Short-interval Intracortical Inhibition Research Articles

Rebalance the Inhibitory System in the Elderly Brain: Influence of Balance Learning on GABAergic Inhibition and Functional Connectivity.

Aging involves complex processes that impact the structure, function, and metabolism of the human brain. Declines in both structural and functional integrity along with reduced local inhibitory tone in the motor areas, as indicated by reduced γ-aminobutyric acid (GABA) levels, are often associated with compromised motor performance in elderly adults. Using multimodal neuroimaging techniques including magnetic resonance spectroscopy (MRS), diffusion magnetic resonance imaging (MRI), functional MRI as well as transcranial magnetic stimulation to assess short-interval intracortical inhibition (SICI), this study explores whether these age-related changes can be mitigated by motor learning. The investigation focused on the effects of long-term balance learning (3 months) on intracortical inhibition, metabolism, structural, and functional connectivity in the cortical sensorimotor network among an elderly cohort. We found that after 3 months of balance learning, subjects significantly improved balance performance, upregulated sensorimotor cortical GABA levels and ventral sensorimotor network functional connectivity (VSN-FC) compared to a passive control group. Furthermore, correlation analysis suggested a positive association between baseline VSN-FC and balance performance, between baseline VSN-FC and SICI, and between improvements in balance performance and upregulation in SICI in the training group, though these correlations did not survive the false discovery rate correction. These findings demonstrate that balance learning has the potential to counteract aging-related decline in functional connectivity and cortical inhibition on the "tonic" (MRS) and "functional" (SICI) level and shed new light on the close interplay between the GABAergic system, functional connectivity, and behavior.

Intensity-Dependent Effects of Low-Frequency Subthreshold rTMS on Primary Motor Cortex Excitability and Interhemispheric Inhibition in Elderly Participants: A Randomized Trial.

Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) protocols targeting primary motor cortex (M1) are used in rehabilitation of neurological diseases for their therapeutic potential, safety, and tolerability. Although lower intensity LF-rTMS can modulate M1 neurophysiology, results are variable, and a systematic assessment of its dose effect is lacking. To determine the dose-response of LF-rTMS on stimulated and non-stimulated M1. In a sham-controlled randomized double-blind crossover study the effect of LF-TMS protocols were determined in 20 right-handed older healthy participants. In 3 sessions, 1 Hz rTMS at 80% (rTMS80), 90% (rTMS90) of motor threshold or sham stimulation were applied to left upper extremity M1. Outcome measures were curve parameters of the stimulus-response curve (maximum motor evoked potential [MEPMAX], slope and the intensity to evoke 50% MEPMAX), short-interval intracortical inhibition (SICI), and interhemispheric inhibition (IHI). Within LF-rTMS sessions, rTMS90, increased MEPMAX in the stimulated M1. Furthermore, rTMS90, increased the slope in the non-stimulated M1. LF-rTMS effects on SICI were dependent on the participants' baseline SICI, hemisphere, and intensity of conditioning pulse. Finally, rTMS90 increased whereas rTMS80 decreased IHI, for both IHI directions. These changes were dependent on baseline IHI and hemisphere and were no longer significant when baseline IHI was accounted for. Intensity of subthreshold LF-rTMS has differential effects on excitation and inhibition of stimulated and non-stimulated M1. The effects were small and were only demonstrated within the LF-rTMS sessions but were not different when compared to sham. rTMS related changes in SICI and IHI were dependent on baseline level. NCT02544503, NCT01726218.

The corticospinal tract in multiple sclerosis: correlation between cortical excitability and magnetic resonance imaging measures.

