Biology subjects

Rothwell, J.

Publications and source records attributed to Rothwell, J..

10 recordsLinked to original sources

bioRxiv2026

Immediate cortical responses to transcranial magnetic stimulation of the human motor leg area

Background: Immediate transcranial evoked potentials (iTEPs) are ultra-early electroencephalographic responses elicited by single-pulse transcranial magnetic stimulation (TMS) of the primary motor cortical hand area (M1-HAND). Their characteristic latency, waveform, and sensitivity to short-interval intracortical inhibition suggest a close relationship to the cortical generators of indirect corticospinal volleys (I-waves). Here, we tested the hypothesis that iTEPs constitute a fundamental physiological response of human motor cortex and therefore generalize across motor representations, including the leg representation (M1-LEG). Methods: Single-pulse TMS was delivered over the motor cortical representation of the right tibialis anterior (TA) in 16 healthy volunteers. In a subset of participants (n=10), stimulus-response curves and paired-pulse short-interval intracortical inhibition (SICI) measures were obtained. Results: TMS of M1-LEG elicited reproducible iTEPs consisting of a slow positive deflection with superimposed high-frequency peaks with topographic maxima in electrodes adjacent to the stimulation site. M1-LEG iTEPs emerged close to active motor threshold and increased in prevalence and amplitude with increasing stimulation intensity. Paired-pulse stimulation produced consistent SICI of the second and third iTEP peaks. M1-LEG stimulation also evoked conventional later TEPs with latencies and polarities closely resembling those recorded after M1-HAND stimulation. Conclusions: TMS of the human M1-LEG elicits robust iTEPs that closely resemble those recorded from M1-HAND in their timing, intensity dependence, and sensitivity to intracortical inhibition. These findings indicate that iTEPs are not specific to M1-HAND but reflect a general physiological response of human motor cortex closely linked to corticospinal I-wave generation. This broadens their utility as a non-invasive probe of excitatory and inhibitory circuit dynamics throughout the human motor system.

neuroscience↗

bioRxiv2026

Opposing modulation of cortical and corticospinal excitability across movement-related beta stages

Discrete voluntary movement depends on rapid changes in neural excitability across cortical and corticospinal circuits, yet how intrinsic movement-related neural states shape multi-level excitability remains unclear. Here, we combined individualized, state-targeted transcranial magnetic stimulation (TMS) with electroencephalography and electromyography recordings during visually cued finger movements to probe excitability across movement-related beta-band dynamics during two complementary experiments. Immediate transsynaptic cortical excitability closely tracked intrinsic beta dynamics, with attenuation of the second immediate TMS-evoked potential during beta desynchronization and recovery during the post-movement beta rebound. In contrast, corticospinal excitability showed the opposite pattern, with larger motor-evoked potentials during beta desynchronization and reduced responses during beta rebound. Together, these findings identify endogenous beta-state dynamics as a key regulator of movement-related cortical excitability and reveal a fundamental dissociation between how intrinsic brain activity tunes local cortical excitability and corticospinal output in humans.

neuroscience↗

bioRxiv2026

Developmental delay in attaining adult levels of motor excitability in children and adolescents with Tourette syndrome: a mega-analysis study

Tourette syndrome (TS) is a neurodevelopmental disorder of childhood onset characterised by vocal and motor tics and is associated with cortical-striatal-thalamic-cortical circuit [CSTC] dysfunction. TS often follows a developmental time course in which tics become increasingly more controlled during adolescence. However, many individuals continue to have debilitating tics into adulthood. This indicates that there may be important differences between adults with TS for whom the clinical phenotype is more stable, and children and adolescents with the disorder who may be undergoing developmental neuroplastic changes linked to the reduction of their tics. Previous studies have used transcranial magnetic stimulation (TMS) to investigate changes in cortical motor excitability in individuals with TS, including measurement of resting motor threshold (RMT). However, the findings from these studies have been mixed, have varied between adult and child samples, and have often been based on small sample sizes. Here we report a multi-centre, mega-analytic, study in which RMT data collected from children and adults with TS at multiple research centres was pooled for analysis. Results confirmed that mean RMT was significantly increased in individuals with TS compared to neurotypical controls. However, this result can be explained by the more important findings that: (a) RMT for adults with TS did not differ from that of neurotypical adults; and (b) the rate that RMT decreases with age during childhood and adolescence is reduced in individuals with TS compared to controls. Thus, while neurotypical individuals reach an adult RMT level by ~12-13 years of age, individuals with TS are substantially delayed in doing so, and do not reach an adult RMT level until much later, at ~24 years of age. We conclude therefore that differences in measures of cortical excitability between children and adolescents with TS and chronologically age-matched neurotypical controls may likely reflect a developmental delay in the maturation of functional brain networks in individuals with TS, which may normalise with age.

neuroscience↗

bioRxiv2026

Direct Assessment of Short-Latency Intracortical Inhibition via Immediate TMS-Evoked Potentials

