Single-pulse Transcranial Magnetic Stimulation Research Articles

TMS-induced phase resets depend on TMS intensity and EEG phase

Objective. The phase of the electroencephalographic (EEG) signal predicts performance in motor, somatosensory, and cognitive functions. Studies suggest that brain phase resets align neural oscillations with external stimuli, or couple oscillations across frequency bands and brain regions. Transcranial Magnetic Stimulation (TMS) can cause phase resets noninvasively in the cortex, thus providing the potential to control phase-sensitive cognitive functions. However, the relationship between TMS parameters and phase resetting is not fully understood. This is especially true of TMS intensity, which may be crucial to enabling precise control over the amount of phase resetting that is induced. Additionally, TMS phase resetting may interact with the instantaneous phase of the brain. Understanding these relationships is crucial to the development of more powerful and controllable stimulation protocols.Approach.To test these relationships, we conducted a TMS-EEG study. We applied single-pulse TMS at varying degrees of stimulation intensity to the motor area in an open loop. Offline, we used an autoregressive algorithm to estimate the phase of the intrinsicµ-Alpha rhythm of the motor cortex at the moment each TMS pulse was delivered.Main results. We identified post-stimulation epochs whereµ-Alpha phase resetting and N100 amplitude depend parametrically on TMS intensity and are significantversusperipheral auditory sham stimulation. We observedµ-Alpha phase inversion after stimulations near peaks but not troughs in the endogenousµ-Alpha rhythm.Significance. These data suggest that low-intensity TMS primarily resets existing oscillations, while at higher intensities TMS may activate previously silent neurons, but only when endogenous oscillations are near the peak phase. These data can guide future studies that seek to induce phase resetting, and point to a way to manipulate the phase resetting effect of TMS by varying only the timing of the pulse with respect to ongoing brain activity.

TDCS and local scalp cooling do not change corticomotor and intracortical excitability in healthy humans

ObjectiveScalp cooling might increase the long-term potentiation (LTP)-like effect of transcranial direct current stimulation (tDCS) by reducing the threshold for after-effects according to metaplasticity and increasing electrical current density reaching the cortical neurons. We aimed to investigate whether priming scalp cooling potentiates the tDCS after-effect on motor cortex excitability. MethodsThis study had a randomized, parallel-arms, sham-controlled, double-blinded design with an adequately powered sample of 105 healthy subjects. Corticomotor and intracortical excitability were assessed with motor evoked potentials (MEP) from transcranial magnetic stimulation (TMS) in short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) paradigms. Subjects were randomly allocated into six intervention groups, including anodal and cathodal tDCS (1-mA/20-min), scalp cooling, and sham. MEPs were recorded before, immediately, and 15 min after the interventions. ResultsWe did not observe changes in MEP amplitude from single-pulse TMS, SICI, and ICF with any intervention protocol. ConclusionAnodal and cathodal tDCS did not have an LTP-like neuromodulatory effect on corticospinal and did not provide detectable GABAergic and glutamatergic neurotransmission changes, which were not influenced by priming scalp cooling. SignificanceWe provide strong evidence that tDCS (1-mA/20-min) does not alter corticomotor and intracortical excitability with or without priming scalp cooling.

TMS-EEG signatures of the effects of transcranial static magnetic field stimulation (tSMS) on cortical excitability

In transcranial static magnetic field stimulation (tSMS), a strong and small magnet placed over the head can modulate cortical functions below the magnet as well as those in the region remote from the magnet. We studied the neuromodulation induced by tSMS using transcranial magnetic stimulation (TMS) combined with simultaneous electroencephalography (EEG) to clarify the neurophysiological underpinnings of tSMS. tSMS or sham stimulation was applied over the left primary motor cortex (M1) for 20 min in 15 healthy subjects. Single pulse TMS was delivered over the left M1 before and after the intervention, while recording EEG. The amplitude around the P30 of the TMS-evoked potentials (TEPs) in the left primary sensorimotor area (SM1) significantly decreased after the real tSMS, and that around the N60 of the TEPs in the right SM1 significantly increased after the real tSMS. In addition, the alpha power of the TMS-induced oscillatory responses (IORs) in the left and right SM1 significantly decreased after the real tSMS. TMS-EEG is a powerful tool for studying local and global cortical reactivity to external stimuli at high temporal resolution. tSMS altered TEPs and IORs both at the stimulated cortex and at the contralateral cortex. These findings would be related to the neurophysiological mechanisms underlying the neuromodulation induced by tSMS.

