced long-term depression (LTD)-like neuroplastic responses is 150% RMT. This is unlikely to simply be a ceiling effect and, we suggest, may be due to changes in the descending volley evoked at higher stimulus intensities. The perceived stress scale appears to be sufficiently sensitive to measure the influence of subject stress on LTD-like neuroplastic responses.

Resistant Against De-depression: LTD-Like Plasticity in the Human Motor Cortex Induced by Spaced cTBS

The long-term depression (LTD)-like changes in human primary motor cortex (M1) excitability induced by continuous theta burst stimulation (cTBS) are subject to reversal (i.e., de-depression) following behavioral engagement of M1, limiting its therapeutic potential under behaviorally relevant conditions. Experiments in animals suggest that the repeated, spaced application of stimulation trains may consolidate synaptic plasticity, making it resistant to reversal by physiological activity. Although there is evidence that repeated cTBS prolongs LTD-like M1 neuroplasticity in humans, whether these effects are resistant to de-depression has not been tested. We investigated whether the neuroplastic effects of paired cTBS trains were resistant to de-depression by a sustained, submaximal voluntary contraction of the hand muscles. In the absence of cTBS, voluntary contraction had no effect on motor evoked potentials (MEPs) recorded from the right first dorsal interosseous muscle. While the LTD-like MEP depression induced by a single cTBS was abolished by subsequent voluntary contraction, paired cTBS induced MEP depression that was resistant to reversal. This MEP depression was also resistant to reversal when an experimental de-depression protocol was used instead of a voluntary contraction. Our findings suggest that repeated cTBS applications consolidate LTD-like M1 neuroplasticity, which may have important implications for the clinical application of cTBS.

Inter-subject variability of LTD-like plasticity in human motor cortex: a matter of preceding motor activation

BACKGROUND Continuous theta burst stimulation (cTBS) of the human primary motor cortex (M1) induces long-term depression (LTD)-like plastic changes in corticospinal excitability, but several studies have reported high inter-subject variability of this effect. Most studies use a tonic voluntary contraction of the target muscle before cTBS to set stimulation intensity; however, it is unclear how this might affect response variability. OBJECTIVE To examine the influence of pre-activation of the target hand muscle on inter-subject response variability to cTBS of the human M1. METHODS The response to cTBS was assessed by changes in motor evoked potential (MEP) amplitude in the right first dorsal interosseous (FDI) muscle. For Study 1, ten healthy subjects attended two sessions. They were instructed in one session to keep their FDI relaxed for the entire testing period (pre-relax), and in the other to perform a 2-min 10% of maximal voluntary tonic contraction 15 min before cTBS (pre-active). For Study 2, data from our previous study were re-analyzed to extend the pre-relax condition to an additional 26 subjects (total n = 36). RESULTS cTBS-induced highly consistent LTD-like MEP depression in the pre-relax condition, but not in the pre-active condition. Inter-subject response variability increased in the pre-active condition. CONCLUSIONS cTBS induces consistent LTD-like plasticity with low inter-subject variability if pre-activation of the stimulated motor cortex is avoided. This affirms a translational potential of cTBS in clinical applications that aim at reducing cortical excitability.

Day differences in the cortisol awakening response predict day differences in synaptic plasticity in the brain

Abstract The cortisol awakening response (CAR) is the most prominent, dynamic and variable part of the circadian pattern of cortisol secretion. Despite this, its precise purpose is unknown. Aberrant patterns of the CAR are associated with impaired physical and mental health and reduced cognitive function, suggesting that it may have a pervasive role or roles. It has been suggested that the CAR primes the brain for the expected demands of the day but the mechanisms underlying this process are unknown. We examined temporal covariation of the CAR and rapid transcranial magnetic stimulation (rTMS)-induced long term depression (LTD)-like responses in the motor cortex. Plasticity was evaluated across 180 measures from five time points on four sessions across nine healthy researcher participants, mean age 25 ± 2.5 years. Plasticity estimates were obtained in the afternoon after measurement of the CAR on 4 days, at least 3 days apart. As both CAR magnitude and rTMS-induced responses are variable across days, we hypothesized that days with larger than individual average CARs would be associated with a greater than individual average plasticity response. This was confirmed by mixed regression modelling where variation in the CAR predicted variation in rTMS-induced responses (df: 1, 148.24; F: 10.41; p = 0.002). As the magnitude of the CAR is regulated by the “master” circadian CLOCK, and synaptic plasticity is known to be modulated by peripheral “slave” CLOCK genes, we suggest that the CAR may be a mediator between the master and peripheral circadian systems to entrain daily levels of synaptic plasticity.