Multiple sclerosis (MS) is a central nervous system disease involving gray and white matters. Transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI) could help identify potential markers of disease evolution, disability, and treatment response. This work evaluates the relationship between intracortical inhibition and facilitation, motor cortex lesions, and corticospinal tract (CST) integrity. Consecutive adult patients with progressive MS were included. Sociodemographic and clinical data were collected. MRI was acquired to assess primary motor cortex lesions (double inversion and phase-sensitive inversion recovery) and CST integrity (diffusion tensor imaging). TMS outcomes were obtained: motor evoked potentials (MEP) latency, resting motor threshold, short-interval intracortical facilitation (ICF) and inhibition. Correlation analysis was performed. Twenty-five patients completed the study (13 females, age: 55.60 ± 11.49 years, Expanded Disability Status Score: 6.00 ± 1.25). Inverse correlations were found between ICF mean and each of CST radial diffusivity (RD) (ρ =-0.56; p < 0.01), CST apparent diffusion coefficient (ADC) (ρ=-0.44; p = 0.03), and disease duration (ρ=-0.46; p = 0.02). MEP latencies were directly correlated with disability scores (ρ = 0.55; p < 0.01). High ADC/RD and low ICF have been previously reported in patients with MS. While the former could reflect structural damage of the CST, the latter could hint towards an aberrant synaptic transmission as well as a depletion of facilitatory compensatory mechanisms that helps overcoming functional decline. The findings suggest concomitant structural and functional abnormalities at later disease stages that would be accompanied with a heightened disability. The results should be interpreted with caution mainly because of the small sample size that precludes further comparisons (e.g., treated vs. untreated patients, primary vs. secondary progressive MS). The role of these outcomes as potential MS biomarkers merit to be further explored.

Examining motor evidence for the pause-then-cancel model of action-stopping: insights from motor system physiology.

Stopping initiated actions is fundamental to adaptive behavior. Longstanding, single-process accounts of action-stopping have been challenged by recent, two-process, "pause-then-cancel" models. These models propose that action-stopping involves two inhibitory processes: 1) a fast Pause process, which broadly suppresses the motor system as the result of detecting any salient event, and 2) a slower Cancel process, which involves motor suppression specific to the cancelled action. A purported signature of the Pause process is global suppression, or the reduced corticospinal excitability (CSE) of task-unrelated effectors early on in action-stopping. However, unlike the Pause process, few (if any) motor system signatures of a Cancel process have been identified. Here, we used single- and paired-pulse transcranial magnetic stimulation (TMS) methods to comprehensively measure the local physiological excitation and inhibition of both responding and task-unrelated motor effector systems during action-stopping. Specifically, we measured CSE, short-interval intracortical inhibition (SICI), and the duration of the cortical silent period (CSP). Consistent with key predictions from the pause-then-cancel model, CSE measurements at the responding effector indicated that additional suppression was necessary to counteract Go-related increases in CSE during action-stopping, particularly at later timepoints. Increases in SICI on Stop-signal trials did not differ across task-related and task-unrelated effectors, or across timepoints. This suggests SICI as a potential source of global suppression. Increases in CSP duration on Stop-signal trials were more prominent at later timepoints and were related to individual differences in CSE. Our study provides further evidence from motor system physiology that multiple inhibitory processes influence action-stopping.NEW & NOTEWORTHY Current debate surrounds whether single- or dual-process models better account for human action-stopping ability. We show that motor suppression of a successfully stopped muscle follows a distinct time course compared with when that same muscle is unrelated to the stopping task. Our results further suggest that distinct local inhibitory neuron populations contribute to these unique sources of suppression. Our study provides evidence from motor system physiology that multiple inhibitory processes influence action-stopping.

Neuromuscular characteristics of eccentric, concentric and isometric contractions of the knee extensors.

We compared voluntary drive and corticospinal responses during eccentric (ECC), isometric (ISOM) and concentric (CON) muscle contractions to shed light on neurophysiological mechanisms underpinning the lower voluntary drive in a greater force production in ECC than other contractions. Sixteen participants (20-33 years) performed ISOM and isokinetic (30°/s) CON and ECC knee extensor contractions (110°-40° knee flexion) in which electromyographic activity (EMG) was recorded from vastus lateralis. Voluntary activation (VA) was measured during ISOM, CON and ECC maximal voluntary contractions (MVCs). Transcranial magnetic stimulation elicited motor-evoked potentials (MEPs) and corticospinal silent periods (CSP) during MVCs and submaximal (30%) contractions, and short-interval intracortical inhibition (SICI) in submaximal contractions. MVC torque was greater (P < 0.01) during ECC (302.6 ± 90.0 Nm) than ISOM (269.8 ± 81.5 Nm) and CON (235.4 ± 78.6 Nm), but VA was lower (P < 0.01) for ECC (68.4 ± 14.9%) than ISOM (78.3 ± 13.1%) and CON (80.7 ± 15.4%). In addition, EMG/torque was lower (P < 0.02) for ECC (1.9 ± 1.1μV.Nm-1) than ISOM (2.2 ± 1.2μV.Nm-1) and CON (2.7 ± 1.6μV.Nm-1), CSP was shorter (p < 0.04) for ECC (0.097 ± 0.03s) than ISOM (0.109 ± 0.02s) and CON (0.109 ± 0.03s), and MEP amplitude was lower (P < 0.01) for ECC (3.46 ± 1.67mV) than ISOM (4.21 ± 2.33mV) and CON (4.01 ± 2.06mV). Similar results were found for EMG/torque and CSP during 30% contractions, but MEP and SICI showed no differences among contractions (p > 0.05). The lower voluntary drive indicated by reduced VA during ECC may be partly explained by lower corticospinal excitability, while the shorter CSP may reflect extra muscle spindle excitation of the motoneurons from vastus lateralis muscle lengthening.

