Objective.Cerebellar transcranial magnetic stimulation (TMS) has been proposed to suppress limb tremors in essential tremor (ET), but mixed results have been reported so far, both when pulses are applied repetitively TMS (rTMS) and in bursts. We aim to investigate the cellular effects of TMS on the cerebellum under ET through numerical simulations.Approach.A computational model of the olivo-cerebello-thalamocortical pathways exhibiting the main neural biomarkers of ET (i.e. circuit-wide tremor-locked neural oscillations) was expanded to incorporate the effects of TMS-induced electric field (E-field) on Purkinje cells. TMS pulse amplitude, frequency, and temporal pattern were varied, and the resultant effects on ET biomarkers were assessed. Four levels of cellular response to TMS were considered, ranging from low to high cell recruitment underneath the coil, and three stimulation patterns were tested, i.e. rTMS, irregular TMS (ir-TMS, pulses were arranged according to Sobol sequences with average frequency matching rTMS), and phase-locked TMS (PL-TMS).Main results.rTMS can suppress ET oscillations, but its efficacy depends on tremor frequency and recruitment level, with these factors shaping a narrow range of effective settings. The ratio between tremor and rTMS frequencies also affects the neural response and further narrows the span of viable settings, while ir-TMS is ineffective. PL-TMS is highly effective and robust against changes to cell recruitment level and tremor frequency. Across all scenarios, PL-TMS provides a rapid (i.e. within seconds) suppression of tremor oscillations and, when both PL-TMS and rTMS are effective, the time to tremor suppression decreases by 50% or more in PL-TMS versus rTMS. At the cellular level, PL-TMS operates by disrupting the synchronization along the olivo-cerebellar loop, and the preferred phases map onto the mid-region of the silent period between complex spikes of the Purkinje cells.Significance.Cerebellar PL-TMS can provide robust suppression of ET oscillations while operating within safety boundaries.

Repetitive TMS (rTMS) is a powerful neuroscientific tool with the potential to noninvasively identify brain-behavior relationships in humans. Early work suggested that certain rTMS protocols (e.g., continuous theta-burst stimulation, intermittent theta-burst stimulation, high-frequency rTMS, low-frequency rTMS) predictably alter the probability that cortical neurons will fire action potentials (i.e., change cortical excitability). However, despite significant methodological, conceptual, and technical advances in rTMS research over the past few decades, overgeneralization of early rTMS findings has led to a stubbornly persistent assumption that rTMS protocols by their nature induce behavioral and/or physiological inhibition or facilitation, even when they are applied to nonmotor cortical sites or under untested circumstances. In this Perspectives article, we offer a "public service announcement" that summarizes the origins of this problematic assumption, highlighting limitations of seminal studies that inspired them and results of contemporary studies that violate them. Next, we discuss problems associated with holding this assumption, including making brain-behavior inferences without confirming the locality and directionality of neurophysiological changes. Finally, we provide recommendations for researchers to eliminate this misguided assumption when designing and interpreting their own work, emphasizing results of recent studies showing that the effects of rTMS on neurophysiological metrics and their associated behaviors can be caused by mechanisms other than binary changes in excitability of the stimulated brain region or network. Collectively, we contend that no rTMS protocol is by its nature either excitatory or inhibitory, and that researchers must use caution with these terms when forming experimental hypotheses and testing brain-behavior relationships.

The cerebellum, once primarily associated with motor functions, has emerged as a critical component in higher cognitive processes and emotional regulation. This paradigm shift frames the cerebellum as an essential focal point for elucidating sophisticated functional brain circuitry. Network neuroscience often maintains a cortical-centric viewpoint, potentially overlooking the significant contributions of the cerebellum in connectome organization. Enhanced recognition and integration of cerebellar aspects in connectomic analyses hold significant potential for elucidating cerebellar circuitry within comprehensive brain networks and in neuropsychiatric conditions where cerebellar involvement is evident. This review explores the intricate anatomy, connectivity, and functional organization of the cerebellum within the broader context of large-scale brain networks. Cerebellar-specific networks are examined, emphasizing their role in supporting diverse cognitive functions via the cerebellum's hierarchical functional organization. The clinical significance of cerebellar connectomics is then addressed, highlighting the interplay between cerebellar circuitry and neurological and psychiatric conditions. The paper concludes by considering neurostimulation treatments and future directions in the field. This comprehensive review underscores the cerebellum's integral role in the human connectome.

Girls who suffer from central precocious puberty (CPP) are at risk of experiencing detrimental psychological and behavioural consequences, along with impaired brain development. However, the mechanism by which puberty hormones affect patients with CPP remains unclear. This study aimed to use degree centrality (DC) analysis to explore the impact of premature activation of the hypothalamic-pituitary-gonadal (HPG) axis on brain functional development in girls with CPP. In this cross-sectional study, thirty-four girls (mean ± SD, 7.89 ± 0.81 years) with CPP and 25 age-matched girls without CPP (mean ± SD, 7.58 ± 0.73 years) underwent resting-state functional magnetic resonance imaging. We used DC analysis to explore brain network properties in CPP girls compared to non-CPP girls. Seed-based FC analysis was performed to identify the connections responsible for the observed differences. Our findings showed that female CPP patients had increased DC in the posterior lobe of the cerebellum and prefrontal areas and increased functional connectivity (FC) between the posterior lobe of the cerebellum and default mode network (DMN) regions relative to age-matched non-CPP girls. Additionally, compared with non-CPP patients, female CPP patients exhibited decreased DC in the bilateral superior parietal gyri and left superior occipital gyrus and reduced FC between the left superior occipital gyrus and right calcarine. A negative correlation was found between basal follicle-stimulating hormone level and DC of the bilateral superior parietal gyri in girls with CPP. The current research provides evidence that premature activation of the HPG axis is associated with the development of cortical function, particularly involving the posterior lobe of the cerebellum, DMN, and prefrontal, parietal, and occipital cortices. Our findings suggest that girls with CPP require attention and early treatment for cognitive and emotional problems as well as brain development in clinical practice.

