Variability in non-invasive brain stimulation studies: reasons and results

Non-invasive brain stimulation techniques (NIBS), such as Theta Burst Stimulation (TBS), Paired Associative Stimulation (PAS) and transcranial Direct Current Stimulation (tDCS), are widely used to probe plasticity in the human motor cortex (M1). Although TBS, PAS and tDCS differ in terms of physiological mechanisms responsible for experimentally-induced cortical plasticity, they all share the ability to elicit long-term potentiation (LTP) and depression (LTD) in M1. However, NIBS techniques are all affected by relevant variability in intra- and inter-subject responses. A growing number of factors contributing to NIBS variability have been recently identified and reported. In this review, we have readdressed the issue of variability in human NIBS studies. We have first briefly discussed the physiological mechanisms responsible for TBS, PAS and tDCS-induced cortical plasticity. Then, we have provided statistical measures of intra- and inter-subject variability, as calculated in previous studies. Finally, we have reported in detail known sources of variability by categorizing them into physiological, technical and statistical factors. Improving knowledge about sources of variability could lead to relevant advances in designing new tailored NIBS protocols in physiological and pathological conditions

An Investigation of Short-Term Plasticity in Human Motor Cortex

Transcranial magnetic stimulation (TMS) produces a transient magnetic field that activates underlying cortical tissue by eliciting an electrical discharge of the neurons in the targeted area. Repetitive TMS (rTMS) uses patterns of repetitive TMS pulses and has been reliably shown to produce changes in the state of cortical excitability outlasting the time of stimulation. One such protocol that has demonstrated states of increased excitability is intermittent theta burst stimulation (iTBS). This method applies high-frequency bursts (50Hz) of pulses every 200 ms in trains of ten bursts. The effects of and differences between rTMS protocols have been investigated since gaining popularity in the 1990’s, however, there are still many unknowns regarding the neurophysiological changes that accompany this plasticity. Much research on these effects takes place in motor cortex due to reliable and quantifiable measures of cortical excitability observed there. Here, I sought to further investigate the effects of iTBS on inter-hemispheric changes in in motor cortex using EEG simultaneously recorded with TMS pulses. That is, I examined if iTBS conducted over right motor cortex would lead to measureable changes in excitability indices of left motor cortex. I quantified changes in right and left motor cortex excitability with measurements of TMS-evoked potentials (TEPs) and motor-evoked potentials (MEPs) elicited through blocks of single pulse TMS immediately following iTBS and 30 minutes post-iTBS. I compared the effects of the iTBS condition to those found in a control condition where a sham version of iTBS was administered. Results indicate differential modulations of cortical TEPs between hemispheres, including an initial enhancement of the P30 in right hemisphere, coinciding with sustained suppression in left hemisphere, and an enhancement of the P190 during left hemisphere stimulation

Inducing and detecting neuroplasticity: insights from TMS-EEG and RS-EEG

Damage to the brain, such as stroke, can lead to severe cognitive and motor disabilities in the affected individuals. Neuroplasticity refers to the intrinsic capacities of the brain to reorganize cortical networks at different spatial and temporal scales, potentially resulting in spontaneous recovery of function after such damage. A better understanding about the measurement and the support of those neuroplastic processes is an important prerequisite to improve therapeutic interventions and ultimately the outcome of the recovery process. This thesis comprises the results of two studies that investigated the ability to induce neuroplasticity using repetitive transcranial magnetic stimulation (TMS) and the ability to measure neuroplasticity using a combination of TMS and electroencephalography (EEG) or resting state (RS)-EEG measurements in cohorts of young and healthy individuals. The first study utilized continuous theta burst stimulation (cTBS) to induce neuroplasticity targeting the primary motor cortex. After-effects on cortical and corticospinal excitability were quantified in terms of TMS-evoked potentials (TEP) and motor-evoked potentials. The study demonstrated that cTBS-induced neuroplasticity leads to significant local and remote changes in cortical excitability that were measurable with TMS-EEG. The modulation of the N45 peak of the TEP suggests that the neuroplastic effects of cTBS are mediated by changes in gamma-aminobutyric acid (GABA)A-mediated cortical inhibition. The second study investigated the suitability of RS-EEG for individualized longitudinal tracking of neuroplastic processes. In this scenario, it is important to distinguish whether observed changes in activity between measurements are attributable to incidental variations in cognitive state or truly related to processes of neuroplastic reorganization. A classification algorithm was adopted to extract individual-specific signatures from EEG oscillations at rest. These signatures were very robust across multiple days and detectable across different cognitive states, indicating a close relationship to the underlying neurophysiology. Using these individual activity pattern, it was possible to distinguish inter-day variations in cognitive state from simulated changes in the neurophysiological organization of the brain with very high accuracy. The current thesis therefore provides important support for the usability of TMS-EEG and RS-EEG as methodological approaches to measure neuroplasticity within healthy and young individuals. Furthermore, cTBS may be used as a strategy to interact with abnormally elevated or reduced levels of GABAA-mediated cortical inhibition. Further studies are required to validate the significance of the current findings and to test whether they can be translated into clinical practice, especially into the realms of stroke recovery

