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Objectives: Strength-duration time constant (SDTC) may now be determined for cortical motor neurones, with activity mediated by transient Na + conductances. The present study determined whether cortical SDTC is abnormal and linked to the pathogenesis of amyotrophic lateral sclerosis., Methods: Cortical SDTC and rheobase were estimated from 17 ALS patients using a controllable pulse parameter transcranial magnetic stimulation (cTMS) device. Resting motor thresholds (RMTs) were determined at pulse widths (PW) of 30, 45, 60, 90 and 120 µs and M-ratio of 0.1, using a figure-of-eight coil applied to the primary motor cortex., Results: SDTC was significantly reduced in ALS patients (150.58 ± 9.98 µs; controls 205.94 ± 13.7 µs, P < 0.01). The reduced SDTC correlated with a rate of disease progression (Rho = -0.440, P < 0.05), ALS functional rating score (ALSFRS-R) score (Rho = 0.446, P < 0.05), and disease duration (R = 0.428, P < 0.05). The degree of change in SDTC was greater in patients with cognitive abnormalities as manifested by an abnormal total Edinburgh Cognitive ALS Screen score (140.5 ± 28.7 µs, P < 0.001) and ALS-specific subscore (141.7 ± 33.2 µs, P = 0.003)., Conclusions: Cortical SDTC reduction was associated with a more aggressive ALS phenotype, or with more prominent cognitive impairment., Significance: An increase in transient Na + conductances may account for the reduction in SDTC, linked to the pathogenesis of ALS., (Copyright © 2024 International Federation of Clinical Neurophysiology. All rights reserved.)

Cortical hyperexcitability is an important pathophysiological mechanism in amyotrophic lateral sclerosis (ALS), reflecting a complex interaction of inhibitory and facilitatory interneuronal processes that evolves in the degenerating brain. The advances in physiological techniques have made it possible to interrogate progressive changes in the motor cortex. Specifically, the direction of transcranial magnetic stimulation (TMS) stimulus within the primary motor cortex can be utilized to influence descending corticospinal volleys and to thereby provide information about distinct interneuronal circuits. Cortical motor function and cognition was assessed in 29 ALS patients with results compared to healthy volunteers. Cortical dysfunction was assessed using threshold-tracking TMS to explore alterations in short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), the index of excitation and stimulus response curves using a figure-of-eight coil with the coil oriented relative to the primary motor cortex in a posterior-anterior, lateral-medial and anterior-posterior direction. Mean SICI, between interstimulus interval of 1-7 ms, was significantly reduced in ALS patients compared to healthy controls when assessed with the coil oriented in posterior-anterior (P = 0.044) and lateral-medial (P = 0.005) but not the anterior-posterior (P = 0.08) directions. A significant correlation between mean SICI oriented in a posterior-anterior direction and the total Edinburgh Cognitive and Behavioural ALS Screen score (Rho = 0.389, P = 0.037) was evident. In addition, the mean SICF, between interstimulus interval 1-5 ms, was significantly increased in ALS patients when recorded with TMS coil oriented in posterior-anterior (P = 0.035) and lateral-medial (P < 0.001) directions. In contrast, SICF recorded with TMS coil oriented in the anterior-posterior direction was comparable between ALS and controls (P = 0.482). The index of excitation was significantly increased in ALS patients when recorded with the TMS coil oriented in posterior-anterior (P = 0.041) and lateral-medial (P = 0.003) directions. In ALS patients, a significant increase in the stimulus response curve gradient was evident compared to controls when recorded with TMS coil oriented in posterior-anterior (P < 0.001), lateral-medial (P < 0.001) and anterior-posterior (P = 0.002) directions. The present study has established that dysfunction of distinct interneuronal circuits mediates the development of cortical hyperexcitability in ALS. Specifically, complex interplay between inhibitory circuits and facilitatory interneuronal populations, that are preferentially activated by stimulation in posterior-to-anterior or lateral-to-medial directions, promotes cortical hyperexcitability in ALS. Mechanisms that underlie dysfunction of these specific cortical neuronal circuits will enhance understanding of the pathophysiological processes in ALS, with the potential to uncover focussed therapeutic targets., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Purpose: Cortical hyperexcitability has been identified as a diagnostic and pathogenic biomarker of amyotrophic lateral sclerosis (ALS). Cortical excitability is assessed by transcranial magnetic stimulation (TMS), a non-invasive neurophysiological technique. The TMS biomarkers exhibiting highest sensitivity for cortical hyperexcitability in ALS remain to be elucidated. A meta-analysis was performed to determine the TMS biomarkers exhibiting the highest sensitivity for cortical hyperexcitability in ALS., Methods: A systematic literature review was conducted of all relevant studies published in the English language by searching PubMed, MEDLINE, Embase and Scopus electronic databases from 1 January 2006 to 28 February 2023. Inclusion criteria included studies reporting the utility of threshold tracking TMS (serial ascending method) in ALS and controls., Results: In total, more than 2500 participants, incorporating 1530 ALS patients and 1102 controls (healthy, 907; neuromuscular, 195) were assessed with threshold tracking TMS across 25 studies. Significant reduction of mean short interval intracortical inhibition (interstimulus interval 1-7 ms) exhibited the highest standardized mean difference with moderate heterogeneity (-0.994, 95% confidence interval -1.12 to -0.873, p < 0.001; Q = 38.61, p < 0.05; I 2  = 40%). The reduction of cortical silent period duration along with an increase in motor evoked potential amplitude and intracortical facilitation also exhibited significant, albeit smaller, standardized mean differences., Conclusion: This large meta-analysis study disclosed that mean short interval intracortical inhibition reduction exhibited the highest sensitivity for cortical hyperexcitability in ALS. Combined findings from this meta-analysis suggest that research strategies aimed at understanding the cause of inhibitory interneuronal circuit dysfunction could enhance understanding of ALS pathogenesis., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

A complex interaction of inhibitory and facilitatory interneuronal processes may underlie development of cortical excitability in the human motor cortex. To determine whether distinct interneuronal processes mediated cortical excitability, threshold tracking transcranial magnetic stimulation was utilised to assess cortical excitability, with figure-of-eight coil oriented in posterior-anterior (PA), anterior-posterior (AP) and latero-medial (LM) directions. Motor evoked potential (MEP) responses were recorded over the contralateral abductor pollicis brevis. Resting motor threshold (RMT), short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF) and intracortical facilitation were recorded. Significant effects of coil orientation were evident on SICI (F = 8.560, P = 0.002) and SICF (F = 7.132, P = 0.003). SICI was greater when recorded with PA (9.7 ± 10.9%, P = 0.029) and AP (13.1 ± 7.0%, P = 0.003) compared to LM (5.2 ± 7.3%) directed currents. SICF was significantly greater with PA (-14.7 ± 8.1%, P = 0.016) and LM (-14.7 ± 8.8%, P = 0.005) compared to AP (-9.1 ± 7.2%) coil orientations. SICI recorded with LM and PA coil orientations were correlated (R = 0.7, P = 0.002), as was SICF recorded with AP vs LM (R = 0.60, P = 0.019) and LM vs PA (R = 0.69, P = 0.002) coil orientations. RMT was significantly smaller with PA compared to AP (P < 0.001) and LM (P = 0.018) stimulation. Recruitment of distinct interneuronal processes with variable cortical orientation and thresholds underlies short interval intracortical inhibition and facilitation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A previous study using traditional paired-pulse TMS methods (amplitude-tracking) has reported differences in resting motor threshold (RMT) and short-interval intracortical inhibition (SICI) between healthy subjects of Caucasian and Han Chinese backgrounds, probably due to differences in the skull shape. The amplitude-tracking method delivers stimuli with constant intensity and causes substantial variabilities in motor-evoked potential amplitudes. To overcome this variability, threshold tracking transcranial magnetic stimulation (TT-TMS) has been developed. The present study aimed to investigate whether racial differences in motor cortical function exist, using TT-TMS. A total of 83 healthy volunteers (30 Caucasians, 25 Han Chinese, and 28 Japanese) were included in the present series. In TT-TMS and nerve conduction studies, electrodes were placed on the dominant limb, with measures recorded from the abductor pollicis brevis muscle. Stimulations were delivered with a circular coil, directly above the primary motor cortex. There were no significant differences at all the SICI intervals between races. Similarly, there were no significant differences in other measures of excitability including mean RMT, intracortical facilitation, and cortical silent period. Contrary to traditional amplitude-tracking TMS, motor cortical excitability and thereby motor cortical function is minimally influenced by racial differences when measured by TT-TMS. Recent studies have disclosed that SICI measured by TT-TMS differentiates amyotrophic lateral sclerosis (ALS) from ALS mimic disorders, with high sensitivity and specificity, in Caucasians. This study suggested that TT-TMS can be applied for the ALS diagnosis in Asian patients, as well as Caucasians. NEW & NOTEWORTHY Threshold tracking transcranial magnetic stimulation (TT-TMS) was applied for Caucasians, Han Chinese, and Japanese. No significant differences were found in TMS excitability indexes among races. Recent studies have disclosed that TT-TMS indexes differentiate amyotrophic lateral sclerosis (ALS) from ALS mimic disorders, with high sensitivity and specificity, in Caucasians. This study suggested that TT-TMS can be applied for the ALS diagnosis in Asian patients, as well as Caucasians.