The relationships of the gut microbiota-inflammation-brain axis in depressive bipolar disorder (BD) remains under-elaborated. Sixty-five unmedicated depressive patients with BD II and 58 controls (HCs) were prospectively enrolled. Resting-state functional MRI data of static and dynamic amplitude of low-frequency fluctuation (ALFF) was measured, and abnormal ALFF masks were subsequently set as regions of interest to calculate whole-brain static functional connectivity (sFC) and dynamic functional connectivity (dFC). Fecal samples were collected to assess gut diversity and enterotypes using 16S amplicon sequencing. Blood samples were also collected, serum was assayed for levels of cytokines (interleukin [IL]-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor [TNF]-α). Patients with BD II exhibited decreased static ALFF values in the left cerebellum Crus II, and decreased cerebellar sFC and dFC to the right inferior parietal lobule and right superior frontal gyrus, respectively. Moreover, higher pro-inflammatory and anti-inflammatory cytokines levels, and increased proinflammatory bacteria and glutamate and gamma-aminobutyric acid metabolism related bacteria were identified in BD II. The interaction of Parabacteroides levels × IL-8 levels was an independent contributor to static ALFF in the left cerebellar Crus II. The findings bridged a gap in the underlying pathophysiological mechanism of the gut microbiota-inflammation-brain axis in BD II depression.

Theta burst stimulation (TBS) has garnered widespread attention in the scientific community, but a comprehensive bibliometric analysis of TBS research remains absent. This study aims to fill this gap by elucidating the characteristics, hotspots, and trends in TBS publications over the past 20 years using bibliometric methods.

We retrieved TBS-related publications from January 1, 2004, to December 31, 2023, from the Web of Science Core Collection (WoSCC). The analysis focused on articles and review articles. Data were processed using the bibliometric package in R software, and CiteSpace and VOSviewer were employed for bibliometric and knowledge mapping analyses.

A total of 1,206 publications were identified, with 858 included in the analysis. The annual publication volume showed a fluctuating upward trend. Leading institutions and authors were predominantly from the United States of America (USA) and European countries. Core journals and publications also primarily originated from these regions. Current research hotspots include the clinical applications and mechanisms of TBS in neurorehabilitation and depression. TBS cerebellar stimulation has emerged as a promising therapeutic target. Future research is likely to focus on dysphagia, cognitive impairments, and post-traumatic stress disorder.

This bibliometric analysis provides an overview of the basic knowledge structure, research hotspots, and development trends in TBS research over the past two decades. The findings offer valuable insights into the evolving landscape of TBS research and its potential directions.

Working memory refers to the process of temporarily storing and manipulating information. The role of the cerebellum in working memory is thought to be achieved through its connections with the prefrontal cortex. Previous studies showed that theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation, of the cerebellum changes its functional connectivity with the prefrontal cortex. Specifically, excitatory intermittent TBS (iTBS) increases, whereas inhibitory continuous TBS (cTBS) decreases this functional connectivity. We hypothesized that iTBS on the cerebellum will improve working memory, whereas cTBS will disrupt it. Sixteen healthy participants (10 women) participated in this study. Bilateral cerebellar stimulation was applied with a figure-of-eight coil at 3 cm lateral and 1 cm below the inion. The participants received iTBS, cTBS, and sham iTBS in three separate sessions in random order. Within 30 min after TBS, the participants performed four working memory tasks: letter 1-Back and 2-Back, digit span forward, and digit span backward. Repeated measures analysis of variance revealed a significant effect of the type of stimulation (iTBS/cTBS/Sham) on performance in the digit span backward task (p = 0.02). The planned comparison showed that the cTBS condition had significantly lower scores than the sham condition (p = 0.01). iTBS and cTBS did not affect performance in the 1- and 2-Back and the digit span forward tasks compared to sham stimulation. The findings support the hypothesis that the cerebellum is involved in working memory, and this contribution may be disrupted by cTBS.

This editorial assesses the advancements in neuronavigation enhanced repetitive transcranial magnetic stimulation for depressive disorder and schizophrenia treatment. Conventional repetitive transcranial magnetic stimulation faces challenges due to the intricacies of brain anatomy and patient variability. Neuronavigation offers innovative solutions by integrating neuroimaging with three-dimensional localization to pinpoint brain regions and refine therapeutic targeting. This systematic review of recent literature underscores the enhanced efficacy of neuronavigation in improving treatment outcomes for these disorders. This editorial highlights the pivotal role of neuronavigation in advancing psychiatric care.

Neuroimaging techniques have been widely used in the study of epilepsy. However, structural and functional changes in the MRI-negative drug-resistant epilepsy (DRE) and the genetic mechanisms behind the structural alterations remain poorly understood. Using structural and functional MRI, we analyzed gray matter volume (GMV) and regional homogeneity (ReHo) in DRE, drug-sensitive epilepsy (DSE) and healthy controls. Gene expression data from Allen human brain atlas and GMV/ReHo were evaluated to obtain drug resistance-related and epilepsy-associated gene expression and compared with real transcriptional data in blood. We found structural and functional alterations in the cerebellum of DRE patients, which may be related to the mechanisms of drug resistance in DRE. Our study confirms that changes in brain morphology and regional activity in DRE patients may be associated with abnormal gene expression related to nervous system development. And SP1, as an important transcription factor, plays an important role in the mechanism of drug resistance.

To investigate the therapeutic benefits of theta burst stimulation on lower-limb motor dysfunction and balance recovery in patients with stroke.

A literature search was performed across CNKI, CBM, WanFang, VIP, PubMed, Embase, Cochrane Library, and Web of Science until November 2023. The Methodological quality of included studies was assessed by using the Cochrane risk-of-bias tool and the PEDro scale, and the meta-analysis was performed by using RevMan 5.3 software. Two independent researchers screened the literature and extracted basic information on participants, interventions, comparisons, outcomes, and studies.

Eight studies, including cTBS and iTBS, with 290 participants meeting the inclusion criteria for this systematic review, and 7 studies including only iTBS with 230 participants were included in this meta-analysis. The methodological quality of the studies included ranged from moderate to high. The results showed iTBS had significantly higher scores on the Berg Balance Scale (BBS) than the control group. (MD = 4.57, 95% CI: 1.76 to 7.38, Z = 3.19, P = .001). Subgroup analysis showed CRB-iTBS markedly improved BBS scores (MD = 4.52, 95% CI: 1.78 to 7.27, Z = 3.23, P = .001), whereas LE M1-iTBS did not exhibit a significant enhancement in BBS scores (MD = 6.10, 95% CI: -7.34 to 19.53, Z = 0.89, P = .37); iTBS showed no significant increase in lower-limb motor function (FMA-LE) (MD = 1.80, 95% CI: -1.10 to 4.69, Z = 1.22, P = .22). Subgroup analysis revealed both CRB-iTBS and LE M1-iTBS interventions were not effective in improving FMA-LE (MD = 3.15, 95% CI: -4.70 to 11.00, Z = .79, P = .43; MD = 1.05, 95% CI: -2.20 to 4.30, Z = .63, P = .53); iTBS significantly reduced the MEP latency (P = .004), but did not show a significant improvement in walking performance (10 MWT), mobility (TUG), or activities of daily living [M(BI)] (P > .05).