Short-interval intracortical inhibition (SICI) is the most widely used neurophysiological index of GABAergic inhibition in the human cortex. However, it is an indirect measure, inferring synaptic inhibition from suppression of peripherally recorded motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). In the standard protocol, a subthreshold conditioning pulse suppresses the MEP evoked by a suprathreshold test pulse delivered 1-5 ms later. Interpretation is further complicated by temporal overlap with short-interval intracortical facilitation (SICF), reflecting excitatory interactions at interstimulus intervals of [~]1.5 and 2.7 ms. To overcome these limitations, we recorded immediate TMS-evoked EEG potentials (iTEPs; 1-10 ms post-stimulus) as a more direct measure of motor cortical activity in 16 healthy volunteers (20-35 years; 7 male). The conventional SICI protocol suppressed only later components of the iTEP, likely corresponding to late corticospinal volleys previously identified in epidural spinal recordings after suprathreshold TMS, while the earliest iTEP component was unaffected. Importantly, later iTEPs were suppressed to a similar extent whether conditioning-test intervals coincided with SICF peaks or troughs, and the magnitude of iTEP suppression correlated with concurrently recorded paired-pulse MEP suppression. SICI also reduced an early TEP component (N15; 10-20 ms), but paired-pulse N15 suppression showed a different dependence on stimulus intensity and did not correlate with MEP suppression. These findings demonstrate that SICI measured via MEPs does not reflect a global index of cortical GABAergic motor cortical inhibition but instead reflects inhibition within specific cortical circuits that can be investigated directly with iTEPs.

neuroscience↗

bioRxiv2025

Recognizing EEG responses to active TMS vs. sham stimulations in different TMS-EEG datasets: a machine learning approach

BackgroundTranscranial Magnetic Stimulation (TMS) with simultaneous Electroencephalogram (TMS-EEG) allows assessing the neurophysiological properties of cortical neurons. However, TMS-evoked EEG potentials (TEPs) can be affected by components unrelated to TMS direct neuronal activation. Accurate, automatic tools are therefore needed to establish the quality of TEPs. ObjectiveTo assess the discriminability of EEG responses to TMS vs. EEG responses to sham stimulations using sequence-to-sequence machine learning (ML). MethodsTwo indipendent TMS-EEG datasets including TMS and several sham stimulation conditions were obtained from the left motor area of healthy volunteers (N=33 across datasets). A Bi-directional Long Short-Term Memory (BiLSTM) ML network was used to label each time point of the EEG signals as pertaining to TMS or sham conditions. Main outcome measures included accuracy at single-trial level and after averaging five to twenty trials. ResultsFor TMS conditions, post-stimulus vs. baseline/pre-stimulus EEG comparisons yielded moderate (60%-75%) single-trial accuracy and high-accuracy (>75%) for 20 trials across datasets, while for sham conditions post- vs. baseline/pre-stimulus EEG comparisons yielded lower accuracy rates than for TMS conditions, except for unmasked auditory stimulation. Furthermore, baseline/pre-stimulus TMS vs. baseline/pre-stimulus sham EEG comparisons showed chance-level accuracy, whereas post-stimulus TMS vs. post-stimulus sham EEG comparisons had moderate (single trial) to high (20 trial) accuracy, except for TMS with and without the click noise masking. Single-subject findings were comparable to group-level results across datasets. ConclusionsTEPs after active TMS are discernible from various sham stimulations even after a handful of trials and at the single-subject level using a BiLSTM ML approach.

neuroscience↗

bioRxiv2024

Failed Double-Blind Replication of Offline 5Hz-rTUS-Induced Corticospinal Excitability

IntroductionTranscranial ultrasound stimulation (TUS) is a promising new form of non-invasive neuromodulation. As a nascent technique, replication of its effects on brain function is important. Of particular interest is offline 5Hz repetitive TUS (5Hz-rTUS), originally reported by Zeng and colleagues [1] to elicit lasting corticospinal excitability increases, with large effect sizes. Material and methodHere, we conducted a pre-registered (https://osf.io/p5n4q) replication of this protocol that benefitted from three additional features: double-blind application of TUS, neuronavigation for consistent TMS positioning, and acoustic simulations to assess M1 target exposure to TUS. Changes in resting motor thresholds (rMT), motor-evoked potential (MEP) amplitude, short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) in response to TUS (5Hz-rTUS vs. sham) were measured in the right first dorsal interosseous (FDI), abductor digiti minimi (ADM) and abductor pollicis brevis (APB) muscles, with unbiased selection of participants. Transducer location was determined by the TMS-hotspot for motor representations of the right FDI, as in the original work. ResultsNo significant effects of 5Hz-TUS (vs sham) were observed. Post-hoc simulations showed considerable variability of the acoustic focus, which was outside the anatomical M1-hand area in 67% of participants - in line with the known poor correspondence of TMS-hotspot location and M1-hand area. ConclusionOur results indicate that the effect sizes of the neuromodulatory effects of 5Hz-rTUS on M1 may be more variable than previously appreciated. We suggest that double-blinding, neuronavigated TMS, individualised acoustic simulations for TUS targeting and pre-registration will aid reproducibility across studies.

