Transcranial Magnetic Stimulation Paradigm Research Articles

Investigation of the transcallosal ventral premotor cortex connection in humans using transcranial magnetic stimulation

Background: The premotor cortex plays a role in the planning of movement. Previous transcranial magnetic stimulation (TMS) studies have shown ipsilateral premotor-to-motor inhibition in healthy subjects at rest. Moreover, this premotor-to-motor inhibition has been found to be modulated during preparation for movement, such as precision grip and whole hand grasp. Cooperation between the bilateral ventral premotor cortices may play a functional role. We aimed to investigate the influence of the contralateral on the ipsilateral ventral premotor cortex.Methods: Fourteen right-handed healthy subjects (six women and eight men; mean age, 37 years; standard deviation, 14 years) completed the study. We used a three single-pulse TMS paradigm (preconditioning, conditioning and test pulse) to sequentially stimulate the right ventral premotor cortex, left ventral premotor cortex and left primary motor cortex.Results: We found that in healthy subjects at rest, stimulating the contralateral ventral premotor cortex resulted in reversal of the resting premotor-to-motor inhibition.Conclusions: Our results suggest that the contralateral ventral premotor cortex exerts an inhibitory influence on the ipsilateral ventral premotor cortex, which may be a component of bi-hemispheric control of manual tasks. This is the first study to evaluate the functional connectivity between the bilateral ventral premotor cortices.

Heightened Reticulospinal Excitability after Severe Corticospinal Damage in Chronic Stroke.

After severe corticospinal tract damage poststroke in humans, some recovery of strength and movement proximally is evident. It is possible that alternate motor pathways, such as the reticulospinal tract, may be upregulated to compensate for the loss of corticospinal tract input. We investigated the extent of reticulospinal tract excitability modulation and its inter-dependence on the severity of corticospinal tract damage after stroke in humans. We used a novel startle conditioned transcranial magnetic stimulation paradigm to elicit ipsilateral motor evoked potentials, an index of reticulospinal tract excitability, in 22 chronic stroke participants with mild to severe corticospinal tract damage and 14 neurotypical age-matched controls. We found that ipsilateral motor evoked potential presence was higher in the paretic arm of people with severe corticospinal tract damage compared to their non-paretic arm, people with mild corticospinal tract damage, and age-matched controls. Interestingly, ipsilateral motor evoked potential presence was correlated with motor impairment across the entire stroke cohort, whereby individuals with worse impairment exhibited more frequent ipsilateral motor evoked potentials (ie, higher reticulospinal tract excitability). Following severe corticospinal tract damage, upregulated reticulospinal tract activity may compensate for a loss of corticospinal tract input, providing some proximal recovery of isolated and within-synergy movements, but deficits in performing out of synergy movements and finger fractionation remain. Interventions aimed at modulating the reticulospinal tract could be beneficial or detrimental to ameliorating motor impairment depending on the degree of reliance on this pathway for residual motor output. ANN NEUROL 2024.

Auditory confounds can drive online effects of transcranial ultrasonic stimulation in humans.

Transcranial ultrasonic stimulation (TUS) is rapidly emerging as a promising non-invasive neuromodulation technique. TUS is already well-established in animal models, providing foundations to now optimize neuromodulatory efficacy for human applications. Across multiple studies, one promising protocol, pulsed at 1000 Hz, has consistently resulted in motor cortical inhibition in humans (Fomenko et al., 2020). At the same time, a parallel research line has highlighted the potentially confounding influence of peripheral auditory stimulation arising from TUS pulsing at audible frequencies. In this study, we disentangle direct neuromodulatory and indirect auditory contributions to motor inhibitory effects of TUS. To this end, we include tightly matched control conditions across four experiments, one preregistered, conducted independently at three institutions. We employed a combined transcranial ultrasonic and magnetic stimulation paradigm, where TMS-elicited motor-evoked potentials (MEPs) served as an index of corticospinal excitability. First, we replicated motor inhibitory effects of TUS but showed through both tight controls and manipulation of stimulation intensity, duration, and auditory masking conditions that this inhibition was driven by peripheral auditory stimulation, not direct neuromodulation. Furthermore, we consider neuromodulation beyond driving overall excitation/inhibition and show preliminary evidence of how TUS might interact with ongoing neural dynamics instead. Primarily, this study highlights the substantial shortcomings in accounting for the auditory confound in prior TUS-TMS work where only a flip-over sham and no active control was used. The field must critically reevaluate previous findings given the demonstrated impact of peripheral confounds. Furthermore, rigorous experimental design via (in)active control conditions is required to make substantiated claims in future TUS studies. Only when direct effects are disentangled from those driven by peripheral confounds can TUS fully realize its potential for research and clinical applications.