Aim: Involvement of the corpus callosum has been identified as a feature of amyotrophic lateral sclerosis (ALS), particularly through neuropathological studies. The aim of the present study was to determine whether alteration in transcallosal function contributed to the development of ALS, disease progression and thereby functional disability., Methods: Transcallosal function and motor cortex excitability were assessed in 17 ALS patients with results compared to healthy controls. Transcallosal inhibition (interstimulus intervals (ISI) of 8-40 ms), short interval intracortical facilitation (SICF) and inhibition (SICI) were assessed in both cerebral hemispheres. Patients were staged utilising clinical and neurophysiological staging assessments., Results: In ALS, there was prominent reduction of transcallosal inhibition (TI) when recorded from the primary and secondary motor cortices compared to controls (F = 23.255, p < 0.001). This reduction of TI was accompanied by features indicative of cortical hyperexcitability, including reduction of SICI and increase in SICF. There was a significant correlation between the reduction in TI and the rate of disease progression (R = -0.825, p < 0.001) and reduction in muscle strength (R = 0.54, p = 0.031)., Conclusion: The present study has established that dysfunction of transcallosal circuits was an important pathophysiological mechanism in ALS, correlating with greater disability and a faster rate of disease progression. Therapies aimed at restoring the function of transcallosal circuits may be considered for therapeutic approaches in ALS., (© 2020 European Academy of Neurology.)

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are well-recognised as an extended disease spectrum. This study hypothesised that cortical hyperexcitability, an early pathophysiological abnormality in ALS, would distinguish cognitive phenotypes, as a surrogate marker of pathological disease burden. 61 patients with ALS, matched for disease duration (pure motor ALS, n = 39; ALS with coexistent FTD, ALS-FTD, n = 12; ALS with cognitive/behavioural abnormalities not meeting FTD criteria, ALS-Cog, n = 10) and 30 age-matched healthy controls. Cognitive function on the Addenbrooke's cognitive examination (ACE) scale, behavioural function on the motor neuron disease behavior scale (MiND-B) and cortical excitability using transcranial magnetic stimulation (TMS) were documented. Cortical resting motor threshold (RMT), lower threshold indicating hyperexcitability, was lower in ALS-FTD (50.2 ± 6.9) compared to controls (64.3 ± 12.6, p < 0.005), while ALS-Cog (63.3 ± 12.7) and ALS (60.8 ± 13.9, not significant) were similar to controls. Short interval intracortical inhibition (SICI) was reduced across all ALS groups compared to controls, indicating hyperexcitability. On receiver operating characteristic curve analysis, RMT differentiated ALS-FTD from ALS (area under the curve AUC = 0.745, p = 0.011). The present study has identified a distinct pattern of cortical excitability across cognitive phenotypes in ALS. As such, assessment of cortical physiology may provide more precise clinical prognostication in ALS.

Objective: Recruitment of interneuronal circuits generating later indirect (I) waves seem to be important in short-interval intracortical inhibition (SICI) and facilitation (SICF) development. This study assessed whether individual variations in intracortical inhibition and facilitation could be explained by variation in recruitment of interneuronal networks., Methods: Cortical excitability was assessed using a figure of eight coil, with motor evoked responses recorded over the contralateral abductor pollicis brevis (APB) muscle. I-wave recruitment was inferred from the measurement of motor evoked potential (MEP) onset latencies, with coil positioned in posterior-to-anterior (early I waves) and anterior-to-posterior (later I waves) directions., Results: Subtle variability in the recruitment of later I-waves (I3) was evident across subjects. Importantly, mean SICI (P < 0.05) was significantly greater in subjects recruiting I3 waves, as were the two SICI peaks at interstimulus intervals of 1 ms (P < 0.05) and 3 ms (P < 0.05). In addition, mean SICF was significantly greater in participants exhibiting an AP-to-LM latency differences of <4 ms (P < 0.01). There was no significant correlation between I-wave recruitment and intracortical facilitation, motor evoked potential amplitude or cortical silent period duration., Conclusions: Differential recruitment of interneuronal networks appears to underlie the generation and individual variations in intracortical inhibition and facilitation., Significance: Investigating cortical interneuronal networks in human diseases may yield novel pathophysiological insights., Competing Interests: Declaration of Competing Interest Dr. Higashihara, Dr. Van den Bos and Dr. Menon report no disclosures. Dr. Kiernan reports other from Editor-in-Chief of Journal of neurology, neurosurgery and psychiatry, non-financial support from Motor Neurone Disease Handbook. Dr. Vucic reports honoraria from Merck Serono Australia, Sanofi Genzyme, and CSL Behring., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To characterise the regional cortical patterns underlying clinical symptomatology in amyotrophic lateral sclerosis (ALS)., Methods: 138 patients prospectively underwent transcranial magnetic stimulation studies from hand and leg cortical regions of each hemisphere, obtaining motor evoked potentials from all four limbs. Patients were categorised by clinical phenotype and underwent clinical and peripheral evaluation of disease., Results: Cortical dysfunction was evident across the motor cortices, with reduction in short-interval intracortical inhibition (SICI) suggesting the presence of widespread cortical hyperexcitability, most prominently from clinically affected regions (hand p < 0.0001; leg p < 0.01). In early disease, cortical abnormalities were asymmetric between hemispheres, focally corresponding to clinical site-of-onset (p < 0.05). Degrees of cortical dysfunction varied between phenotypes, with the bulbar-onset cohort demonstrating greatest reduction in SICI (p = 0.03)., Conclusions: The pattern of cortical dysfunction appears linked to clinical evolution in ALS, with early focal asymmetry preceding widespread changes in later disease. Cortical differences across phenotypes may influence clinical variability., Significance: This is the first study to extensively map cortical abnormalities from multiple motor regions across hemispheres. The early cortical signature mirrors symptom laterality, supporting a discrete region of disease onset. Phenotypes appear to exist within a pathophysiological continuum, but cortical heterogeneity may mediate observed differences in clinical outcome., Competing Interests: Declaration of Competing Interest None of the authors have potential conflicts of interest to be disclosed., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

