Modulating Visuomotor Sequence Learning by Repetitive Transcranial Magnetic Stimulation: What Do We Know So Far?

Predictive processes and numerous cognitive, motor, and social skills depend heavily on sequence learning. The visuomotor Serial Reaction Time Task (SRTT) can measure this fundamental cognitive process. To comprehend the neural underpinnings of the SRTT, non-invasive brain stimulation stands out as one of the most effective methodologies. Nevertheless, a systematic list of considerations for the design of such interventional studies is currently lacking. To address this gap, this review aimed to investigate whether repetitive transcranial magnetic stimulation (rTMS) is a viable method of modulating visuomotor sequence learning and to identify the factors that mediate its efficacy. We systematically analyzed the eligible records (n = 17) that attempted to modulate the performance of the SRTT with rTMS. The purpose of the analysis was to determine how the following factors affected SRTT performance: (1) stimulated brain regions, (2) rTMS protocols, (3) stimulated hemisphere, (4) timing of the stimulation, (5) SRTT sequence properties, and (6) other methodological features. The primary motor cortex (M1) and the dorsolateral prefrontal cortex (DLPFC) were found to be the most promising stimulation targets. Low-frequency protocols over M1 usually weaken performance, but the results are less consistent for the DLPFC. This review provides a comprehensive discussion about the behavioral effects of six factors that are crucial in designing future studies to modulate sequence learning with rTMS. Future studies may preferentially and synergistically combine functional neuroimaging with rTMS to adequately link the rTMS-induced network effects with behavioral findings, which are crucial to develop a unified cognitive model of visuomotor sequence learning

Manipulating neuronal communication by using low-intensity repetitive transcranial magnetic stimulation combined with electroencephalogram

Repetitive transcranial magnetic stimulation (rTMS) modulates ongoing brain rhythms by activating neuronal structures and evolving different neuronal mechanisms. In the current work, the role of stimulation strength and frequency for brain rhythms was studied. We hypothesized that a weak oscillating electric field induced by low-intensity rTMS could induce entrainment effects in the brain. To test the hypothesis, we conducted three separate experiments, in which we stimulated healthy human participants with rTMS. We individualized stimulation parameters using computational modeling of induced electric fields in the targets and individual frequency estimated by electroencephalography (EEG). We demonstrated the immediately induced entrainment of occipito-parietal and sensorimotor mu-alpha rhythm by low-intensity rTMS that resulted in phase and amplitude changes measured by EEG. Additionally, we found long-lasting corticospinal excitability changes in the motor cortex measured by motor evoked potentials from the corresponding musle.2021-11-2

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

Hand choice is unaffected by high frequency continuous theta burst transcranial magnetic stimulation to the posterior parietal cortex

The current study used a high frequency TMS protocol known as continuous theta burst stimulation (cTBS) to test a model of hand choice that relies on competing interactions between the hemispheres of the posterior parietal cortex. Based on the assumption that cTBS reduces cortical excitability, the model predicts a significant decrease in the likelihood of selecting the hand contralateral to stimulation. An established behavioural paradigm was used to estimate hand choice in each individual, and these measures were compared across three stimulation conditions: cTBS to the left posterior parietal cortex, cTBS to the right posterior parietal cortex, or sham cTBS. Our results provide no supporting evidence for the interhemispheric competition model. We find no effects of cTBS on hand choice, independent of whether the left or right posterior parietal cortex was stimulated. Our results are nonetheless of value as a point of comparison against prior brain stimulation findings that, in contrast, provide evidence for a causal role for the posterior parietal cortex in hand choice

Effects of transcranial magnetic stimulation on reactive response inhibition

Reactive response inhibition cancels impending actions to enable adaptive behavior in ever-changing environments and has wide neuropsychiatric implications. A canonical paradigm to measure the covert inhibition latency is the stop-signal task (SST). To probe the cortico-subcortical network underlying motor inhibition, transcranial magnetic stimulation (TMS) has been applied over central nodes to modulate SST performance, especially to the right inferior frontal cortex and the presupplementary motor area. Since the vast parameter spaces of SST and TMS enabled diverse implementations, the insights delivered by emerging TMS-SST studies remain inconclusive. Therefore, a systematic review was conducted to account for variability and synthesize converging evidence. Results indicate certain protocol specificity through the consistent perturbations induced by online TMS, whereas offline protocols show paradoxical effects on different target regions besides numerous null effects. Ancillary neuroimaging findings have verified and dissociated the underpinning network dynamics. Sources of heterogeneity in designs and risk of bias are highlighted. Finally, we outline best-practice recommendations to bridge methodological gaps and subserve the validity as well as replicability of future work.</p

Intermittent Theta-Burst Stimulation Reverses the After-Effects of Contralateral Virtual Lesion on the Suprahyoid Muscle Cortex: Evidence From Dynamic Functional Connectivity Analysis

