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• A model of motor-evoked potential formation gives a realistic electromyogram in response to TMS. • The model reproduces effects of short-interval intracortical inhibition, intracortical facilitation and long-interval intracortical inhibition. • A link between existing neural field modeling and realistic outcome measures of TMS is provided. To develop a population-based biophysical model of motor-evoked potentials (MEPs) following transcranial magnetic stimulation (TMS). We combined an existing MEP model with population-based cortical modeling. Layer 2/3 excitatory and inhibitory neural populations, modeled with neural-field theory, are stimulated with TMS and feed layer 5 corticospinal neurons, which also couple directly but weakly to the TMS pulse. The layer 5 output controls mean motoneuron responses, which generate a series of single motor-unit action potentials that are summed to estimate a MEP. A MEP waveform was generated comparable to those observed experimentally. The model captured TMS phenomena including a sigmoidal input–output curve, common paired pulse effects (short interval intracortical inhibition, intracortical facilitation, long interval intracortical inhibition) including responses to pharmacological interventions, and a cortical silent period. Changes in MEP amplitude following theta burst paradigms were observed including variability in outcome direction. The model reproduces effects seen in common TMS paradigms. The model allows population-based modeling of changes in cortical dynamics due to TMS protocols to be assessed in terms of changes in MEPs, thus allowing a clear comparison between population-based modeling predictions and typical experimental outcome measures. [ABSTRACT FROM AUTHOR]

Cortical oscillatory activities play a role in regulating several brain functions in humans. However, whether motor resonant oscillations (i.e. β and γ) modulate long-term depression (LTD)-like plasticity of the primary motor cortex (M1) is still unclear. To address this issue, we combined transcranial alternating current stimulation (tACS), a technique able to entrain cortical oscillations, with continuous theta burst stimulation (cTBS), a transcranial magnetic stimulation (TMS) protocol commonly used to induce LTD-like plasticity in M1. Motor evoked potentials (MEPs) elicited by single-pulse TMS, short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were evaluated before and 5, 15 and 30 min after cTBS alone or cTBS delivered during β-tACS (cTBS-β) or γ-tACS (cTBS-γ). Moreover, we tested the effects of β-tACS (alone) on short-latency afferent inhibition (SAI) and γ-tACS on SICI in order to verify whether tACS-related interneuronal modulation contributes to the effects of tACS-cTBS co-stimulation. cTBS-γ turned the expected after-effects of cTBS from inhibition to facilitation. By contrast, responses to cTBS-β were similar to those induced by cTBS alone. β- and γ-tACS did not change MEPs evoked by single-pulse TMS. β-tACS reduced SAI and γ-tACS reduced SICI. However, the degree of γ-tACS-induced modulation of SICI did not correlate with the effects of cTBS-γ. γ-tACS reverses cTBS-induced plasticity of the human M1. γ-oscillations may therefore regulate LTD-like plasticity mechanisms. • γ-tACS turned the expected after-effects of cTBS from inhibition to facilitation. • The after-effects of cTBS were not modified by a concurrent stimulation with β-tACS. • γ-tACS, given alone, reduced SICI and β-tACS reduced SAI. • The effects of γ-tACS on cTBS did not correlate with γ-tACS-induced changes of SICI. [ABSTRACT FROM AUTHOR]

Highlights • Continuous theta burst stimulation (cTBS) is a relatively new neuromodulation technique that requires further validation. • Across three studies cTBS targeting the left dlPFC revealed reliable attenuating effects on executive functions. • However, this effect was not universal in that 61.8% of participants showed the expected response. • cTBS effects were more pronounced for those with stronger baseline executive function performance. Abstract Despite the increasing use of continuous theta burst (cTBS) protocols targeting the prefrontal cortex in clinical and research settings, very little is known regarding the interindividual factors that influence the magnitude and duration of cTBS aftereffects. The few existing studies have predominantly focussed on motor and corticospinal excitability, and the applicability of such findings to prefrontal modulation remains unclear. The current investigation aggregated published data from our laboratory to (1) assess the reproducibility of the effects of cTBS targeting the left dorsolateral prefrontal cortex (dlPFC) on executive function task performance, and (2) determine which factors are associated with individual differences in cTBS responsivity. Data from 76 healthy young adult female participants aged 19–26 (M = 20.6; SD = 1.6) were included in the analyses. Significant attenuations in executive function task performance from baseline were observed following active cTBS. However, these effects were not totally universal in that cTBS-induced attenuation of executive functions was observed in 61.8% of participants (i.e., responders). In addition, baseline task performance was a significant predictor of the magnitude of the cTBS-induced change in task performance in that cTBS effect was larger for individuals with higher baseline executive control abilities than those with lower abilities. Together, these data provide a quantitative estimate of the degree to which healthy participants may vary in the responsiveness to prefrontal cTBS, and potential moderating factors. [ABSTRACT FROM AUTHOR]