Objective: The pathophysiological processes underlying amyotrophic lateral sclerosis (ALS) need to be better understood, although cortical dysfunction has been implicated. Previous transcranial magnetic stimulation (TMS) studies have assessed cortical dysfunction from the hand. The aim of the present study was to determine whether cortical dysfunction was evident across representations of three body regions, and to relate these changes to clinical features of ALS., Methods: In this cross-sectional study, threshold tracking TMS was undertaken in 60 sporadic ALS patients, with motor evoked potential (MEP) responses recorded over the hand (abductor pollicis brevis), lower limb (tibialis anterior), and bulbar (trapezius) regions. The cross-sectional findings were compared to 28 age- and gender-matched controls., Results: Cortical dysfunction was evident across the representation of the three body regions, although the degree and nature of the dysfunction varied. Cortical hyperexcitability, as heralded by reduced short interval intracortical inhibition (SICI), was evident in all cortical regions (hand, P < 0.01; leg, P < 0.05; bulbar, P < 0.05) in ALS patients when compared with healthy control subjects. Importantly, features of cortical hyperexcitability seemed more prominent in clinically affected body regions and correlated with functional disability and muscle weakness. Cortical inexcitability was more prominent in the leg (P < 0.001) and bulbar regions (P < 0.01) when compared with controls., Interpretation: The nature of cortical dysfunction varied across the body regions in ALS, with cortical hyperexcitability being more prominent in the upper limbs while cortical inexcitability was more evident in the lower limbs and bulbar regions. The findings suggest a heterogeneity of cortical pathophysiological processes in ALS., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Purpose: Clinical application of transcranial magnetic stimulation (TMS) has rapidly increased but the majority of studies have targeted upper limb muscles, with few exploring the lower-limb. Differences of coil choice have added to methodological difficulties of lower-limb studies and have challenged consistent interpretation of these parameters. The aims of this study were to determine the optimal coil choice for assessing lower-limb cortical excitability and assess laterality of normal cortical function., Methods: 69 recordings were undertaken from the tibialis anterior muscle from 48 healthy participants. Three coil types currently used in lower-limb studies (90 mm circular; 70 mm figure-of-8; and 110 mm double cone) were explored using single pulse TMS and paired-pulse threshold tracking TMS (TT-TMS) paradigms, with peripheral function also assessed. Cortical symmetry was ascertained with bilateral recordings (dominant versus non-dominant muscles)., Results: The double-cone coil showed greatest efficacy, with significantly lower resting motor thresholds (49.0 ± 2.3%, p<0.0005) and greater intracortical facilitation compared to the alternate coil choices. Using the double-cone coil, paired-pulse TT-TMS generated an averaged short interval intracortical inhibition of 11.3 ± 1.2%, with an averaged intracortical facilitation of -6.1 ± 1.9%. There were no differences between dominant and non-dominant hemispheres., Conclusions: The present study identified key differences in cortical parameters between the currently utilised coils for lower-limb TMS. Specifically, this indicates the importance of standardizing the lower-limb TMS protocol, particularly for accurate interpretation in disease pathology., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To determine the relative contribution of inhibitory and facilitatory circuits in the development of cortical hyperexcitability in amyotrophic lateral sclerosis (ALS)., Methods: In this cross-sectional study, cortical excitability was assessed in 27 patients with ALS, and results compared to 25 healthy controls. In addition, a novel neurophysiologic measure of cortical function, short-interval intracortical facilitation (SICF), was assessed reflecting activity of the facilitatory circuits., Results: There was a significant increase in SICF (ALS -18.51 ± 1.56%, controls -8.52 ± 1.21%, p < 0.001) in patients with ALS that was accompanied by a reduction of short-interval intracortical inhibition (ALS 3.94 ± 1.29%, controls 14.23 ± 1.18%, p < 0.001) and cortical silent period duration ( p = 0.034). The index of excitation, a biomarker reflecting the contribution of inhibitory and facilitatory circuit activity, was significantly increased in patients with ALS (82.79 ± 6.01%) compared to controls (36.15 ± 3.44, p < 0.001), suggesting a shift toward cortical excitation. Increased excitation correlated with upper motor neuron signs ( R 2 = 0.235, p = 0.016) and greater functional disability as reflected by a correlation with the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score ( R 2 = 0.335, p = 0.002)., Conclusions: The present study established that cortical hyperexcitability is a key contributor to ALS pathophysiology, mediated through dysfunction of inhibitory and facilitatory intracortical circuits. Therapies aimed at restoring the cortical inhibitory imbalance provide novel avenues for future therapeutic targets., (© 2018 American Academy of Neurology.)

The aim of the present study was to determine whether significant differences in cortical excitability were evident across different body regions in healthy humans. Threshold tracking transcranial magnetic stimulation (TMS) was undertaken in 28 healthy controls. Short-interval intracortical inhibition [SICI between interstimulus intervals (ISI) 1-7 ms], intracortical facilitation (ICF, between ISI 10-30 ms), resting motor threshold (RMT), cortical silent period (CSP) duration (generated at stimulus intensity 150% RMT), and motor evoked potential amplitude were recorded from the abductor pollicis brevis (APB), tibialis anterior (TA), and trapezius muscles. These muscles were selected as they are frequently affected in neurodegenerative diseases, such as amyotrophic lateral sclerosis. SICI and ICF are measured as a percentage difference between conditioned and an unconditioned test response. SICI was significantly greater when recorded over the APB (9.9 ± 1.5%) and TA (8.6 ± 1.4%) muscles compared with the trapezius (4.5 ± 1.9%, P < 0.05). The CSP duration was significantly shorter (CSP trapezius , 131.0 ± 6.3 ms; CSP TA , 175.7 ± 9.9 ms; CSP APB, 188.3 ± 4.0 ms; P < 0.001) and ICF greater ( P < 0.01) in the trapezius muscle. There were no significant correlations between inhibitory and facilitatory processes recorded across the three muscles. The present study established significant differences in cortical excitability across three body regions, with evidence of more prominent inhibition and less facilitation in the limb muscles. NEW & NOTEWORTHY Cortical excitability of muscles with differing motor functions was assessed using threshold tracking transcranial magnetic stimulation. Significantly greater intracortical inhibition and less facilitation were evident over the limb muscles. These findings could relate to differences in the functional organization of the corticomotoneuronal system innervating different muscle regions.

Objective: To evaluate corticomotoneuronal integrity in monomelic amyotrophy using threshold tracking transcranial magnetic stimulation (TT-TMS)., Methods: Cortical excitability studies were prospectively performed in 8 monomelic amyotrophy patients and compared to 21 early-onset amyotrophic lateral sclerosis (ALS) patients and 40 healthy controls. Motor evoked potentials responses were recorded over abductor pollicis brevis., Results: Maximal motor evoked potential (MEP/CMAP ratio) was significantly increased in monomelic amyotrophy compared with controls (monomelic amyotrophy 51.2±12.4%; control 22.7±2.1%, p=0.04). Averaged short-interval intracortical inhibition (SICI, ISI 1-7ms) in monomelic amyotrophy patients was similar to controls (monomelic amyotrophy 9.6±2.1%; control 10.0±0.9%, p=0.98). However, it was significantly reduced in early-onset ALS in comparison with monomelic amyotrophy patients (monomelic amyotrophy 9.6±2.1%; ALS 2.3±1.7%, p<0.001). Averaged SICI is a good parameter (area under the curve 0.79, p=0.02) to discriminate between monomelic amyotrophy and early-onset ALS patients., Conclusions: TT-TMS technique has identified normal cortical function in monomelic amyotrophy, a feature that distinguishes it from early-onset ALS. The greater corticomotoneuronal projections to spinal motoneurons may represent central nervous system adaptive change in monomelic amyotrophy., Significance: Corticomotoneuronal dysfunction does not drive the lower motor neurone loss presented in monomelic amyotrophy., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: The present study aimed to investigate alterations in cortical function in amyotrophic lateral sclerosis (ALS) related to disease progression., Methods: In total, clinical assessments were evaluated in 189 ALS patients, combined with assessment of cortical function utilising threshold tracking transcranial magnetic stimulation. Results were compared with disease stage. Disease stage was defined in three ways: (1) as a proportion of disease duration in deceased patients; (2) from the time of ALS onset; and (3) using the ALS rating scale-revised (ALSFRS-R)., Results: Prospective studies in ALS patients demonstrated decreased neurophysiological index (p<0.0001) and decreased compound muscle action potential (CMAP) (p<0.0001), combined with abnormalities of central function including prolonged central motor conduction time (CMCT) (p<0.05), increased motor evoked potential/CMAP amplitude ratio (p<0.0001) and decreased short interval intracortical inhibition (SICI) (p<0.001). SICI at 3ms (p<0.05, β=-0.21) and averaged SICI (p<0.05, β=-0.21) decreased with disease progression, measured using proportion of disease duration. Alternatively, using time from disease onset, CMCT prolonged with disease progression (p<0.01, β=0.25), while ALSFRS-R decline correlated with decreased SICI at 3ms (p<0.01, β=0.20)., Conclusions: Clinical measures combined with assessment of cortical function established that SICI decreased with disease progression., Significance: These findings may suggest dysfunction of inhibitory interneurons with disease progression., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Introduction: Threshold tracking paired-pulse transcranial magnetic stimulation (TTTMS) examines cortical function and is useful for diagnosis of motor neuron disorders. Differences in cortical function have been identified between dominant and non-dominant limbs using constant stimulus methods, but they remain unclear, potentially due to methodological differences. In this study we aimed to clarify differences in cortical function between dominant and non-dominant limbs using TTTMS., Methods: Single-pulse TMS, TTTMS, and nerve conduction studies were performed in 25 healthy, right-handed participants by recording from the abductor pollicis brevis muscle., Results: There were no side-to-side differences observed in resting motor threshold, motor evoked potential (MEP) amplitude, MEP latency, central motor conduction time, cortical silent period, short-interval intracortical inhibition and facilitation, compound muscle action potential (CMAP) amplitude, CMAP latency, F-wave latency, or neurophysiological index., Conclusions: These findings suggest that, when using TTTMS, there are no differences in cortical function between dominant and non-dominant hemispheres. Muscle Nerve 55: 424-427, 2017., (© 2016 Wiley Periodicals, Inc.)