Mechano-responses of quadriceps muscles evoked by transcranial magnetic stimulation.

Mechanomyography (MMG) may be used to quantify very small motor responses resulting from muscle activation, voluntary or involuntary. The purpose of this study was to investigate the MMG mean peak amplitude (MPA) and area under the curve (AUC) and the corresponding mechanical responses following delivery of transcranial magnetic stimulation (TMS) to the knee extensors. Fourteen adults (23±1 years) received single TMS pulses at intensities from 30-80 % maximum stimulator output to elicit muscle responses in the relaxed knee extensors while seated. An accelerometer-based sensor was placed on the rectus femoris (RF) and vastus lateralis (VL) muscle bellies to measure the MMG signal. Pearson correlation revealed a positive linear relationship between MMG MPA and TMS intensity for RF (r=0.569; p<0.001) and VL (r=0.618; p<0.001). TMS intensity of≥60 % maximum stimulator output produced significantly higher MPA than at 30 % TMS intensity and evoked measurable movement at the knee joint. MMG MPA was positively correlated to AUC (r=0.957 for RF and r=0.603 for VL; both p<0.001) and knee extension angle (r=0.596 for RF and r=0.675 for VL; both p<0.001). In conclusion, MMG captured knee extensor mechanical responses at all TMS intensities with the response increasing with increasing TMS intensity. These findings suggest that MMG can be an additional tool for assessing muscle activation.

Seizure Induced by Single-Pulse TMS Delivered to Lesioned Hemisphere in Stroke

Abstract Transcranial magnetic stimulation (TMS) is used for therapeutic and research purposes, but it is still important to establish safety guidelines and recommendations mainly related to serious adverse effect (SAE). As part of this, safety reports need to be published. Our report highlights a case of a male patient who was a 30-year-old with a history of hemorrhagic stroke following an accidental seizure episode during a single-pulse TMS.

Modulation of motor cortex inhibition during manual dexterity tasks: an adaptive threshold hunting study.

Background: The ability to perform intricate movements is crucial for human motor function. The neural mechanisms underlying precision and power grips are incompletely understood. Corticospinal output from M1 is thought to be modulated by GABAA-ergic intracortical networks within M1. Objectives: To investigate the contribution of M1 intracortical inhibition to fine motor control using adaptive threshold hunting with paired-pulse TMS during pinching and grasping tasks. We hypothesised that SICI could be assessed during voluntary activation, and that corticomotor excitability and SICI modulation would be greater during pinch than grasp reflecting corticospinal control. Methods: Seventeen healthy participants performed gradual pinch and grasp tasks. Using an adaptive threshold-hunting method, paired-pulse TMS was applied in the anterior-posterior current direction to assess cortical excitability and SICI in the dominant FDI muscle. SICI and corticomotor excitability were analysed using an LMM. MEP latencies were obtained in LM, PA and AP current directions and compared using paired t-tests. Results: MEP latencies were prolonged with PA and AP coil orientations compared to LM, with AP showing the largest latency. During single-pulse TMS, there was no difference in the TMS intensity required to reach the MEP target during pinching and grasping. Greater inhibition was found during pinching compared to grasping. Conclusion: ATH with paired-pulse TMS permits investigation of intracortical inhibitory networks and their modulation during the performance of dexterous motor tasks revealing a greater modulation of GABAA-ergic inhibition contributing to SICI during pinching compared to grasping.

Motor-evoked potentials as biomarkers for sexual arousal?