Based the current study, iTBS can increase patients' balance function. The CRB-iTBS protocol is more effective than the LE M1-iTBS protocol. Additionally, iTBS may be a promising therapy tending to enhance lower-limb motor function, walking performance, mobility, and activities of daily living.

Repeated exposure to word forms and meanings improves lexical knowledge acquisition. However, the roles of domain-general and language-specific brain regions during this process remain unclear. To investigate this, we applied intermittent theta burst stimulation over the domain-general (group left dorsolateral prefrontal cortex) and domain-specific (Group L IFG) brain regions, with a control group receiving sham intermittent theta burst stimulation. Intermittent theta burst stimulation effects were subsequently assessed in functional magnetic resonance imaging using an artificial word learning task which consisted of 3 learning phases. A generalized psychophysiological interaction analysis explored the whole brain functional connectivity, while dynamic causal modeling estimated causal interactions in specific brain regions modulated by intermittent theta burst stimulation during repeated exposure. Compared to sham stimulation, active intermittent theta burst stimulation improved word learning performance and reduced activation of the left insula in learning phase 2. Active intermittent theta burst stimulation over the domain-general region increased whole-brain functional connectivity and modulated effective connectivity between brain regions during repeated exposure. This effect was not observed when active intermittent theta burst stimulation was applied to the language-specific region. These findings suggest that the domain-general region plays a crucial role in word formation rule learning, with intermittent theta burst stimulation enhancing whole-brain connectivity and facilitating efficient information exchange between key brain regions during new word learning.

Cerebellar intermittent theta burst stimulation (iTBS) modulates the excitability of the cerebral cortex and may enhance attentional performance. To date, few studies have conducted iTBS on healthy subjects for one week and used electroencephalography (EEG) to investigate the effect of multiple stimulation sessions on resting-state functional brain networks and the daily stimulation effect on attentional performance.

16 healthy subjects participated in a one-week experiment, receiving bilateral cerebellar iTBS or sham stimulation and engaging in multi-task attentional training. The primary measures were the one-week attentional performance and pre- and post-experiment resting-state EEG activities. Amplitude Envelope Correlation (AEC) was used to construct the functional connectivity in the eye-open (EO) and eye-closed (EC) phases.

At least three sessions of iTBS were required to enhance multi-task performance significantly, whereas only one or two sessions failed to elicit the improvement. Compared with the control group, iTBS induced significant changes in PSD, AEC functional connectivity, and AEC network properties during the EO phase, while it had little effect during the EC phase. During the EO phase, the network property changes of the iTBS subject were correlated with improved attentional performance.

The multi-task performance requires multiple stimulations to enhance. iTBS affects the resting-state alpha band brain activities during the EO rather than the EC phase. The AEC network properties may serve as a biomarker to assess the attentional potential of healthy subjects.

The Posterior Fossa Society, an international multidisciplinary group, hosted its first global meeting designed to share the current state of the evidence across the multidisciplinary elements of pediatric post-operative cerebellar mutism syndrome (pCMS). The agenda included keynote talks from world-leading speakers, compelling abstract presentations and engaging discussions led by members of the PFS special interest groups.

This paper is a synopsis of the first global meeting, a 3-day program held in Liverpool, England, UK, in September 2022.

Topics included nosology, patient and family experience, cerebellar modulation of cognition, and cerebellar cognitive affective syndrome. In addition, updates from large-scale studies were shared as well as abstracts across neuroradiology, neurosurgery, diagnosis/scoring, ataxia, and rehabilitation.

Based on data-driven evidence and discussions, each special interest group created research priorities to target before the second global meeting, in the spring of 2024.

Transcranial Direct Current Stimulation (tDCS) has emerged as a promising tool for enhancing social cognition. The posterior cerebellum, which is part of the mentalizing network, has been implicated in social processes. In our combined tDCS-fMRI study, we investigated the effects of offline anodal cerebellar tDCS on activation in the cerebellum during social action prediction. Forty-one participants were randomly assigned to receive either anodal (2 mA) or sham (0 mA) stimulation over the midline of the posterior cerebellum for 20 min. Twenty minutes post stimulation, participants underwent a functional MRI scan to complete a social action prediction task, during which they had to correctly order randomly presented sentences that described either actions of social agents (based on their personality traits) or events of objects (based on their characteristics). As hypothesized, our results revealed that participants who received anodal cerebellar tDCS exhibited increased activation in the posterior cerebellar Crus 2 and lobule IX, and in key cerebral mentalizing areas, including the medial prefrontal cortex, temporo-parietal junction, and precuneus. Contrary to our hypotheses, participants who received anodal stimulation demonstrated faster responses to non-social objects compared to social agents, while sham participants showed no significant differences. We did not find a significant relationship between electric field magnitude, neural activation and behavioral outcomes. These findings suggest that tDCS targeting the posterior cerebellum selectively enhances activation in social mentalizing areas, while only facilitating behavioral performance of non-social material, perhaps because of a ceiling effect due to familiarity with social processing.

The efficacy of bright light therapy (BLT) in ameliorating depression has been validated. The present study is to investigate the changes of depressive symptoms, cognitive function and cerebellar functional connectivity (FC) following BLT in individuals with subthreshold depression (StD).

Participants were randomly assigned to BLT group (N = 47) or placebo (N = 41) in this randomized controlled trial between March 2020 and June 2022. Depression severity and cognitive function were assessed, as well as resting-state functional MRI scan was conducted before and after 8-weeks treatment. Seed-based whole-brain static FC (sFC) and dynamic FC (dFC) analyses of the bilateral cerebellar subfields were conducted. Besides, a multivariate regression model examined whether baseline brain FC was associated with changes of depression severity and cognitive function during BLT treatment.

After 8-week BLT treatment, individuals with StD showed improved depressive symptoms and attention/vigilance cognitive function. BLT also increased sFC between the right cerebellar lobule IX and left temporal pole, and decreased sFC within the cerebellum, and dFC between the right cerebellar lobule IX and left medial prefrontal cortex. Moreover, the fusion of sFC and dFC at baseline could predict the improvement of attention/vigilance in response to BLT.

