Background: the use of combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) for the functional evaluation of the cerebral cortex in health and disease is becoming increasingly common. However, there is still some ambiguity regarding the extent to which brain responses to auditory and somatosensory stimulation contribute to the TMS-evoked potential (TEP). Objective/Hypothesis: to measure separately the contribution of auditory and somatosensory stimulation caused by TMS, and to assess their contribution to the TEP waveform, when stimulating the motor cortex (M1). Methods: 19 healthy volunteers underwent 7 blocks of EEG recording. To assess the impact of auditory stimulation on the TEP waveform, we used a standard figure of eight coil, with or without masking with a continuous noise reproducing the specific time-varying frequencies of the TMS click, stimulating at 90% of resting motor threshold. To further characterise auditory responses due to the TMS click, we used either a standard or a sham figure of eight coil placed on a pasteboard cylinder that rested on the scalp, with or without masking. Lastly, we used electrical stimulation of the scalp to investigate the possible contribution of somatosensory activation. Results: auditory stimulation induced a known pattern of responses in electrodes located around the vertex, which could be suppressed by appropriate noise masking. Electrical stimulation of the scalp alone only induced similar, non-specific scalp responses in the in the central electrodes. TMS, coupled with appropriate masking of sensory input, resulted in specific, lateralized responses at the stimulation site, lasting around 300 ms. Conclusions: if careful control of confounding sources is applied, TMS over M1 can generate genuine, lateralized EEG activity. By contrast, sensory evoked responses, if present, are represented by nonspecific, late (100e200 ms) components, located at the vertex, possibly due to saliency of the stimuli. Notably, the latter can confound the TEP if masking procedures are not properly used.

BackgroundThe somatosensory temporal discrimination threshold (STDT) measures the ability to perceive two stimuli as being sequential. Precisely how the single cerebral structures contribute in controlling the STDT is partially known and no information is available about whether STDT can be modulated by plasticity-inducing protocols.Methodology/Principal FindingsTo investigate how the cortical and cerebellar areas contribute to the STDT we used transcranial magnetic stimulation and a neuronavigation system. We enrolled 18 healthy volunteers and 10 of these completed all the experimental sessions, including the control experiments. STDT was measured on the left hand before and after applying continuous theta-burst stimulation (cTBS) on the right primary somatosensory area (S1), pre-supplementary motor area (pre-SMA), right dorsolateral prefrontal cortex (DLPFC) and left cerebellar hemisphere. We then investigated whether intermittent theta-burst stimulation (iTBS) on the right S1 improved the STDT. After right S1 cTBS, STDT values increased whereas after iTBS to the same cortical site they decreased. cTBS over the DLPFC and left lateral cerebellum left the STDT statistically unchanged. cTBS over the pre-SMA also left the STDT statistically unchanged, but it increased the number of errors subjects made in distinguishing trials testing a single stimulus and those testing paired stimuli.Conclusions/SignificanceOur findings obtained by applying TBS to the cortical areas involved in processing sensory discrimination show that the STDT is encoded in S1, possibly depends on intrinsic S1 neural circuit properties, and can be modulated by plasticity-inducing TBS protocols delivered over S1. Our findings, giving further insight into mechanisms involved in somatosensory temporal discrimination, help interpret STDT abnormalities in movement disorders including dystonia and Parkinson's disease.

Objective: high frequency repetitive somatosensory stimulation (HF-RSS), which is a patterned electric stimulation applied to the skin through surface electrodes, improves two-point discrimination, somatosensory temporal discrimination threshold (STDT) and motor performance in humans.However, the mechanisms which underlie this changes are still unknown. In particular, we hypothesize that refinement of inhibition might be responsible for the improvement in spatial and temporal perception. Methods: fifteen healthy subjects underwent 45 minutes of HF-RSS. Before and after the intervention several measures of inhibition in the primary somatosensory area (S1), such as paired-pulse somatosensory evoked potentials (pp-SEP), high-frequency oscillations (HFO), and STDT were tested, as well as tactile spatial acuity and short intracortical inhibition (SICI). Results:HF-RSS increased inhibition in S1 tested by pp-SEP and HFO; these changes were correlated with improvement in STDT. HF-RSS also enhanced bumps detection, while there was no change in grating orientation test. Finally there was an increase in SICI, suggesting widespread changes in cortical sensorimotor interactions. Conclusions: these findings suggest that HF-RSS can improve spatial and temporal tactile abilities by increasing the effectiveness of inhibitory interactions in the somatosensory system. Moreover, HF-RSS induces changes in cortical sensorimotor interaction.Significance: HF-RSS is a repetitive electric stimulation technique able to modify the effectiveness of inhibitory circuitry in the somatosensory system and primary motor cortex. 4

