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Abstract: Objective: To determine the effect of globus pallidus internus (GPi) deep brain stimulation (DBS) on motor cortex plasticity in patients with primary generalised dystonia. Methods: We studied 10 patients with primary generalised dystonia (5 DYT1+, 5 idiopathic, 5 female, mean age 42) following GPi DBS and 10 healthy subjects. Motor cortex plasticity was assessed using transcranial magnetic stimulation (TMS) paired associative stimulation (PAS) of motor cortex and median nerve, a method which has been shown in healthy subjects to produce LTP-like effects. Thresholds and TMS intensity to produce a resting motor evoked potential (MEP) of 1 mV were determined. Resting MEP amplitude and stimulus response curves were recorded before and after PAS. Patients were recorded ON and OFF DBS in separate sessions. Results: The mean TMS intensity to produce a resting MEP of 1 mV was 54% of maximum stimulator output when OFF and 52% ON DBS. Fifteen minutes after PAS the resting MEP amplitude increased in patients OFF DBS and in control subjects whereas it decreased in patients ON DBS. Similarly, after PAS, the mean amplitude of the stimulus response curve increased OFF DBS, but this effect was abolished with DBS ON. Furthermore, patients who had the largest clinical response to chronic DBS also had the largest difference in the effect of PAS with DBS ON vs. OFF. Conclusions: After PAS, patients with primary generalised dystonia showed a similar pattern of increased motor cortex excitability as healthy subjects when GPi DBS was OFF but not with GPi DBS ON. These results suggest that GPi DBS may reduce LTP-like motor cortex plasticity, which could contribute to its mechanism of action in dystonia. [Copyright &y& Elsevier]

Abstract: Somatosensory-evoked potentials (SEPs) are attenuated by movement. This phenomenon of ‘gating’ reflects sensorimotor integration for motor control. The frontal N30 component after median nerve stimulation was shown to be reduced in amplitude prior to hand movement. To investigate the mechanism of this sensory gating, we recorded median SEPs immediately before and after application of monophasic very low-frequency (0.2 Hz) repetitive transcranial magnetic stimulation (rTMS) of 250 stimuli over motor cortex (MC), premotor cortex (PMC), or supplementary motor area (SMA) in 9 healthy volunteers. The stimulus intensity for MC or PMC was set 85% of the resting motor threshold for the hand muscle, and that for SMA was at the active motor threshold for the leg muscle. SEPs showed significant increases in amplitudes of the frontal N30 component after PMC stimulation, but not after SMA or MC stimulation. Low-frequency (1 Hz) biphasic stimulation over PMC showed no significant N30 changes in 6 out of 9 subjects tested, indicating the effect being specific for 0.2 Hz monophasic stimulation. To examine the functional anatomy of the N30 change, single photon emission computed tomography was performed immediately before and after monophasic 0.2 Hz rTMS over PMC in all the 9 subjects. Regional cerebral blood flow showed significant increases mainly in PMC and prefrontal cortex, indicating the involvement of these cortical areas in sensory input gating for motor control. [Copyright &y& Elsevier]

Saccadic chronostasis refers to the subjective temporal lengthening of the first visual stimulus perceived after an eye movement. It has been quantified using a duration discrimination task. Most models of human duration discrimination hypothesise an internal clock. These models could explain chronostasis as a transient increase in internal clock speed due to arousal following a saccade, leading to temporal overestimation. Two experiments are described which addressed this hypothesis by parametrically varying the duration of the stimuli that are being judged. Changes in internal clock speed predict chronostasis effects proportional to stimulus duration. No evidence for proportionality was found. Two further experiments assessed the appropriateness of the control conditions employed. Results indicated that the chronostasis effect is constant across a wide range of stimulus durations and does not reflect the pattern of visual stimulation experienced during a saccade, suggesting that arousal is not critical. Instead, alternative processes, such as one affecting the onset of timing (i.e., the time of internal clock switch closure) are implicated. Further research is required to select between these alternatives. [Copyright &y& Elsevier]