Voluntary contraction leads to facilitation of motor-evoked potentials (MEPs) producing greater amplitude, shorter onset latency, and prolonged duration of the electromyography potential. Whereas hyperexcitability of spinal motoneurons and changes in descending corticospinal volleys have been proposed as putative mechanisms for changes in MEP amplitude and onset latency, a contribution of propriospinal interneurons, exerting modulatory effects on α-motoneurons, has been proposed as a potential explanation for prolongation of MEP duration. The aim of the present study is to gain further insight into the physiological processes underlying changes in MEP duration. Transcranial magnetic stimulation (TMS) studies were undertaken on 30 healthy controls, using a 90-mm circular coil, with MEPs recorded at rest and during facilitation, produced by contraction of abductor pollicis brevis. In the same experiment, short interval-intracortical inhibition (SICI) was recorded at rest. Facilitation resulted in a significant prolongation of MEP duration, which increased with stimulus intensity and was accompanied by an increase in MEP amplitude. The main effect (TMS intensity × activation state) was correlated with MEP duration ( F = 10.9, P < 0.001), whereas TMS intensity ( F = 30.5, P < 0.001) and activation state ( F = 125.8, P < 0.001) in isolation were correlated with MEP amplitude. There was a significant inverse relationship between SICI and MEP duration at rest (R 2 = 0.141, P = 0.041) and during facilitation (R 2 = 0.340, P = 0.001). The present findings suggest that similar physiological processes mediate changes in the facilitated MEP duration and amplitude and that both cortical and nonpropriospinal spinal mechanisms contribute to changes in MEP duration. NEW & NOTEWORTHY Muscle contraction is associated with a significant increase in motor-evoked potential (MEP) duration and amplitude. Whereas the increase in MEP duration was linear, the amplitude increase exhibited a ceiling effect. Importantly, the MEP duration increase strongly correlated with short interval-intracortical inhibition, a biomarker of motor cortical function. This suggests that whereas similar physiological processes contribute to changes in facilitated MEP duration and amplitude, cortical mechanisms appear to contribute to MEP duration changes., (Copyright © 2017 the American Physiological Society.)

Objective: Spinocerebellar ataxia type 3 (SCA3) is an inherited neurodegenerative disorder characterized by cerebellar ataxia and variable expression of clinical features beyond the cerebellum. To gain further insights into disease pathophysiology, the present study explored motor cortex function in SCA3 to determine whether cortical dysfunction was present and if this contributed to the development of clinical manifestations., Methods: Clinical phenotyping and longitudinal assessments were combined with central (threshold-tracking transcranial magnetic stimulation) and peripheral (nerve excitability) techniques in 11 genetically characterized SCA3 patients., Results: Short-interval intracortical inhibition was significantly reduced in presymptomatic and symptomatic SCA3 patients (-1.3±1.4%) compared to healthy controls (10.3±0.7%, P<0.0005), with changes evident prior to clinical onset of ataxia and related to worsening severity (R=-0.78, P<0.005). Central motor conduction time was also significantly prolonged in presymptomatic and symptomatic SCA3 patients (7.5±0.4ms) compared to healthy controls (5.3±0.2ms, P<0.0005) and related to clinical severity (R=0.81, P<0.005). Markers of peripheral motor neurodegeneration and excitability did not correlate with cortical hyperexcitability or ataxia., Conclusions: Simultaneous investigation of clinical status, and central and peripheral nerve function has identified progressive cortical dysfunction in SCA3 patients related to the development of ataxia., Significance: These findings suggest alteration in cortical activity is associated with SCA3 pathogenesis and neurodegeneration., (Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Riluzole is an established therapy for amyotrophic lateral sclerosis (ALS), although its effects are modest, prolonging survival by three months on average. While the neuroprotective effects of riluzole appear to be mediated by inhibition of glutaminergic transmission and antagonization of Na + channel function, the duration of these effects remains to be elucidated. Consequently, the present study combined assessment of cortical and peripheral function to determine the longitudinal effects of riluzole in ALS patients. Assessment of cortical function by threshold tracking transcranial magnetic stimulation (TMS) combined with peripheral nerve function excitability studies were longitudinally undertaken on 19 sporadic ALS patients, with assessment occurring at baseline, four, eight, and 12 weeks post riluzole initiation. Baseline results were compared to 31 healthy controls. Results showed that, at baseline, cortical hyperexcitability was a feature of ALS as indicated by a marked reduction in averaged short interval intracortical inhibition [SICI] (3.6 ± 6.9%, p < 0.0001) and cortical silent period duration (p < 0.05) as well as an increase in motor evoked potential amplitude (p < 0.05). Riluzole therapy resulted in individual patient increase in SICI of 4.3% (p < 0.01) and 5.2% (p < 0.01) at four and eight weeks, respectively. At a peripheral level, riluzole therapy lead to a transient increase at four weeks in the relative refractory period (p < 0.05), superexcitability (p < 0.05) and late subexcitability (p < 0.05), all of which returned to baseline levels eight weeks after initiation of riluzole. In conclusion, the present study has established that riluzole exerts transient effects on cortical and axonal hyperexcitability, potentially accounting for the modest clinical effectiveness in ALS.

Objective: To study the relationship between cortical function and survival in amyotrophic lateral sclerosis (ALS)., Methods: A total of 216 referrals were screened, and participants with familial ALS or an inexcitable cortex were excluded. Clinical measures and phenotyping from 169 patients with sporadic ALS were combined with an assessment of cortical function using threshold tracking transcranial magnetic stimulation with indices including short interval intracortical inhibition (SICI). Peripheral nerve studies were collected, incorporating compound muscle action potential amplitude. Clinical prognostic factors were recorded longitudinally, including ALS Functional Rating Scale-Revised (ALSFRS-R)., Results: Compared to 109 healthy controls, 169 patients had reduced SICI (p < 0.0001). In survival analysis, 105 patients progressed to death with an estimated median survival time of 37 months. In patients with less than 2 years disease duration (n = 140), those with bulbar onset (p = 0.017), rapid vital capacity (VC) decline (p < 0.0001), rapid ALSFRS-R decline (p < 0.0001), and reduced averaged SICI (p = 0.047) had a poorer prognosis. Multivariate analysis identified rapid VC decline (p < 0.0001), rapid ALSFRS-R decline (p = 0.0060), and reduced averaged SICI (p = 0.011) as factors independently associated with a shorter survival., Conclusions: Cortical dysfunction appears to be a prognostic marker in patients with ALS within 2 years of disease onset, such that patients with reduced averaged SICI, indicative of intracortical hyperexcitability, demonstrated a worse prognosis., (© 2016 American Academy of Neurology.)

Objective: Recently, the utility of threshold tracking paired-pulse transcranial magnetic stimulation (TTTMS), to measure changes in cortical excitabilitability, has been established for diagnostic purposes across a range of neurological diseases. However, the impact of healthy aging on the GABA-ergic intracortical inhibitory system remains unclear. To improve the clinical applicability, TTTMS was performed across an age spectrum., Methods: TTTMS, single-pulse TMS and nerve conduction studies (NCS) were performed in 113 healthy subjects aged between 20 and 83years (57 male and 56 female)., Results: Prolonged motor evoked potential (MEP) latency, increased central motor conduction time, decreased compound muscle action potential (CMAP) amplitude, prolonged F-wave latency and decreased neurophysiological index (NI), calculated from CMAP amplitude, latency and F-wave frequency, were observed as subjects aged. In contrast, short interval intracortical inhibition (SICI) and facilitation did not change. Compared to females, males exhibited a reduced SICI and NI along with longer MEP, CMAP with prolonged F-wave latencies. Multivariate analyses revealed similar results., Conclusion: Utilizing clinically applicable TTTMS protocols, findings suggest that GABA mediated intracortical inhibition may be greater in females but does not significantly change with age., Significance: These findings may better inform the interpretation of diagnostic TTTMS studies in the clinical setting., (Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Evolution of changes in intracortical excitability following stroke, particularly in the contralesional hemisphere, is being increasingly recognized in relation to maximizing the potential for functional recovery., Objective: The present study utilized a prospective longitudinal design over a 12-month period from stroke onset, to investigate the evolution of intracortical excitability involving both motor cortices and their relationship to recovery, and whether such changes were influenced by baseline stroke characteristics., Methods: Thirty-one patients with acute unilateral ischemic stroke were recruited from a tertiary hospital stroke unit. Comprehensive clinical assessments and cortical excitability were undertaken at stroke onset using a novel threshold-tracking paired-pulse transcranial magnetic stimulation technique, and repeated at 3-, 6-, and 12-month follow-up in 17 patients who completed the longitudinal assessment., Results: Shortly following stroke, short-interval intracortical inhibition (SICI) was significantly reduced in both lesioned and contralesional hemispheres that correlated with degree of recovery over the subsequent 3 months. Over the follow-up period, ipsilesional SICI remained reduced in all patient groups, while SICI over the contralesional hemisphere remained reduced only in the groups with cortical stroke or more baseline functional impairment., Conclusions: The current study has demonstrated that evolution of intracortical excitability, particularly over the contralesional hemisphere, may vary between patients with differing baseline stroke and clinical characteristics, suggesting that ongoing contralesional network recruitment may be necessary for those patients who have significant disruptions to the integrity of ipsilesional motor pathways. Results from the present series have implications for the development of neuromodulatory brain stimulation protocols to harness and thereby facilitate stroke recovery., (© The Author(s) 2015.)