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

Transcranial magnetic stimulation combined with functional magnetic resonance imaging: From target identification to prediction of therapeutic effects in stroke patients

Repetitive transcranial magnetic stimulation (rTMS), particularly theta-burst stimulation (TBS), can be applied to modulate cortical excitability beyond the period of stimulation (Huang et al., 2005). Consequently, rTMS is regarded to have high therapeutic potential for treatment of various psychiatric and neurological diseases related to cortical hypo- or hyperexcitability such as stroke (Ridding & Rothwell, 2007). Whether rTMS induced effects are sufficiently robust to be useful in clinical settings is currently under intense investigation. The most challenging problem appears to be considerably high variability in rTMS induced effects both, across studies (Hoogendam et al., 2010) and individual patients (Ameli et al., 2009). Hence, the major goal of the present thesis was to improve rTMS intervention strategies in stroke patients suffering from chronic motor hand deficits by multimodal uses of (repetitive) TMS with state-of-the-art neuroimaging techniques. Sources of variance across studies are likely to be methodological in origin. They might result from different strategies to identify the cortical rTMS target position. Individual functional magnetic resonance (fMRI) data have been demonstrated to yield best spatial approximations of the most excitable TMS position compared to other techniques (Sparing et al., 2008). However, there is still a considerably large spatial mismatch between the cortical position showing highest movement-related fMRI signal and the cortical position yielding highest muscle responses when stimulated with TMS of up to 14 mm (Bastings et al., 1998; Boroojerdi et al., 1999; Herwig et al., 2002; Krings et al., 1997; Lotze et al., 2003; Sparing et al., 2008; Terao et al., 1998). The underlying cause of this spatial mismatch is unknown. Hence, the aim of the first study (Study I) of the present thesis was to test the hypothesis that the spatial mismatch between positions with highest fMRI signal change and positions with highest TMS excitability might be caused by the widely-used Gradient-Echo blood oxygenation level dependent (GRE-BOLD) fMRI technique. GRE-BOLD signal has been demonstrated to occur further downstream from the site of neural activity in large veins running on the cerebral surface (Uludag et al., 2009). Consequently, we tested the hypothesis that alternative fMRI sequences may localize neural activity (i) closer to the anatomical motor hand area, i.e. Brodmann Area 4 (BA4), and (ii) closer to the optimal TMS position than GRE-BOLD. The following alternative fMRI techniques were tested: (i) Spin-Echo (SE-BOLD) assessing blood oxygenation level dependent signal changes with decreased sensitivity for the macrovasculature at high magnetic fields (≥ 3 Tesla, Uludag et al., 2009) and (ii) arterial spin labelling (ASL), assessing local changes in cerebral blood flow (ASL-CBF) which have been shown to occur in close proximity to synaptic activity (Duong et al., 2000). GRE-BOLD, SE-BOLD, and ASL-CBF signal changes during right thumb abductions were obtained from 15 healthy young subjects at 3 Tesla. In 12 subjects, brain tissue at fMRI peak voxel coordinates was stimulated with neuronavigated TMS to investigate whether spatial differences between fMRI techniques are functionally relevant, i.e. impact on motor-evoked potentials (MEPs) recorded from a contralateral target muscle, which is involved in thumb abductions. A systematic TMS motor mapping was performed to identify the most excitable TMS position (i.e. the TMS hotspot) and the centre-of-gravity (i.e. the TMS CoG), which considers the spatial