The current study identified that BLT improved depressive symptoms and attention/vigilance, as well as changed cerebellum-DMN connectivity, especially in the cerebellar-frontotemporal and cerebellar internal FC. In addition, the fusion features of sFC and dFC at pre-treatment could serve as an imaging biomarker for the improvement of attention/vigilance cognitive function after BLT in StD.

Chronic pain poses a widespread and distressing challenge; it can be resistant to conventional therapies, often having significant side effects. Non-invasive brain stimulation (NIBS) techniques offer promising avenues for the safe and swift modulation of brain excitability. NIBS approaches for chronic pain management targeting the primary motor area have yielded variable outcomes. Recently, the cerebellum has emerged as a pivotal hub in human pain processing; however, the clinical application of cerebellar NIBS in chronic pain treatment remains limited. This review delineates the cerebellum's role in pain modulation, recent advancements in NIBS for cerebellar activity modulation, and novel biomarkers for assessing cerebellar function in humans. Despite notable progress in NIBS techniques and cerebellar activity assessment, studies targeting cerebellar NIBS for chronic pain treatment are limited in number. Nevertheless, positive outcomes in pain alleviation have been reported with cerebellar anodal transcranial direct current stimulation. Our review underscores the potential for further integration between cerebellar NIBS and non-invasive assessments of cerebellar function to advance chronic pain treatment strategies.

The cerebellum is emerging as a promising target for noninvasive brain stimulation (NIBS). A systematic review was conducted to evaluate the effects of cerebellar NIBS on both motor and other symptoms in stroke rehabilitation, its impact on functional ability, and potential side effects (PROSPERO number: CRD42022365697). A systematic electronic database search was performed by using PubMed Central (PMC), EMBASE, and Web of Science, with a cutoff date of November 2023. Data extracted included study details, NIBS methodology, outcome measures, and results. The risk of bias in eligible studies was also assessed. Twenty-two clinical studies involving 1016 participants were finally included, with a focus on outcomes related to post-stroke motor recovery (gait and balance, muscle spasticity, and upper limb dexterity) and other functions (dysphagia and aphasia). Positive effects were observed, especially on motor functions like gait and balance. Some efficiency was also observed in dysphagia rehabilitation. However, findings on language recovery were preliminary and inconsistent. A slight improvement in functional ability was noted, with no serious adverse effects reported. Further studies are needed to explore the effects of cerebellar NIBS on post-stroke non-motor deficits and to understand how cerebellar engagement can facilitate more precise treatment strategies for stroke rehabilitation.

Transcranial magnetic stimulation is a noninvasive technique that can be used to evoke distributed network-level effects. Previous work demonstrated that the Hippocampal-Cortical Network responds preferably (i.e., greater memory improvement and increases in hippocampal-network connectivity) to continuous theta-burst stimulation protocol relative to intermittent theta-burst and to 20-Hz rTMS. Here, these data were further analyzed to characterize effects of continuous versus intermittent theta-burst stimulation on network-level connectivity measures - as well as local connectedness - via resting-state fMRI. In contrast to theories that propose continuous and intermittent theta-burst cause local inhibitory versus excitatory effects, respectively, both protocols caused local decreases in fMRI connectivity around the stimulated parietal site. While iTBS caused decreases in connectivity across the hippocampal-cortical network, cTBS caused increases and decreases in connectivity across the network. cTBS had no effect on the parietal-cortical network, whereas iTBS caused decreases in the right parietal cortex (contralateral hemisphere to the stimulation target). These findings suggest that continuous theta-burst may have entrained the endogenous hippocampal-cortical network, whereas the intermittent train was unable to maintain entrainment that may have yielded the long-lasting effects measured in this study (i.e., within 20-min post-stimulation). Furthermore, these effects were specific to the hippocampal-cortical network, which has a putative endogenous functionally-relevant theta rhythm, and not to the parietal network. These results add to the growing body of evidence that suggests effects of theta-burst stimulation are not fully characterized by excitatory/inhibitory theories. Further work is required to understand local and network-level effects of noninvasive stimulation.

Repetitive transcranial magnetic stimulation (rTMS) for alleviating negative symptoms and cognitive dysfunction in schizophrenia commonly targets the left dorsolateral prefrontal cortex (LDLPFC). However, the therapeutic effectiveness of rTMS at this site remains inconclusive and increasingly, studies are focusing on cerebellar rTMS. Recently, prolonged intermittent theta-burst stimulation (iTBS) has emerged as a rapid-acting form of rTMS with promising clinical benefits. This study explored the cognitive and neurophysiological effects of prolonged iTBS administered to the LDLPFC and cerebellum in a healthy cohort. 50 healthy participants took part in a cross-over study and received prolonged (1800 pulses) iTBS targeting the LDLPFC, cerebellar vermis, and sham iTBS. Mixed effects repeated measures models examined cognitive and event-related potentials (ERPs) from 2-back (P300, N200) and Stroop (N200, N450) tasks after stimulation. Exploratory non-parametric cluster-based permutation tests compared ERPs between conditions. There were no significant differences between conditions for behavioural and ERP outcomes on the 2-back and Stroop tasks. Exploratory cluster-based permutation tests of ERPs did not identify any significant differences between conditions. We did not find evidence that a single session of prolonged iTBS administered to either the LDLPFC or cerebellum could cause any cognitive or ERP changes compared to sham in a healthy sample.

Mal de Debarquement Syndrome (MdDS) is a rare central vestibular disorder characterised by a constant sensation of motion (rocking, swaying, bobbing), which typically arises after motion experiences (e.g. sea, air, and road travel), though can be triggered by non-motion events. The current standard of care is non-specific medications and interventions that only result in mild-to-moderate improvements. The vestibular ocular reflex (VOR) rehabilitation protocol, a specialised form of rehabilitation, has shown promising results in reducing symptoms amongst people with MdDS. Accumulating evidence suggests that it may be possible to augment the effects of VOR rehabilitation via non-invasive brain stimulation protocols, such as theta burst stimulation (TBS).

The aim of this randomised controlled trial was to evaluate the effectiveness of intermittent TBS (iTBS) over the dorsolateral prefrontal cortex in enhancing the effectiveness of a subsequently delivered VOR rehabilitation protocol in people with MdDS. Participants were allocated randomly to receive either Sham (n = 10) or Active (n = 10) iTBS, followed by the VOR rehabilitation protocol. Subjective outcome measures (symptom ratings and mental health scores) were collected 1 week pre-treatment and for 16 weeks post-treatment. Posturography (objective outcome) was recorded each day of the treatment week.