Contralateral intermittent theta burst stimulation (iTBS) can potentially improve swallowing disorders with unilateral lesion of the swallowing cortex. However, the after-effects of iTBS on brain excitability remain largely unknown. Here, we investigated the alterations of temporal dynamics of inter-regional connectivity induced by iTBS following continuous TBS (cTBS) in the contralateral suprahyoid muscle cortex. A total of 20 right-handed healthy subjects underwent cTBS over the left suprahyoid muscle motor cortex and then immediately afterward, iTBS was applied to the contralateral homologous area. All of the subjects underwent resting-state functional magnetic resonance imaging (Rs-fMRI) pre- and post-TBS implemented on a different day. We compared the static and dynamic functional connectivity (FC) between the post-TBS and the baseline. The whole-cortical time series and a sliding-window correlation approach were used to quantify the dynamic characteristics of FC. Compared with the baseline, for static FC measurement, increased FC was found in the precuneus (BA 19), left fusiform gyrus (BA 37), and right pre/post-central gyrus (BA 4/3), and decreased FC was observed in the posterior cingulate gyrus (PCC) (BA 29) and left inferior parietal lobule (BA 39). However, in the dynamic FC analysis, post-TBS showed reduced FC in the left angular and PCC in the early windows, and in the following windows, increased FC in multiple cortical areas including bilateral pre- and postcentral gyri and paracentral lobule and non-sensorimotor areas including the prefrontal, temporal and occipital gyrus, and brain stem. Our results indicate that iTBS reverses the aftereffects induced by cTBS on the contralateral suprahyoid muscle cortex. Dynamic FC analysis displayed a different pattern of alteration compared with the static FC approach in brain excitability induced by TBS. Our results provide novel evidence for us in understanding the topographical and temporal aftereffects linked to brain excitability induced by different TBS protocols and might be valuable information for their application in the rehabilitation of deglutition

Imaging cortical plasticity in the human motor system

Intermittent theta-burst stimulation (iTBS) is a novel form of repetitive transcranial magnetic stimulation (rTMS) inducing increases in cortical excitability that last beyond stimulation. Compared to conventional rTMS protocols iTBS induces strong and long-lasting aftereffects with shorter stimulation time and less stimulation intensity. However, mechanisms underlying iTBS-induced aftereffects as well as factors contributing to a high inter-individual variability between subjects are still poorly understood. The aim of the present study was to gain some new insights into these mechanisms by combining non-invasive brain stimulation with neuroimaging and connectivity analyses of the human motor system. Previous studies suggested a link between rTMS aftereffects and activity as well as connectivity of the stimulated region. However, the mechanisms underlying iTBS-induced plasticity on the systems level are still incompletely understood. Hence, the aim of the first study of the present thesis was to investigate how neural activity and connectivity of the motor system are related to aftereffects of iTBS. Therefore, 12 healthy, right-handed volunteers underwent functional magnetic resonance imaging (fMRI) during rest (resting-state fMRI, rs-fMRI) and while performing a simple hand motor task. Based on this data, resting-state functional connectivity (rsFC) and task-induced activation as well as task-related effective connectivity were assessed. In separate sessions, aftereffects of iTBS applied over the left, primary motor cortex (M1) and the parieto-occipital vertex (sham) were tested for up to 25 min by measuring motor-evoked potentials (MEPs). High MEP increases post stimulation correlated with low movement-induced blood oxygenation level dependent (BOLD) activity in the stimulated M1. MEP changes also correlated positively with the effective connectivity between M1 and different premotor regions. However, no correlation could be found for rsFC. Therefore, our data suggest that changes in cortical plasticity induced by iTBS not only depend on local properties of the stimulated region, but also on activity-dependent properties of the cortical motor system. Furthermore, different studies recently aimed at enhancing iTBS aftereffects by increasing the dose. However, no additive aftereffects could be observed. This may result from the incomplete understanding of the mechanisms underlying the dose-dependent induction of cortical plasticity in humans. The second study, therefore, aimed at investigating the dose-dependency of iTBS aftereffects by applying multiple stimulation blocks within a short time-interval. Possible mechanisms underlying cortical plasticity should be revealed by combining iTBS with connectivity analyses of the motor system. 16 healthy, right-handed subjects received three serially applied blocks of iTBS with an interstimulus-interval of 15 min. Each subject underwent M1- and sham-iTBS in two separate sessions. Aftereffects were tested on both MEP amplitudes as well as rsFC leading to a total of four sessions: M1-iTBS_MEPs, sham-iTBS_MEPs, M1_rs-fMRI, sham_rs-fMRI. For the first time, a dose-dependent buildup of aftereffects after the third block could be found both on the local level (MEPs) as well as on the systems level (rsFC). These increases in MEP amplitudes and rsFC were not linearly correlated, thus, possibly representing two parallel mechanisms underlying iTBS-induced plasticity. Of note, similar dose-dependent alterations of cortical protein expression of distinct subgroups of GABAergic inhibitory interneurons were observed following multiple iTBS blocks in an animal model. Hence, possibly suggesting a similar mechanism to be involved in iTBS aftereffects in humans. Recently, a considerable number of studies addressing the variability of TBS aftereffects reported strong variations across subjects often resulting in no overall effects on the group level. The reasons for this variability remain poorly understood. Moreover, the question arises whether non-responders to iTBS can be turned into responders by increasing the dose. Therefore, in the third study, the data of the second study were re-analyzed with respect to the individual susceptibility to iTBS. Subjects were grouped into responders (n=7) and non-responders (n=9) according to their increase in MEP amplitudes after one iTBS block. When taking the individual responsiveness to iTBS into account a higher rsFC between M1 and premotor areas before stimulation could be found for non-responders compared to responders. Interestingly, non-responders to iTBS after one block could not be turned into responders by increasing the dose, i.e., applying a second or third block of iTBS. In contrast, responders after one block of iTBS featured a dose-dependent increase in MEP amplitudes as well as rsFC after all three iTBS blocks. Hence, our data suggest that responsiveness to iTBS at the local level (i.e., M1 excitability) is related to the capability of modulating network connectivity of the stimulated region (i.e., motor network). A ceiling effect at the systems level might underlie non-responsiveness to iTBS since higher levels of pre-interventional connectivity precluded a further increase upon iTBS. Taken together, the findings of the present thesis add to the understanding of the mechanisms underlying iTBS aftereffects as well as the factors contributing to the high inter-individual variability. Furthermore, our data might help to improve the usefulness of iTBS in both basic research and as a therapeutic intervention