Motor cortex excitability may represent the neuronal endpoint of motivational processes and was shown to be modulated by both sexual arousal and deceptive behavior. This is the first study to investigate the influence of lying and sex in heterosexual women and men based on motor-evoked potentials (MEPs) measured while viewing sexually arousing pictures. Sixteen heterosexual couples were shown 360 trials consisting of pictures displaying both almost naked females and males and neutral control images. In a subsequent forced-choice question about wanting to see the respective pictures fully naked, they were instructed to either answer in agreement with or opposite to their sexual preference. Participants went through 2 blocks of answering truthfully and 2 blocks of lying, with these 4 blocks being shown in a randomized alternating order. To measure cortical excitability, MEPs were used, evoked by single transcranial magnetic stimulation pulses between image presentation and response. In normalized MEPs, women and men showed higher amplitudes for preferred over non-preferred sexual stimuli, but only on a descriptive level. Planned contrasts showed higher non-normalized MEPs for lying in all picture categories. Direct comparisons to a preliminary study showed overall lower effect sizes. Both sexes tend to show higher MEPs in response to their sexually preferred stimuli. MEPs are not stable markers for willful volitionally controlled deception although lying does increase cortical excitability. The present experimental design does not seem valid enough to serve as a diagnostic marker for sexual preference or paraphilia and malingering. This is the first study investigating whether sexual motivational stimuli modulate MEPs in women, while also examining the influence of lying for both sexes. The sample was too small for some found effects to be significant. Also, the experimental setup may have been less suited for female participants in comparison to male ones. The operationalization of sexual motivation via MEPs seems to highly depend on different experimental factors including the sex of the participants, induced motivation, and lying.

Noninvasive brain stimulation to improve motor outcomes after stroke.

This review highlights recent developments in noninvasive brain stimulation (NIBS) techniques and applications for improving motor outcomes after stroke. Two promising areas of development relate to deep brain neuromodulation and the use of single-pulse transcranial magnetic stimulation (TMS) within a prediction tool for predicting upper limb outcome for individual patients. Systematic reviews highlight the inconsistent effect sizes of interventional NIBS for motor outcome after stroke, as well as limited evidence supporting the interhemispheric competition model. To improve the therapeutic efficacy of NIBS, studies have leveraged metaplasticity and priming approaches. Transcranial temporal interference stimulation (tTIS) and low-intensity focused ultrasound stimulation (LIFUS) are emerging NIBS techniques with potential for modulating deeper brain structures, which may hold promise for stroke neurorehabilitation. Additionally, motor evoked potential (MEP) status obtained with single-pulse TMS is a prognostic biomarker that could be used to tailor NIBS for individual patients. Trials of interventional NIBS to improve stroke outcomes may be improved by applying NIBS in a more targeted manner. This could be achieved by taking advantage of NIBS techniques that can be targeted to deeper brain structures, using biomarkers of structural and functional reserve to stratify patients, and recruiting patients in more homogeneous time windows.

Repetitive Transcranial Magnetic Stimulation Modulates Brain Connectivity in Children with Self-limited Epilepsy with Centrotemporal Spikes.

Interictal epileptiform discharges (IEDs) alter brain connectivity in children with epilepsy; this connectivity change may be a mechanism by which epilepsy induces cognitive deficits. Here, we test whether repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique, modulates connectivity and reduces IEDs in children with epilepsy. Nineteen children with self-limited epilepsy with centrotemporal spikes (SeLECTS) participated in a cross-over study comparing the impact of active vs. sham rTMS on IEDs and brain connectivity. SeLECTS is an epilepsy syndrome affecting the motor cortex, and prior studies show that motor cortices become pathologically hyper-connected to frontal and temporal language cortices. Using a crossover design, we compared the effect of single doses of active versus sham motor cortex rTMS. Connectivity, which was quantified by the weighted phase lag index (wPLI), was measured before and after rTMS using single pulses of TMS combined with EEG (spTMS-EEG). Analyses focused on six regions: bilateral motor cortices and bilateral inferior frontal and superior temporal regions. IEDs were counted in the five minutes before and after rTMS. Active, but not sham, rTMS significantly and globally decreased wPLI connectivity between multiple regions, with the greatest reductions seen in the superior temporal region connections in the stimulated hemisphere. Additionally, there was a trend suggesting that rTMS decreases IED frequency. These findings underscore the potential of low-frequency rTMS to target pathologic hyperconnectivity and reduce IEDs in children with SeLECTS and potentially other pediatric epilepsy syndromes, offering a promising avenue for therapeutic intervention.