Survival in a suddenly-changing environment requires animals not only to detect salient stimuli, but also to promptly respond to them by initiating or revising ongoing motor processes. We recently discovered that the large vertex brain potentials elicited by sudden supramodal stimuli are strongly coupled with a multiphasic modulation of isometric force, a phenomenon that we named cortico-muscular resonance (CMR). Here, we extend our investigation of the CMR to the time-frequency domain. We show that (i) both somatosensory and auditory stimuli evoke a number of phase-locked and non-phase-locked modulations of EEG spectral power. Remarkably, (ii) some of these phase-locked and non-phase-locked modulations are also present in the Force spectral power. Finally, (iii) EEG and Force time-frequency responses are correlated in two distinct regions of the power spectrum. An early, low-frequency region (∼4 Hz) reflects the previously-described coupling between the phase-locked EEG vertex potential and force modulations. A late, higher-frequency region (beta-band, ∼20 Hz) reflects a second coupling between the non-phase-locked increase of power observed in both EEG and Force. In both time-frequency regions, coupling was maximal over the sensorimotor cortex contralateral to the hand exerting the force, suggesting an effect of the stimuli on the tonic corticospinal drive. Thus, stimulus-induced CMR occurs across at least two different types of cortical activities, whose functional significance in relation to the motor system should be investigated further. We propose that these different types of corticomuscular coupling are important to alter motor behaviour in response to salient environmental events. • We delivered salient stimuli to humans exerting a constant isometric force. • The stimuli evoked several modulations of both EEG and Force spectral power. • Some of these modulations were coupled across EEG and Force. • The coupled modulations were both phase-locked (∼4 Hz) and non-phase-locked (∼20 Hz). • Stimulus-induced corticomuscular coupling involves two types of cortical activity. [ABSTRACT FROM AUTHOR]

• Cerebellar-cortical connectivity at rest and during motor learning can be measured by cerebellar TMS-EEG. • The discrepancies between two recent cerebellar TMS-EEG are discussed. • A reasonable and consistent methodology in this field is necessary. In their commentary on our recently published paper about electroencephalographic responses induced by cerebellar transcranial magnetic stimulation (Fong et al., 2023), Gassmann and colleagues (Gassmann et al., 2023b) try to explain the differences between our results and their own previous work on the same topic. We agree with them that many of the differences arise from our use of a different magnetic stimulation coil. However, two unresolved questions remain. (1) Which method is most likely to achieve optimal activation of cerebellar output? (2) To what extent are the evoked cerebellar responses contaminated by concomitant sensory input? We highlight the role of careful experimental design and of combining electrophysiological and behavioural data to obtain reliable TMS-EEG data. [ABSTRACT FROM AUTHOR]

• Concurrent TMS and EEG can probe the cerebellocerebral network. • Somatosensory and auditory control experiments can reveal EEG activity caused by output from cerebellum. • A single cerebellar stimulus evokes two contralateral cortical potentials: P80 and N110. • The amplitude of cerebellar evoked cortical potentials is influenced by motor learning. Connections between the cerebellum and the cortex play a critical role in learning and executing complex behaviours. Dual-coil transcranial magnetic stimulation (TMS) can be used non-invasively to probe connectivity changes between the lateral cerebellum and motor cortex (M1) using the motor evoked potential as an outcome measure (cerebellar-brain inhibition, CBI). However, it gives no information about cerebellar connections to other parts of cortex. We used electroencephalography (EEG) to investigate whether it was possible to detect activity evoked in any areas of cortex by single-pulse TMS of the cerebellum (cerebellar TMS evoked potentials, cbTEPs). A second experiment tested if these responses were influenced by the performance of a cerebellar-dependent motor learning paradigm. In the first series of experiments, TMS was applied over either the right or left cerebellar cortex, and scalp EEG was recorded simultaneously. Control conditions that mimicked auditory and somatosensory inputs associated with cerebellar TMS were included to identify responses due to non-cerebellar sensory stimulation. We conducted a follow-up experiment that evaluated whether cbTEPs are behaviourally sensitive by assessing individuals before and after learning a visuomotor reach adaptation task. A TMS pulse over the lateral cerebellum evoked EEG responses that could be distinguished from those caused by auditory and sensory artefacts. Significant positive (P80) and negative peaks (N110) over the contralateral frontal cerebral area were identified with a mirrored scalp distribution after left vs. right cerebellar stimulation. The P80 and N110 peaks were replicated in the cerebellar motor learning experiment and changed amplitude at different stages of learning. The change in amplitude of the P80 peak was associated with the degree of learning that individuals retained following adaptation. Due to overlap with sensory responses, the N110 should be interpreted with caution. Cerebral potentials evoked by TMS of the lateral cerebellum provide a neurophysiological probe of cerebellar function that complements the existing CBI method. They may provide novel insight into mechanisms of visuomotor adaptation and other cognitive processes. [ABSTRACT FROM AUTHOR]