Auditory confounds can drive online effects of transcranial ultrasonic stimulation in humans

Transcranial ultrasonic stimulation (TUS) is rapidly emerging as a promising non-invasive neuromodulation technique. TUS is already well-established in animal models, providing foundations to now optimize neuromodulatory efficacy for human applications. Across multiple studies, one promising protocol, pulsed at 1000 Hz, has consistently resulted in motor cortical inhibition in humans (Fomenko et al., 2020). At the same time, a parallel research line has highlighted the potentially confounding influence of peripheral auditory stimulation arising from TUS pulsing at audible frequencies. In this study, we disentangle direct neuromodulatory and indirect auditory contributions to motor inhibitory effects of TUS. To this end, we include tightly matched control conditions across four experiments, one preregistered, conducted independently at three institutions. We employed a combined transcranial ultrasonic and magnetic stimulation paradigm, where TMS-elicited motor-evoked potentials (MEPs) served as an index of corticospinal excitability. First, we replicated motor inhibitory effects of TUS but showed through both tight controls and manipulation of stimulation intensity, duration, and auditory masking conditions that this inhibition was driven by peripheral auditory stimulation, not direct neuromodulation. Furthermore, we consider neuromodulation beyond driving overall excitation/inhibition and show preliminary evidence of how TUS might interact with ongoing neural dynamics instead. Primarily, this study highlights the substantial shortcomings in accounting for the auditory confound in prior TUS-TMS work where only a flip-over sham and no active control was used. The field must critically reevaluate previous findings given the demonstrated impact of peripheral confounds. Furthermore, rigorous experimental design via (in)active control conditions is required to make substantiated claims in future TUS studies. Only when direct effects are disentangled from those driven by peripheral confounds can TUS fully realize its potential for research and clinical applications.

Effects of the motor cortical theta-burst transcranial-focused ultrasound stimulation on the contralateral motor cortex.

Theta-burst transcranial ultrasound stimulation (tbTUS) increases primary motor cortex (M1) excitability for at least 30min. However, the remote effects of focal M1 tbTUS on the excitability of other cortical areas are unknown. Here, we examined the effects of left M1 tbTUS on right M1 excitability. An 80s train of active or sham tbTUS was delivered to the left M1 in 20healthy subjects. Before and after the tbTUS, we measured: (1) corticospinal excitability using motor-evoked potential (MEP) amplitudes from single-pulse transcranial magnetic stimulation (TMS) of left and right M1; (2) interhemispheric inhibition (IHI) from left to right M1 and from right to left M1 using a dual-site paired-pulse TMS paradigm; and (3) intracortical circuits of the right M1 with short-interval intracortical inhibition and intracortical facilitation (ICF) using paired-pulse TMS. Left M1 tbTUS decreased right M1 excitability as shown by decreased MEP amplitudes, increased right M1 ICF and decreased short-interval IHI from left to right hemisphere at interstimulus interval (ISI) of 10ms but not long-interval IHI at interstimulus interval of 40ms. The study showed that left M1 tbTUS can change the excitability of remote cortical areas with decreased right M1 excitability and interhemispheric inhibition. The remote effects of tbTUS should be considered when it is used in neuroscience research and as a potential neuromodulation treatment for brain disorders. KEY POINTS: Transcranial ultrasound stimulation (TUS) is a novel non-invasive brain stimulation technique for neuromodulation with the advantages of being able to achieve high spatial resolution and target deep brain structures. A repetitive TUS protocol, with an 80s train of theta burst patterned TUS (tbTUS), has been shown to increase primary motor cortex (M1) excitability, as well as increase alpha and beta movement-related spectral power in distinct brain regions. In this study, we examined on the effects of the motor cortical tbTUS on the excitability of contralateral M1measured with MEPs elicited by transcranial magnetic stimulation. We showed that left M1 tbTUS decreased right M1 excitability and left-to-right M1 interhemispheric inhibition, and increased intracortical facilitation of right M1. These results lead to better understand the effects of tbTUS and can help the development of tbTUS for the treatment of neurological and psychiatric disorders and in neuroscience research.

