Changes in Cortical Activation by Transcranial Magnetic Stimulation Due to Coil Rotation Are Not Attributable to Cranial Muscle Activation.

Transcranial magnetic stimulation coupled with electroencephalography (TMS-EEG) allows for the study of brain dynamics in health and disease. Cranial muscle activation can decrease the interpretability of TMS-EEG signals by masking genuine EEG responses and increasing the reliance on preprocessing methods but can be at least partly prevented by coil rotation coupled with the online monitoring of signals; however, the extent to which changing coil rotation may affect TMS-EEG signals is not fully understood. Our objective was to compare TMS-EEG data obtained with an optimal coil rotation to induce motor evoked potentials (M1standard) while rotating the coil to minimize cranial muscle activation (M1emg). TMS-evoked potentials (TEPs), TMS-related spectral perturbation (TRSP), and intertrial phase clustering (ITPC) were calculated in both conditions using two different preprocessing pipelines based on independent component analysis (ICA) or signal-space projection with source-informed reconstruction (SSP-SIR). Comparisons were performed with cluster-based correction. The concordance correlation coefficient was computed to measure the similarity between M1standard and M1emg TMS-EEG signals. TEPs, TRSP, and ITPC were significantly larger in M1standard than in M1emg conditions; a lower CCC than expected was also found. These results were similar across the preprocessing pipelines. While rotating the coil may be advantageous to reduce cranial muscle activation, it may result in changes in TMS-EEG signals; therefore, this solution should be tailored to the specific experimental context.

Consensus for experimental design in electromyography (CEDE) project: Checklist for reporting and critically appraising studies using EMG (CEDE-Check).

The diversity in electromyography (EMG) techniques and their reporting present significant challenges across multiple disciplines in research and clinical practice, where EMG is commonly used. To address these challenges and augment the reproducibility and interpretation of studies using EMG, the Consensus for Experimental Design in Electromyography (CEDE) project has developed a checklist (CEDE-Check) to assist researchers to thoroughly report their EMG methodologies. Development involved a multi-stage Delphi process with seventeen EMG experts from various disciplines. After two rounds, consensus was achieved. The final CEDE-Check consists of forty items that address four critical areas that demand precise reporting when EMG is employed: the task investigated, electrode placement, recording electrode characteristics, and acquisition and pre-processing of EMG signals. This checklist aims to guide researchers to accurately report and critically appraise EMG studies, thereby promoting a standardised critical evaluation, and greater scientific rigor in research that uses EMG signals. This approach not only aims to facilitate interpretation of study results and comparisons between studies, but it is also expected to contribute to advancing research quality and facilitate clinical and other practical applications of knowledge generated through the use of EMG.

Probing intrahemispheric interactions with a novel dual-site TMS setup.

OBJECTIVE: Using dual-site transcranial magnetic stimulation (dsTMS), the effective connectivity between the primary motor cortex (M1) and adjacent brain areas such as the dorsal premotor cortex (PMd) can be investigated. However, stimulating two brain regions in close proximity (e.g., ±2.3 cm for intrahemispheric PMd-M1) is subject to considerable spatial restrictions that potentially can be overcome by combining two standard figure-of-eight coils in a novel dsTMS setup. METHODS: After a technical evaluation of its induced electric fields, the dsTMS setup was tested in vivo (n = 23) by applying a short-interval intracortical inhibition (SICI) protocol. Additionally, the intrahemispheric PMd-M1 interaction was probed. E-field modelling was performed using SimNIBS. RESULTS: The technical evaluation yielded no major alterations of the induced electric fields due to coil overlap. In vivo, the setup reliably elicited SICI. Investigating intrahemispheric PMd-M1 interactions was feasible (inter-stimulus interval 6 ms), resulting in modulation of M1 output. CONCLUSIONS: The presented dsTMS setup provides a novel way to stimulate two adjacent brain regions with fewer technical and spatial limitations than previous attempts. SIGNIFICANCE: This dsTMS setup enables more accurate and repeatable targeting of brain regions in close proximity and can facilitate innovation in the field of effective connectivity.

Changes in cerebellar output abnormally modulate cortical myoclonus sensorimotor hyperexcitability.