Noninvasive neurostimulation methods such as transcranial direct current stimulation (tDCS) can elicit long-lasting, polarity-dependent changes in neocortical excitability. In a previous concurrent tDCS-fMRI study of overt picture naming, we reported significant behavioural and regionally specific neural facilitation effects in left inferior frontal cortex (IFC) with anodal tDCS applied to left frontal cortex (Holland et al., 2011). Although distributed connectivity effects of anodal tDCS have been modelled at rest, the mechanism by which ‘on-line’ tDCS may modulate neuronal connectivity during a task-state remains unclear. Here, we used Dynamic Causal Modelling (DCM) to determine: (i) how neural connectivity within the frontal speech network is modulated during anodal tDCS; and, (ii) how individual variability in behavioural response to anodal tDCS relates to changes in effective connectivity strength. Results showed that compared to sham, anodal tDCS elicited stronger feedback from inferior frontal sulcus (IFS) to ventral premotor (VPM) accompanied by weaker self-connections within VPM, consistent with processes of neuronal adaptation. During anodal tDCS individual variability in the feedforward connection strength from IFS to VPM positively correlated with the degree of facilitation in naming behaviour. These results provide an essential step towards understanding the mechanism of ‘online’ tDCS paired with a cognitive task. They also identify left IFS as a ‘top-down’ hub and driver for speech change. [ABSTRACT FROM AUTHOR]

The neuromodulatory effects of repetitive transcranial magnetic stimulation (rTMS) have been mostly investigated by peripheral motor-evoked potentials (MEPs). New TMS-compatible EEG systems allow a direct investigation of the stimulation effects through the analysis of TMS-evoked potentials (TEPs). We investigated the effects of 1-Hz rTMS over the primary motor cortex (M1) of 15 healthy volunteers on TEP evoked by single pulse TMS over the same area. A second experiment in which rTMS was delivered over the primary visual cortex (V1) of 15 healthy volunteers was conducted to examine the spatial specificity of the effects. Single-pulse TMS evoked four main components: P30, N45, P60 and N100. M1-rTMS resulted in a significant decrease of MEP amplitude and in a significant increase of P60 and N100 amplitude. There was no effect after V1-rTMS. 1-Hz rTMS appears to increase the amount of inhibition following a TMS pulse, as demonstrated by the higher N100 and P60, which are thought to originate from GABAb-mediated inhibitory post-synaptic potentials. Our results confirm the reliability of the TMS-evoked N100 as a marker of cortical inhibition and provide insight into the neuromodulatory effects of 1-Hz rTMS. The present finding could be of relevance for therapeutic and diagnostic purposes. [ABSTRACT FROM AUTHOR]

Abstract: Functional magnetic resonance imaging (fMRI) studies in humans have hitherto failed to demonstrate activity changes in the direct vicinity of transcranial magnetic stimulation (TMS) that cannot be attributed to re-afferent somatosensory feedback or a spread of excitation. In order to investigate the underlying activity changes at the site of stimulation as well as in remote connected regions, we applied short trains of high-intensity (110% of resting motor threshold) and low-intensity (90% of active motor threshold) repetitive TMS (rTMS; 3 Hz, 10 s duration) over the presumed location of the left dorsal premotor cortex (PMd) during fMRI. Signal increases in the direct vicinity of the stimulated PMd were observed during rTMS at 110% RMT. However, positive BOLD MRI responses were observed with rTMS at both 90% and 110% RMT in connected brain regions such as right PMd, bilateral PMv, supplementary motor area, somatosensory cortex, cingulate motor area, left posterior temporal lobe, cerebellum, and caudate nucleus. Responses were generally smaller during low-intensity rTMS. The results indicate that short trains of TMS can modify local hemodynamics in the absence of overt motor responses. In addition, premotor rTMS cannot only effectively stimulate cortico-cortical but also cortico-subcortical connections even at low stimulation intensities. [Copyright &y& Elsevier]

Abstract: We investigated the differential effects of levodopa medication and STN stimulation on finger force control in Parkinson subjects grasping to lift an object and performing vertical point-to-point movements of a hand-held object. The experiments were conducted in four treatment conditions: off-drug/off-stimulation, off-drug/on-stimulation, on-drug/off-stimulation and on-drug/on-stimulation. We found that the bradykinesia in Parkinsonian subjects improved by both levodopa medication and STN stimulation. As compared to healthy subjects, excessive grip force was observed in all Parkinson subjects, regardless of the treatment condition. This force excess was most pronounced in the on-drug condition and ameliorated by STN stimulation. We observed reliable correlations between the amount of force overflow and the severity of levodopa-induced dyskinesias in the on-drug condition. Despite some similarities regarding therapeutic effects on bradykinesia, our findings contrast with earlier observations with respect to the differential effects of levodopa and STN stimulation on the scaling of fingertip forces in Parkinson''s disease. While levodopa causes an overshoot of fingertip forces, STN stimulation appears to be sufficient to alleviate, but not normalise the force excess. STN stimulation enables Parkinson subjects to scale grip force more accurately to the loads arising from voluntary manipulation of hand-held objects. [Copyright &y& Elsevier]