The paired-pulse TMS paradigm of short intracortical inhibition is mediated by a reduction of repetitive motor neuron discharges.

Transcranial magnetic stimulation (TMS) causes repetitive spinal motoneuron discharges (repMNDs), but the effects of short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) on repMNDs remain unknown. Triple stimulation technique (TST) and the extended TST-protocols that include a fourth and fifth stimulation, the Quadruple (QuadS) and Quintuple (QuintS) stimulation, respectively, offer a precise estimate of cortical and spinal motor neuron discharges, including repMNDs. The objective of our study was to explore the effects of SICI and ICF on repMNDs. We explored conventional paired-pulse TMS protocols of SICI and ICF with the TMS, TST, the QuadS, and the QuintS protocols, in a randomized study design in 20 healthy volunteers. We found significantly less repMNDs in the SICI paradigm compared with a single-pulse TMS (SP-TMS). No significant difference was observed in the ICF paradigm. There was a significant inter- and intrasubject variability in both SICI and ICF. We demonstrate a significant reduction of repMNDs in SICI, which may result from the suppression of later I-waves and mediate the inhibition of motor-evoked potential (MEP). There is no increase in repMNDs in ICF suggesting another mechanism underlying facilitation. This study provides the proof that a reduction of repMNDs mediates the inhibition seen in SICI.NEW & NOTEWORTHY Significant reduction of repetitive motor neuron discharges (repMNDs) in short-interval intracortical inhibition (SICI) may result from the suppression of later I-waves and mediate the inhibition of motor-evoked potential (MEP). There is no change in the number of repMNDs in intracortical facilitation (ICF). There was a significant variability in SICI and ICF in healthy subjects.

Mapping the Cortical Representation of Paraspinal Muscles Using Transcranial Magnetic Stimulation Optimized in People With Chronic Back Pain.

Chronic low back pain (CLBP) is a global burden with an unknown etiology. Reorganization of the cortical representation of paraspinal muscles in the primary motor cortex (M1) may be related to the pathology. Single-pulse transcranial magnetic stimulation (TMS), commonly used to map the functional organization of M1, is not potent enough to stimulate the cortical maps of paraspinal muscles in M1 in CLBP patients with reduced corticospinal excitability (CSE) with intensities even as high as maximum stimulator output (100% MSO). This makes TMS mapping impractical for these patients. The aim of this study was to increase the practicality of TMS mapping for people with CLBP. This study included eight men and ten women who had CLBP for over three months. A biphasic paired-pulse TMS paradigm, conjunct anticipatory postural adjustment (APA), and maximal voluntary activation of paraspinal muscles (MVC) were used to facilitate TMS mapping. TMS mapping was possible in all CLBP participants, with TMS intensities <50% of the MSO. Reorganization in terms of an anterior and lateral shift of the center of gravity (COG) of the cortical maps of paraspinal muscles was observed in all participants with CLBP, and a reduced number of discrete peaks was found in 33%. The facilitation of the CSE to paraspinal muscles makes TMS mapping more practical and tolerable in people with CLBP, lowering the risk of seizure and discomfort associated with high-intensity TMS pulses. Conventional transcranial magnetic stimulation (TMS) brain mapping is not optimal for patients with Chronic low back pain (CLBP).Paired-pulse TMS dramatically lessens the energy needed for brain mapping.Maximal voluntary contraction of back muscles facilitates TMS mapping.Anticipatory postural activity of back muscles enhances the efficacy of TMS mapping. Chronic low back pain (CLBP) is a social, emotional, and economic burden and the leading cause of disability worldwide. Yet the etiology of the CLBP is unknown. The persistence of aberrant or antalgic movement patterns observed in people with CLBP has been suggested as a possible cause of pain chronification by inducing continuous damage to sensitive structures of the lumbar spine. It is well known that the brain is in charge of the production and planning of movements, so it is likely that abnormal movement patterns also stem from the abnormalities in the brain. However, until recently, human knowledge about the structure and function of the brain has been very limited. The invention of noninvasive and painless brain imaging and stimulating techniques such as transcranial magnetic stimulation (TMS) during the last decades has augmented our knowledge about the structure and function of the brain. Modification in terms of shift, shrinkage, or expansion of areas of the brain devoted to movement control or sensation of the back muscles has been documented in CLBP via these techniques, which are argued to relate to pain chronification but need further clarification. Yet monitoring the course of CLBP via TMS, despite its many potentials, is challenging. This could be due to the reduced cortical drive to back muscles in CLBP patients and the small area devoted to control of back muscles in the brain in general that increases the brain threshold to TMS in people with CLBP. The aim of this study was to tailor an approach to make TMS more applicable for CLBP patients by reducing the threshold to TMS. This could be achieved by engaging back muscles in anticipatory postural activity in combination with maximal voluntary activation of these muscles, along with TMS paradigms that induce intracortical facilitation.