Multisensory integration and motor resonance in the primary motor cortex

Humans are endowed with a motor system that resonates to speech sounds, but whether concurrent visual information from lip movements can improve speech perception at a motor level through multisensory integration mechanisms remains unknown. Therefore, the aim of the study was to explore behavioral and neurophysiological correlates of multisensory influences on motor resonance in speech perception. Motor-evoked potentials (MEPs), by single pulse transcranial magnetic stimulation (TMS) applied over the left lip muscle (orbicularis oris) representation in the primary motor cortex, were recorded in healthy participants during the presentation of syllables in unimodal (visual or auditory) or multisensory (audio-visual) congruent or incongruent conditions. At the behavioral level, subjects showed better syllable identification in the congruent audio-visual condition as compared to the unimodal conditions, hence showing a multisensory enhancement effect. Accordingly, at the neurophysiological level, increased MEPs amplitudes were found in the congruent audio-visual condition, as compared to the unimodal ones. Incongruent audio-visual syllables resulting in illusory percepts did not increase corticospinal excitability, which in fact was comparable to that induced by the real perception of the same syllable. In conclusion, seeing and hearing congruent bilabial syllables increases the excitability of the lip representation in the primary motor cortex, hence documenting that multisensory integration can facilitate speech processing by influencing motor resonance. These findings highlight the modulation role of multisensory processing showing that it can boost speech perception and that multisensory interactions occur not only within higher-order regions, but also within primary motor areas, as shown by corticospinal excitability changes.

Personalized whole-brain activity patterns predict human corticospinal tract activation in real-time.

Transcranial magnetic stimulation (TMS) interventions could feasibly treat stroke-related motor impairments, but their effects are highly variable. Brain state-dependent TMS approaches are a promising solution to this problem, but inter-individual variation in lesion location and oscillatory dynamics can make translating them to the poststroke brain challenging. Personalized brain state-dependent approaches specifically designed to address these challenges are therefore needed. As a first step towards this goal, we tested a novel machine learning-based EEG-TMS system that identifies personalized brain activity patterns reflecting strong and weak corticospinal tract (CST) output (strong and weak CST states) in healthy adults in real-time. Participants completed a single-session study that included the acquisition of a TMS-EEG-EMG training dataset, personalized classifier training, and real-time EEG-informed single pulse TMS during classifier-predicted personalized CST states. MEP amplitudes elicited in real-time during personalized strong CST states were significantly larger than those elicited during personalized weak and random CST states. MEP amplitudes elicited in real-time during personalized strong CST states were also significantly less variable than those elicited during personalized weak CST states. Personalized CST states lasted for ~1-2 seconds at a time and ~1 second elapsed between consecutive similar states. Individual participants exhibited unique differences in spectro-spatial EEG patterns between personalized strong and weak CST states. Our results show for the first time that personalized whole-brain EEG activity patterns predict CST activation in real-time in healthy humans. These findings represent a pivotal step towards using personalized brain state-dependent TMS interventions to promote poststroke CST function.

Evidence for a Causal Dissociation of the McGurk Effect and Congruent Audiovisual Speech Perception via TMS to the Left pSTS.

Congruent visual speech improves speech perception accuracy, particularly in noisy environments. Conversely, mismatched visual speech can alter what is heard, leading to an illusory percept that differs from the auditory and visual components, known as the McGurk effect. While prior transcranial magnetic stimulation (TMS) and neuroimaging studies have identified the left posterior superior temporal sulcus (pSTS) as a causal region involved in the generation of the McGurk effect, it remains unclear whether this region is critical only for this illusion or also for the more general benefits of congruent visual speech (e.g., increased accuracy and faster reaction times). Indeed, recent correlative research suggests that the benefits of congruent visual speech and the McGurk effect rely on largely independent mechanisms. To better understand how these different features of audiovisual integration are causally generated by the left pSTS, we used single-pulse TMS to temporarily disrupt processing within this region while subjects were presented with either congruent or incongruent (McGurk) audiovisual combinations. Consistent with past research, we observed that TMS to the left pSTS reduced the strength of the McGurk effect. Importantly, however, left pSTS stimulation had no effect on the positive benefits of congruent audiovisual speech (increased accuracy and faster reaction times), demonstrating a causal dissociation between the two processes. Our results are consistent with models proposing that the pSTS is but one of multiple critical areas supporting audiovisual speech interactions. Moreover, these data add to a growing body of evidence suggesting that the McGurk effect is an imperfect surrogate measure for more general and ecologically valid audiovisual speech behaviors.