Prefrontal cortex (PFC) plays an important role in emotional processing and therefore is one of the most frequently targeted regions for non-invasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS) in clinical trials, especially in the treatment of emotional disorders. As an approach to enhance the effectiveness of rTMS, continuous theta burst stimulation (cTBS) has been demonstrated to be efficient and safe. However, it is unclear how cTBS affects brain processes related to emotion. In particular, psychophysiological studies on the underlying neural mechanisms are sparse. In the current study, we investigated how the cTBS influences emotional processing when applied over the right PFC. Participants performed an emotion recognition Go/NoGo task, which asked them to select a GO response to either happy or fearful faces after the cTBS or after sham stimulation, while 64-channel electroencephalogram (EEG) was recorded. EEG oscillation was examined using event-related spectral perturbation (ERSP) in a time-interval between 170 and 310 ms after face stimuli onset. In the sham group, we found a significant difference in the alpha band between response to happy and fearful stimuli but that effect did not exist in the cTBS group. The alpha band activity at the scalp was reduced suggesting the excitatory effect at the brain level. The beta and gamma band activity was not sensitive to cTBS intervention. The results of the current study demonstrate that cTBS does affect emotion processing and the effect is reflected in changes in EEG oscillations in the alpha band specifically. The results confirm the role of prefrontal cortex in emotion processing. We also suggest that this pattern of cTBS results elucidates mechanisms by which mood improvement in depressive disorders is achieved using cTBS intervention. [ABSTRACT FROM AUTHOR]

Time perception in the millisecond and second ranges is thought to be processed by different neural mechanisms. However, whether there is a sharp boundary between these ranges and whether they are implemented in the same, overlapped or separate brain areas is still not certain. To probe the role of the right dorsolateral prefrontal cortex (dlPFC), the right supplementary motor area (SMA), and the cerebellum on time perception, we temporarily altered their activity on healthy volunteers on separate sessions using transcranial magnetic stimulation with the continuous Theta Burst Stimulation (cTBS) protocol. A control session was reserved for the stimulation of the primary somatosensory cortex (S1). Before and after stimulation, participants were tested on a temporal categorization task using intervals in the hundreds and thousands of milliseconds ranges, as well as on a pitch categorization task which was used as a further control. We then looked for changes in the Relative Threshold and the Constant Error, which, respectively, reflect participants’ sensitivity to interval duration and their accuracy at setting an interval that acts as a boundary between categories. We found that after cTBS in all of the studied regions, the Relative Threshold, but not the Constant Error, was affected and only when hundreds of milliseconds intervals were being categorized. Categorization of thousands of milliseconds intervals and of pitch was not affected. These results suggest that the fronto-cerebellar circuit is particularly involved in the estimation of intervals in the hundreds of milliseconds range. [ABSTRACT FROM AUTHOR]

Sleep deprivation (SD) is a common condition associated with a variety of nervous system diseases, and has a negative impact on emotional and cognitive function. Continuous theta burst stimulation (cTBS) is known to improve cognition and emotion function in normal situations as well as in various types of dysfunction, but the mechanism remains unknown. We used two-photon in vivo imaging to explore the effect of cTBS on glymphatic pathway clearance in normal and SD C57BL/6J mice. Aquaporin-4 (AQP4) polarization was detected by immunofluorescence. Anxiety-like behaviors was measured using open field tests. We found that SD reduced influx efficiency along the peri-vascular space (PVS), disturbed AQP4 polarization and induced anxiety-like behaviors. CTBS significantly attenuated the decrease in efficiency of solute clearance usually incurred with SD, restored the loss of AQP4 polarization and improved anxiety-like behavior in SD animals. Our results implied that cTBS had the potential to protect against neuronal dysfunction induced by sleep disorders. [ABSTRACT FROM AUTHOR]