The use of theta burst stimulation in patients with schizophrenia - A systematic review.

Transcranial magnetic stimulation (TMS) can offer therapeutic benefits and provide value in neurophysiological research. One of the newer TMS paradigms is theta burst stimulation (TBS) which can be delivered in two patterns: continuous (cTBS - inducing LTD-like effects) and intermittent (iTBS - inducing LTP-like effects). This review paper aims to explore studies that have utilized TBS protocols over different areas of the cortex to study the neurophysiological functions and treatment of patients with schizophrenia. PubMed was searched using the following keywords "schizophrenia", "schizoaffective", or "psychosis", and "theta burst stimulation". Out of the 90 articles which were found, thirty met review inclusion criteria. The inclusion criteria included studying the reported effect (clinical, physiological, or both) of at least one session of TBS on human subjects, and abstracts (at minimum) must have been in English. The main target areas included prefrontal cortex (12 studies - 10 dorsolateral prefrontal cortex (DLPFC), 2 dorsomedial prefrontal cortex (DMPFC)) vermal cerebellum (5), and temporo-parietal cortex (8). Other target areas included inferior parietal lobe (2), and motor cortex (3). TBS neurophysiological effect was explored in 5 studies using functional magnetic resonance image (fMRI), magnetic resonance spectroscopy (MRS), electroencephalography (EEG), electromyography (EMG) and positron emission topography (PET) scan. Overall, TBS can offer great therapeutic potential as it is well-tolerated, feasible, and has few, if any, adverse effects. TBS may be targeted to treat specific symptomatology, as an augmenting intervention to pharmacotherapy, or even improving patient's insight into their diagnosis.

The antidepressant effect of intermittent theta burst stimulation (iTBS): study protocol for a randomized double-blind sham-controlled trial

BackgroundIntermittent theta burst stimulation (iTBS) when applied over the left dorsolateral prefrontal cortex (DLPFC) has been shown to be equally effective and safe to treat depression compared to traditional repetitive transcranial magnetic stimulation (rTMS) paradigms. This protocol describes a funded single-centre, double-blind, randomized placebo-controlled, clinical trial to investigate the antidepressive effects of iTBS and factors associated with an antidepressive response.MethodsIn this trial, outpatients (N = 96, aged 22–65 years) meeting the diagnostic criteria for at least moderate depression (Montgomery and Aasberg Depression Rating Scale score ≥ 20) will be enrolled prospectively and receive ten, once-a-day sessions of either active iTBS or sham iTBS to the left DLPFC, localized via a neuronavigation system. Participants may have any degree of treatment resistance. Prior to stimulation, participants will undergo a thorough safety screening and a brief diagnostic assessment, genetic analysis of brain-derived neurotropic factor, 5-HTTLPR and 5-HT1A, and cerebral MRI assessments. A selection of neuropsychological tests and questionnaires will be administered prior to stimulation and after ten stimulations. An additional follow-up will be conducted 4 weeks after the last stimulation. The first participant was enrolled on June 4, 2022. Study completion will be in December 2027. The project is approved by the Regional Ethical Committee of Medicine and Health Sciences, Northern Norway, project number 228765. The trial will be conducted according to Good Clinical Practice and published safety guidelines on rTMS treatment.DiscussionThe aims of the present trial are to investigate the antidepressive effect of a 10-session iTBS protocol on moderately depressed outpatients and to explore the factors that can explain the reduction in depressive symptoms after iTBS but also a poorer response to the treatment. In separate, but related work packages, the trial will assess how clinical, cognitive, brain imaging and genetic measures at baseline relate to the variability in the antidepressive effects of iTBS.Trial registrationClinicalTrials.gov NCT05516095. Retrospectively registered on August 25, 2022.