Variability in neural excitability and plasticity induction in the human cortex: A brain stimulation study

BACKGROUND The potential of non-invasive brain stimulation (NIBS) for both probing human neuroplasticity and the induction of functionally relevant neuroplastic change has received significant interest. However, at present the utility of NIBS is limited due to high response variability. One reason for this response variability is that NIBS targets a diffuse cortical population and the net outcome to stimulation depends on the relative levels of excitability in each population. There is evidence that the relative excitability of complex oligosynaptic circuits (late I-wave circuits) as assessed by transcranial magnetic stimulation (TMS) is useful in predicting NIBS response. OBJECTIVE Here we examined whether an additional marker of cortical excitability, MEP amplitude variability, could provide additional insights into response variability following application of the continuous theta burst stimulation (cTBS) NIBS protocol. Additionally we investigated whether I-wave recruitment was associated with MEP variability. METHODS Thirty-four healthy subjects (15 male, aged 18-35 years) participated in two experiments. Experiment 1 investigated baseline MEP variability and cTBS response. Experiment 2 determined if I-wave recruitment was associated with MEP variability. RESULTS Data show that both baseline MEP variability and late I-wave recruitment are associated with cTBS response, but were independent of each other; together, these variables predict 31% of the variability in cTBS response. CONCLUSIONS This study provides insight into the physiological mechanisms underpinning NIBS plasticity responses and may facilitate development of more reliable NIBS protocols.

Spaced noninvasive brain stimulation: prospects for inducing long-lasting human cortical plasticity

Neuroplasticity is critical for learning, memory, and recovery of lost function following neurological damage. Noninvasive brain stimulation (NIBS) techniques can induce neuroplastic changes in the human cortex that are behaviorally relevant, raising the exciting possibility that these techniques might be therapeutically beneficial for neurorehabilitation following brain injury. However, the short duration and instability of induced effects currently limits their usefulness. To date, trials investigating the therapeutic value of neuroplasticity-inducing NIBS have used either single or multiple treatment sessions, typically repeated once-daily for 1 to 2 weeks. Although multiple stimulation sessions are presumed to have cumulative effects on neuroplasticity induction, there is little direct scientific evidence to support this “once-daily” approach. In animal models, the repeated application of stimulation protocols spaced using relatively short intervals (typically of the order of minutes) induces long-lasting and stable changes in synaptic efficacy. Likewise, learning through spaced repetition facilitates the establishment of long-term memory. In both cases, the spacing interval is critical in determining the outcome. Emerging evidence in healthy human populations suggests that the within-session spacing of NIBS protocols may be an effective approach for significantly prolonging the duration of induced neuroplastic changes. Similar to findings in the animal and learning literature, the interval at which spaced NIBS is applied seems to be a critical factor influencing the neuroplastic response. In this Point of View article, we propose that to truly exploit the therapeutic opportunities provided by NIBS, future clinical trials should consider the optimal spacing interval for repeated applications.

A comparison of two methods for estimating 50% of the maximal motor evoked potential

OBJECTIVES Two commonly-used methods for setting stimulus intensities in transcranial magnetic brain stimulation studies were compared to determine which best approximated a motor evoked potential (MEP) of 50% of the maximal MEP amplitude (SI50); a suprathreshold intensity relative to resting motor threshold (rMT) or adjusting the intensity to evoke an MEP amplitude of 1mV. METHODS Corticomotor stimulus-response curves and rMT for the right first dorsal interosseous (FDI) muscle of 176 subjects (aged 10-74 years) were retrospectively analysed. RESULTS Regardless of subject age or sex, SI50 occurred at 127.5 ± 11.3% rMT. Except in young children, MEPs of 1 mV were significantly smaller than those evoked at SI50. CONCLUSIONS In the inactive FDI muscle, a stimulus intensity of 127-128% rMT consistently gives the best approximation of SI50 in most subjects, except perhaps young children. SIGNIFICANCE Setting TMS stimulus intensities relative to rMT provides a less variable inter-subject comparator, with respect to individual differences in corticomotor input-output characteristics, than adjusting the stimulator output to give an absolute MEP magnitude.

Neuroplastic Modulation of Inhibitory Motor Cortical Networks by Spaced Theta Burst Stimulation Protocols

BACKGROUND Continuous theta burst stimulation (cTBS) suppresses the excitability of motor networks responsible for generating motor evoked potentials (MEPs), and may also modulates the excitability of inhibitory motor networks. However, its effects on intracortical inhibition are modest in comparison to the effects on MEPs. The repeated, spaced, application of cTBS protocols results in more MEP suppression than seen with a single cTBS protocol, but whether this approach is also effective at modulating intracortical inhibition has not been tested. OBJECTIVE To determine whether the paired application of cTBS effectively modulates the excitability of intracortical inhibitory motor networks. METHODS Single and paired-pulse transcranial magnetic stimulation (TMS) were used to assess resting motor threshold (RMT), MEP amplitude, short-interval intracortical inhibition (SICI), and long-interval intracortical inhibition (LICI) before and during two time periods (0-10 and 30-40 min) following application of either a single or paired cTBS protocols. RESULTS Both the single and paired cTBS conditions induced a significant reduction in both MEP amplitudes and the level of SICI. While paired cTBS produced a significantly greater MEP suppression than single cTBS, the effects on SICI were similar. Neither single nor paired cTBS had an effect on RMT or LICI. CONCLUSIONS Although the repeated application of cTBS protocols may be effective for enhancing modulation of the MEP-generating excitatory motor networks, these findings suggest that this approach offers little advantage when targeting intracortical inhibitory networks.