neuroscience↗

bioRxiv2022

A revised calcium-dependent model of theta-burst transcranial magnetic stimulation

Calcium dependency is presently an essential assumption in modelling the neuromodulatory effects of transcranial magnetic stimulation (TMS). Among the various neuromodulatory TMS protocols, theta-burst stimulation (TBS) at present is the fastest intervention to generate strong effects. A decade ago, Y.Z. Huang et al. developed a first neuromodulation model to explain the bidirectional effects of TBS based on postsynaptic intracellular calcium concentration elevation. We discover, however, that the published computer code is not consistent with the model formulations in the corresponding paper. Further analysis confirms that the computer model with an index confusion was used for fitting the experimental results, running the simulation, and plotting the corresponding figures in the original publication. This paper intends to fix the computer code and additionally create a non-convex optimisation solution for re-calibrating the model. After re-calibration, the revised model outperforms the initial model in accuracy describing the MEP amplitudes of TBS-induced after-effects under specific situations.

neuroscience↗

bioRxiv2020

Non-invasive Amelioration of Essential Tremor via Phase-Locked Disruption of its Temporal Coherence

Aberrant neural oscillations hallmark numerous brain disorders. Here, we first report a method to track the phase of neural oscillations in real-time via endpoint-corrected Hilbert transform (ecHT) that mitigates the characteristic Gibbs distortion. We then used ecHT to show that the aberrant neural oscillation that hallmarks essential tremor (ET) syndrome, the most common adult movement disorder, can be noninvasively suppressed via electrical stimulation of the cerebellum phase-locked to the tremor. The tremor suppression is sustained after the end of the stimulation and can be phenomenologically predicted. Finally, using feature-based statistical-learning and neurophysiological-modelling we show that the suppression of ET is mechanistically attributed to a disruption of the temporal coherence of the oscillation via perturbation of the tremor generating a cascade of synchronous activity in the olivocerebellar loop. The suppression of aberrant neural oscillation via phase-locked driven disruption of temporal coherence may represent a powerful neuromodulatory strategy to treat brain disorders.

neuroscience↗

bioRxiv2017

Brain state and polarity dependent modulation of brain networks by transcranial direct current stimulation

Transcranial direct current stimulation (TDCS) has been widely used to improve cognitive function. However, current deficiencies in mechanistic understanding hinders wider applicability. To clarify its physiological effects, we acquired fMRI whilst simultaneously acquiring TDCS to the right inferior frontal gyrus (rIFG) of healthy human participants, a region involved in coordinating activity within brain networks. TDCS caused widespread modulation of network activity depending on brain state ( rest or choice reaction time task) and polarity (anodal or cathodal). During task, TDCS increased salience network activation and default mode network deactivation, but had the opposite effect during rest. Furthermore, there was an interaction between brain state and TDCS polarity, with cathodal effects more pronounced during task performance and anodal effects more pronounced during rest. Overall, we show that rIFG TDCS produces brain state and polarity dependent effects within large-scale cognitive networks, in a manner that goes beyond predictions from the current literature.

neuroscience↗

bioRxiv2017

tDCS changes in motor excitability are specific to orientation of current flow

Measurements and models of current flow in the brain during transcranial Direct Current Stimulation (tDCS) indicate stimulation of regions in-between electrodes. Moreover, the cephalic cortex result in local fluctuations in current flow intensity and direction, and animal studies suggest current flow direction relative to cortical columns determines response to tDCS. Here we test this idea by measuring changes in cortico-spinal excitability by Transcranial Magnetic Stimulation Motor Evoked Potentials (TMS-MEP), following tDCS applied with electrodes aligned orthogonal (across) or parallel to M1 in the central sulcus. Current flow models predicted that the orthogonal electrode montage produces consistently oriented current across the hand region of M1 that flows along cortical columns, while the parallel electrode montage produces none-uniform current directions across the M1 cortical surface. We find that orthogonal, but not parallel, orientated tDCS modulates TMS-MEPs. We also show modulation is sensitive to the orientation of the TMS coil (PA or AP), which is through to select different afferent pathways to M1. Our results are consistent with tDCS producing directionally specific neuromodulation in brain regions in-between electrodes, but shows nuanced changes in excitability that are presumably current direction relative to column and axon pathway specific. We suggest that the direction of current flow through cortical target regions should be considered for targeting and dose-control of tDCS.\n\nHighlights O_LIDirection of current flow is important for tDCS after-effects.\nC_LIO_LItDCS modulates excitability between two electrodes.\nC_LIO_LItDCS differentially modulates PA and AP inputs into M1.\nC_LI\n\nAbbreviations\n\nFundingThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

neuroscience↗