distribution of excitability in the pericentral region. Euclidean distances between TMS and fMRI positions were calculated for each fMRI technique. Results indicated that highest SE-BOLD and ASL-CBF signal changes occurred in the anterior wall of the central sulcus (BA4), whereas highest GRE-BOLD signal changes occurred significantly closer to the gyral surface where most large draining veins are located. fMRI techniques were not significantly different from each other in Euclidean distances to optimal TMS positions since optimal TMS positions were located considerably more anterior (and slightly surprisingly in premotor cortex (BA6) and not BA4). Stimulation of brain tissue at GRE-BOLD peak voxel coordinates with TMS resulted in significantly higher MEPs (compared to SE-BOLD and ASL-CBF coordinates). This was probably the case because GRE-BOLD positions tended to be located at the gyral crown, which was slightly (but not significantly) closer to the TMS hotspot position. Taken together, findings of Study I suggest that spatial differences between fMRI and TMS positions are not caused by spatial unspecificity of the widely-used GRE-BOLD fMRI technique. Hnece, other factors such as complex interactions between brain tissue and the TMS induced electric field (Opitz et al., 2011), could be the underlying cause. Identification of the cortical rTMS target position is particularly challenging in stroke patients since reorganization processes after stroke may shift both, fMRI and TMS positions in unknown direction and extend (Rossini et al., 1998). In the second study (Study II) of the present thesis, we therefore tested whether findings obtained from healthy young subjects in Study I do also apply to chronic stroke patients and older (i.e. age-matched) healthy control subjects. In this study, arterial spin labelling (ASL) was used to assess CBF and BOLD signal changes simultaneously during thumb abductions with the affected/non-dominant and the unaffected/dominant hand in 15 chronic stroke patients and 13 age-matched healthy control subjects at 3 Tesla. Brain tissue at fMRI peak voxel coordinates was stimulated with neuronavigated TMS to test whether spatial differences are functionally relevant and impact on MEPs. Systematic TMS motor mappings were performed for both hemispheres in overall 12 subjects (6 stroke patients and 6 healthy subjects). Euclidean distances between fMRI and TMS positions were calculated for each hemisphere and fMRI technique. In line with results of Study I, highest ASL-CBF signal changes were located in the anterior wall of the central sulcus (BA4), whereas highest ASL-BOLD signal changes occurred significantly closer to the gyral surface. In contrast to Study I, there were no significant differences between ASL-CBF and ASL-BOLD positions in MEPs when stimulated with neuronavigated TMS, which suggests that spatial differences (in depth) were not functionally relevant for TMS applications. In line with Study I, there were no significant differences between fMRI techniques in Euclidean distances to optimal TMS positions, since optimal TMS positions were located considerably more anterior than fMRI positions (in premotor cortex, i.e. BA6). Stroke patients showed overall larger displacements (between fMRI and TMS positions) on the ipsilesional (but not the contralesional) hemisphere compared to healthy subjects. However, none of the fMRI techniques yielded positions significantly closer to the optimal TMS position. Hence, functional reorganization may impact on spatial congruence between fMRI and TMS, but the effect is similar for ASL-CBF and ASL-BOLD. Pathomechanisms underlying stroke induced motor deficits are still poorly understood but a simplified model of hemispheric competition has been suggested, which proposes relative