Objective: To determine whether cortical hyperexcitability preceded the development of lower motor neuron (LMN) dysfunction in sporadic amyotrophic lateral sclerosis (ALS)., Methods: Cortical excitability studies were undertaken in 24 ALS patients with motor evoked potential (MEP) recorded over the abductor pollicis brevis (APB) muscle. In the same sitting, LMN function of the target APB muscle was assessed utilising qualitative and quantitative electromyography techniques along with axonal excitability studies., Results: At time of assessment, the anatomical and functional integrity of the lower motor neuronal circuits innervating the target APB muscle was preserved in all patients, confirmed by a normal CMAP amplitude (P=0.37), absence of fasciculations, or features of neurogenic change. Despite this apparent 'normality' cortical dysfunction was evident, with significant reduction of short interval intracortical inhibition (P<0.01), resting motor threshold (P<0.05) and cortical silent period duration (P<0.001), along with increases in MEP amplitude (P<0.05) and intracortical facilitation (P<0.05)., Conclusion: The findings in the present study suggest that cortical hyperexcitability occurs upstream to a seemingly intact lower motor neuronal system., Significance: Corticomotoneuronal dysfunction appears to be a primary event in ALS, suggesting a cortical origin of the disease., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Assessment of upper motor neuron (UMN) function in amyotrophic lateral sclerosis (ALS) remains clinically based. Given the potential difficulties in identifying UMN signs, objective biomarkers of UMN dysfunction are important. Consequently, the present study assessed utility of cortical thickness analysis combined with threshold tracking transcranial magnetic stimulation (TMS) as biomakers of UMN dysfunction in ALS. Cortical thickness analysis and threshold tracking TMS studies were undertaken on 25 ALS patients and results were compared to healthy control subjects, with different control groups used for each technique. Structural and functional abnormalities were evident in both motor cortices in the ALS cohort and were heralded by marked reduction of short-interval intracortical inhibition (SICI RAPB 1.4 ± 2.4%; SICI LAPB 3.6 ± 1.9%; SICI CONTROLS10.5 ± 1.1%, p <0.01), resting motor threshold (p <0.05) and cortical silent period duration (p <0.001) combined with increase in MEP amplitude (p <0.05) and intracortical facilitation (p <0.05). Significant cortical thinning was evident in the bitemporal regions (p <0.05), while precentral gyrus cortical thinning was evident in 56% of cases and when combined with TMS abnormalities disclosed UMN dysfunction in 88% of cases. In conclusion, findings from the present study establish that a combination of structural and functional assessment of corticomotoneurons may increase the yield of objectively identifying UMN dysfunction in ALS.

Introduction: Differences in cortical and axonal excitability may underlie preferential atrophy of abductor pollicis brevis (APB) and first dorsal interosseous (FDI) in amyotrophic lateral sclerosis, termed the split-hand. Consequently, this study aimed to determine whether differences in excitability follow a split-hand pattern across the intrinsic hand muscles., Methods: Excitability studies were undertaken using threshold tracking techniques in 26 healthy controls with responses recorded over APB, FDI, and abductor digiti minimi., Results: Short interval intracortical inhibition was significantly greater from the APB and FDI. In addition, motor evoked potential amplitude was greater, while cortical silent period was longer from APB and FDI. At a peripheral level, the strength-duration time constant was greater when recorded over APB., Conclusions: This study establishes that differences in cortical excitability follow the split-hand pattern in healthy controls, a finding potentially explained by evolution of specialized activity of APB/FDI in complex hand tasks. Muscle Nerve 49: 836-844, 2014., (Copyright © 2014 Wiley Periodicals, Inc.)

Background: Corticobasal syndrome (CBS) is characterized by multifaceted motor system dysfunction and cognitive disturbance; distinctive clinical features include limb apraxia and visuospatial dysfunction. Transcranial magnetic stimulation (TMS) has been used to study motor system dysfunction in CBS, but the relationship of TMS parameters to clinical features has not been studied. The present study explored several hypotheses; firstly, that limb apraxia may be partly due to visuospatial impairment in CBS. Secondly, that motor system dysfunction can be demonstrated in CBS, using threshold-tracking TMS, and is linked to limb apraxia. Finally, that atrophy of the primary motor cortex, studied using voxel-based morphometry analysis (VBM), is associated with motor system dysfunction and limb apraxia in CBS., Methods: Imitation of meaningful and meaningless hand gestures was graded to assess limb apraxia, while cognitive performance was assessed using the Addenbrooke's Cognitive Examination - Revised (ACE-R), with particular emphasis placed on the visuospatial subtask. Patients underwent TMS, to assess cortical function, and VBM., Results: In total, 17 patients with CBS (7 male, 10 female; mean age 64.4+/- 6.6 years) were studied and compared to 17 matched control subjects. Of the CBS patients, 23.5% had a relatively inexcitable motor cortex, with evidence of cortical dysfunction in the remaining 76.5% patients. Reduced resting motor threshold, and visuospatial performance, correlated with limb apraxia. Patients with a resting motor threshold <50% performed significantly worse on the visuospatial sub-task of the ACE-R than other CBS patients. Cortical function correlated with atrophy of the primary and pre-motor cortices, and the thalamus, while apraxia correlated with atrophy of the pre-motor and parietal cortices., Conclusions: Cortical dysfunction appears to underlie the core clinical features of CBS, and is associated with atrophy of the primary motor and pre-motor cortices, as well as the thalamus, while apraxia correlates with pre-motor and parietal atrophy.

Limited evidence to date has demonstrated changes in excitability that develops over the contralateral motor cortex after a cerebellar infarct. As such, the present study investigated changes in excitability over the contra- (contraM1) and ipsilateral motor cortices (ipsiM1), in patients with acute cerebellar infarct, to determine whether the changes may have functional relevance. Paired-pulse transcranial magnetic stimulation, combined with detailed clinical assessment, was undertaken in ten patients presenting with acute unilateral cerebellar infarct. Studies were undertaken within 1 week of ictus and followed longitudinally at 3-, 6-, and 12-month periods. Comparisons were made with 15 age-matched controls. Immediately following a stroke, short-interval intracortical inhibition (SICI) was significantly reduced over the contraM1 in all patients (P = 0.01), while reduced over the ipsiM1 in those with severe functional impairment (P = 0.01). Moreover, ipsiM1 SICI correlated with impairment (r = 0.69, P = 0.03), such that less SICI was observed in those patients with most impairment. Cortical excitability changes persisted over the follow-up period in the context of clinical improvement. Following an acute cerebellar infarct, excitability abnormalities develop over both motor cortices, more prominently in patients with severe functional impairment. The cortical changes, particularly over the ipsilateral motor cortex, may represent a functionally relevant plastic process that may guide future therapeutic strategies to better facilitate recovery.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the motor neurons in the motor cortex, brainstem and spinal cord. A combination of upper and lower motor neuron dysfunction comprises the clinical ALS phenotype. Although the ALS phenotype was first observed by Charcot over 100 years ago, the site of ALS onset and the pathophysiological mechanisms underlying the development of motor neuron degeneration remain to be elucidated. Transcranial magnetic stimulation (TMS) enables non-invasive assessment of the functional integrity of the motor cortex and its corticomotoneuronal projections. To date, TMS studies have established motor cortical and corticospinal dysfunction in ALS, with cortical hyperexcitability being an early feature in sporadic forms of ALS and preceding the clinical onset of familial ALS. Taken together, a central origin of ALS is supported by TMS studies, with an anterograde transsynaptic mechanism implicated in ALS pathogenesis. Of further relevance, TMS techniques reliably distinguish ALS from mimic disorders, despite a compatible peripheral disease burden, thereby suggesting a potential diagnostic utility of TMS in ALS. This review will focus on the mechanisms underlying the generation of TMS measures used in assessment of cortical excitability, the contribution of TMS in enhancing the understanding of ALS pathophysiology and the potential diagnostic utility of TMS techniques in ALS.

Introduction: Maladaptive plasticity involving the unaffected hemisphere (UH) in stroke patients may contribute to post-stroke deficits, including spasticity. We investigated the central and peripheral effects of botulinum toxin in post-stroke spasticity to determine whether there is modulation of cortical processes in the UH., Methods: Transcranial magnetic stimulation and peripheral nerve excitability studies were undertaken in 5 stroke patients with upper limb spasticity before (T1) and 6 weeks after (T2) botulinum injection., Results: Transcranial magnetic stimulation demonstrated inexcitable motor cortices of the affected hemisphere at T1 and T2, and short-interval intracortical inhibition (SICI) in the UH was significantly reduced at T1. At T2, SICI in the UH increased significantly compared with T1, normalizing to controls, and was found to be associated with clinical improvements in spasticity. Peripheral excitability parameters were unchanged after injection., Conclusion: Cortical excitability changes were demonstrated in UH, suggesting that the clinical benefits of botulinum toxin relate to modulation of abnormal central reorganization (maladaptive plasticity) in post-stroke spasticity., (Copyright © 2012 Wiley Periodicals, Inc., a Wiley company.)