Significant improvements in subjective and objective outcomes were reported across both treatment groups over time, but no between-group differences were observed.

These findings support the effectiveness of the VOR rehabilitation protocol in reducing MdDS symptoms. Further research into iTBS is required to elucidate whether the treatment has a role in the management of MdDS. TRN: ACTRN12619001519145 (Date registered: 04 November 2019).

People living with HIV (PLWHA) smoke at three times the rate of the general population and respond poorly to cessation strategies. Previous studies examined repetitive transcranial magnetic stimulation (rTMS) over left dorsolateral prefrontal cortex (L. dlPFC) to reduce craving, but no studies have explored rTMS among PLWHA who smoke. The current pilot study compared the effects of active and sham intermittent theta-burst stimulation (iTBS) on resting state functional connectivity (rsFC), cigarette cue attentional bias, and cigarette craving in PLWHA who smoke.

Eight PLWHA were recruited (single-blind, within-subject design) to receive one session of iTBS (n=8) over the L. dlPFC using neuronavigation and, four weeks later, sham iTBS (n=5). Cigarette craving and attentional bias assessments were completed before and after both iTBS and sham iTBS. rsFC was assessed before iTBS (baseline) and after iTBS and sham iTBS.

Compared to sham iTBS, iTBS enhanced rsFC between the L. dlPFC and bilateral medial prefrontal cortex and pons. iTBS also enhanced rsFC between the right insula and right occipital cortex compared to sham iTBS. iTBS also decreased cigarette craving and cigarette cue attentional bias.

iTBS could potentially offer a therapeutic option for smoking cessation in PLWHA.

Improvement of functional movements after supratentorial stroke occurs through spontaneous biological recovery and training-induced reorganization of remnant neural networks. The cerebellum, through its connectivity with the cortex, brainstem and spinal cord, is actively engaged in both recovery and reorganization processes within the cognitive and sensorimotor systems. Noninvasive cerebellar stimulation (NiCBS) offers a safe, clinically feasible and potentially effective way to modulate the excitability of spared neural networks and promote movement recovery after supratentorial stroke. NiCBS modulates cerebellar connectivity to the cerebral cortex and brainstem, as well as influences the sensorimotor and frontoparietal networks.

Our objective was twofold: (a) to conduct a scoping review of studies that employed NiCBS to influence motor recovery and learning in individuals with stroke, and (b) to present a theory-driven framework to inform the use of NiCBS to target distinct stroke-related deficits.

A scoping review of current research up to August 2023 was conducted to determine the effect size of NiCBS effect on movement recovery of upper extremity function, balance, walking and motor learning in humans with stroke.

Calculated effect sizes were moderate to high, offering promise for improving upper extremity, balance and walking outcomes after stroke. We present a conceptual framework that capitalizes on cognitive-motor specialization of the cerebellum to formulate a synergy between NiCBS and behavioral interventions to target specific movement deficits.

NiCBS enhances recovery of upper extremity impairments, balance and walking after stroke. Physiologically-informed synergies between NiCBS and behavioral interventions have the potential to enhance recovery. Finally, we propose future directions in neurophysiological, behavioral, and clinical research to move NiCBS through the translational pipeline and augment motor recovery after stroke.

Neural plasticity is the ability of the brain to alter itself functionally and structurally as a result of its experience. However, longitudinal changes in functional connectivity of the brain are still unrevealed in Alzheimer's disease (AD). This study aims to discover the significant connections (SCs) between brain regions for AD stages longitudinally using correlation transfer function (CorrTF) as a new biomarker for the disease progression. The dataset consists of: 29 normal controls (NC), and 23, 24, and 23 for early, late mild cognitive impairments (EMCI, LMCI), and ADs, respectively, along three distant visits. The brain was divided into 116 regions using the automated anatomical labeling atlas, where the intensity time series is calculated, and the CorrTF connections are extracted for each region. Finally, the standard t-test and ANOVA test were employed to investigate the SCs for each subject's visit. No SCs, along three visits, were found For NC subjects. The most SCs were mainly directed from cerebellum in case of EMCI and LMCI. Furthermore, the hippocampus connectivity increased in LMCI compared to EMCI whereas missed in AD. Additionally, the patterns of longitudinal changes among the different AD stages compared to Pearson Correlation were similar, for SMC, VC, DMN, and Cereb networks, while differed for EAN and SN networks. Our findings define how brain changes over time, which could help detect functional changes linked to each AD stage and better understand the disease behavior.

Understanding behavior in aging has benefited greatly from cognitive neuroscience. Our foundational understanding of the brain in advanced age is based on what now amounts to several decades of work demonstrating differences in brain structure, network organization, and function. Earlier work in this field was focused primarily on the prefrontal cortex and hippocampus. More recent evidence has expanded our understanding of the aging brain to also implicate the cerebellum. Recent frameworks have suggested that the cerebellum may act as scaffolding for cortical function, and there is an emerging literature implicating the structure in Alzheimer's disease. At this juncture, there is evidence highlighting the potential importance of the cerebellum in advanced age, though the field of study is relatively nascent. Here, we provide an overview of key findings in the literature as it stands now and highlight several key future directions for study with respect to the cerebellum in aging.

The cerebellum contributes to the precise timing of non-motor and motor functions, and cerebellum abnormalities have been implicated in psychosis pathophysiology. In this study, we explored the effects of cerebellar theta burst stimulation (TBS), an efficient transcranial magnetic stimulation protocol, on temporal discrimination and self-reported mood and psychotic symptoms.

We conducted a case-crossover study in which patients with psychosis (schizophrenias, schizoaffective disorders, or bipolar disorders with psychotic features) were assigned to three sessions of TBS to the cerebellar vermis: one session each of intermittent (iTBS), continuous (cTBS), and sham TBS. Of 28 enrolled patients, 26 underwent at least one TBS session, and 20 completed all three. Before and immediately following TBS, participants rated their mood and psychotic symptoms and performed a time interval discrimination task (IDT). We hypothesized that cerebellar iTBS and cTBS would modulate these measures in opposing directions, with iTBS being adaptive and cTBS maladaptive.

