Cortical excitability varies across different muscles.

The dying forward hypothesis of motor neuron disease (MND) suggests that corticomotoneurons induce excitotoxic anterior horn cell death, with involvement of the glutamatergic neurotransmitter system. The aim of the present study was to apply novel threshold tracking transcranial magnetic stimulation (TMS) techniques in conjunction with peripheral nerve excitability studies in MND patients to further investigate the dying forward hypothesis and possibly determine the site of disease onset. Studies were undertaken in 23 MND patients using a 90-mm circular coil connected to a BiStim magnetic stimulator for cortical studies and electrical stimulation for peripheral nerve excitability studies. Motor-evoked potentials and compound muscle action potentials (CMAPs) were recorded from the right abductor pollicis brevis in the same setting. Measures of cortical and peripheral nerve excitability were correlated with clinical and neurophysiological parameters of disease severity. Short-interval intracortical inhibition (SICI) was significantly reduced in MND patients compared with controls (MND group = 3.6 +/- 0.8%; controls = 8.5 +/- 1.0%, P < 0.001), most prominently in MND patients with limb-onset disease. Changes in intracortical inhibition were accompanied by alterations in the magnetic stimulus-response curve, cortical silent period duration and resting motor threshold, all indicative of cortical hyperexcitability. Although the reduction in SICI was more pronounced in MND patients with less severe disease, as assessed by the CMAP amplitude, it remained evident even in MND patients with advanced disease. Measures of peripheral disease burden, namely the CMAP amplitude (r = -0.6) and neurophysiological index (r = -0.6), correlated with cortical hyperexcitability changes, as did the strength-duration time constant (r = -0.6), a peripheral marker of axonal excitability. Simultaneous assessment of central and peripheral nerve excitability has established the presence of co-existent upper and lower motor neuron dysfunction, with cortical hyperexcitability an early feature in MND.

New Forms of ALS/MND Defined by Mutations in New Genes

Corticomotoneuronal function in asymptomatic SOD-1 mutation carriers

The identification of the chromosome 9 open reading frame 72 (c9orf72) gene hexanucleotide repeat expansion represents a major advance in the understanding of amyotrophic lateral sclerosis (ALS) pathogenesis. The pathophysiological mechanism by which the c9orf72 gene expansion leads to neurodegeneration is not yet elucidated. Cortical hyperexcitability is potentially an important pathophysiological process in sporadic ALS and familial ALS (FALS). To investigate whether cortical hyperexcitability forms the pathophysiological basis of c9orf72 FALS using the threshold-tracking transcranial magnetic stimulation technique. Prospective case-control single-center study that took place at hospitals and outpatient clinics from January 1, 2013, to January 1, 2015. Clinical and functional assessments along with transcranial magnetic stimulation studies were taken on 15 patients with c9orf72 FALS and 11 asymptomatic expansion carriers of c9orf72 who were longitudinally followed up for 3 years. Results were compared with 73 patients with sporadic ALS and 74 healthy control participants. Cortical excitability variables, including short-interval intracortical inhibition, were measured in patients with c9orf72 FALS and results were compared with asymptomatic c9orf72 carriers, patients with sporadic ALS, and healthy control participants. Mean (SD) short-interval intracortical inhibition was significantly reduced in patients with c9orf72 FALS (1.2% [1.8%]) and sporadic ALS (1.6% [1.2%]) compared with asymptomatic c9orf72 expansion carriers (10.2% [1.8%]; F = 16.1; P < .001) and healthy control participants (11.8% [1.0%]; F = 16.1; P < .001). The reduction of short-interval intracortical inhibition was accompanied by an increase in intracortical facilitation (P < .01) and motor-evoked potential amplitude (P < .05) as well as a reduction in the resting motor threshold (P < .05) and cortical silent period duration (P < .001). This study establishes cortical hyperexcitability as an intrinsic feature of symptomatic c9orf72 expansion-related ALS but not asymptomatic expansion carriers.

16.: Cortical excitability in hereditary spastic paraparesis patients with SPAST mutations

Primary objective: To evaluate excitability and inhibition of the motor cortex acutely and longitudinally following mild traumatic brain injury (mTBI).Research design: A longitudinal paired case-control design was used to examine cortical excitability and inhibition in 15 adults who had sustained an mTBI (mean age = 20.8 ± 1.2 years) and 15 matched control participants (mean age = 21.1 ± 1.3 years).Methods and procedures: Participants visited the lab within 72 hours of injury and again at 1, 2, 4 and 8 weeks post-injury. During each visit, transcranial magnetic stimulation was used to examine resting motor threshold (RMT), motor evoked potential peak-to-peak amplitude (MEPamp) and cortical silent period (CSP) duration of the first dorsal interosseous muscle.Main outcomes and results: There were no differences between groups in RMT (p = 0.10) or MEPamp (p = 0.22) at 72 hours post-injury or across the 2-month testing period (p ≥ 0.68), indicating similar cortical excitability. However, the CSP duration was higher in individuals with mTBI, indicating greater intra-cortical inhibition compared with the control group at 72 hours post-injury (p = 0.03) and throughout the 2 months of recovery (p = 0.009).Conclusions: mTBI appeared to have little effect on cortical excitability, but an acute and long-lasting effect on intra-cortical inhibition.