Riluzole, a benzothiazole derivative, has been shown to be effective in prolonging survival in amyotrophic lateral sclerosis. The mechanisms by which riluzole exerts neuroprotective effects in amyotrophic lateral sclerosis remains to be fully elucidated, although inhibition of glutamatergic transmission and modulation of Na+ channel function have been proposed. In an attempt to determine the mechanisms by which riluzole exerts neuroprotective effects, in particular to dissect the relative contributions of inhibition of glutamatergic transmission and Na+ channel modulation, the present study utilized a combination of cortical and peripheral axonal excitability approaches to monitor changes in excitability and function in patients with amyotrophic lateral sclerosis. Cortical assessment was undertaken by utilising the threshold tracking transcranial magnetic stimulation (TMS) technique and combined with peripheral axonal excitability studies in 25 patients with amyotrophic lateral sclerosis. Studies were performed at baseline and repeated when patients were receiving riluzole 100 mg/day. At the time of second testing all patients were tolerating the medication well. Motor evoked potential and compound muscle action potential responses were recorded over the abductor pollicis brevis muscle. At baseline, features of cortical hyperexcitability were evident in patients with amyotrophic lateral sclerosis, indicated by marked reduction in short interval intracortical inhibition (P < 0.001) and cortical silent period duration (P < 0.001), as well as an increase in the motor evoked potential amplitude (P < 0.01). Riluzole therapy partially normalized cortical excitability by significantly increasing short interval intracortical inhibition (short interval intracortical inhibitionbaseline 0.5 ± 1.8%; short interval intracortical inhibitionON riluzole 7.9 ± 1.7%, P < 0.01). In contrast, riluzole did not exert any modulating effect on cortical silent period duration (P = 0.45) or motor evoked potential amplitude (P = 0.31). In terms of peripheral nerve function, axonal excitability studies established that, relative to control subjects, patients with amyotrophic lateral sclerosis had significant increases in depolarizing threshold electrotonus [amyotrophic lateral sclerosisbaseline TEd (90-100 ms) 49.1 ± 1.8%; controlsTEd (90-100 ms) 45.2 ± 0.6%, P < 0.01] and superexcitability (amyotrophic lateral sclerosisbaseline 30.1 ± 2.3%; control subjects 23.4 ± 1.0%, P < 0.01) at baseline. Following institution of riluzole therapy there was a significant reduction in superexcitability (amyotrophic lateral sclerosisbaseline 30.1 ± 2.3%; amyotrophic lateral sclerosisON riluzole 27.3 ± 2.3%, P < 0.05) and refractoriness at 2 ms (amyotrophic lateral sclerosisbaseline 98.7 ± 10.7%; amyotrophic lateral sclerosisON riluzole 67.8 ± 9.3%, P < 0.001). In conclusion, the present study has established that riluzole exerts effects on both central and peripheral nerve function, interpreted as partial normalization of cortical hyperexcitability and reduction of transient Na+ conductances. Taken together, these findings suggest that the neuroprotective effects of riluzole in amyotrophic lateral sclerosis are complex, with evidence of independent effects across both compartments of the nervous system.

Objective: To gain further insight into disease pathophysiologic process and potential adaptations through investigating whether cortical dysfunction or plasticity is a feature of spinal muscle atrophy (SMA)., Design: Prospective, double-center study., Setting: Outpatient clinics and research institute., Participants: Clinical assessments, combined with threshold-tracking transcranial magnetic stimulation techniques, were completed in 11 genetically characterized patients with SMA., Main Outcome Measures: Clinical, functional, and neurophysiologic variables were compared between the 11 patients with SMA types 2 and 3, 24 healthy control participants, and 81 patients with amyotrophic lateral sclerosis (ALS) serving as disease controls., Results: Maximal motor-evoked potential amplitude as a percentage of the compound muscle action potential was significantly increased in patients with SMA compared with the healthy controls but was similar to that in ALS (SMA, mean [SE], 39.7% [4.0%]; ALS, 38.8% [2.8%]; controls, 20.3% [2.5%]; F = 10.1; P < .001). In contrast, short-interval intracortical inhibition (SMA, 14.4% [1.6%]; ALS, 4.3% [1.8%]; controls, 17.0% [2.3%]; F = 11.4; P < .001) and cortical silent-period duration (SMA, 204.4 [9.8] milliseconds; ALS, 182.7 [5.2] milliseconds; controls, 208.8 [3.7] milliseconds; F = 4.8; P = .01), similar between SMA patients and healthy controls, were significantly larger when compared with the findings in ALS. Of relevance, peripheral disease burden as measured by the compound muscle action potential amplitude (SMA, 6.3 [0.8] mV; ALS, 5.9 [0.4] mV; controls, 11.8 [0.5] mV; F = 35.5; P < .001) and Neurophysiological Index (SMA, 0.7 [0.2]; ALS, 0.7 [0.1]; controls, 3.1 [0.2]; F = 108.2; P < .001), were significantly reduced in both SMA and ALS patients when compared with healthy controls., Conclusions: Taken together, findings from the present study suggest that despite spinal motoneuron degeneration there remains preservation of corticomotoneuronal function in SMA. The greater corticomotoneuronal projections to surviving spinal motoneurons likely represent an adaptive response to spinal motoneuron degeneration in SMA.

Background: Gray matter atrophy has been implicated in the development of secondary progressive multiple sclerosis (SPMS). Cortical function may be assessed by transcranial magnetic stimulation (TMS). Determining whether cortical dysfunction was a feature of SPMS could be of pathophysiological significance., Objectives: Consequently, novel paired-pulse threshold tracking TMS techniques were used to assess whether cortical dysfunction was a feature of SPMS., Methods: Cortical excitability studies were undertaken in 15 SPMS, 25 relapsing-remitting MS patients (RRMS) and 66 controls., Results: Short interval intracortical inhibition (SPMS 3.0 ± 2.1%; RRMS 12.8 ± 1.7%, p < 0.01; controls 10.5 ± 0.7%, p < 0.01) and motor evoked potential (MEP) amplitude (SPMS 11.5 ± 2.2%; RRMS 26.3 ± 3.6%, p <0.05; controls 24.7 ± 1.8%, p < 0.01) were reduced in SPMS, while intracortical facilitation (SPMS -5.2 ± 1.9%; RRMS -2.0 ± 1.4, p < 0.05; controls -0.9 ± 0.7, p < 0.01) and resting motor threshold were increased (SPMS 67.5 ± 4.5%; RRMS 56.0 ± 1.5%, p < 0.01; controls 59.0 ± 1.1%, p < 0.001). Further, central motor conduction time was prolonged in SPMS (9.1 ± 1.2 ms, p < 0.001) and RRMS (7.0 ± 0.9 ms, p < 0.05) patients compared with controls (5.5 ± 0.2 ms). The observed changes in cortical function correlated with the Expanded Disability Status Scale., Conclusion: Together, these findings suggest that cortical dysfunction is associated with disability in MS, and documentation of such cortical dysfunction may serve to quantify disease severity in MS.

Although fatigue is frequently reported in amyotrophic lateral sclerosis (ALS), the underlying mechanisms remain to be elucidated. Cortical excitability studies were utilized to determine the contribution of central mechanisms to development of fatigue and weakness in ALS. Threshold-tracking transcranial magnetic stimulation (TMS) studies were undertaken in 16 ALS patients and 22 normal controls using a 90-mm circular coil. TMS studies were performed at baseline, immediately after a voluntary contraction (VC) period of 120 s duration (three VC periods), and at 5, 10 and 20 min after last VC. At baseline, there was a significant reduction of short-interval intracortical inhibition (SICI) at interstimulus interval of 1 ms (ALS 2.3 ± 2.3%; controls 9.5 ± 2.5%, p < 0.01) and 3 ms (ALS5.1 ± 3.4%; controls 16.8 ± 1.7%, p < 0.01) in ALS patients. Although there was a significant reduction of SICI post-VC in controls at ISI 1 ms (p < 0.05) and ISI 3 ms (p < 0.05), there was no significant change in ALS patients at ISI 1 ms (p = 0.15) or 3 ms (p = 0.31). The changes in cortical excitability correlated with fatigue (R = 0.59, p < 0.05). In conclusion, maladaptation of cortical processes related to degeneration of inhibitory GABAergic intracortical circuits, is a feature of ALS that significantly correlates with development of fatigue and weakness.