Peripheral-Central Interplay for Fatiguing Unresisted Repetitive Movements: A Study Using Muscle Ischaemia and m1 Neuromodulation

[Abstract] Maximal-rate rhythmic repetitive movements cannot be sustained for very long, even if unresisted. Peripheral and central mechanisms of fatigue, such as the slowing of muscle relaxation and an increase in M1-GABAb inhibition, act alongside the reduction of maximal execution rates. However, maximal muscle force appears unaffected, and it is unknown whether the increased excitability of M1 GABAergic interneurons is an adaptation to the waning of muscle contractility in these movements. Here, we observed increased M1 GABAb inhibition at the end of 30 s of a maximal-rate finger-tapping (FT) task that caused fatigue and muscle slowdown in a sample of 19 healthy participants. The former recovered a few seconds after FT ended, regardless of whether muscle ischaemia was used to keep the muscle slowed down. Therefore, the increased excitability of M1-GABAb circuits does not appear to be mediated by afferent feedback from the muscle. In the same subjects, continuous (inhibitory) and intermittent (excitatory) theta-burst stimulation (TBS) was used to modulate M1 excitability and to understand the underlying central mechanisms within the motor cortex. The effect produced by TBS on M1 excitability did not affect FT performance. We conclude that fatigue during brief, maximal-rate unresisted repetitive movements has supraspinal components, with origins upstream of the motor cortex

Numerical modelling of plasticity induced by Quadri-pulse stimulation

Quadri-pulse stimulation (QPS), a type of repetitive transcranial magnetic stimulation (rTMS), can induce a considerable aftereffect on cortical synapses. Human experiments have shown that the type of effect on synaptic efficiency (in terms of potentiation or depression) depends on the time interval between pulses. The maturation of biophysically-based models, which describe the physiological properties of plasticity mathematically, offers a beneficial framework to explore induced plasticity for new stimulation protocols. To model the QPS paradigm, a phenomenological model based on the knowledge of spike timing-dependent plasticity (STDP) mechanisms of synaptic plasticity was utilized where the cortex builds upon the platform of neuronal population modeling. Induced cortical plasticity was modeled for both conventional monophasic pulses and unidirectional pulses generated by the cTMS device, in a total of 117 different scenarios. For the conventional monophasic stimuli, the results of the predictive model broadly follow what is typically seen in human experiments. Unidirectional pulses can produce a similar range of plasticity. Additionally, changing the pulse width had a considerable effect on the plasticity (approximately 20% increase). As the width of the positive phase increases, the size of the potentiation will also increase. The proposed model can generate predictions to guide future plasticity experiments. Estimating the plasticity and optimizing the rTMS protocols might effectively improve the safety implications of TMS experiments by reducing the number of delivered pulses to participants. Finding the optimal stimulation protocol with the maximum potentiation/depression can lead to the design of a new TMS pulse generator device with targeted hardware and control algorithms