The long-term effects of intermittent theta burst stimulation on Alzheimer's disease-type pathologies in APP/PS1 mice

Intermittent theta burst stimulation (iTBS), an emerging and highly efficient paradigm of repetitive transcranial magnetic stimulation (rTMS), has been demonstrated to mitigate cognitive impairment in Alzheimer's disease. Previous clinical studies have shown that the cognitive improvement of iTBS could last several weeks after treatment. Nonetheless, it is largely uncertain how the long-term effects of iTBS treatment are sustained. To investigate whether iTBS has a long-term effect on AD-type pathologies, 6-month-old APP/PS1 mice are administrated with 30 consecutive days of iTBS treatment. After a 2-month interval, morphological alterations in the brain are examined by immunohistochemistry and immunofluorescence staining, while levels of associated proteins are assessed by Western blot at the age of 9 months. We find that iTBS treatment significantly diminishes Aβ burden in the cerebral cortex and hippocampus of APP/PS1 mice. Moreover, we observe that iTBS treatment inhibits the expression of BACE1 and elevates the level of IDE, suggesting that the reduction of Aβ load could be attributed to the inhibition of Aβ production and facilitation of Aβ degradation. Furthermore, iTBS treatment attenuates neuroinflammation, neuronal apoptosis, and synaptic loss in APP/PS1 mice. Collectively, these data indicate that 1 month of iTBS treatment ameliorates pathologies in the brain of AD mice for at least 2 months. We provide the novel evidence that iTBS may exert after-effects on AD-type pathologies via inhibition of Aβ production and facilitation of Aβ degradation.

Effects of theta burst stimulation on the coherence of local field potential during working memory task in rats

Theta burst stimulation (TBS), a highly efficient repetitive transcranial magnetic stimulation (rTMS) paradigm, has been widely used to modulate the working memory (WM) ability in experimental and clinical study. However, the underly neuroelectrophysiological mechanism remains unclear. The aim of this study was to compare the effect of iTBS, cTBS and rTMS on WM and explore the neural oscillatory communication changes in PFC involved in spatial WM task. 18 rats were treated by iTBS, cTBS and rTMS respectively (n = 6 each), while the rats in control group (n = 6) received no stimulation. T-maze WM task was used to assess the rats’ performance of WM after stimulation. Local field potentials (LFPs) were recorded from a microelectrode array implanted in the medial prefrontal cortex (mPFC) while the rats were performing the WM task. Functional connectivity (FC) strength was assessed by LFP–LFP coherence calculations. The results showed that the rats from the rTMS group and iTBS group are able to reach criteria in less time than the control group's duration of the T-maze task. The power and the coherence value of rTMS and iTBS groups show a significant increase in the theta-band and gamma-band activity, wheras there are no significant differences of the energy and the coherence value between the cTBS group and the control group in theta-band. Furthermore, significantly positive correlations were observed between changes of memory performance during the WM task and the changes of the coherence value of the LFPs. In conclusion, these results indicate that rTMS and iTBS may improve the ability of WM by modulating the neural activity and connectivity in PFC.

Dose and time-dependence of acute intermittent theta-burst stimulation on hippocampus-dependent memory in parkinsonian rats.

The treatment options for cognitive impairments in Parkinson's disease (PD) are limited. Repetitive transcranial magnetic stimulation has been applied in various neurological diseases. However, the effect of intermittent theta-burst stimulation (iTBS) as a more developed repetitive transcranial magnetic stimulation paradigm on cognitive dysfunction in PD remains largely unclear. Our aim was to explore the effect of acute iTBS on hippocampus-dependent memory in PD and the mechanism underlying it. Different blocks of iTBS protocols were applied to unilateral 6-hydroxidopamine-induced parkinsonian rats followed by the behavioral, electrophysiological and immunohistochemical analyses. The object-place recognition and hole-board test were used to assess hippocampus-dependent memory. Sham-iTBS and 1 block-iTBS (300 stimuli) didn't alter hippocampus-dependent memory, hippocampal theta rhythm and the density of c-Fos- and parvalbumin-positive neurons in the hippocampus and medial septum. 3 block-iTBS (900 stimuli) alleviated 6-hydroxidopamine-induced memory impairments, and increased the density of hippocampal c-Fos-positive neurons at 80 min post-stimulation but not 30 min compared to sham-iTBS. Interestingly, 3 block-iTBS first decreased and then increased normalized theta power during a period of 2 h following stimulation. Moreover, 3 block-iTBS decreased the density of parvalbumin-positive neurons in the medial septum at 30 min post-stimulation compared to sham-iTBS. The results indicate that multiple blocks of iTBS elicit dose and time-dependent effects on hippocampus-dependent memory in PD, which may be attributed to changes in c-Fos expression and the power of theta rhythm in the hippocampus.