Effect of cerebrospinal dual-site magnetic stimulation on freezing of gait in Parkinson’s disease

Addressing levodopa-unresponsive freezing of gait (FOG) in Parkinson’s disease (PD) presents a significant challenge. A randomized double-blinded trial evaluated the effects of repetitive transcranial magnetic stimulation (rTMS) in conjunction with transcutaneous magnetic spinal cord stimulation among 57 PD individuals experiencing levodopa-unresponsive FOG. Patients were randomized to receive dual-site stimulation involving bilateral primary motor cortex of the lower leg (M1-LL) and the lumbar spinal cord, single-site stimulation targeting bilateral M1-LL alone, or sham stimulation for 10 sessions. Low-frequency rTMS induced remarkable improvements in FOG, gait, and motor functions compared to sham at 1 day and 1 month postintervention. Notably, the dual-site protocol demonstrated superior efficacy in mitigating FOG and improving gait compared to the single-site approach, which correlated with a pronounced increase in short-interval intracortical inhibition of the abductor pollicis brevis. These findings underscore the potential of the cerebrospinal dual-site regimen as a promising approach for levodopa-unresponsive FOG and gait in PD.

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.

Investigation of Metaplasticity Associated with Transcranial Focused Ultrasound Neuromodulation in Humans.

Low-intensity transcranial focused ultrasound stimulation (TUS) is a novel technique for noninvasive brain stimulation (NIBS). TUS delivered in a theta (5 Hz) burst pattern (tbTUS) induces plasticity in the human primary motor cortex (M1) for 30-60 min, showing promise for therapeutic development. Metaplasticity refers to activity-dependent changes in neural functions governing synaptic plasticity; depotentiation is the reversal of long-term potentiation (LTP) by a subsequent protocol with no effect alone. Metaplasticity can enhance plasticity induction and clinical efficacy of NIBS protocols. In our study, we compared four NIBS protocol combinations to investigate metaplasticity on tbTUS in humans of either sex. We delivered four interventions: (1) sham continuous theta burst stimulation with 150 pulses (cTBS150) followed by real tbTUS (tbTUS only), (2) real cTBS150 followed by sham tbTUS (cTBS only), (3) real cTBS150 followed by real tbTUS (metaplasticity), and (4) real tbTUS followed by real cTBS150 (depotentiation). We measured motor-evoked potential amplitude, short-interval intracortical inhibition, long-interval intracortical inhibition, intracortical facilitation (ICF), and short-interval intracortical facilitation before and up to 90 min after plasticity intervention. Plasticity effects lasted at least 60 min longer when tbTUS was primed with cTBS150 compared with tbTUS alone. Plasticity was abolished when cTBS150 was delivered after tbTUS. cTBS150 alone had no significant effect. No changes in M1 intracortical circuits were observed. Plasticity induction by tbTUS can be modified in manners consistent with homeostatic metaplasticity and depotentiation. This substantiates evidence that tbTUS induces LTP-like processes and suggests that metaplasticity can be harnessed in the therapeutic development of TUS.

Neurophysiological effects of a combined treatment of lovastatin and minocycline in patients with fragile X syndrome: Ancillary results of the LOVAMIX randomized clinical trial.