Microsaccades that occur during periods of fixation are modulated by various cognitive processes and have an impact on visual processing. A network of brain areas is involved in microsaccade generation, including the superior colliculus and frontal eye field (FEF) which are involved in modulating microsaccade rate and direction after the appearance of a visual cue (referred to as microsaccade cueing modulation). Although the neural mechanisms underlying microsaccade cueing modulations have been demonstrated in monkeys, limited research has investigated a causal role of these areas in humans. By applying continuous theta-burst transcranial magnetic stimulation (cTBS) over the right FEF and vertex, we investigated the role of human FEF in modulating microsaccade responses after the appearance of a visual target in a visual- and memory-delay saccade task. After target appearance, microsaccade rate was initially suppressed but then increased in both cTBS conditions. More importantly, in the visual-delay task, microsaccades after target appearance were directed to the ipsilateral side more often with FEF, compared to vertex stimulation. Moreover, microsaccades were directed towards the target location, then to the opposite location of the target in both tasks, with larger effects in the visual-, compared to, memory-delay task. This microsaccade direction modulation was delayed after FEF stimulation in the memory-delay task. Overall, some microsaccade cueing modulations were moderately disrupted after FEF cTBS, suggesting a causal role for involvement of the human FEF in microsaccade generation after presentation of salient stimuli. [ABSTRACT FROM AUTHOR]

The present study investigated the role of the precuneus in memory encoding of abstract and concrete words, with the combination of functional Magnetic Resonance Imaging (fMRI) and continuous Theta Burst Stimulation (cTBS) techniques. The memory encoding process was scanned in the fMRI to detect the regions of interest for the difference in memory formation of these two types of words. The real and sham cTBS stimulations were applied over the left precuneus. The fMRI results showed that the left precuneus was deactivated for the memory encoding of both types of words, with concrete words inducing significantly more deactivation. The cTBS stimulation over the left precuneus significantly reduced the reaction time of retrieval of abstract words but not concrete words. It is concluded that precuneus plays a role in modulating the abstract but not the concrete verbal memory encoding. • This study examines the role of precuneus in verbal episodic memory with combination of fMRI and cTBS. • The precuneus was deactivated for the episodic memory encoding of abstract and concrete words. • The precuneus was deactivated significantly less for the episodic encoding of abstract words than that of the concrete words. • The cTBS stimulation over precuneus significantly reduced the reaction time of retrieval of abstract words instead of concrete words. [ABSTRACT FROM AUTHOR]

Objective: To determine whether the intensity of transcranial magnetic stimulation (TMS) used to probe changes in corticospinal excitability influences the measured plasticity response to theta burst stimulation (TBS) of the human primary motor cortex. Methods: Motor evoked potential (MEP) input/output (I/O) curves were recorded before and following continuous TBS (cTBS) (Experiment 1; n = 18) and intermittent TBS (iTBS) (Experiment 2; n = 18). Results: The magnitude and consistency of MEP depression induced by cTBS was greatest when probed using stimulus intensities at or above 150% of resting motor threshold (RMT). In contrast, facilitation of MEPs following iTBS was strongest and most consistent at 110% of RMT. Conclusions: The plasticity response to both cTBS and iTBS is influenced by the stimulus intensity used to probe the induced changes in corticospinal excitability. [ABSTRACT FROM AUTHOR]

Objective The present study investigated the effects of continuous theta-burst stimulation (cTBS) over primary somatosensory (SI) and motor (M1) cortices on motor-evoked potentials (MEPs) and short-latency afferent inhibition (SAI). Methods MEPs and SAI were recorded from the first dorsal interosseous (FDI) muscle of the right hand following 30 Hz cTBS over left-hemisphere SI and M1 delivered to the same participants in separate sessions. Measurements were taken before and up to 60 min following cTBS. Results CTBS over M1 suppressed MEPs and did not alter SAI. In contrast cTBS over SI facilitated MEPs and decreased median and digital nerve evoked SAI. Conclusions These findings indicate that SAI amplitude is influenced by cTBS over SI but not M1, suggesting an important role for SI in the modulation of this circuit. These data provide further evidence that cTBS over SI versus M1 has opposite effects on corticospinal excitability. Significance To date, plasticity-inducing TMS protocols delivered over M1 have failed to modulate SAI, and the present research continues to support these findings. However, in young adults, cTBS over SI acts to reduce SAI and simultaneously increase corticospinal excitability. Future studies may investigate the potential to modulate SAI via targeting neural activity within SI. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: Objective: The application of repetitive transcranial magnetic stimulation (rTMS) in bursts at theta frequencies (TBS) may produce lasting neuroplastic changes in the human cortex. However, there exists high variability in subjects’ responses, possibly due to non-optimal stimulation characteristics. Here we compare the efficacy of two variations of continuous TBS (cTBS) for producing neuroplastic change in the human primary motor cortex (M1). Methods: The two cTBS paradigms were: (1) standard cTBS (cTBSstd) (three stimuli at 50Hz, repeated at 5Hz), and (2) modified cTBS (cTBSmod) (three stimuli at 30Hz, repeated at 6Hz with intensity). Motor evoked potentials (MEPs) were recorded from the right first dorsal interosseous muscle before, as well as at 0, 5, 10, 20 and 30min following each paradigm. Results: Both cTBSstd (P =0.05) and cTBSmod (P <0.0001) induced a suppression of MEP amplitudes. However, MEP suppression following cTBSmod was greater (ANOVARM; P =0.02). Experiments using magnetic brainstem stimulation provided evidence that cTBSmod induced MEP suppression through cortical mechanisms. Conclusions: The neuroplastic response of the human M1 to cTBS is highly dependent on the stimulation parameters employed. Significance: These findings may have significant implications for the clinical application of cTBS paradigms. [Copyright &y& Elsevier]