No Polarity-specific Modulation of Prefrontal-to-M1 Interhemispheric Inhibition by Transcranial Direct Current Stimulation Over the Lateral Prefrontal Cortex

The lateral prefrontal cortex (PFC) plays a variety of crucial roles in higher-order cognitive functions. Previous works have attempted to modulate lateral PFC function by applying non-invasive transcranial direct current stimulation (tDCS) and demonstrated positive effects on performance of tasks involving cognitive processes. The neurophysiological underpinning of the stimulation effects, however, remain poorly understood. Here, we explored the neurophysiological after-effects of tDCS over the lateral PFC by assessing changes in the magnitude of interhemispheric inhibition from the lateral PFC to the contralateral primary motor cortex (PFC-M1 IHI). Using a dual-site transcranial magnetic stimulation paradigm, we assessed PFC-M1 IHI before and after the application of tDCS over the right lateral PFC. We conducted a double-blinded, crossover, and counterbalanced design where 15 healthy volunteers participated in three sessions during which they received either anodal, cathodal, and sham tDCS. In order to determine whether PFC-M1 IHI could be modulated at all, we completed the same assessment on a separate group of 15 participants as they performed visuo-motor reaction tasks that likely engage the lateral PFC. The results showed that tDCS over the right lateral PFC did not modulate the magnitude of PFC-M1 IHI, whereas connectivity changed when Go/NoGo decisions were implemented in reactions during the motor tasks. Although PFC-M1 IHI is sensitive enough to be modulated by behavioral manipulations, tDCS over the lateral PFC does not have substantial modulatory effects on PFC to M1 functional connectivity, or at least not to the degree that can be detected with this measure.

Effects of the Left M1 iTBS on Brain Semantic Network Plasticity in Patients with Post-Stroke Aphasia: A Preliminary Study.

The left primary motor area (M1) stimulation has recently been revealed to promote post-stroke aphasia (PSA) recovery, of which a plausible mechanism might be the semantic and/or the mirror neuron system reorganization, but the direct evidence is still scarce. The aim of this study was to explore the functional connectivity (FC) alterations induced by the left M1 intermittent theta burst stimulation (iTBS), a new transcranial magnetic stimulation paradigm, in the semantic and mirror neuron systems of PSA patients. Sixteen PSA patients accepted the left M1 iTBS and underwent a resting-state functional magnetic resonance image (fMRI) scanning before and immediately after the first session of iTBS, of which six underwent another fMRI scanning after twenty sessions of iTBS. Three brain networks covering the semantic and the mirror neuron systems were constructed using the fMRI data, and the FC alterations following one-session iTBS were investigated in the networks. Additional seed-based FC analyses were conducted to explore the longitudinal FC patterns changes during the course of multi-session iTBS. The Aphasia quotient of the Chinese version of the western aphasia battery (WAB-AQ) was used to assess the severity of the language impairments of the participants. The relationship between the longitudinal WAB-AQ and network FC changes was analyzed by Spearman's correlation coefficients in the multi-session iTBS sub-group. Decreased FCs were noted in the bilateral semantic rather than in the mirror neuron networks following one-session of iTBS (p < 0.05, network based statistical corrected). Longitudinal seed-based FC analyses revealed changing FC ranges along the multi-session iTBS course, extending beyond the semantic networks. No significant relationship was found between the longitudinal WAB-AQ and network FC changes in the multi-session iTBS sub-group. The left M1 iTBS might induce FC changes in the semantic system of PSA patients. This research was registered on the Chinese Clinical Trial Registry website (http://www.chictr.org.cn/index.aspx), and the registration number is ChiCTR2100041936.

Continuous theta burst stimulation-induced suppression of the right fronto-thalamic-cerebellar circuit accompanies improvement in language performance in poststroke aphasia: A resting-state fMRI study.