Fragile X syndrome (FXS) is the primary hereditary cause of intellectual disability and autism spectrum disorder. It is characterized by exacerbated neuronal excitability, and its correction is considered an objective measure of treatment response in animal models, a marker albeit rarely used in clinical trials. Here, we used an extensive transcranial magnetic stimulation (TMS) battery to assess the neurophysiological effects of a therapy combining two disease-modifying drugs, lovastatin (40 mg) and minocycline (100 mg), administered alone for 8 weeks and in combination for 12 weeks, in 19 patients (mean age of 23.58 ± 1.51) with FXS taking part in the LOVAmix trial. The TMS battery, which included the resting motor threshold, short-interval intracortical inhibition, long-interval intracortical inhibition, corticospinal silent period, and intracortical facilitation, was completed at baseline after 8 weeks of monotherapy (visit 2 of the clinical trial) and after 12 weeks of dual therapy (visit 4 of the clinical trial). Repeated measure ANOVAs were performed between baseline and visit 2 (monotherapy) and visit 3 (dual therapy) with interactions for which monotherapy the participants received when they began the clinical trial. Results showed that dual therapy was associated with reduced cortical excitability after 20 weeks. This was reflected by a significant increase in the resting-motor threshold after dual therapy compared to baseline. There was a tendency for enhanced short-intracortical inhibition, a marker of GABAa-mediated inhibition after 8 weeks of monotherapy compared to baseline. Together, these results suggest that a combined therapy of minocycline and lovastatin might act on the core neurophysiopathology of FXS. This trial was registered at clinicaltrials.gov (NCT02680379).

People with hip osteoarthritis have reduced quadriceps voluntary activation and altered motor cortex function

AimsCompare quadriceps voluntary activation, corticospinal and intracortical excitability between people with and without hip osteoarthritis (OA). Exploratory objectives include quantifying the association of corticospinal/intracortical excitability with voluntary activation, corticospinal/intracortical excitability with hip related pain, and motor threshold with motor cortex inhibition and facilitation. MethodsCase-control study including participants with clinically and radiologically confirmed hip OA and non-OA controls. Quadriceps voluntary activation was assessed using twitch interpolation via femoral nerve stimulation. Single- and paired-pulse transcranial magnetic stimulation over the motor cortex assessed resting motor threshold (RMT), active motor threshold (AMT), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and silent period. Generalized linear models assessed outcomes (p ​< ​0.05). ResultsWe included 17 hip OA (76% female) and 24 controls (92% female) with a mean (standard deviation) age of 58.7 (7.9) years. Compared to controls, people with hip OA had reduced quadriceps voluntary activation (β ​= ​-5.29, 95% confidence intervals [CI], -0.79–-9.79) and increased ICF (β ​= ​0.22, 95%CI, 0.01–0.43). People with hip OA did not differ from controls in RMT (β ​= ​−4.76, 95%CI, −14.08–4.56), AMT (β ​= ​−2.13, 95%CI, −7.12-2.86), SICI (β ​= ​−0.02, 95%CI, −0.15-0.006) or silent period (β= 8.72, 95%CI, −24.75–42.20). More facilitation was associated with increased hip pain (β= 24.55, 95%CI, 6.93–42.18), and more inhibition was associated with less voluntary activation (β= 10.50, 95%CI, 2.00–18.99). ConclusionPeople with hip OA demonstrate reduced quadriceps voluntary activation and complex changes in motor cortex excitability compared to controls. These findings suggest that hip OA can alter quadriceps neuromuscular function (facilitation associated with pain, inhibition associated with activation), thus having implications for rehabilitation.

The influence of menstrual phase on synaptic plasticity induced via intermittent theta-burst stimulation

BackgroundOvarian hormones influence the propensity for short-term plasticity induced by repetitive transcranial magnetic stimulation (rTMS). Estradiol appears to enhance the propensity for neural plasticity. It is currently unknown how progesterone influences short-term plasticity induced by rTMS. ObjectiveThe present research investigates whether the luteal versus follicular phase of the menstrual cycle influence short-term plasticity induced by intermittent theta-burst stimulation (iTBS). We tested the hypothesis that iTBS would increase motor evoked potentials (MEPs) during the follicular phase. Further, we explored the effects of the luteal phase on iTBS-induced neural plasticity. MethodTwenty-nine adult females participated in a placebo-controlled study that delivered real and sham iTBS to the left primary motor cortex in separate sessions corresponding to the follicular phase (real iTBS), luteal phase (real iTBS), and a randomly selected day (sham iTBS). Outcomes included corticospinal excitability as measured by the amplitude of MEPs and short-interval intracortical inhibition (SICI) recorded from the right first dorsal interosseous muscle before and following iTBS (612 pulses). ResultsMEP amplitude was increased following real iTBS during the follicular condition. No significant changes in MEP amplitude were observed during the luteal or sham visits. SICI was unchanged by iTBS irrespective of menstrual phase. ConclusionThese findings suggest women experience a variable propensity for iTBS-induced short-term plasticity across the menstrual cycle. This information is important for designing studies aiming to induce plasticity via rTMS in women.