Cortical myoclonus is produced by abnormal neuronal discharges within the sensorimotor cortex, as demonstrated by electrophysiology. Our hypothesis is that the loss of cerebellar inhibitory control over the motor cortex, via cerebello-thalamo-cortical connections, could induce the increased sensorimotor cortical excitability that eventually causes cortical myoclonus. To explore this hypothesis, in the present study we applied anodal transcranial direct current stimulation over the cerebellum of patients affected by cortical myoclonus and healthy controls and assessed its effect on sensorimotor cortex excitability. We expected that anodal cerebellar transcranial direct current stimulation would increase the inhibitory cerebellar drive to the motor cortex and therefore reduce the sensorimotor cortex hyperexcitability observed in cortical myoclonus. Ten patients affected by cortical myoclonus of various aetiology and 10 aged-matched healthy control subjects were included in the study. All participants underwent somatosensory evoked potentials, long-latency reflexes and short-interval intracortical inhibition recording at baseline and immediately after 20 min session of cerebellar anodal transcranial direct current stimulation. In patients, myoclonus was recorded by the means of surface EMG before and after the cerebellar stimulation. Anodal cerebellar transcranial direct current stimulation did not change the above variables in healthy controls, while it significantly increased the amplitude of somatosensory evoked potential cortical components, long-latency reflexes and decreased short-interval intracortical inhibition in patients; alongside, a trend towards worsening of the myoclonus after the cerebellar stimulation was observed. Interestingly, when dividing patients in those with and without giant somatosensory evoked potentials, the increment of the somatosensory evoked potential cortical components was observed mainly in those with giant potentials. Our data showed that anodal cerebellar transcranial direct current stimulation facilitates-and does not inhibit-sensorimotor cortex excitability in cortical myoclonus syndromes. This paradoxical response might be due to an abnormal homeostatic plasticity within the sensorimotor cortex, driven by dysfunctional cerebello-thalamo-cortical input to the motor cortex. We suggest that the cerebellum is implicated in the pathophysiology of cortical myoclonus and that these results could open the way to new forms of treatment or treatment targets.

Sensorimotor integration in cranial muscles tested by short- and long-latency afferent inhibition.

OBJECTIVE: To compressively investigate sensorimotor integration in the cranial-cervical muscles in healthy adults. METHODS: Short- (SAI) and long-latency afferent (LAI) inhibition were probed in the anterior digastric (AD), the depressor anguli oris (DAO) and upper trapezius (UT) muscles. A transcranial magnetic stimulation pulse over primary motor cortex was preceded by peripheral stimulation delivered to the trigeminal, facial and accessory nerves using interstimulus intervals of 15-25 ms and 100-200 ms for SAI and LAI respectively. RESULTS: In the AD, both SAI and LAI were detected following trigeminal nerve stimulation, but not following facial nerve stimulation. In the DAO, SAI was observed only following trigeminal nerve stimulation, while LAI depended only on facial nerve stimulation, only at an intensity suprathreshold for the compound motor action potential (cMAP). In the UT we could only detect LAI following accessory nerve stimulation at an intensity suprathreshold for a cMAP. CONCLUSIONS: The results suggest that integration of sensory inputs with motor output is profoundly influenced by the type of sensory afferent involved and by the functional role played by the target muscle. SIGNIFICANCE: Data indicate the importance of taking into account the sensory receptors involved as well as the function of the target muscle when studying sensorimotor integration, both in physiological and neurological conditions.

Rethinking the neurophysiological concept of cortical myoclonus.

Cortical myoclonus is thought to result from abnormal electrical discharges arising in the sensorimotor cortex. Given the ease of recording of cortical discharges, electrophysiological features of cortical myoclonus have been better characterized than those of subcortical forms, and electrophysiological criteria for cortical myoclonus have been proposed. These include the presence of giant somatosensory evoked potentials, enhanced long-latency reflexes, electroencephalographic discharges time-locked to individual myoclonic jerks and significant cortico-muscular connectivity. Other features that are assumed to support the cortical origin of myoclonus are short-duration electromyographic bursts, the presence of both positive and negative myoclonus and cranial-caudal progression of the jerks. While these criteria are widely used in clinical practice and research settings, their application can be difficult in practice and, as a result, they are fulfilled only by a minority of patients. In this review we reappraise the evidence that led to the definition of the electrophysiological criteria of cortical myoclonus, highlighting possible methodological incongruencies and misconceptions. We believe that, at present, the diagnostic accuracy of cortical myoclonus can be increased only by combining observations from multiple tests, according to their pathophysiological rationale; nevertheless, larger studies are needed to standardise the methods, to resolve methodological issues, to establish the diagnostic criteria sensitivity and specificity and to develop further methods that might be useful to clarify the pathophysiology of myoclonus.