Continuous theta burst stimulation (cTBS) is a specific paradigm of repetitive transcranial magnetic stimulation (rTMS) with an inhibitory effect on cortical excitability for up to 60 min after less than 1 min of stimulation. The right posterior superior temporal gyrus (pSTG), homotopic to Wernicke's area in the left hemisphere, may be a potential stimulation target based on its critical role in semantic processing. The objective of this study was to explore whether cTBS over the right pSTG can promote language improvements in aphasic patients and the underlying mechanism. A total of 34 subjects with aphasia were randomly assigned to undergo 15 sessions of either 40-s inhibitory cTBS over the right pSTG (the cTBS group) or sham stimulation (the sham group), followed by 30 min of speech and language therapy. Subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI), and the aphasia quotient (AQ) of the Chinese version of the Western Aphasia Battery (WAB) was calculated before and after the intervention. This randomized controlled trial was registered in the Chinese Clinical Trial Registry (No. ChiCTR210052962). After treatment, the language performance of the cTBS group was higher than that of the sham group in terms of the WAB-AQ score (p = 0.010) and the WAB scores for auditory comprehension (p = 0.022) and repetition (p = 0.035). The fractional amplitude of low-frequency fluctuations (fALFF) was significantly decreased in the pars triangularis of the inferior frontal gyrus (IFG), right middle frontal gyrus, right thalamus, and left cerebellar crus I. Clusters in the left orbitofrontal cortex exhibited increased fALFF. The change in WAB comprehension scores were significantly correlated with the change in the fALFF of the right IFG pars triangularis in both groups. Greatly increased functional connectivity was observed between the right pars triangularis and left paracingulate gyrus and between the right pSTG and right angular gyrus and the posterior cingulate gyrus with pre-and post-treatment between the two groups. Our findings indicate that cTBS of the right pSTG may improve language production by suppressing intrinsic activity of the right fronto-thalamic-cerebellar circuit and enhancing the involvement of the right temporoparietal region.

Efficacy and Safety of Bilateral Sequential Theta Burst Transcranial Magnetic Stimulation in Bipolar Depression: Result From an Observational Study

The majority of functional impairment in bipolar disorder occurs during the depressed phase of illness, which is frequently resistant to established interventions. In attempting to meet the ongoing need for experimental treatments, transcranial magnetic stimulation (TMS) trials have had varying effects on bipolar depression. The variable efficacy of TMS for bipolar depression highlights an unmet need to define the most optimal TMS settings for the specific syndrome of bipolar depression, and suggests the need for augmented TMS paradigms.

Intracortical facilitation and inhibition in human primary motor cortex during motor skill acquisition

The primary motor cortex (M1) is critical for movement execution, but its role in motor skill acquisition remains elusive. Here, we examine the role of M1 intracortical circuits during skill acquisition. Paired-pulse transcranial magnetic stimulation (TMS) paradigms of short-interval intracortical facilitation (SICF) and inhibition (SICI) were used to assess excitatory and inhibitory circuits, respectively. We hypothesised that intracortical facilitation and inhibition circuits in M1 would be modulated to support acquisition of a novel visuomotor skill. Twenty-two young, neurologically healthy adults trained with their nondominant hand on a skilled and non-skilled sequential visuomotor isometric finger abduction task. Electromyographic recordings were obtained from the nondominant first dorsal interosseous (FDI) muscle. Corticomotor excitability, SICF, and SICI were examined before, at the midway point, and after the 10-block motor training. SICI was assessed using adaptive threshold-hunting procedures. Task performance improved after the skilled, but not non-skilled, task training, which likely reflected the increase in movement speed during training. The amplitudes of late SICF peaks were modulated with skilled task training. There was no modulation of the early SICF peak, SICI, and corticomotor excitability with either task training. There was also no association between skill acquisition and SICF or SICI. The findings indicate that excitatory circuitries responsible for the generation of late SICF peaks, but not the early SICF peak, are modulated in motor skill acquisition for a sequential visuomotor isometric finger abduction task.

Motor Resonance During Action Observation and Its Relevance to Virtual Clinical Consultations: Observational Study Using Transcranial Magnetic Stimulation.