Ultra-high frequency repetitive TMS at subthreshold intensity induces suprathreshold motor response via temporal summation

Objective.The transcranial magnetic stimulation (TMS) coil induces an electric field that diminishes rapidly upon entering the brain. This presents a challenge in achieving focal stimulation of a deep brain structure. Neuronal elements, including axons, dendrites, and cell bodies, exhibit specific time constants. When exposed to repetitive TMS pulses at a high frequency, there is a cumulative effect on neuronal membrane potentials, resulting in temporal summation. This study aims to determine whether TMS pulse train at high-frequency and subthreshold intensity could induce a suprathreshold response.Approach.As a proof of concept, we developed a TMS machine in-house that could consistently output pulses up to 250 Hz, and performed experiments on 22 awake rats to test whether temporal summation was detectable under pulse trains at 100, 166, or 250 Hz.Main results.Results revealed that TMS pulses at 55% maximum stimulator output (MSO, peak dI/dt= 68.5 A/μs at 100% MSO, pulse width = 48μs) did not induce motor responses with either single pulses or pulse trains. Similarly, a single TMS pulse at 65% MSO failed to evoke a motor response in rats; however, a train of TMS pulses at frequencies of 166 and 250 Hz, but not at 100 Hz, successfully triggered motor responses and MEP signals, suggesting a temporal summation effect dependent on both pulse intensities and pulse train frequencies.Significance.We propose that the temporal summation effect can be leveraged to design the next-generation focal TMS system: by sequentially driving multiple coils at high-frequency and subthreshold intensity, areas with the most significant overlapping E-fields undergo maximal temporal summation effects, resulting in a suprathreshold response.

Corticospinal excitability at rest outside of a task does not differ from task intertrial intervals in healthy adults.

Human corticospinal excitability (CSE) modulates during movement, when muscles are active, but also at rest, when muscles are not active. These changes in resting motor system excitability can be transient or longer lasting. Evidence from transcranial magnetic stimulation (TMS) studies suggests even relatively short periods of motor learning on the order of minutes can have lasting effects on resting CSE. Whether individuals are able to return CSE to out-of-task resting levels during the intertrial intervals (ITI) of behavioral tasks that do not include an intended motor learning component is an important question. Here, in twenty-five healthy young adults, we used single-pulse TMS and electromyography (EMG) to measure motor evoked potentials (MEPs) during two different resting contexts: (1) prior to engaging in the response task during which participants were instructed only to rest (out-of-task), and (2) ITI of a choice-reaction time task (in-task). In both contexts, five TMS intensities were used to evaluate possible differences in recruitment of corticospinal (CS) output across a range of inputs. We hypothesized resting state CSE would be greater during ITI than out-of-task rest, reflected in larger MEP amplitudes. Contrary to our hypothesis, we observed no significant difference in MEP amplitudes between out-of-task rest and in-task ITI, and instead found evidence of equivalence, indicating that humans are able to return to a stable motor resting state within seconds after a response. These data support the interpretation that rest is a uniform motor state in the healthy nervous system. In the future, our data may be a useful reference for motor disorder populations with an impaired ability to return to rest.