A Novel Paired Somatosensory-Cerebellar Stimulation Induces Plasticity on Cerebellar-Brain Connectivity.

The cerebellum receives and integrates a large amount of sensory information that is important for motor coordination and learning. The aim of the present work was to investigate whether peripheral nerve and cerebellum paired associative stimulation (cPAS) could induce plasticity in both the cerebellum and the cortex. In a cross-over design, we delivered right median nerve electrical stimulation 25 or 10 ms before applying transcranial magnetic stimulation over the cerebellum. We assessed changes in motor evoked potentials (MEP), somatosensory evoked potentials (SEP), short-afferent inhibition (SAI), and cerebellum-brain inhibition (CBI) immediately, and 30 min after cPAS. Our results showed a significant reduction in CBI 30 minutes after cPAS, with no discernible changes in MEP, SEP, and SAI. Notably, cPAS10 did not produce any modulatory effects on these parameters. In summary, cPAS25 demonstrated the capacity to induce plasticity effects in the cerebellar cortex, leading to a reduction in CBI. This novel intervention may be used to modulate plasticity mechanisms and motor learning in healthy individuals and patients with neurological conditions.

A Reflection on Motor Overflow, Mirror Phenomena, Synkinesia and Entrainment.

In patients with movement disorders, voluntary movements can sometimes be accompanied by unintentional muscle contractions in other body regions. In this review, we discuss clinical and pathophysiological aspects of several motor phenomena including mirror movements, dystonic overflow, synkinesia, entrainment and mirror dystonia, focusing on their similarities and differences. These phenomena share some common clinical and pathophysiological features, which often leads to confusion in their definition. However, they differ in several aspects, such as the body part showing the undesired movement, the type of this movement (identical or not to the intentional movement), the underlying neurological condition, and the role of primary motor areas, descending pathways and inhibitory circuits involved, suggesting that these are distinct phenomena. We summarize the main features of these fascinating clinical signs aiming to improve the clinical recognition and standardize the terminology in research studies. We also suggest that the term "mirror dystonia" may be not appropriate to describe this peculiar phenomenon which may be closer to dystonic overflow rather than to the classical mirror movements.

Reply to: "Reflecting the causes of variability of EEG responses elicited by cerebellar TMS".

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.

EEG responses induced by cerebellar TMS at rest and during visuomotor adaptation.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Botulinum toxin antibody titres: measurement, interpretation, and practical recommendations.

Botulinum toxin (BT) therapy may be blocked by antibodies (BT-AB) resulting in BT-AB induced therapy failure (ABF). BT-AB may be detected by the mouse lethality assay (MLA), the mouse diaphragm assay (MDA) and the sternocleidomastoid test (SCMT). For the first time, we wanted to compare all three BT-AB tests and correlate them to subjective complaint of complete or partial secondary therapy failure in 37 patients with cervical dystonia (25 females, 12 males, age 51.2 ± 11.4 years, disease duration 12.4 ± 6.3 years). Complaint of therapy failure was not correlated with any of the BT-AB tests. MDA and MLA are closely correlated, indicating that the MDA might replace the MLA as the current gold standard for BT-AB measurement. The SCMT is closely correlated with MDA and MLA confirming that BT-AB titres and BT's paretic effect are in a functional balance: low BT-AB titres are reducing BT's paretic effect only marginally, whereas high BT-AB titres may completely block it. When therapy failure is classified as secondary and permanent, BT-AB evaluation is recommended and any BT-AB test may be applied. For MDA > 10 mU/ml, MLA > 3 and SCMT < 25%, ABF is highly likely. MDA < 0.6 mU/ml are therapeutically irrelevant. They are neither correlated with pathologic MLA nor with pathologic SCMT. They should not be the basis for treatment decisions, such as switching dystonia therapy to deep brain stimulation. All other results are intermediate results. Their interactions with therapy efficacy is unpredictable. In these cases, BT-AB tests should be repeated or one or two additional test methods should be applied.

Short- and long-interval intracortical inhibition in EPM1 is related to genotype.