Cortical inexcitability in ALS: correlating a clinical phenotype

BackgroundCortical inexcitability, a less studied feature of upper motor neuron (UMN) dysfunction in amyotrophic lateral sclerosis (ALS), was identified in a large cross-sectional cohort of ALS patients and their demographic...

Physiological Biomarkers of Upper Motor Neuron Dysfunction in ALS.

Upper motor neuron (UMN) dysfunction is an important feature of amyotrophic lateral sclerosis (ALS) for the diagnosis and understanding of pathogenesis. The identification of UMN signs forms the basis of ALS diagnosis, although may be difficult to discern, especially in the setting of severe muscle weakness. Transcranial magnetic stimulation (TMS) techniques have yielded objective physiological biomarkers of UMN dysfunction in ALS, enabling the interrogation of cortical and subcortical neuronal networks with diagnostic, pathophysiological, and prognostic implications. Transcranial magnetic stimulation techniques have provided pertinent pathogenic insights and yielded novel diagnostic and prognostic biomarkers. Cortical hyperexcitability, as heralded by a reduction in short interval intracortical inhibition (SICI) and an increase in short interval intracortical facilitation (SICF), has been associated with lower motor neuron degeneration, patterns of disease evolution, as well as the development of specific ALS clinical features including the split hand phenomenon. Reduction in SICI has also emerged as a potential diagnostic aid in ALS. More recently, physiological distinct inhibitory and facilitatory cortical interneuronal circuits have been identified, which have been shown to contribute to ALS pathogenesis. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction. Resting-state EEG is a novel neurophysiological technique developed for directly interrogating cortical neuronal networks in ALS, that have yielded potentially useful physiological biomarkers of UMN dysfunction. The present review discusses physiological biomarkers of UMN dysfunction in ALS, encompassing conventional and novel TMS techniques developed to interrogate the functional integrity of the corticomotoneuronal system, focusing on pathogenic, diagnostic, and prognostic utility.

Effects of motor cortical and peripheral axonal hyperexcitability on survival in amyotrophic lateral sclerosis

BackgroundIncreased ‘cortical’ and ‘peripheral’ excitability are reportedly associated with shorter survival in amyotrophic lateral sclerosis (ALS) patients, suggesting that hyperexcitability contributes to motor neuron death. However, whether upper or lower...

Simulating tDCS electrode placement to stimulate both M1 and SMA enhances motor performance and modulates cortical excitability depending on current flow direction.

The conventional method of placing transcranial direct current stimulation (tDCS) electrodes is just above the target brain area. However, this strategy for electrode placement often fails to improve motor function and modulate cortical excitability. We investigated the effects of optimized electrode placement to induce maximum electrical fields in the leg regions of both M1 and SMA, estimated by electric field simulations in the T1and T2-weighted MRI-based anatomical models, on motor performance and cortical excitability in healthy individuals. A total of 36 healthy volunteers participated in this randomized, triple-blind, sham-controlled experiment. They were stratified by sex and were randomly assigned to one of three groups according to the stimulation paradigm, including tDCS with (1) anodal and cathodal electrodes positioned over FCz and POz, respectively, (A-P tDCS), (2) anodal and cathodal electrodes positioned over POz and FCz, respectively, (P-A tDCS), and (3) sham tDCS. The sit-to-stand training following tDCS (2 mA, 10 min) was conducted every 3 or 4 days over 3 weeks (5 sessions total). Compared to sham tDCS, A-P tDCS led to significant increases in the number of sit-to-stands after 3 weeks training, whereas P-A tDCS significantly increased knee flexor peak torques after 3 weeks training, and decreased short-interval intracortical inhibition (SICI) immediately after the first session of training and maintained it post-training. These results suggest that optimized electrode placement of the maximal EF estimated by electric field simulation enhances motor performance and modulates cortical excitability depending on the direction of current flow.

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.

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.