Reaction time (RT) in the IDT decreased significantly after iTBS vs. Sham (LS-mean difference = -73.3, p = 0.0001, Cohen's d = 1.62), after iTBS vs. cTBS (LS-mean difference = -137.6, p < 0.0001, d = 2.03), and after Sham vs. cTBS (LS-mean difference = -64.4, p < 0.0001, d = 1.33). We found no effect on IDT accuracy. We did not observe any effects on symptom severity after correcting for multiple comparisons.

We observed a frequency-dependent dissociation between the effects of iTBS vs. cTBS to the cerebellar midline on the reaction time of interval discrimination in patients with psychosis. iTBS showed improved (adaptive) while cTBS led to worsening (maladaptive) speed of response. These results demonstrate behavioral target engagement in a cognitive dimension of relevance to patients with psychosis and generate testable hypotheses about the potential therapeutic role of cerebellar iTBS in this clinical population.

clinicaltrials.gov, identifier NCT02642029.

The notion that the cerebellum is devoted exclusively to motor control has been replaced by a more sophisticated understanding of its role in neurological function, one that includes cognition and emotion. Early clinical reports, as well as physiological and behavioral studies in animal models, raised the possibility of a nonmotor role for the cerebellum. Anatomical studies demonstrate cerebellar connectivity with the distributed neural circuits linked with autonomic, sensorimotor, vestibular, associative and limbic/paralimbic brain areas. Identification of the cerebellar cognitive affective syndrome in adults and children underscored the clinical relevance of the role of the cerebellum in cognition and emotion. It opened new avenues of investigation into higher order deficits that accompany the ataxias and other cerebellar diseases, as well as the contribution of cerebellar dysfunction to neuropsychiatric and neurocognitive disorders. Brain imaging studies demonstrate the complexity of cerebellar functional topography, revealing a double representation of the sensorimotor cerebellum in the anterior lobe and lobule VIII and a triple cognitive representation in the cerebellar posterior lobe, as well as representation in the cerebellum of the intrinsic connectivity networks identified in the cerebral hemispheres. This paradigm shift in thinking about the cerebellum has been advanced by the theories of dysmetria of thought and the universal cerebellar transform, harmonizing the dual anatomic realities of homogeneously repeating cerebellar cortical microcircuitry set against the heterogeneous and topographically arranged cerebellar connections with extracerebellar structures. This new appreciation of the cerebellar incorporation into circuits that subserve cognition and emotion enables deeper understanding and improved care of our patients with cerebellar ataxias and novel cerebellar-based approaches to therapy in neuropsychiatry.

The continuous decline of executive abilities with age is mirrored by increased neural activity of domain-general networks during task processing. So far, it remains unclear how much domain-general networks contribute to domain-specific processes such as language when cognitive demands increase. The current neuroimaging study explored the potential of intermittent theta-burst stimulation (iTBS) over a domain-general hub to enhance executive and semantic processing in healthy middle-aged to older adults.

We implemented a cross-over within-subject study design with three task-based neuroimaging sessions per participant. Using an individualized stimulation approach, each participant received once effective and once sham iTBS over the pre-supplementary motor area (pre-SMA), a region of domain-general control. Subsequently, task-specific stimulation effects were assessed in functional MRI using a semantic and a non-verbal executive task with varying cognitive demand.

Effective stimulation increased activity only during semantic processing in visual and dorsal attention networks. Further, iTBS induced increased seed-based connectivity in task-specific networks for semantic and executive conditions with high cognitive load but overall reduced whole-brain coupling between domain-general networks. Notably, stimulation-induced changes in activity and connectivity related differently to behavior: While stronger activity of the parietal dorsal attention network was linked to poorer semantic performance, its enhanced coupling with the pre-SMA was associated with more efficient semantic processing.

iTBS modulates networks in a task-dependent manner and generates effects at regions remote to the stimulation site. These neural changes are linked to more efficient semantic processing, which underlines the general potential of network stimulation approaches in cognitive aging.

Post-traumatic stress disorder (PTSD) and anxiety disorders are among the most prevalent psychiatric conditions worldwide sharing many clinical manifestations and, most likely, neural mechanisms as suggested by neuroimaging research. While the so-called fear circuitry and traditional limbic structures of the brain, particularly the amygdala, have been extensively studied in sufferers of these disorders, the cerebellum has been relatively underexplored. The aim of this paper was to present a mini-review of functional (task-activity or resting-state connectivity) and structural (gray matter volume) results on the cerebellum as reported in magnetic resonance imaging studies of patients with PTSD or anxiety disorders (49 selected studies in 1,494 patients). While mixed results were noted overall, e.g., regarding the direction of effects and anatomical localization, cerebellar structures like the vermis seem to be highly involved. Still, the neurofunctional and structural alterations reported for the cerebellum in excessive anxiety and trauma are complex, and in need of further evaluation.

Transcranial magnetic stimulation is a widely used brain intervention technique in clinical settings. In recent years, the role of the cerebellum in learning and memory has become one of the hotspots in the field of cognitive neuroscience. In this study, we recruited 36 healthy college or graduate students as subjects and divided them into groups, with 10 to 14 subjects in each group. We performed 5 Hz and 20 Hz repeated transcranial magnetic stimulation and sham stimulation on the Crus II subregion of the cerebellum in different groups, then let them complete the 2-back working memory task before and after the stimulation. We simultaneously recorded the electroencephalogram in the experiment and analyzed the data. We found that after repeated transcranial magnetic stimulation of the cerebellum at 5 Hz and 20 Hz, the N170 and P300 event-related potential components in the prefrontal cortex showed significant differences compared to those in the sham stimulation group. Using phase-locked values to construct brain networks and conduct further analysis, we discovered that stimulation frequencies of 5 Hz and 20 Hz had significant effects on the local and global efficiency of brain networks in comparison to the sham stimulation group. The results showed that repeated transcranial magnetic stimulation on cerebellar targets can effectively affect the subjects' working memory tasks. Repeated transcranial magnetic stimulation at 5 Hz and 20 Hz could enhance the excitatory responses of the frontal lobes. After stimulation at 5 Hz and 20 Hz, the efficiency of the brain network significantly improved.

Episodic memory decline is a major signature of both normal and pathological aging. Many neural regions have been implicated in the processes subserving both episodic memory and typical aging decline. Here, we demonstrate that the cerebellum is causally involved episodic memory under aging. We show that a 12-day neurostimulation program delivered to the right cerebellum led to improvements in episodic memory performance under healthy aging that long outlast the stimulation period - healthy elderly individuals show episodic memory improvement both immediately after the intervention program and in a 4-month follow-up. These results demonstrate the causal relevance of the cerebellum in processes associated with long-term episodic memory, potentially highlighting its role in regulating and maintaining cognitive processing. Moreover, they point to the importance of non-pharmacological interventions that prevent or diminish cognitive decline in healthy aging.