Abstract: Repetitive transcranial magnetic stimulation (rTMS) to the human primary motor cortex (M1) causes bidirectional changes in corticospinal excitability depending on the stimulation frequency used. We used functional brain imaging to compare the effects of 5 Hz and 1 Hz-rTMS on local and inter-regional connectivity within the motor system. Regional cerebral blood flow (rCBF) was measured as a marker of synaptic activity at rest and during freely selected finger movements. We hypothesized that increased cortical excitability induced by 5 Hz-rTMS over M1 has an opposite effect on the synaptic activity and the connectivity of the motor network from the decreased cortical excitability induced by 1 Hz-rTMS. rTMS at both frequencies induced similar changes in rCBF at the site of stimulation and within areas of the motor network engaged by the task. The two frequencies showed different effects on movement-related coupling between motor areas. Connectivity analyses also indicated a differential effect of 5 and 1 Hz-rTMS on motor network connectivity, suggesting a role for an inferomedial portion of left M1 and left dorsal premotor cortex in maintaining performance. These results suggest that rapid reorganization of the motor system occurs to maintain task performance during periods of altered cortical excitability. This reorganization differs according to the modulation of excitability which is a function of rTMS frequency. This study extends the work of Lee et al. (Lee, L., Siebner, H.R., Rowe, J.B., Rizzo, V. Rothwell, J.C. Frackowiak, R.S. Friston, K.J., 2003. Acute remapping within the motor system induced by low-frequency repetitive transcranial magnetic stimulation. J. Neurosci. 23, 5308–5318.) by providing evidence that the pattern of acute reorganization in the motor network following rTMS depends on the direction of conditioning. [Copyright &y& Elsevier]

To elucidate changes in human brain activity evoked by repetitive transcranial magnetic stimulation (rTMS), sub- and suprathreshold rTMS (4 Hz, 10 s) over the left primary sensorimotor cortex (M1/S1) was interleaved with blood-oxygenation-level-dependent (BOLD) echo-planar imaging of primary and secondary motor areas. Suprathreshold rTMS over left M1/S1 caused marked increases in BOLD signal in the stimulated area and SMA-proper in seven of eight subjects. By contrast, we found no change in BOLD signal in the stimulated M1/S1, when rTMS was given at intensities that were subthreshold for inducing motor responses in the contralateral hand. However, five of eight subjects showed consistent increases in BOLD MRI signal in the SMA-proper and, to a lesser extent, in bilateral lateral premotor cortex (LPMC) during subthreshold rTMS. A decrease in BOLD MRI signal was found in contralateral (right) M1/S1 in 6/8 subjects across all conditions. No significant changes were observed in the pre-SMA. The results support the notion that BOLD MRI responses to suprathreshold rTMS over M1/S1 are dominated by neuronal activity related to reafferent processing of TMS-induced hand movements. At subthreshold intensity, a short train of high-frequency rTMS seems to predominantly modulate activity of corticocortical connections which link the stimulated area with remote frontal premotor areas. [Copyright &y& Elsevier]

We explored the aftereffects of two premotor 1 Hz rTMS sessions on motor cortex excitability in healthy humans. In experiment 1, 11 healthy right-handed volunteers received 20-min submotor threshold 1 Hz rTMS trains over the left premotor cortex on 2 consecutive days. Left motor cortex excitability was determined at baseline, immediately after, 30, 60, 120 min, and 24 h after each rTMS session. We measured motor thresholds, amplitudes of motor-evoked potentials, silent periods, and paired-pulse excitability at interstimulus intervals (ISI) of 3–7, 10, and 15 ms. In experiment 2, 5 volunteers received two identical rTMS trains on Days 1 and 7. Measurements were carried out on Day 1 (first rTMS train), Day 2, and Day 7 (second rTMS train). In experiment 1 there was a selective increase of paired pulse facilitation at an ISI of 7 ms after rTMS lasting for less than 30 min on Day 1. This effect was also present after rTMS on Day 2. However, it persisted for at least 2 h. In experiment 2 the same extra facilitation was induced by rTMS on Days 1 and 7 but not on Day 2. It lasted for less than 30 min on both Day 1 and Day 7. We conclude that 1 Hz premotor rTMS leads to cumulative plastic changes of intrinsic motor cortex excitability when repeated within 24 h but not after 1 week, implying the formation of memory after the first rTMS train lasting more than a day but less than a week. [Copyright &y& Elsevier]