Test-retest reliability of intrahemispheric dorsal premotor and primary motor cortex dual-site TMS connectivity measures

ObjectiveInvestigating the optimal interstimulus interval (ISI) and the 24-hour test–retest reliability for intrahemispheric dorsal premotor cortex (PMd) – primary motor cortex (M1) connectivity using dual-site transcranial magnetic stimulation (dsTMS). MethodsIn 21 right-handed adults, left intrahemispheric PMd–M1 connectivity has been investigated with a stacked-coil dsTMS setup (conditioning stimulus: 75% of resting motor threshold; test stimulus: eliciting MEPs of 1–1.5 mV) at ISIs of 3, 5–8, and 10 ms. Additionally, M1–M1 short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were investigated to assess comparability to standard paired-pulse setups. ResultsConditioning PMd led to significant inhibition of M1 output at ISIs of 3 and 5 ms, whereas 10 ms resulted in facilitation (all, p < 0.001), with a fair test–retest reliability for 3 (ICC: 0.47) and 6 ms (ICC: 0.44) ISIs. Replication of SICI (p < 0.001) and ICF (p = 0.017) was successful, with excellent test–retest reliability for SICI (ICC: 0.81). ConclusionThis dsTMS setup can probe the inhibitory and facilitatory PMd–M1 connections, as well as reliably replicate SICI and ICF paradigms. SignificanceThe stacked-coil dsTMS setup for investigating intrahemispheric PMd–M1 connectivity offers promising possibilities to better understand motor control.

Excitation/inhibition imbalance in schizophrenia: a meta-analysis of inhibitory and excitatory TMS-EMG paradigms

Cortical excitation-inhibition (E/I) imbalance is a potential model for the pathophysiology of schizophrenia. Previous research using transcranial magnetic stimulation (TMS) and electromyography (EMG) has suggested inhibitory deficits in schizophrenia. In this meta-analysis we assessed the reliability and clinical potential of TMS-EMG paradigms in schizophrenia following the methodological recommendations of the PRISMA guideline and the Cochrane Handbook. The search was conducted in three databases in November 2022. Included articles reported Short-Interval Intracortical Inhibition (SICI), Intracortical Facilitation (ICF), Long-Interval Intracortical Inhibition (LICI) and Cortical Silent Period (CSP) in patients with schizophrenia and healthy controls. Meta-analyses were conducted using a random-effects model. Subgroup analysis and meta-regressions were used to assess heterogeneity. Results of 36 studies revealed a robust inhibitory deficit in schizophrenia with a significant decrease in SICI (Cohen’s d: 0.62). A trend-level association was found between SICI and antipsychotic medication. Our findings support the E/I imbalance hypothesis in schizophrenia and suggest that SICI may be a potential pathophysiological characteristic of the disorder.

Plasticity-Induced Effects of Theta Burst Transcranial Ultrasound Stimulation in Parkinson's Disease.

Low-intensity transcranial ultrasound stimulation (TUS) is a noninvasive brain stimulation (NIBS) technique with high spatial specificity. Previous studies showed that TUS delivered in a theta burst pattern (tbTUS) increased motor cortex (MI) excitability up to 30 minutes due to long-term potentiation (LTP)-like plasticity. Studies using other forms of NIBS suggested that cortical plasticity may be impaired in patients with Parkinson's disease (PD). The aim was to investigate the neurophysiological effects of tbTUS in PD patients off and on dopaminergic medications compared to healthy controls. We studied 20 moderately affected PD patients in on and off dopaminergic medication states (7 with and 13 without dyskinesia) and 17 age-matched healthy controls in a case-controlled study. tbTUS was applied for 80 seconds to the MI. Motor-evoked potentials (MEP), short-interval intracortical inhibition (SICI), and short-interval intracortical facilitation (SICF) were recorded at baseline, and at 5 minutes (T5), T30, and T60 after tbTUS. Motor Unified Parkinson's Disease Rating Scale (mUPDRS) was measured at baseline and T60. tbTUS significantly increased MEP amplitude at T30 compared to baseline in controls and in PD patients on but not in PD patients off medications. SICI was reduced in PD off medications compared to controls. tbTUS did not change in SICI or SICF. The bradykinesia subscore of mUPDRS was reduced at T60 compared to baseline in PD on but not in the off medication state. The presence of dyskinesia did not affect tbTUS-induced plasticity. tbTUS-induced LTP plasticity is impaired in PD patients off medications and is restored by dopaminergic medications. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.