Virtual clinical interactions have increased tremendously since the onset of the COVID-19 pandemic. While they certainly have their advantages, there also exist potential limitations, for example, in establishing a therapeutic alliance, discussing complex clinical scenarios, etc. This may be due to possible disruptions in the accurate activation of the human mirror neuron system (MNS), a posited physiological template for effective social communication. This study aimed to compare motor resonance, a putative marker of MNS activity, estimated using transcranial magnetic stimulation (TMS) elicited while viewing virtual (video-based) and actual or real (enacted by a person) actions in healthy individuals. We hypothesized that motor resonance will be greater during real compared to virtual action observation. We compared motor resonance or motor-evoked potential (MEP) facilitation during the observation of virtual (presented via videos) and real (enacted in person) actions, relative to static image observation in healthy individuals using TMS. The MEP recordings were obtained by 2 single-pulse (neuronal membrane excitability-driven) TMS paradigms of different intensities and 2 paired-pulse (cortical gamma-aminobutyric acid-interneuron-driven) TMS paradigms. This study comprised 64 participants. Using the repeated measures ANOVA, we observed a significant time effect for MEP facilitation from static to virtual and real observation states when recorded using 3 of the 4 TMS paradigms. Post hoc pairwise comparisons with Benjamini-Hochberg false discovery rate correction revealed significant MEP facilitation in both virtual and real observation states relative to static image observation; however, we also observed a significant time effect between the 2 action observation states (real > virtual) with 2 of the 4 TMS paradigms. Our results indicate that visual cues expressed via both virtual (video) or real (in person) modes elicit physiological responses within the putative MNS, but this effect is more pronounced for actions presented in person. This has relevance to the appropriate implementation of digital health solutions, especially those pertaining to mental health.

High-frequency oscillations-based precise temporal resolution of short latency afferent inhibition in the human brain

ObjectiveSensorimotor integration is a crucial process for adaptive behaviour and can be explored non-invasively with a conditioned transcranial magnetic stimulation (TMS) paradigm - i.e. short-latency afferent inhibition (SAI). To gain insight into the sensorimotor integration phenomenon, we used two different approaches to combine peripheral and cortical stimulation in the SAI paradigm, measuring not only the latency of low frequency somatosensory evoked potentials (SEPs) but also the peaks of high frequency oscillations (HFOs) underlying SEPs. MethodsThe interstimulus intervals (ISIs) between the electrical stimulation of the median nerve and the motor cortex magnetic stimulation were determined relative to the latency of the earliest SEPs cortical potential (N20) or the HFOs peaks. In particular, the first and last negative and positive peaks of HFOs were extracted through a custom-made MATLAB script. ResultsThirty-three healthy subjects participated in this study. We found out that muscle responses after TMS were suppressed when ISIs were comprised between –1 to +3 ms relative to the N20 peak and at all ISIs relative to HFOs peaks, except for the first negative peak. ConclusionsCoupling peripheral and cortical stimulation at early interstimulus intervals – before the SEPs N20 peak - may modulate muscle response. SignificanceOur findings confirm that afferent inhibition is produced both through a direct (thalamus-motor cortex) and indirect (thalamus-somatosensory-motor cortex) pathway.

Spatially bivariate EEG-neurofeedback can manipulate interhemispheric inhibition.

Human behavior requires inter-regional crosstalk to employ the sensorimotor processes in the brain. Although external neuromodulation techniques have been used to manipulate interhemispheric sensorimotor activity, a central controversy concerns whether this activity can be volitionally controlled. Experimental tools lack the power to up- or down-regulate the state of the targeted hemisphere over a large dynamic range and, therefore, cannot evaluate the possible volitional control of the activity. We addressed this difficulty by using the recently developed method of spatially bivariate electroencephalography (EEG)-neurofeedback to systematically enable the participants to modulate their bilateral sensorimotor activities. Here, we report that participants learn to up- and down-regulate the ipsilateral excitability to the imagined hand while maintaining constant contralateral excitability; this modulates the magnitude of interhemispheric inhibition (IHI) assessed by the paired-pulse transcranial magnetic stimulation (TMS) paradigm. Further physiological analyses revealed that the manipulation capability of IHI magnitude reflected interhemispheric connectivity in EEG and TMS, which was accompanied by intrinsic bilateral cortical oscillatory activities. Our results show an interesting approach for neuromodulation, which might identify new treatment opportunities, e.g., in patients suffering from a stroke.