OBJECTIVE: Progressive myoclonic epilepsy type 1 (EPM1) is caused by biallelic alterations in the CSTB gene, most commonly dodecamer repeat expansions. Although transcranial magnetic stimulation (TMS)-induced long-interval intracortical inhibition (LICI) was previously reported to be normal in EPM1, short-interval intracortical inhibition (SICI) was reduced. We explored the association between these measures and the clinical and genetic features in a separate group of patients with EPM1. METHODS: TMS combined with electromyography was performed under neuronavigation. LICI was induced with an inter-stimulus interval (ISI) of 100 ms, and SICI with ISIs of 2 and 3 ms, and their means (mSICIs) were expressed as the ratio of conditioned to unconditioned stimuli. LICI and mSICI were compared between patients and controls. Nonparametric correlation was used to study the association between inhibition and parameters of clinical severity, including the Unified Myoclonus Rating Scale (UMRS); among patients with EPM1 due to biallelic expansion repeats, also the association with the number of repeats was assessed. RESULTS: The study protocol was completed in 19 patients (15 with biallelic expansion repeats and 4 compound heterozygotes), and 7 healthy, age- and sex-matched control participants. Compared to controls, patients demonstrated significantly less SICI (median mSICI ratio 1.18 vs 0.38; p < .001). Neither LICI nor SICI was associated with parameters of clinical severity. In participants with biallelic repeat expansions, the number of repeats in the more affected allele (greater repeat number [GRN]) correlated with LICI (rho = 0.872; p < .001) and SICI (rho = 0.689; p = .006). SIGNIFICANCE: Our results strengthen the finding of deranged γ-aminobutyric acid (GABA)ergic inhibition in EPM1. LICI and SICI may have use as markers of GABAergic impairment in future trials of disease-modifying treatment in this condition. Whether a higher number of expansion repeats leads to greater GABAergic impairment warrants further study.

Consensus for experimental design in electromyography (CEDE) project: Single motor unit matrix.

The analysis of single motor unit (SMU) activity provides the foundation from which information about the neural strategies underlying the control of muscle force can be identified, due to the one-to-one association between the action potentials generated by an alpha motor neuron and those received by the innervated muscle fibers. Such a powerful assessment has been conventionally performed with invasive electrodes (i.e., intramuscular electromyography (EMG)), however, recent advances in signal processing techniques have enabled the identification of single motor unit (SMU) activity in high-density surface electromyography (HDsEMG) recordings. This matrix, developed by the Consensus for Experimental Design in Electromyography (CEDE) project, provides recommendations for the recording and analysis of SMU activity with both invasive (needle and fine-wire EMG) and non-invasive (HDsEMG) SMU identification methods, summarizing their advantages and disadvantages when used during different testing conditions. Recommendations for the analysis and reporting of discharge rate and peripheral (i.e., muscle fiber conduction velocity) SMU properties are also provided. The results of the Delphi process to reach consensus are contained in an appendix. This matrix is intended to help researchers to collect, report, and interpret SMU data in the context of both research and clinical applications.

Standard intensities of transcranial alternating current stimulation over the motor cortex do not entrain corticospinal inputs to motor neurons.

Transcranial alternating current stimulation (TACS) is commonly used to synchronize a cortical area and its outputs to the stimulus waveform, but gathering evidence for this based on brain recordings in humans is challenging. The corticospinal tract transmits beta oscillations (∼21 Hz) from the motor cortex to tonically contracted limb muscles linearly. Therefore, muscle activity may be used to measure the level of beta entrainment in the corticospinal tract due to TACS over the motor cortex. Here, we assessed whether TACS is able to modulate the neural inputs to muscles, which would provide indirect evidence for TACS-driven neural entrainment. In the first part of the study, we ran simulations of motor neuron (MN) pools receiving inputs from corticospinal neurons with different levels of beta entrainment. Results suggest that MNs are highly sensitive to changes in corticospinal beta activity. Then, we ran experiments on healthy human subjects (N = 10) in which TACS (at 1 mA) was delivered over the motor cortex at 21 Hz (beta stimulation), or at 7 Hz or 40 Hz (control conditions) while the abductor digiti minimi or the tibialis anterior muscle were tonically contracted. Muscle activity was measured using high-density electromyography, which allowed us to decompose the activity of pools of motor units innervating the muscles. By analysing motor unit pool activity, we observed that none of the TACS conditions could consistently alter the spectral contents of the common neural inputs received by the muscles. These results suggest that 1 mA TACS over the motor cortex given at beta frequencies does not entrain corticospinal activity. KEY POINTS: Transcranial alternating current stimulation (TACS) is commonly used to entrain the communication between brain regions. It is challenging to find direct evidence supporting TACS-driven neural entrainment due to the technical difficulties in recording brain activity during stimulation. Computational simulations of motor neuron pools receiving common inputs in the beta (∼21 Hz) band indicate that motor neurons are highly sensitive to corticospinal beta entrainment. Motor unit activity from human muscles does not support TACS-driven corticospinal entrainment.