Abstract: Objectives: Somatosensory evoked potentials (SEPs) were used to index somatosensory–somatosensory interhemispheric interactions and highlight potential mechanisms by which TMS alters contralateral somatosensory cortex excitability. Methods: Fifteen healthy individuals participated in three sessions on separate days. On each day participants received either: (1) continuous theta burst (cTBS), (2) 1Hz repetitive transcranial magnetic stimulation (rTMS) or (3) control TMS over left somatosensory cortex. SEPs from right somatosensory cortex were recorded before and after TMS while participants were at rest, performed sensorimotor tracking or the sustained attention to response task (SART). Left-handed tracking performance was also indexed. Results: N20–P27 amplitude was increased following 1Hz rTMS while participants were at rest. This increased amplitude was not observed during right-handed tracking or the SART. N20–P27 amplitude was not influenced by cTBS or control TMS. P15–N20 and N34–P50 SEP components were not influenced by TMS. Right- and left-handed tracking performance was not transiently influenced by TMS. Conclusions: The results support TMS induced somatosensory–somatosensory interactions and offer converging evidence for an intercortical, rather that intracortical, mechanism that mediates contralateral sensory processing. These interactions appear to be dependent on concurrent attention/task demands. Significance: Somatosensory–somatosensory interactions are reflected by intercortical mechanisms that are state and task dependent. [Copyright &y& Elsevier]

Background: Because standard repetitive transcranial magnetic stimulation (rTMS) protocols exhibit post-stimulus effects of short duration, novel protocols such as theta burst stimulation (TBS), are promising approaches to enhance the effectiveness of rTMS. However, little is known about the side effect profile of such protocols. Thus, the present study explores whether TBS is safe particularly in terms of effects on cognition, mood, and electroencephalogram (EEG) measures in healthy subjects. Methods: Twenty-four healthy volunteers participated in 2 randomized, placebo-controlled, cross-over experiments and underwent continuous TBS (cTBS), intermittent TBS (iTBS), and shamTBS either over the left dorsolateral prefrontal cortex (DLPFC, n = 12) or the medial prefrontal cortices (mPFC, n = 12). Clinical side effects, performance in a neuropsychological battery, mood changes, and resting EEG were recorded. Results: Neither a seizure nor epileptiform EEG activity was observed. The most prominent side effect was the occurrence of vagal reactions during TBS; otherwise no serious side effects were found. Standardized low-resolution brain electromagnetic tomography showed current density changes in the α2 band after iTBS of the DLPFC, which remained detectable up to 50 min after stimulation. The few changes in neuropsychological performance were concordant with stimulation site. No impact on mood was detected. Conclusions: Although TBS protocols of the human prefrontal cortex seem to be safe in healthy subjects, future studies need to address the occurrence of vagal reactions. Excitatory and inhibitory properties of motor cortex TBS might not be transferable to prefrontal sites, and the action of specific TBS protocols needs to be further investigated prior to clinical application. [Copyright &y& Elsevier]

Microsaccade is a type of fixational eye movements that is modulated by various sensory and cognitive processes, and impact our visual perception. Although studies in monkeys have demonstrated a functional role for the superior colliculus and frontal eye field (FEF) in controlling microsaccades, our understanding of the neural mechanisms underlying the generation of microsaccades is still limited. By applying continuous theta-burst stimulation (cTBS) over the right FEF and the vertex, we investigated the role of the FEF in generating human microsaccade responses evoked by salient stimuli or by changes in background luminance. We observed higher microsaccade rates prior to target appearance, and larger rebound in microsaccade occurrence following salient stimuli, when disruptive cTBS was applied over FEF compared to vertex stimulation. Moreover, the microsaccade direction modulation after changes in background luminance was disrupted with FEF stimulation. Together, our results constitute the first evidence of FEF modulation in human microsaccade responses. • We examined the role of the frontal eye field (FEF) in human microsaccade responses using continuous theta-burst stimulation. • Higher microsaccade rates prior to target appearance were observed in FEF, compared to, vertex stimulation. • Larger rebound in microsaccade occurrence following salient stimuli was obtained with FEF stimulation. • The microsaccade direction modulation after background luminance changes was disrupted with FEF stimulation. • The FEF is involved in the control of human microsaccade generation. [ABSTRACT FROM AUTHOR]