hypoexcitability of the ipsilesional hemisphere and hyperexcitability of the contralesional hemisphere leading to pathologically increased interhemispheric inhibition from the contralesional onto the ipsilesional hemisphere during movements of the paretic hand (Duque et al., 2005; Grefkes et al., 2008b, 2010; Murase et al., 2004). In line with the model of hemispheric competition, both increasing excitability of the ipsilesional hemisphere (Khedr et al., 2005; Talelli et al., 2007) as well as decreasing excitability of the contralesional hemisphere (Fregni et al., 2006; Di Lazzaro et al., 2008a) have been demonstrated to normalize cortical excitability towards physiological levels and/or ameliorate motor performance of the stroke affected hand. However, there is considerably high inter-individual variance and some patients may even show deteriorations of motor performance after rTMS (Ameli et al., 2009). Therefore, the aim of the third study (Study III) was to identify reliable predictors for TBS effects on motor performance of the affected hand in stroke patients, which appears essential for successful implementation of TBS in neurorehabilitation. Overall, 13 chronic stroke patients with unilateral motor hand deficit and 12 age-matched healthy control subjects were included in the study. All patients received 3 different TBS interventions on 3 different days: (i) intermittent TBS (iTBS, facilitatory) over the primary motor cortex (M1) of the ipsilesional hemisphere, (ii) continuous TBS (cTBS, inhibitory) over M1 of the contralesional hemisphere, and (iii) either iTBS or cTBS over a control stimulation site (to control for placebo effects). Motor performance was measured before and after each TBS session with 3 different motor tasks and an overall motor improvement score was calculated. All subjects participated in an fMRI experiment, in which they performed rhythmic fist closures with their affected/non-dominant and unaffected/dominant hand. A laterality index (LI), reflecting laterality of fMRI signal in cortical motor areas was calculated. Effective connectivity, i.e. the direct or indirect causal influence that activity in one area exerts on activity of another area (Friston et al., 1993a), was inferred from fMRI data by means of dynamic causal modelling (DCM). Due to relatively high inter-individual variance, neither iTBS nor cTBS was significantly different from control TBS in terms of average behavioural (or electrophysiological) changes over the group of patients. However, beneficial effects of iTBS over the ipsilesional hemisphere were predicted by a unilateral fMRI activation pattern during movements of the affected hand and by the integrity of the cortical motor network. The more pronounced the promoting influence from the ipsilesional supplementary motor area (SMA) onto ipsilesional M1 and the more pronounced the inhibitory effect originating from ipsilesional M1 onto contralesional M1, the better was the behavioural response to facilitatory iTBS applied to the ipsilesional hemisphere. No significant correlations were found for behavioural improvements following cTBS or behavioural changes of the unaffected hand. Taken together, Study III yielded promising results indicating that laterality of fMRI signal and integrity of the motor network architecture constitute promising predictors for response to iTBS. In patients in whom the connectivity pattern of the ipsilesional motor network resembled physiological network connectivity patterns (i.e. preserved inhibition of the contralesional hemisphere and supportive role of the SMA of the ipsilesional hemisphere), beneficial effects of iTBS over the ipsilesional hemisphere could be observed. In contrast, patients with severely disturbed motor networks did not respond to iTBS or even deteriorated