Validation of the number of pulses required for TMS-EEG in the prefrontal cortex considering test feasibility

BackgroundTranscranial magnetic stimulation (TMS) combined with electroencephalography (EEG), TMS-EEG, is a useful neuroscientific tool for the assessment of neurophysiology in the human cerebral cortex. Theoretically, TMS-EEG data is expected to have a better data quality as the number of stimulation pulses increases. However, since TMS-EEG testing is a modality that is examined on human subjects, the burden on the subject and tolerability of the test must also be carefully considered. MethodIn this study, we aimed to determine the number of stimulation pulses that satisfy the reliability and validity of data quality in single-pulse TMS (spTMS) for the dorsolateral prefrontal cortex (DLPFC). TMS-EEG data for (1) 40-pulse, (2) 80-pulse, (3) 160-pulse, and (4) 240-pulse conditions were extracted from spTMS experimental data for the left DLPFC of 20 healthy subjects, and the similarities between TMS-evoked potentials (TEP) and oscillations across the conditions were evaluated. ResultsAs a result, (2) 80-pulse and (3) 160-pulse conditions showed highly equivalent to the benchmark condition of (4) 240-pulse condition. However, (1) 40-pulse condition showed only weak to moderate equivalence to the (4) 240-pulse condition. Thus, in the DLPFC TMS-EEG experiment, 80 pulses of stimulations was found to be a reasonable enough number of pulses to extract reliable TEPs, compared to 160 or 240 pulses. ConclusionsThis is the first substantial study to examine the appropriate number of stimulus pulses that are reasonable and feasible for TMS-EEG testing of the DLPFC.

Neurophysiological markers of disease severity and cognitive dysfunction in major depressive disorder: A TMS-EEG study

BackgroundTranscranial magnetic stimulation-electroencephalography (TMS-EEG) is a powerful technique to study the neuropathology and biomarkers of major depressive disorder (MDD). This study investigated cortical activity and its relationship with clinical symptoms and cognitive dysfunction in MDD patients by indexing TMS-EEG biomarkers in the dorsolateral prefrontal cortex (DLPFC). Methods133 patients with MDD and 76 healthy individuals participated in this study. Single-pulse TMS was performed on the left DLPFC to obtain TMS-evoked potential (TEP) indices. TMS-EEG waveforms and components were determined by global mean field amplitude. We used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to measure participants’ cognitive function. ResultsPatients with MDD had a lower excitatory P180 index compared to healthy controls, and P180 amplitude was negatively correlated with the severity of depressive and anxiety symptoms in patients with MDD. In the MDD group, P30 amplitude was negatively associated with RBANS Visuospatial/ Constructional index and total score. ConclusionsTMS-EEG findings suggest that abnormal cortical excitation and inhibition induced by TMS on the DLPFC are associated with the severity of clinical symptoms and cognitive dysfunction in patients with MDD. P180 and P30 have the potential to serve as neurophysiological biomarkers of clinical symptoms and cognitive dysfunction in MDD patients, respectively.

Tactile versus motor imagery: differences in corticospinal excitability assessed with single-pulse TMS

Tactile Imagery (TI) remains a fairly understudied phenomenon despite growing attention to this topic in recent years. Here, we investigated the effects of TI on corticospinal excitability by measuring motor evoked potentials (MEPs) induced by single-pulse transcranial magnetic stimulation (TMS). The effects of TI were compared with those of tactile stimulation (TS) and kinesthetic motor imagery (kMI). Twenty-two participants performed three tasks in randomly assigned order: imagine finger tapping (kMI); experience vibratory sensations in the middle finger (TS); and mentally reproduce the sensation of vibration (TI). MEPs increased during both kMI and TI, with a stronger increase for kMI. No statistically significant change in MEP was observed during TS. The demonstrated differential effects of kMI, TI and TS on corticospinal excitability have practical implications for devising the imagery-based and TS-based brain–computer interfaces (BCIs), particularly the ones intended to improve neurorehabilitation by evoking plasticity changes in sensorimotor circuitry.

Exploring the Influence of Inter-Trial Interval on the Assessment of Short-Interval Intracortical Inhibition.