Somatosensory temporal discrimination threshold (STDT) is defined as the shortest time interval necessary for a pair of tactile stimuli to be perceived as separate. Although STDT is altered in several neurological disorders, its neural bases are not entirely clear. We used continuous theta burst stimulation (cTBS) to condition the excitability of the primary somatosensory cortex in healthy humans to examine its possible contribution to STDT. Excitability was assessed using the recovery cycle of the N20 component of somatosensory evoked potentials (SEP) and the area of high-frequency oscillations (HFO). cTBS increased STDT and reduced inhibition in the N20 recovery cycle at an interstimulus interval of 5 ms. It also reduced the amplitude of late HFO. All three effects were correlated. There was no effect of cTBS over the secondary somatosensory cortex on STDT, although it reduced the N120 component of the SEP. STDT is assessed conventionally with a simple ascending method. To increase insight into the effect of cTBS, we measured temporal discrimination with a psychophysical method. cTBS reduced the slope of the discrimination curve, consistent with a reduction of the quality of sensory information caused by an increase in noise. We hypothesize that cTBS reduces the effectiveness of inhibitory interactions normally used to sharpen temporal processing of sensory inputs. This reduction in discriminability of sensory input is equivalent to adding neural noise to the signal.

Continuous theta-burst stimulation (cTBS) is a repetitive transcranial magnetic stimulation paradigm reported to decrease the excitability of the stimulated cortical area and which is thought to reflect a form of inhibitory synaptic plasticity. However, since its introduction, the effect of cTBS has shown a remarkable variability in its effects, which are often quantified by measuring the amplitude of motor evoked potentials (MEPs). Part of this inconsistency in experimental results might be due to an intrinsic variability of TMS effects caused by genetic or neurophysiologic factors. However, it is also possible that MEP only reflect the excitability of a sub-population of output neurons; resting EEG power and measures combining TMS and electroencephalography (TMS-EEG) might represent a more thorough reflection of cortical excitability. The aim of the present study was to verify the robustness of several predictors of cTBS response, such as I wave recruitment and baseline MEP amplitude, and to test cTBS after-effects on multiple neurophysiologic measurements such as MEP, resting EEG power, local mean field power (LMFP), TMS-related spectral perturbation (TRSP), and inter-trial phase clustering (ITPC). As a result, we were not able to confirm either the expected decrease of MEP amplitude after cTBS or the ability of I wave recruitment and MEP amplitude to predict the response to cTBS. Resting EEG power, LMFP, TRSP, and ITPC showed a more consistent trend toward a decrease after cTBS. Overall, our data suggest that the effect of cTBS on corticospinal excitability is variable and difficult to predict with common electrophysiologic markers, while its effect might be clearer when probed with combined TMS and EEG.