Recently, 2 physiologically distinct phases of short-interval intracortical inhibition (SICI) have been identified, a larger phase at interstimulus interval (ISI) 3 ms and a smaller phase at ISI 1 ms. While the former is mediated by synaptic processes, the mechanisms underlying the first phase of SICI remain a matter of debate. Separately, it is known that fatiguing hand exercise reduces SICI, a measure of cortical excitability. Consequently, the present study assessed effects of fatiguing hand exercise on the 2 SICI phases, using threshold tracking transcranial magnetic stimulation techniques, to yield further information on underlying mechanisms. Studies were undertaken on 22 subjects, with SICI assessed at baseline, after each voluntary contraction (VC) period of 120 s and 5, 10, and 20 min after last VC, with responses recorded over abductor pollicis brevis. Exercise resulted in significant reduction of SICI at ISI 1 ms (SICI(baseline) 9.5 ± 2.7%; SICI(MAXIMUM REDUCTION) 2.5 ± 2.5%, P < 0.05) and 3 ms (SICI(baseline) 16.8 ± 1.7%; SICI(MAXIMUM REDUCTION) 11.6 ± 2.1%, P < 0.05), with the time course of reduction being different for the 2 phases. Taken together, findings from the present study suggest that synaptic processes were the predominant mechanism underlying the different phases of SICI.

Familial amyotrophic lateral sclerosis (FALS) is an inherited neurodegenerative disorder of the motor neurons. While 10-15% of cases are caused by mutations in the copper/zinc superoxide-dismutase-1 (SOD-1) gene, the dying-forward hypothesis, in which corticomotoneurons induce anterograde excitotoxic motoneuron degeneration, has been proposed as a potential mechanism. The present study applied novel threshold tracking transcranial magnetic stimulation techniques to investigate the mechanisms underlying neurodegeneration in FALS. Studies were undertaken in 14 asymptomatic and 3 pre-symptomatic SOD-1 mutation carriers, followed longitudinally for up to 3-years. The pre-symptomatic subjects were asymptomatic at the time of their initial study but developed symptoms during the follow-up period. Results were compared to 7 SOD-1 FALS patients, 50 sporadic ALS patients and 55 normal controls. Short-interval intracortical inhibition (SICI) was significantly reduced in SOD-1 FALS (-1.2 +/- 0.6%) and sporadic ALS patients (-0.7 +/- 0.3%) compared to asymptomatic SOD-1 mutation carriers (9.8 +/- 1.5%, P<0.00001) and normal controls (8.5 +/- 1.0%, P<0.00001). SICI reduction was accompanied by increases in intracortical facilitation, motor evoked potential amplitudes and the slope of the magnetic stimulus-response curve. In two pre-symptomatic SOD-1 mutation carriers SICI was completely absent (SICI patient 1, -3.2%; patients 2, -1.3%), while in one subject there was a 32% reduction in SICI prior to symptom onset. These three individuals subsequently developed clinical features of ALS. Simultaneous investigation of central and peripheral excitability has established that cortical hyperexcitability develops in clinically affected SOD-1 FALS patients, similar to that seen in sporadic ALS patients, thereby suggesting that a similar pathophysiological process in evident in both familial and sporadic ALS patients. In addition, the present study has established that cortical hyperexcitability precedes the development of clinical symptoms in pre-symptomatic carriers of the SOD1 mutation, thereby suggesting that cortical hyperexcitability underlies neurodegeneration in FALS.

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.

Cortical hyperexcitability is an important pathophysiological mechanism in amyotrophic lateral sclerosis (ALS), reflecting a complex interaction of inhibitory and facilitatory interneuronal processes that evolves in the degenerating brain. The advances in physiological techniques have made it possible to interrogate progressive changes in the motor cortex. Specifically, the direction of transcranial magnetic stimulation (TMS) stimulus within the primary motor cortex can be utilized to influence descending corticospinal volleys and to thereby provide information about distinct interneuronal circuits. Cortical motor function and cognition was assessed in 29 ALS patients with results compared to healthy volunteers. Cortical dysfunction was assessed using threshold-tracking TMS to explore alterations in short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), the index of excitation and stimulus response curves using a figure-of-eight coil with the coil oriented relative to the primary motor cortex in a posterior-anterior, lateral-medial and anterior-posterior direction. Mean SICI, between interstimulus interval of 1–7 ms, was significantly reduced in ALS patients compared to healthy controls when assessed with the coil oriented in posterior-anterior (P = 0.044) and lateral-medial (P = 0.005) but not the anterior-posterior (P = 0.08) directions. A significant correlation between mean SICI oriented in a posterior-anterior direction and the total Edinburgh Cognitive and Behavioural ALS Screen score (Rho = 0.389, P = 0.037) was evident. In addition, the mean SICF, between interstimulus interval 1–5 ms, was significantly increased in ALS patients when recorded with TMS coil oriented in posterior-anterior (P = 0.035) and lateral-medial (P < 0.001) directions. In contrast, SICF recorded with TMS coil oriented in the anterior-posterior direction was comparable between ALS and controls (P = 0.482). The index of excitation was significantly increased in ALS patients when recorded with the TMS coil oriented in posterior-anterior (P = 0.041) and lateral-medial (P = 0.003) directions. In ALS patients, a significant increase in the stimulus response curve gradient was evident compared to controls when recorded with TMS coil oriented in posterior-anterior (P < 0.001), lateral-medial (P < 0.001) and anterior-posterior (P = 0.002) directions. The present study has established that dysfunction of distinct interneuronal circuits mediates the development of cortical hyperexcitability in ALS. Specifically, complex interplay between inhibitory circuits and facilitatory interneuronal populations, that are preferentially activated by stimulation in posterior-to-anterior or lateral-to-medial directions, promotes cortical hyperexcitability in ALS. Mechanisms that underlie dysfunction of these specific cortical neuronal circuits will enhance understanding of the pathophysiological processes in ALS, with the potential to uncover focussed therapeutic targets. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease that, at present, has no effective cure. Evidence of increased circulating glutamate and hyperexcitability of the motor cortex in patients with amyotrophic lateral sclerosis have provided an empirical support base for the 'dying forward' excitotoxicity hypothesis. The hypothesis postulates that increased activation of upper motor neurons spreads pathology to lower motor neurons in the spinal cord in the form of excessive glutamate release, which triggers excitotoxic processes. Many clinical trials have focused on therapies that target excitotoxicity via dampening neuronal activation, but not all are effective. As such, there is a growing tension between the rising tide of evidence for the 'dying forward' excitotoxicity hypothesis and the failure of therapies that target neuronal activation. One possible solution to these contradictory outcomes is that our interpretation of the current evidence requires revision in the context of appreciating the complexity of the nervous system and the limitations of the neurobiological assays we use to study it. In this review we provide an evaluation of evidence relevant to the 'dying forward' excitotoxicity hypothesis and by doing so, identify key gaps in our knowledge that need to be addressed. We hope to provide a road map from hyperexcitability to excitotoxicity so that we can better develop therapies for patients suffering from amyotrophic lateral sclerosis. We conclude that studies of upper motor neuron activity and their synaptic output will play a decisive role in the future of amyotrophic lateral sclerosis therapy. [ABSTRACT FROM AUTHOR]

Aim: Involvement of the corpus callosum has been identified as a feature of amyotrophic lateral sclerosis (ALS), particularly through neuropathological studies. The aim of the present study was to determine whether alteration in transcallosal function contributed to the development of ALS, disease progression and thereby functional disability. Methods: Transcallosal function and motor cortex excitability were assessed in 17 ALS patients with results compared to healthy controls. Transcallosal inhibition (interstimulus intervals (ISI) of 8–40 ms), short interval intracortical facilitation (SICF) and inhibition (SICI) were assessed in both cerebral hemispheres. Patients were staged utilising clinical and neurophysiological staging assessments. Results: In ALS, there was prominent reduction of transcallosal inhibition (TI) when recorded from the primary and secondary motor cortices compared to controls (F = 23.255, p < 0.001). This reduction of TI was accompanied by features indicative of cortical hyperexcitability, including reduction of SICI and increase in SICF. There was a significant correlation between the reduction in TI and the rate of disease progression (R = −0.825, p < 0.001) and reduction in muscle strength (R = 0.54, p = 0.031). Conclusion: The present study has established that dysfunction of transcallosal circuits was an important pathophysiological mechanism in ALS, correlating with greater disability and a faster rate of disease progression. Therapies aimed at restoring the function of transcallosal circuits may be considered for therapeutic approaches in ALS. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether primary lateral sclerosis (PLS) represents part of the amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum of diseases.Methods: Comprehensive assessment was taken on 21 patients with PLS and results were compared to patients diagnosed with pure motor ALS (n = 27) and ALS-FTD (n = 12). Clinical features, Addenbrooke’s Cognitive Examination (ACE) scores, Motor Neuron Disease Behaviour (Mind-B) scores, motor disability on the ALS functional rating scale (ALSFRS) and survival times were documented. Motor cortex excitability was evaluated using transcranial magnetic stimulation (TMS).Results: Global cognition was impaired in PLS (mean total ACE score 82.5 ± 13.6), similar to ALS-FTD (mean total ACE score 76.3 ± 7.7, p > 0.05) while behavioural impairments were not prominent. TMS revealed that resting motor threshold (RMT) was significantly higher in PLS (75.5 ± 6.2) compared ALS-FTD (50.1 ± 7.2, p < 0.001) and ALS (62.3 ± 12.6, p = 0.046). Average short-interval intracortical inhibition (SICI) was similar in all three patient groups. The mean survival time was longest in PLS (217.4 ± 22.4 months) and shortest in ALS-FTD (38.5 ± 4.5 months, p = 0.002). Bulbar onset disease (β = − 0.45, p = 0.007) and RMT (β = 0.54, p = 0.001) were independent predictors of global cognition while motor scores (β = 0.47, p = 0.036) and SICI (β = 0.58, p = 0.006) were significantly associated with ALSFRS.Conclusion: The cognitive profile in PLS resembles ALS-FTD, without prominent behavioural disturbances. A higher RMT in PLS than ALS and ALS-FTD is consistent with differential cortical motor neuronal abnormalities and more severe involvement of corticospinal axons while SICI, indicative of inhibitory interneuronal dysfunction was comparable with ALS and ALS-FTD. Overall, while these findings support the notion that PLS lies on the ALS-FTD spectrum, the mechanisms underlying slow disease progression are likely to be distinct in PLS. [ABSTRACT FROM AUTHOR]