The pathophysiology of catamenial diseases such as epilepsy is unclear. Therefore, we investigated changes in cortical excitability during anovulatory and ovulatory cycles. Using transcranial magnetic stimulation (TMS), eight healthy women were investigated during anovulatory and 12 during ovulatory cycles. On days 8, -14, -7 and 2 of the cycle, resting motor threshold (RMT), cortical silent period (CSP), intracortical inhibition (ICI) and intracortical facilitation (ICF) were investigated. Repeated-measures analysis of variance (anova) and nonparametric methods were used for statistical analysis. A trend was seen for group by phase interaction regarding ICI (F = 2.5, P = 0.10). ICI varied during anovulatory cycles (median: 51.0% on day 8; 45.3% on day -14, 51.0% on day -7, and 28.6% on day 2; P = 0.040), mainly because of an increased inhibition on day 2. ICI was more pronounced in anovulatory cycles on day -14 (P = 0.021), -7 (P = 0.048) and 2 (P = 0.018) compared to ovulatory women who did not show intraindividual changes (P = 0.56). RMT, CSP and ICF showed no significant changes during anovulatory or ovulatory cycles. The results suggest fluctuations in cortical excitability during anovulatory cycles, possibly due to the withdrawal of 'excitatory' oestrogens that initiate menses in anovulatory cycles.

We used transcranial magnetic stimulation (TMS) of motor cortex, including a novel four-pulse superconditioning (TMSsc) paradigm, in repeated examinations of motor-evoked potentials (MEPs) in eight subjects with motor neuron disease (MND), including seven with amyotrophic lateral sclerosis (ALS). The goals were: (1) to look for evidence of cortical hyperexcitability, including a reduction in short-interval intracortical inhibition (SICI); and (2) to examine the utility of using TMSsc for quantifying upper motor neuron function during MND progression. Testing of abductor pollicis brevis (APB) and tibialis anterior (TA) muscles bilaterally was carried out every 3months in MND subjects for up to 2years; results were compared to those from a cohort of 15 control subjects. Measures of SICI were not significantly different between control and MND subjects for either APB or TA muscles. Other measures of cortical excitability, including TMS threshold and MEP amplitude, were consistent with lowered cortical excitability in MND subjects. Certain combinations of superconditioning TMS were capable of causing stronger inhibition or facilitation of MEPs compared to dual-pulse TMS, for both APB and TA target muscles. Moreover, there were multiple cases in which target muscles unresponsive to strong single-pulse TMS, whether at rest or when tested with an active contraction, showed an MEP in response to TMSsc optimized for facilitation. Our findings suggest that a multi-faceted neurophysiologic protocol for examining upper motor neuron function in MND subjects might benefit from inclusion of TMSsc testing.

Cyclical excitability of the motor cortex in patients with catamenial epilepsy: A transcranial magnetic stimulation study

The aim of this study was to assess differences between people with episodic migraine and healthy controls in some neurophysiological and clinical outcomes, which, in turn, may highlight the differences in sensory processing, especially in cortical excitability, pain processing, and executive function. A cross-sectional study was performed, including the following outcomes: pressure pain thresholds with algometry; resting motor threshold, short-interval intracortical inhibition, and intracortical facilitation with transcranial magnetic stimulation; and executive functions with the trail making test and the frontal assessment battery. Thirty adults with migraine (36 ± 10 years) and 30 healthy controls (29 ± 14 years) were included in this study. Compared with the healthy controls, participants with migraine presented lower pressure pain thresholds values in all the assessed muscles ( P < 0.001), lower resting motor threshold (-10.5% of the stimulator output, 95% CI: -16.8 to -4.2, P = 0.001, Cohen d = 0.869) and higher short-interval intracortical inhibition motor-evoked potential's amplitude at 3 ms (0.25, 95% CI: 0.05 to 0.46, P = 0.015, Cohen d = 0.662), and worse performances both in trail making test (7.1, 95% CI: 0.9 to 13.4, P = 0.027, Cohen d = 0.594) and frontal assessment battery (-1.1, 95% CI: -1.7 to -0.5, P = 0.001, Cohen d = 0.915). Participants with migraine presented significant differences in cortical excitability, executive functions, and pressure pain thresholds, compared with healthy controls.