Dopamine increases risky choice while D2 blockade shortens decision time.

Dopamine is crucially involved in decision-making and overstimulation within dopaminergic pathways can lead to impulsive behaviour, including a desire to take risks and reduced deliberation before acting. These behavioural changes are side effects of treatment with dopaminergic drugs in Parkinson disease, but their likelihood of occurrence is difficult to predict and may be influenced by the individual's baseline endogenous dopamine state, and indeed correlate with sensation-seeking personality traits. We here collected data on a standard gambling task in healthy volunteers given either placebo, 2.5 mg of the dopamine antagonist haloperidol or 100/25 mg of the dopamine precursor levodopa in a within-subject design. We found an increase in risky choices on levodopa. Choices were, however, made faster on haloperidol with no effect of levodopa on deliberation time. Shortened deliberation times on haloperidol occurred in low sensation-seekers only, suggesting a correlation between sensation-seeking personality trait and baseline dopamine levels. We hypothesise that levodopa increases risk-taking behaviour via overstimulation at both D1 and D2 receptor level, while a single low dose of haloperidol, as previously reported (Frank and O'Reilly 2006), may block D2 receptors pre- and post-synaptically and may paradoxically lead to higher striatal dopamine acting on remaining striatal D1 receptors, causing speedier decision without influencing risk tolerance. These effects could also fit with a recently proposed computational model of the basal ganglia (Moeller and Bogacz 2019; Moeller et al. 2021). Furthermore, our data suggest that the actual dopaminergic drug effect may be dependent on the individual's baseline dopamine state, which may influence our therapeutic decision as clinicians in the future.

The Effect of Coil Orientation on the Stimulation of the Pre-Supplementary Motor Area: A Combined TMS and EEG Study.

Studies using transcranial magnetic stimulation (TMS) have demonstrated the importance of direction and intensity of the applied current when the primary motor cortex (M1) is targeted. By varying these, it is possible to stimulate different subsets of neural elements, as demonstrated by modulation of motor evoked potentials (MEPs) and motor behaviour. The latter involves premotor areas as well, and among them, the presupplementary motor area (pre-SMA) has recently received significant attention in the study of motor inhibition. It is possible that, similar to M1, different neuronal populations can be activated by varying the direction and intensity of TMS; however, the absence of a direct electrophysiological outcome has limited this investigation. The problem can be solved by quantifying direct cortical responses by means of combined TMS and electroencephalography (TMS-EEG). We investigated the effect of variable coil orientations (0°, 90°, 180° and 270°) and stimulation intensities (100%, 120% and 140% of resting motor threshold) on local mean field potential (LMFP), transcranial evoked potential (TEP) peaks and TMS-related spectral perturbation (TRSP) from pre-SMA stimulation. As a result, early and late LMFP and peaks were larger, with the coil handle pointing posteriorly (0°) and laterally (90°). This was true also for TRSP in the ß-γ range, but, surprisingly, θ-α TRSP was larger with the coil pointing at 180°. A 90° orientation activated the right M1, as shown by MEPs elicitation, thus limiting the spatial specificity of the stimulation. These results suggest that coil orientation and stimulation intensity are critical when stimulating the pre-SMA.

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

OBJECTIVE: Calcium dependency is presently an essential assumption in modelling the neuromodulatory effects of transcranial magnetic stimulation. Y.Z.Huang et al.developed the first neuromodulation model to explain the bidirectional effects of theta-burst stimulation (TBS) based on the postsynaptic intracellular calcium concentration elevation. However, we discover that the published computer code is not consistent with the model formulation, neither do the parameters and derived plots consequently match the formulations. Here we intend to fix the computer code and re-calibrate the model. METHODS: We corrected the affected difference equations and re-calibrated the revised model with experimental data using non-convex optimisation based on a L2 penalty. RESULTS: The revised model outperforms the initial model in characterising the relative motor-evoked potential levels of TBS-induced after-effects in various conditions. CONCLUSIONS: We corrected the inconsistencies in the previous model and computer code and provided a complete calibration to support the research that is based on it. SIGNIFICANCE: This work improves the accuracy and secures the scope of the model, which is necessary to retain a rich body of research resulting from the model. Furthermore, this model provides both a quantitative model for several parameters of TBS and a basic model foundation for future refinement.