Repetitive transcranial magnetic stimulation (TMS), when applied to the dorsolateral prefrontal cortex (dlPFC), treats depression. Therapeutic effects are hypothesized to arise from propagation of local dlPFC stimulation effects across distributed networks; however, the mechanisms of this remain unresolved. dlPFC contains representations of different networks. As such, dlPFC TMS may exert different effects depending on the network being stimulated. Here, to test this, we applied high-frequency TMS to two nearby dlPFC targets functionally embedded in distinct anti-correlated networks-the default and salience networks- in the same individuals in separate sessions. Local and distributed TMS effects were measured with combined 18fluorodeoxyglucose positron emission tomography and functional magnetic resonance imaging. Identical TMS patterns caused opposing effects on local glucose metabolism: metabolism increased at the salience target following salience TMS but decreased at the default target following default TMS. At the distributed level, both conditions increased functional connectivity between the default and salience networks, with this effect being dramatically larger following default TMS. Metabolic and haemodynamic effects were also linked: across subjects, the magnitude of local metabolic changes correlated with the degree of functional connectivity changes. These results suggest that TMS effects upon dlPFC are network specific. They also invoke putative antidepressant mechanisms of TMS: network de-coupling.

Theta burst stimulation (TBS) is associated with the modulation of a range of clinical, cognitive, and behavioural outcomes, but specific neurobiological effects remain somewhat unclear. This systematic literature review investigated resting-state and task-based functional magnetic resonance imaging (fMRI) outcomes post-TBS in healthy human adults. Fifty studies that applied either continuous-or intermittent-(c/i) TBS, and adopted a pretest-posttest or sham-controlled design, were included. For resting-state outcomes following stimulation applied to motor, temporal, parietal, occipital, or cerebellar regions, functional connectivity generally decreased in response to cTBS and increased in response to iTBS, though there were some exceptions to this pattern of response. These findings are mostly consistent with the assumed long-term depression (LTD)/long-term potentiation (LTP)-like plasticity effects of cTBS and iTBS, respectively. Task-related outcomes following TBS were more variable. TBS applied to the prefrontal cortex, irrespective of task or state, also produced more variable responses, with no consistent patterns emerging. Individual participant and methodological factors are likely to contribute to the variability in responses to TBS. Future studies assessing the effects of TBS via fMRI must account for factors known to affect the TBS outcomes, both at the level of individual participants and of research methodology.

BYLEMANS, T., et al. Mentalizing and narrative coherence in autistic adults: Cerebellar sequencing and prediction. NEUROSCI BIOBEHAV REV, 2022. - This review focuses on autistic adults and serves 4 purposes: (1) providing an overview of their difficulties regarding mentalizing (understanding others' mental states) and narrative coherence (structured storytelling), (2) highlighting the relations between both skills by examining behavioral observations and shared neural substrates, (3) providing an integrated perspective regarding novel diagnostic tools and support services, and (4) raising awareness of adult autism. We suggest that mentalizing and narrative coherence are related at the behavioral level and neural level. In addition to the traditional mentalizing network, the cerebellum probably serves as an important hub in shared cerebral networks implicated in mentalizing and narrative coherence. Future autism research and support services should tackle new questions within a framework of social cerebellar (dys)functioning.

Default-mode network (DMN) may be the earliest affected network and is associated with cognitive decline in Alzheimer's disease (AD). Repetitive transcranial magnetic stimulation (rTMS) may help to modulate DMN plasticity. Still, stimulation effects substantially vary across studies and individuals. Global left frontal cortex (gLFC) connectivity, a substitute for reserve capacity, may contribute to the heterogeneous physiological effects of neuro-navigated rTMS. This study investigated the effects of left angular gyrus-navigated rTMS on DMN connectivity in different reserve capacity participants. gLFC connectivity, was computed through resting-state fMRI correlations. Thirty-one prodromal AD patients were divided into low connection group (LCG) and high connection group (HCG) by the median of gLFC connectivity. Distinct reserve capacity impacts on DMN in response to rTMS were identified in these two groups. Then, brain-behavior relationships were examined. gLFC connectivity within a certain range is directly proportional to cognitive reserve ability (i.e., LCG), and the effectiveness of functional connectivity beyond this range decreases (i.e, HCG). Moreover, LCG exhibited increased DMN connectivity and significantly positive memory improvements, while HCG showed a contrary connectivity decline and maintained or slightly improved their cognitive function after neuro-navigated rTMS treatment. The prodromal AD patients with the distinct reserve capacity may benefit differently from left angular gyrus-navigated rTMS, which may lead to increasing attention in defining personalized medicine approach of AD.

Repetitive TMS has been used as an alternative treatment for various neurological disorders. However, most TMS mechanism studies in rodents have been based on the whole brain stimulation, the lack of rodent-specific focal TMS coils restricts the proper translation of human TMS protocols to animal models. In this study, we designed a new shielding device, which was made of high magnetic permeability material, to enhance the spatial focus of animal-use TMS coils. With the finite element method, we analyzed the electromagnetic field of the coil with and without the shielding device. Furthermore, to assess the shielding effect in rodents, we compared the c-fos expression, the ALFF and ReHo values in different groups following a 15 min 5 Hz rTMS paradigm. We found that a smaller focality with an identical core stimulation intensity was achieved in the shielding device. The 1 T magnetic field was reduced from 19.1 mm to 13 mm in diameter, and 7.5 to 5.6 mm in depth. However, the core magnetic field over 1.5 T was almost the same. Meanwhile, the area of electric field was reduced from 4.68 cm² to 4.19 cm², and 3.8 mm to 2.6 mm in depth. Similar to this biomimetic data, the c-fos expression, the ALFF and ReHo values showed more limited cortex activation with the use of the shielding device. However, compared to the rTMS group without the shielding application, more subcortical regions, like the striatum (CPu), the hippocampus, the thalamus, and the hypothalamus were also activated in the shielding group. This indicated that more deep stimulation may be achieved by the shielding device. Generally, compared with the commercial rodents' TMS coil (15 mm in diameter), TMS coils with the shielding device achieved a better focality (~6 mm in diameter) by reducing at least 30% of the magnetic and electric field. This shielding device may provide a useful tool for further TMS studies in rodents, especially for more specific brain area stimulation.