Assessment of upper motor neuron (UMN) function in amyotrophic lateral sclerosis (ALS) remains clinically based. Given the potential difficulties in identifying UMN signs, objective biomarkers of UMN dysfunction are important. Consequently, the present study assessed utility of cortical thickness analysis combined with threshold tracking transcranial magnetic stimulation (TMS) as biomakers of UMN dysfunction in ALS. Cortical thickness analysis and threshold tracking TMS studies were undertaken on 25 ALS patients and results were compared to healthy control subjects, with different control groups used for each technique. Structural and functional abnormalities were evident in both motor cortices in the ALS cohort and were heralded by marked reduction of short-interval intracortical inhibition (SICIRAPB1.4 ± 2.4%; SICILAPB3.6 ± 1.9%; SICICONTROLS10.5 ± 1.1%,p <0.01), resting motor threshold (p <0.05) and cortical silent period duration (p <0.001) combined with increase in MEP amplitude (p <0.05) and intracortical facilitation (p <0.05). Significant cortical thinning was evident in the bitemporal regions (p <0.05), while precentral gyrus cortical thinning was evident in 56% of cases and when combined with TMS abnormalities disclosed UMN dysfunction in 88% of cases. In conclusion, findings from the present study establish that a combination of structural and functional assessment of corticomotoneurons may increase the yield of objectively identifying UMN dysfunction in ALS. [ABSTRACT FROM PUBLISHER]

While task-dependent changes in motor cortical outputs have been previously reported, the issue of whether such changes are specific for complex hand tasks remains unresolved. The aim of the present study was to determine whether cortical inhibitory tone and cortical output were greater during precision grip and power grip. Motor cortex excitability was undertaken by using the transcranial magnetic stimulation threshold tracking technique in 15 healthy subjects. The motor-evoked potential ( MEP) responses were recorded over the abductor pollicis brevis ( APB), with the hand in the following positions: (1) rest, (2) precision grip and (3) power grip. The MEP amplitude ( MEP amplitude REST 23.6 ± 3.3%; MEP amplitude PRECISION GRIP 35.2 ± 5.6%; MEP amplitude POWER GRIP 19.6 ± 3.4%, F = 2.4, P < 0.001) and stimulus-response gradient ( SLOPEREST 0.06 ± 0.01; SLOPEPRCISION GRIP 0.15 ± 0.04; SLOPE POWER 15.9 ± 2.7%, F = 2.6, P < 0.05). The present study suggests that changes in motor cortex excitability are specific for precision grip, with functional coupling of descending corticospinal pathways controlling thumb and finger movements potentially forming the basis of these cortical changes. [ABSTRACT FROM AUTHOR]GRIP 0.07 ± 0.01, P < 0.05) were significantly increased during precision grip. Short interval intracortical inhibition ( SICI) was significantly reduced during the precision grip ( SICI REST 15.0 ± 2.3%; SICI PRECISION GRIP 9.7 ± 1.5%, SICI POWER GRIP 15.9 ± 2.7%, F = 2.6, P < 0.05). The present study suggests that changes in motor cortex excitability are specific for precision grip, with functional coupling of descending corticospinal pathways controlling thumb and finger movements potentially forming the basis of these cortical changes. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The diagnosis of amyotrophic lateral sclerosis (ALS) relies on stringent clinical criteria, resulting in diagnostic delay and inevitably the institution of appropriate therapy. Cortical hyperexcitability, as assessed by the novel threshold tracking transcranial magnetic stimulation (TTTMS) technique, appears as an early feature of ALS. Consequently, the present study assessed the diagnostic utility of threshold tracking TMS and developed algorithms to aid the diagnosis of ALS. Methods: Prospective studies were undertaken on a cohort of 156 consecutive patients with neuromuscular symptoms (104 ALS and 52 lower motor neuron syndrome, non-ALS syndrome, NALS) and 62 healthy controls. Results: Short-interval intracortical inhibition (SICI) was significantly reduced in ALS patients (2.4±0.9%) compared to NALS (8.7±0.8%, P <0.0001) and controls (10.6±0.8%, P <0.0001). The MEP amplitude and intracortical facilitation were increased, while the cortical silent period duration was reduced in ALS, all indicative of cortical hyperexcitability. Analysis of receiver operating characteristic curves suggested that threshold tracking TMS distinguished ALS from NALS, with averaged (area under curve 0.76, P <0.0001) and peak SICI 3ms (area under curve 0.73, P <0.0001) being the most robust diagnostic markers. Conclusions: The presence of cortical hyperexcitability distinguishes ALS from mimic disorders. Significance: The threshold tracking TMS techniques may prove useful as a diagnostic investigation for ALS. [Copyright &y& Elsevier]

Introduction Transcranial magnetic stimulation (TMS) is a useful, non-invasive tool that can explore the functional integrity of the primary motor cortex and corticomotor pathways. Although the application of TMS has rapidly increased in the last decade using upper limb muscle targets, there remains a relative paucity of lower limb studies. Additionally, the paired-pulse TMS paradigms that have been applied to explore lower limb cortical parameters have shown significant variability in motor evoked potential (MEP) amplitudes, questioning the reliability and clinical utility of this technique. Threshold tracking TMS (TT-TMS) was recently developed to overcome such methodological problems, but this protocol has been limited to upper limb studies. Importantly, the inherent differences in upper and lower limb normal cortical function and the differing pattern of disease in lower limb predominant neurological disorders highlights the need for a more robust understanding of lower limb corticomotoneuronal function. Thus, the aim of the present study was to employ TT-TMS to establish lower limb cortical parameters and to investigate side-to-side differences to determine laterality of normal cortical function. Methods Studies were performed in 40 healthy participants recording from the tibialis anterior muscle bilaterally. Three common coil choices (90 mm circular coil, 70 mm figure-8 coil, 110 mm double cone coil) were explored. Single-pulse TMS, paired-pulse TT-TMS and nerve conduction studies were performed. Results The double cone coil had the greatest efficacy, generating a significantly lower resting motor threshold than the circular ( p  = 0.04) or figure-8 ( p  = 0.01) coils. Paired-pulse TT-TMS generated an averaged short interval intracortical inhibition of 11.3 ± 1.2%, with an averaged intracortical facilitation of −8.5 ± 1.1%. Central motor conduction time (CMCT) was 8.9 ± 0. 6 ms.There were no differences between dominant and non-dominant sides for all single (RMT, MEP latency, MEP amplitude, MEP/CMAP ratio, CSP and CMCT) and paired-pulse TT-TMS parameters (peak SICI 1 ms, peak SICI 3 ms, averaged SICI and ICF). Similarly, peripheral measures of nerve function were not significantly different between the dominant and non-dominant hemispheres for all measures tested. Conclusion This study successfully assessed cortical excitability and corticospinal pathways from the lower limbs using TT-TMS, establishing normative data, symmetry of normal cortical function, and validating the double cone coil for future studies. These findings can now be applied to explore further aspects of lower limb physiology and used for the clinical interpretation of motor cortical dysfunction across a range of neurological diseases. Together with previously established upper limb TT-TMS, this study will now inevitably allow for a more comprehensive evaluation of normal neuronal processes and patterns of disease across a larger area of cortical representation. [ABSTRACT FROM AUTHOR]