Detection of motor-evoked potentials below the noise floor: rethinking the motor stimulation threshold.

Objective. Motor-evoked potentials (MEPs) are among the most prominent responses to brain stimulation, such as supra-threshold transcranial magnetic stimulation and electrical stimulation. Understanding of the neurophysiology and the determination of the lowest stimulation strength that evokes responses requires the detection of even smaller responses, e.g. from single motor units. However, available detection and quantization methods suffer from a large noise floor. This paper develops a detection method that extracts MEPs hidden below the noise floor. With this method, we aim to estimate excitatory activations of the corticospinal pathways well below the conventional detection level.Approach. The presented MEP detection method presents a self-learning matched-filter approach for improved robustness against noise. The filter is adaptively generated per subject through iterative learning. For responses that are reliably detected by conventional detection, the new approach is fully compatible with established peak-to-peak readings and provides the same results but extends the dynamic range below the conventional noise floor.Main results. In contrast to the conventional peak-to-peak measure, the proposed method increases the signal-to-noise ratio by more than a factor of 5. The first detectable responses appear to be substantially lower than the conventional threshold definition of 50µV median peak-to-peak amplitude.Significance. The proposed method shows that stimuli well below the conventional 50µV threshold definition can consistently and repeatably evoke muscular responses and thus activate excitable neuron populations in the brain. As a consequence, the input-output (IO) curve is extended at the lower end, and the noise cut-off is shifted. Importantly, the IO curve extends so far that the 50µV point turns out to be closer to the center of the logarithmic sigmoid curve rather than close to the first detectable responses. The underlying method is applicable to a wide range of evoked potentials and other biosignals, such as in electroencephalography.

Is it possible to compare inhibitory and excitatory intracortical circuits in face and hand primary motor cortex?

Face muscles are important in a variety of different functions, such as feeding, speech and communication of non-verbal affective states, which require quite different patterns of activity from those of a typical hand muscle. We ask whether there are differences in their neurophysiological control that might reflect this. Fifteen healthy individuals were studied. Standard single- and paired-pulse transcranial magnetic stimulation (TMS) methods were used to compare intracortical inhibitory (short interval intracortical inhibition (SICI); cortical silent period (CSP)) and excitatory circuitries (short interval intracortical facilitation (SICF)) in two typical muscles, the depressor anguli oris (DAO), a face muscle, and the first dorsal interosseous (FDI), a hand muscle. TMS threshold was higher in DAO than in FDI. Over a range of intensities, resting SICF was not different between DAO and FDI, while during muscle activation SICF was stronger in FDI than in DAO (P = 0.012). At rest, SICI was stronger in FDI than in DAO (P = 0.038) but during muscle contraction, SICI was weaker in FDI than in DAO (P = 0.034). We argue that although many of the difference in response to the TMS protocols could result from the difference in thresholds, some, such as the reduction of resting SICI in DAO, may reflect fundamental differences in the physiology of the two muscle groups. KEY POINTS: Transcranial magnetic stimulation (TMS) single- and paired-pulse protocols were used to investigate and compare the activity of facilitatory and inhibitory intracortical circuits in a face (depressor anguli oris; DAO) and hand (first dorsal interosseous; FDI) muscles. Several TMS intensities and interstimulus intervals were tested with the target muscles at rest and when voluntarily activated. At rest, intracortical inhibitory activity was stronger in FDI than in DAO. In contrast, during muscle contraction inhibitory activity was stronger in DAO than in FDI. As many previous reports have found, the motor evoked potential threshold was higher in DAO than in FDI. Although many of the differences in response to the TMS protocols could result from the difference in thresholds, some, such as the reduction of resting short interval intracortical inhibition in DAO, may reflect fundamental differences in the physiology of the two muscle groups.

Transcranial magnetic stimulation of the brain: What is stimulated? - A consensus and critical position paper.

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.