Long-term depression (LTD) is a form of physiologic plasticity that is important for reversal learning and may be linked to major depression. Few studies have examined LTP-like plasticity in patients with depression. It is unclear if continuous theta burst stimulation (cTBS) induced LTD is altered in depression patients. Here we recruited 29 healthy control subjects and 31 female patients with depression. We performed cTBS protocol on left motor cortex and employed motor evoked potentials (MEPs) response to measure LTD-like plasticity. Peripheral molecules were measured for correlation analyses to cortical plasticity. Our results revealed persistent LTD-like plasticity deficits in female patients with depression. LTD-like plasticity was impaired in patients with depression despite the fact that peripheral concentrations of BDNF were comparable to that of healthy subjects. Conclusions: Our findings provide evidence for impaired LTD-like plasticity in patients with depression which may be an important mechanism linked to the pathophysiology and treatment of this disorder. • Our results revealed persistent LTD-like plasticity deficits in female patients with depression. • LTD-like plasticity was impaired in MDD despite the fact that BDNF were comparable to that of healthy subjects. • Impaired LTD-like plasticity may an important mechanism linked to the pathophysiology and treatment of this disorder. [ABSTRACT FROM AUTHOR]

• cTBS modulates the excitability of pyramidal neuron in cortex by enhancing phasic inhibition. • In chronic phase of stroke, phasic inhibition is elevated while glutamate-mediated excitatory signaling remains normal. • In chronic phase of stroke, the enhanced phasic inhibition by cTBS promotes stroke recovery. Continuous theta burst stimulation (cTBS) has been widely recognized as a therapeutic treatment for ischemic stroke, but the underlying mechanism is still elusive. Here, we investigated the protective effects of cTBS in the posterior parietal cortex during the chronic phase of stroke in the photothrombotic ischemic model. Infarction volume and neuron excitability in the peri-infarct area were assessed using immunohistochemistry and whole-cell patch-clamp. Spatial cognitive function was measured using the Morris water maze. Gamma-Amino butyric acid (GABA) interneurons were responsive to cTBS, and cTBS induced elevated phasic inhibition rather than tonic inhibition. Given that GABA -A -mediated phasic inhibition was elevated during the chronic phase of ischemic stroke for 30 days and was beneficial for stroke recovery, we investigated the therapeutic potential of cTBS in promoting functional recovery and found that the elevated phasic inhibition by cTBS improved spatial cognitive function in the photothrombotic stroke mouse model with induction in the posterior parietal cortex. Our study indicates the mechanism by which cTBS may modify the excitability of the brain cortex and provides novel insight into the potential of cTBS to protect against neuronal dysfunction in ischemic stroke. [ABSTRACT FROM AUTHOR]

Objective Continuous tetha burst stimulation (cTBS) protocol mainly consists of 3 stimulus bursts repeating every 200 ms at 50 Hz and It has been interpreted that cTBS had inhibitory effects on human motor cortex. On the other hand, there are some reports that 50 Hz cTBS had variability within and between subjects on cortical excitability. In addition, little was known about the effect of different cTBS modalities. The objective of this study is to investigate the effects of 50 Hz, 30 Hz and 100 Hz cTBS on motor cortical excitability healthy subjects. Method Resting motor treshold (rMT), short interval intracortical inhibition (SICI), intracortical facilitation (ICF) and motor evoked potential (MEP) amplitude were studied in 30 healthy subjects. Conditioning stimuli was 80% of rMT and test stimuli was 120% of rMT during SICI and ICF studies. rMT, MEP, SICI and ICF tests were repeated at just after and 30 min later than first 30, 50 and 100 Hz cTBS studies. Results In consistent with the current literature 50 Hz cTBS has inhibitory effects on MEP responses. 30 Hz cTBS has more greater inhibition than 50 Hz cTBS. On the other hand 100 Hz cTBS has facilitatory effects on cortical excitability. Discussion The effects of cTBS on motor cortical excitability depend on the studied paradigm. These results should be considered for selection of the research protocols or therapeutic application of cTBS. [ABSTRACT FROM AUTHOR]