Transcranial magnetic stimulation (TMS) is a non-invasive technique for focal brain stimulation based on electromagnetic induction where a fluctuating magnetic field induces a small intracranial electric current in the brain. For more than 35 years, TMS has shown promise in the diagnosis and treatment of neurological and psychiatric disorders in adults. In this review, we provide a brief introduction to the TMS technique with a focus on repetitive TMS (rTMS) protocols, particularly theta-burst stimulation (TBS), and relevant rTMS-derived metrics of brain plasticity. We then discuss the TMS-EEG technique, the use of neuronavigation in TMS, the neural substrate of TBS measures of plasticity, the inter- and intraindividual variability of those measures, effects of age and genetic factors on TBS aftereffects, and then summarize alterations of TMS-TBS measures of plasticity in major neurological and psychiatric disorders including autism spectrum disorder, schizophrenia, depression, traumatic brain injury, Alzheimer's disease, and diabetes. Finally, we discuss the translational studies of TMS-TBS measures of plasticity and their therapeutic implications.

Transcranial magnetic stimulation (TMS) modulation over the cerebellum, primary motor cortex, and supplementary motor cortex individually can improve the balance function of patients with stroke. However, whether their combination could have a better balance modulation effect is uncertain. Therefore, we hypothesized that performing TMS over a combination of these targets can regulate the balance function of patients with stroke. We compared the effects of one-session TMS on eye-open and eye-closed balance conditions in patients with stroke, using different target pairs of unilateral cerebellar (CB-single), cerebellar-primary motor cortex (CB-M1), and cerebellar-supplementary motor area (CB-SMA) targets. A total of 31 patients with stroke were enrolled and randomly divided into three groups to receive single sessions of intermittent theta burst stimulation each. Functional near-infrared spectrum data on resting and standing task states (eye-open and eye-closed) and center of pressure parameters (eye-open and eye-closed) were collected before and after the intervention. Compared with the results in the CB-single group, five intergroup differences in the changes in the center of pressure parameters in the CB-M1 group and two significant differences in the CB-SMA group were observed after one session of intermittent theta burst stimulation. In the CB-SMA group, 12 out of the 14 parameters improved significantly in the EC condition after the intervention. Meanwhile, the functional near-infrared spectrum results showed that the CB-SMA group exhibited a significant inhibitory pattern in the resting-state functional connectivity, which was not observed in the other two groups. In conclusion, we believe that paired targeting of the CB-SMA can reshape the brain network and improve the balance function of patients with stroke.

Background: Mild cognitive impairment (MCI) is a condition between normal aging and dementia; nearly 10-15% of MCI patients develop dementia annually. There are no effective interventions for MCI progression. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has attempted to improve the overall cognitive function of MCI patients. However, it does not affect episodic memory improvement. Methods: In this study, we engaged 15 clinically diagnosed MCI patients and normal controls to explore the effect of dual-targeted rTMS on progressing cognitive function, particularly episodic memory in MCI patients. Resting-state EEG recordings and neuropsychological assessments were conducted before and after the intervention. EEG features were extracted using an adaptive algorithm to calculate functional connectivity alterations in relevant brain regions and the mechanisms of altered brain functional networks in response to dual-target rTMS. Results: The study revealed that the functional brain connectivity between the right posterior cingulate gyrus (PCC) and the right dorsal caudate nucleus (DC) was significantly reduced in MCI patients compared to normal controls (p < 0.001). Dual-target rTMS increased the strength of the reduced functional connectivity (p < 0.001), which was related to cognitive enhancement (p < 0.05). Conclusion: This study provides a new stimulation protocol for rTMS intervention. Improving the functional connectivity of the right PCC to the right DC is a possible mechanism by which rTMS improves overall cognitive and memory function in MCI patients.

Transcranial magnetic stimulation (TMS) is used to treat multiple psychiatric and neurological conditions by manipulating activity in particular brain networks and circuits, but individual responses are highly variable. In clinical settings, TMS coil placement is typically based on either group average functional maps or scalp heuristics. Here, we found that this approach can inadvertently target different functional networks in depressed patients due to variability in their functional brain organization. More precise TMS targeting should be feasible by accounting for each patient's unique functional neuroanatomy. To this end, we developed a targeting approach, termed targeted functional network stimulation (TANS). The TANS approach improved stimulation specificity in silico in 8 highly sampled patients with depression and 6 healthy individuals and in vivo when targeting somatomotor functional networks representing the upper and lower limbs. Code for implementing TANS and an example dataset are provided as a resource.

Transcranial (electro)magnetic stimulation (TMS) is currently the method of choice to non-invasively induce neural activity in the human brain. A single transcranial stimulus induces a time-varying electric field in the brain that may evoke action potentials in cortical neurons. The spatial relationship between the locally induced electric field and the stimulated neurons determines axonal depolarization. The induced electric field is influenced by the conductive properties of the tissue compartments and is strongest in the superficial parts of the targeted cortical gyri and underlying white matter. TMS likely targets axons of both excitatory and inhibitory neurons. The propensity of individual axons to fire an action potential in response to TMS depends on their geometry, myelination and spatial relation to the imposed electric field and the physiological state of the neuron. The latter is determined by its transsynaptic dendritic and somatic inputs, intrinsic membrane potential and firing rate. Modeling work suggests that the primary target of TMS is axonal terminals in the crown top and lip regions of cortical gyri. The induced electric field may additionally excite bends of myelinated axons in the juxtacortical white matter below the gyral crown. Neuronal excitation spreads ortho- and antidromically along the stimulated axons and causes secondary excitation of connected neuronal populations within local intracortical microcircuits in the target area. Axonal and transsynaptic spread of excitation also occurs along cortico-cortical and cortico-subcortical connections, impacting on neuronal activity in the targeted network. Both local and remote neural excitation depend critically on the functional state of the stimulated target area and network. TMS also causes substantial direct co-stimulation of the peripheral nervous system. Peripheral co-excitation propagates centrally in auditory and somatosensory networks, but also produces brain responses in other networks subserving multisensory integration, orienting or arousal. The complexity of the response to TMS warrants cautious interpretation of its physiological and behavioural consequences, and a deeper understanding of the mechanistic underpinnings of TMS will be critical for advancing it as a scientific and therapeutic tool.