Comparison of low frequency repetitive transcranial magnetic stimulation parameters on motor cortex excitability in normal subjects

Transcranial magnetic stimulation (TMS) has been applied to a growing number of psychiatric disorders as a neurophysiological probe, a primary brain-mapping tool, and a candidate treatment. Although most investigations have focused on the treatment of major depression, increasing attention has been paid to anxiety disorders. The aim of this study is to summarize published findings about the application of TMS as a putative treatment for anxiety disorders. TMS neurophysiological and mapping findings, both clinical and preclinical, have been included when relevant. We searched Medline, PsycInfo, and the Cochrane Library from 1980 to January 2009 for the terms 'generalized anxiety disorder', 'social anxiety disorder', 'social phobia', 'panic', 'anxiety', or 'posttraumatic stress disorder' in combination with 'TMS', 'cortex excitability', 'rTMS', 'motor threshold', 'motor evoked potential', 'cortical silent period', 'intracortical inhibition', 'neuroimaging', or 'intracortical facilitation'. Most of the therapeutic experiences with repetitive TMS available in the literature are in the form of case reports, not controlled or blinded studies. Stimulation of the right dorsolateral prefrontal cortex, especially at high frequencies, has been reported to reduce anxiety symptoms in posttraumatic stress disorder and panic disorder; nevertheless, results are mixed. A specific role for the right dorsolateral prefrontal cortex in the posttraumatic stress disorder symptom core can be hypothesized. TMS remains an investigational intervention that has not yet gained approval for the clinical treatment of any anxiety disorder. Clinical sham-controlled trials are scarce. Many of these trials have supported the idea that TMS has a significant effect, but in some studies, the effect is small and short lived. The neurobiological correlates suggest possible efficacy for the treatment of social anxiety that still has to be investigated.

Attention-deficit/hyperactivity disorder (ADHD) currently lacks a universally accepted biomarker or diagnostic test, underscoring the need for objective and effective assessment methods. Transcranial magnetic stimulation (TMS) has emerged as a promising tool for both assessing cortical excitability and providing therapeutic interventions. This study conducted two independent meta-analyses to evaluate: 1) the potential of TMS in assessing cortical excitability, and 2) its therapeutic efficacy in managing ADHD symptoms. A systematic search was conducted in EMBASE, MEDLINE, PsycINFO, ClinicalTrials, and PubMed following PRISMA guidelines. The "cortical excitability" meta-analysis included studies comparing TMS-EMG or TMS-EEG neurophysiological measures between ADHD patients and healthy controls. The "therapeutic" meta-analysis focused on randomized controlled trials (RCTs) evaluating repetitive TMS (rTMS) effects on ADHD symptoms. Standardized mean differences (SMDs) were calculated for pooled effect sizes. In the "cortical excitability" meta-analysis, 17 studies were included, demonstrating significantly reduced short-interval intracortical inhibition (SICI) in ADHD compared to healthy controls (pooled SMD = 0.65, 95% CI: 0.41-0.88, P < 0.00001). No significant differences were observed for motor evoked potentials (MEP), motor thresholds (aMT/rMT), cortical silent period (cSP), ipsilateral silent period (iSP), or intracortical facilitation (ICF). The "therapeutic" meta-analysis, encompassing 8 samples from 7 studies, demonstrated that rTMS significantly improved ADHD symptoms compared to control conditions (pooled SMD = 0.45, 95% CI: 0.19-0.70, P = 0.0006). This study highlights the potential of TMS as both a diagnostic and therapeutic tool in ADHD. Reduced SICI appears to be a key neurophysiological marker of ADHD, reflecting cortical GABAergic dysfunction. Additionally, rTMS shows promise in alleviating ADHD symptoms, though further studies are needed to confirm long-term therapeutic benefits and optimize stimulation protocols. https://www.crd.york.ac.uk/prospero/, identifier CRD42024507867.

BackgroundTask-specific dystonia (TSFD) is a disabling movement disorder. Effective treatment options are currently limited. Zolpidem was reported to improve primary focal and generalized dystonia in a proportion of patients. The mechanisms underlying its therapeutic effects have not yet been investigated. MethodsWe conducted a randomized, double-blind, placebo-controlled, crossover trial of single-dose zolpidem in 24 patients with TSFD. Patients were clinically assessed using Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), Writers' Cramp Rating Scale (WCRS), and Visual Analogue Scale (VAS), before and after receiving placebo and zolpidem. Transcranial magnetic stimulation was conducted on placebo and zolpidem to compare corticospinal excitability – active and resting motor thresholds (AMT and RMT), resting and active input/output curves and intracortical excitability - cortical silent period (CSP), short-interval intracortical inhibition curve (SICI), long-interval intracortical inhibition (LICI) and intracortical facilitation (ICF). Eight patients underwent brain FDG-PET imaging on zolpidem and placebo. ResultsZolpidem treatment improved TSFD. Zolpidem compared to placebo flattened rest and active input/output curves, reduced ICF and was associated with hypometabolism in the right cerebellum and hypermetabolism in the left inferior parietal lobule and left cingulum. Correlations were found between changes in dystonia severity on WCRS and changes in active input/output curve and in brain metabolism, respectively. Patients with lower RMT, and higher rest and active input/output curves exhibited better response to zolpidem compared to placebo. ConclusionsZolpidem improved TSFD by reducing corticomotor output and influencing crucial nodes in higher-order sensory and motor networks.

EPA-1506 – Impact of brain-derived neurotrophic factor (BDNF) gene polymorphism on cortical inhibition in schizophrenia