Background Apart from motor symptoms, multiple deficits of sensory processing have been demonstrated in dystonia. The most consistent behavioural measure of this is abnormal somatosensory temporal discrimination threshold, which has recently been associated with physiological measures of reduced inhibition within the primary somatosensory area. High‐frequency repetitive sensory stimulation is a patterned electric stimulation applied to the skin through surface electrodes that has been recently reported to shorten somatosensory temporal discrimination in healthy subjects and to increase the resting level of excitability in several different types of inhibitory interaction in the somatosensory and even motor areas. Objectives We tested whether high‐frequency repetitive sensory stimulation could augment cortical inhibition and, in turn, ameliorate somatosensory temporal discrimination in cervical dystonia. Methods Somatosensory temporal discrimination and a number of electrophysiological measures of sensorimotor inhibition and facilitation were measured before and after 45 minutes of high‐frequency repetitive sensory stimulation. Results As compared with a group of healthy volunteers of similar age, in whom high‐frequency repetitive sensory stimulation increased inhibition and shortened somatosensory temporal discrimination, patients with cervical dystonia showed a consistent, paradoxical response: they had reduced suppression of paired‐pulse somatosensory evoked potentials, as well as reduced high‐frequency oscillations, lateral inhibition, and short interval intracortical inhibition. Somatosensory temporal discrimination deteriorated after the stimulation protocol, and correlated with reduced measures of inhibition within the primary somatosensory cortex. Conclusions We suggest that patients with dystonia have abnormal homeostatic inhibitory plasticity within the sensorimotor cortex and that this is responsible for their paradoxical response to high‐frequency repetitive sensory stimulation. © 2018 International Parkinson and Movement Disorder Society

BackgroundSomatosensory temporal discrimination threshold is often prolonged in patients with dystonia. Previous evidence suggested that this might be caused by impaired somatosensory processing in the time domain. Here, we tested if other markers of reduced inhibition in the somatosensory system might also contribute to abnormal somatosensory temporal discrimination in dystonia.MethodsSomatosensory temporal discrimination threshold was measured in 19 patients with isolated cervical dystonia and 19 age‐matched healthy controls. We evaluated temporal somatosensory inhibition using paired‐pulse somatosensory evoked potentials, spatial somatosensory inhibition by measuring the somatosensory evoked potentials interaction between simultaneous stimulation of the digital nerves in thumb and index finger, and Gamma‐aminobutyric acid‐ergic (GABAergic) sensory inhibition using the early and late components of high‐frequency oscillations in digital nerves somatosensory evoked potentials.ResultsWhen compared with healthy controls, dystonic patients had longer somatosensory temporal discrimination thresholds, reduced suppression of cortical and subcortical paired‐pulse somatosensory evoked potentials, less spatial inhibition of simultaneous somatosensory evoked potentials, and a smaller area of the early component of the high‐frequency oscillations. A logistic regression analysis found that paired pulse suppression of the N20 component at an interstimulus interval of 5 milliseconds and the late component of the high‐frequency oscillations were independently related to somatosensory temporal discrimination thresholds. “Dystonia group” was also a predictor of enhanced somatosensory temporal discrimination threshold, indicating a dystonia‐specific effect that independently influences this threshold.ConclusionsIncreased somatosensory temporal discrimination threshold in dystonia is related to reduced activity of inhibitory circuits within the primary somatosensory cortex. © 2016 International Parkinson and Movement Disorder Society.

Cortical tremor is a fine rhythmic oscillation involving distal upper limbs, linked to increased sensorimotor cortex excitability, as seen in cortical myoclonus. Cortical tremor is the hallmark feature of autosomal dominant familial cortical myoclonic tremor and epilepsy (FCMTE), a syndrome not yet officially recognized and characterized by clinical and genetic heterogeneity. Non-coding repeat expansions in different genes have been recently recognized to play an essential role in its pathogenesis. Cortical tremor is considered a rhythmic variant of cortical myoclonus and is part of the ‘spectrum of cortical myoclonus’, i.e. a wide range of clinical motor phenomena, from reflex myoclonus to myoclonic epilepsy, caused by abnormal sensorimotor cortical discharges. The aim of this update is to provide a detailed analysis of the mechanisms defining cortical tremor, as seen in FCMTE. After reviewing the clinical and genetic features of FCMTE, we discuss the possible mechanisms generating the distinct elements of the cortical myoclonus spectrum, and how cortical tremor fits into it. We propose that the spectrum is due to the evolution from a spatially limited focus of excitability to recruitment of more complex mechanisms capable of sustaining repetitive activity, overcoming inhibitory mechanisms that restrict excitatory bursts, and engaging wide areas of cortex. Finally, we provide evidence for a possible common denominator of the elements of the spectrum, i.e. the cerebellum, and discuss its role in FCMTE, according to recent genetic findings.