Short-interval intracortical inhibition (SICI) is a common paired-pulse transcranial magnetic stimulation (TMS) measure used to assess primary motor cortex (M1) interneuron activity in healthy populations and in neurological disorders. Many of the parameters of TMS stimulation to most accurately measure SICI have been determined. However, one TMS parameter that has not been investigated is the time between SICI trials (termed inter-trial interval; ITI). This is despite a series of single-pulse TMS studies which have reported that motor evoked potential (MEP) amplitude were suppressed for short, but not long ITIs in approximately the initial ten trials of a TMS block of 20-30 trials. The primary purpose was to examine the effects of ITI on the quantification of SICI at rest. A total of 23 healthy adults completed an experimental session that included four SICI trial blocks. Each block utilized a different ITI (4, 6, 8, and 10 s) and was comprised of a total of 26 SICI trials divided into three epochs. ANOVA revealed that the main effects for ITI and epoch as well as their interaction were all non-statistically significant for SICI. We conclude that the shorter (4-6 s) ITIs used in studies investigating SICI should not alter the interpretation of M1 activity, while having the advantages of being more comfortable to participants and reducing the experimental time needed to evaluate perform single and paired-pulse TMS experiments.

Topographically selective motor inhibition under threat of pain.

Pain-related motor adaptations may be enacted predictively at the mere threat of pain, before pain occurrence. Yet, in humans, the neurophysiological mechanisms underlying motor adaptations in anticipation of pain remain poorly understood. We tracked the evolution of changes in corticospinal excitability (CSE) as healthy adults learned to anticipate the occurrence of lateralized, muscle-specific pain to the upper limb. Using a Pavlovian threat conditioning task, different visual stimuli predicted pain to the right or left forearm (experiment 1) or hand (experiment 2). During stimuli presentation before pain occurrence, single-pulse transcranial magnetic stimulation was applied over the left primary motor cortex to probe CSE and elicit motor evoked potentials from target right forearm and hand muscles. The correlation between participants' trait anxiety and CSE was also assessed. Results showed that threat of pain triggered corticospinal inhibition specifically in the limb where pain was expected. In addition, corticospinal inhibition was modulated relative to the threatened muscle, with threat of pain to the forearm inhibiting the forearm and hand muscles, whereas threat of pain to the hand inhibited the hand muscle only. Finally, stronger corticospinal inhibition correlated with greater trait anxiety. These results advance the mechanistic understanding of pain processes showing that pain-related motor adaptations are enacted at the mere threat of pain, as sets of anticipatory, topographically organized motor changes that are associated with the expected pain and are shaped by individual anxiety levels. Including such anticipatory motor changes into models of pain may lead to new treatments for pain-related disorders.

Effects of Anti-CGRP Monoclonal Antibodies on Neurophysiological and Clinical Outcomes: A Combined Transcranial Magnetic Stimulation and Algometer Study.

the aim of this study was to investigate the neurophysiological effect of anti-CGRP monoclonal antibodies on central and peripheral levels in migraine patients. An observational cohort study in patients with migraine was performed. All subjects underwent Single-Pulse and Paired-Pulse Transcranial Magnetic Stimulation, as well as a Pressure Pain Threshold assessment. The same protocol was repeated three and four months after the first injection of anti-CGRP monoclonal antibodies. A total of 11 patients with a diagnosis of migraine and 11 healthy controls were enrolled. The main findings of this study are the significant effects of anti-CGRP mAb treatment on the TMS parameters of intracortical inhibition and the rise in the resting motor threshold in our group of patients affected by resistant migraine. The clinical effect of therapy on migraine is associated with the increase in short-interval intracortical inhibition (SICI), resting motor threshold (RMT), and Pressure Pain Threshold (PPT). In all patients, all clinical headache parameters improved significantly 3 months after the first injection of mAbs and the improvement was maintained at the 1-month follow-up. At baseline, migraineurs and HCs had significant differences in all TMS parameters and in PPT, while at follow-up assessment, no differences were observed on RMT, SICI, and PPT between the two groups. After anti-CGRP monoclonal antibody injection, a significant increase in the intracortical inhibition, in the motor threshold, and in the Pressure Pain Threshold in critical head areas was observed in patients with migraine, which was related to significant clinical benefits. Anti-CGRP monoclonal antibodies improved clinical and neurophysiological outcomes, reflecting a normalization of cortical excitability and peripheral and central sensitization. By directly acting on the thalamus or hypothalamus and indirectly on the trigeminocervical complex, treatment with anti-CGRP monoclonal antibodies may modulate central sensorimotor excitability and peripheral sensitization pain.