Modulation of I-wave generating pathways by TBS: a model of plasticity induction

KEY POINTS: • Mechanisms underlying plasticity induction by repetitive transcranial magnetic stimulation protocols such as intermittent theta-burst stimulation (iTBS) remain poorly understood. • Individual response to iTBS is associated with recruitment of late indirect wave (I-wave) generating pathways that can be probed by the onset latency of TMS applied to primary motor cortex (M1) at different coil orientations. • We found an association between late I-wave recruitment (reflected by AP-LM latency, i.e. the excess latency of motor evoked potentials (MEPs) generated by TMS with an anterior-posterior (AP) orientation over the latency of MEPs evoked by direct activation of corticospinal axons using latero-medial (LM) stimulation) and changes in cortical excitability following iTBS, confirming previous studies. •AP-LM latency significantly decreased following iTBS, and this decrease correlated with the iTBS-induced increase in cortical excitability across subjects. •Plasticity in the motor network may in part derive from a modulation of excitability and recruitment of late I-wave generating cortical pathways. ABSTRACT: Plasticity-induction following theta burst transcranial stimulation (TBS) varies considerably across subjects, and underlying neurophysiological mechanisms remain poorly understood, representing a challenge for scientific and clinical applications. In human motor cortex (M1), recruitment of indirect waves (I-waves) can be probed by the excess latency of motor evoked potentials (MEPs) elicited by TMS with an anterior-posterior (AP) orientation over the latency of MEPs evoked by direct activation of corticospinal axons using latero-medial (LM) stimulation, referred to as "AP-LM latency" difference. Importantly, AP-LM latency has been shown to predict individual responses to TBS across subjects. We, therefore, hypothesized that the plastic changes in corticospinal excitability induced by TBS are the result, at least in part, of changes in excitability of these same I-wave generating pathways. We investigated in 20 healthy subjects whether intermittent TBS (iTBS) modulates I-wave recruitment as reflected by changes in the AP-LM latency. As expected, we found that AP-LM latencies before iTBS were associated with iTBS-induced excitability changes. A novel finding was that iTBS reduced the AP-LM latency, and that this correlated significantly with changes in cortical excitability observed following iTBS: subjects with the largest reductions in AP-LM latencies had the largest increases in cortical excitability following iTBS. Our findings suggest that plasticity-induction by iTBS may derive from the modulation of I-wave generating pathways projecting onto M1, accounting for the predictive potential of I-wave recruitment. The excitability of I-wave generating may serve a critical role in modulating motor cortical excitability and hence represent a promising target for novel rTMS protocols

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

Development of Low-Frequency Repetitive Transcranial Magnetic Stimulation as a Tool to Modulate Visual Disorders: Insights from Neuroimaging

Repetitive transcranial magnetic stimulation (rTMS) has become a popular neuromodulation technique, increasingly employed to manage several neurological and psychological conditions. Despite its popular use, the underlying mechanisms of rTMS remain largely unknown, particularly at the visual cortex. Moreover, the application of rTMS to modulate visual-related disorders is under-investigated. The goal of the present research was to address these issues. I employ a multitude of neuroimaging techniques to gain further insight into neural mechanisms underlying low-frequency (1 Hz) rTMS to the visual cortex. In addition, I begin to develop and refine clinical low-frequency rTMS protocols applicable to visual disorders as an alternative therapy where other treatment options are unsuccessful or where there are simply no existing therapies. One such visual disorder that can benefit from rTMS treatment is the perception of visual hallucinations that can occur following visual pathway damage in otherwise cognitively healthy individuals. In Chapters 23, I investigate the potential of multiday low-frequency rTMS to the visual cortex to alleviate continuous and disruptive visual hallucinations consequent to occipital injury. Combining rTMS with magnetic resonance imaging techniques reveals functional and structural cortical changes that lead to the perception of visual hallucinations; and rTMS successfully attenuates these anomalous visual perceptions. In Chapters 45, I compare the effects of alternative doses of low-frequency rTMS to the visual cortex on neurotransmitter levels and intrinsic functional connectivity to gain insight into rTMS mechanisms and establish the most effective protocol. Differential dose-dependent effects are observed on neurotransmitter levels and functional connectivity that suggest the choice of protocol critically depends on the neurophysiological target. Collectively, this work provides a basic framework for the use of low-frequency rTMS and neuroimaging in clinical application for visual disorders

From micro to macro:unravelling the underlying mechanisms of Transcranial Magnetic Stimulation (TMS)

This PhD research investigated the underlying mechanisms of transcranial magnetic stimulation (TMS). TMS is a form of non-invasive brain stimulation, which is used both in research to alter brain activity and in the clinic where it is a treatment option for many neuropsychiatric disorders such as major depression. However, not a lot is known about how TMS actually works. This research took an interdisciplinary approach to better understand the mechanisms of TMS. On the microscopic level, it used human neurons which were grown in the lab and stimulated with TMS to look for changes in plasticity such as neuronal firing, gene expression, and morphology. On the macroscopic level, the researcher stimulated human participants and measured indirect outcomes of plasticity, using multimodal setups such as combined TMS-EEG and TMS-EEG-fMRI. Better understanding the mechanisms of TMS is very important. If we fully understand how TMS works, we can optimize stimulation protocols, promoting increased responsiveness and better treatment outcomes in the clinic

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