Direct interrogation of cortical interneuron circuits in amyotrophic lateral sclerosis.

Cortical hyperexcitability is a key pathogenic feature of amyotrophic lateral sclerosis (ALS), believed to be mediated through complex interplay of cortical interneurons. To date, there has been no technological approach to facilitate the direct capture of cortical interneuron function. Through combination of transcranial magnetic stimulation (TMS) with advanced EEG, the present study examined GABA-ergic dysfunction in ALS, through recording focussed cortical output whilst applying TMS over the primary motor cortex contralateral to the site of symptom onset. Using both a single pulse and novel inhibitory paired-pulse paradigms, TMS-EEG studies were undertaken on 21 ALS patients and results compared to healthy controls. TMS responses captured by EEG form a discrete waveform known as the transcranial evoked potential (TEP), with positive (P) or upward deflections occurring at 30ms (P30), 60 ms (P60) and 190 ms (P190) after TMS stimulus. Negative (N) or downward deflections occur at 44 ms (N44), 100 ms (N100) and 280ms (N280) after T,MS stimulus. The single pulse TEPs recorded in ALS patients demonstrated novel differences suggestive of cortical GABA-ergic dysfunction. When compared to controls, the N100 component was significantly reduced (P<0.05) while the P190 component increased (P<0.05) in ALS patients. Additionally, the N44 component correlated with muscle weakness (r=-0.501, P<0.05). These finding were supported by reduced paired pulse inhibition of TEP components in ALS patients (P60, P<0.01; N100, P<0.005), consistent with dysfunction of cortical interneuronal GABAA-ergic circuits. Further, the reduction in SICI, as reflected by changes in paired-pulse inhibition of the N100 component, was associated with longer disease duration in ALS patients (r=-0.698, P<0.001). In conclusion, intensive and focussed interrogation of the motor cortex utilising novel TMS-EEG combined technologies has established localised dysfunction of GABA-ergic circuits, supporting the notion that cortical hyperexcitability is mediated by cortical disinhibition in ALS. Dysfunction of GABA-ergic circuits correlated with greater clinical disability and disease duration implying pathophysiological significance.

Cortical inexcitability in ALS: correlating a clinical phenotype.

BACKGROUND: Cortical inexcitability, a less studied feature of upper motor neuron (UMN) dysfunction in amyotrophic lateral sclerosis (ALS), was identified in a large cross-sectional cohort of ALS patients and their demographic and clinical characteristics were contrasted with normal or hyperexcitable ALS cohorts to assess the impact of cortical inexcitability on ALS phenotype and survival. METHODS: Threshold-tracking transcranial magnetic stimulation (TMS) technique with measurement of mean short interval intracortical inhibition (SICI) differentiated ALS patients into three groups (1) inexcitable (no TMS response at maximal stimulator output in the setting of preserved lower motor neuron (LMN) function), (2) hyperexcitable (SICI≤5.5%) and (3) normal cortical excitability (SICI>5.5%). Clinical phenotyping and neurophysiological assessment of LMN function were undertaken, and survival was recorded in the entire cohort. RESULTS: 417 ALS patients were recruited, of whom 26.4% exhibited cortical inexcitability. Cortical inexcitability was associated with a younger age of disease onset (p<0.05), advanced Awaji criteria (p<0.01) and Kings stage (p<0.01) scores. Additionally, patients with cortical inexcitability had higher UMN score (p<0.01), lower revised ALS Functional Rating Scale score (p<0.01) and reduced upper limb strength score (MRC UL, p<0.01). Patient survival (p=0.398) was comparable across the groups, despite lower riluzole use in the cortical inexcitability patient group (p<0.05). CONCLUSION: The present study established that cortical inexcitability was associated with a phenotype characterised by prominent UMN signs, greater motor and functional decline, and a younger age of onset. The present findings inform patient management and could improve patient stratification in clinical trials.

Physiological Biomarkers of Upper Motor Neuron Dysfunction in ALS.

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

Novel approaches to assessing upper motor neuron dysfunction in motor neuron disease/amyotrophic lateral sclerosis: IFCN handbook chapter.

Identifying upper motor neuron (UMN) dysfunction is fundamental to the diagnosis and understanding of disease pathogenesis in motor neuron disease (MND). The clinical assessment of UMN dysfunction may be difficult, particularly in the setting of severe muscle weakness. From a physiological perspective, transcranial magnetic stimulation (TMS) techniques provide objective biomarkers of UMN dysfunction in MND and may also be useful to interrogate cortical and network function. Single, paired- and triple pulse TMS techniques have yielded novel diagnostic and prognostic biomarkers in MND, and have provided important pathogenic insights, particularly pertaining to site of disease onset. Cortical hyperexcitability, as heralded by reduced short interval intracortical inhibition (SICI) and increased short interval intracortical facilitation, has been associated with the onset of lower motor neuron degeneration, along with patterns of disease spread, development of specific clinical features such as the split hand phenomenon, and may provide an indication about the rate of disease progression. Additionally, reduction of SICI has emerged as a potential diagnostic aid in MND. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction in MND. Separately, sophisticated brain imaging techniques have uncovered novel biomarkers of neurodegeneration that have bene associated with progression. The present review will discuss the utility of TMS and brain neuroimaging derived biomarkers of UMN dysfunction in MND, focusing on recently developed TMS techniques and advanced neuroimaging modalities that interrogate structural and functional integrity of the corticomotoneuronal system, with an emphasis on pathogenic, diagnostic, and prognostic utility.

Reduction in short interval intracortical inhibition from the early stage reflects the pathophysiology in amyotrophic lateral sclerosis: A meta-analysis study.

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; I2 = 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.

Distinct neuronal circuits mediate cortical hyperexcitability in amyotrophic lateral sclerosis.

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.

Utility of split hand index with different motor unit number estimation techniques in ALS.

OBJECTIVE: Utility of the split hand index (SI) in amyotrophic lateral sclerosis (ALS) has been reported when using the compound muscle action potential (CMAP) amplitude method (SICMAP amp). A motor unit number index (MUNIX) based SI method (SIMUNIX) was purported to exhibit higher sensitivity. The present study assessed the clinical utility of SI, derived by CMAP amplitude, MUNIX and MScan-MUNE (SIMScanFit-MUNE) methods, in ALS. METHODS: Sixty-two consecutive patients with neuromuscular symptoms (36 ALS and 26 ALS-mimics) were prospectively recruited. The SI was derived by dividing the product of the CMAP amplitude, MUNIX and MScan-MUNE values recorded over first dorsal interosseous and abductor pollicis brevis by values recorded over abductor digit minimi. RESULTS: SICMAP amp, SIMUNIX and SIMScanFit-MUNE were significantly reduced in ALS, with SICMAP amp (area under curve (AUC) = 0.801) and SIMScanFit-MUNE (AUC = 0.805) exhibiting greater diagnostic utility than SIMUNIX (AUC = 0.713). SICMAP amp and SIMScanFit-MUNE exhibited significant correlations with clinical measures of functional disability and weakness of intrinsic hand muscles. CONCLUSIONS: SI differentiated ALS from mimic disorders, with SICMAP amp and SIMScanFit-MUNE exhibiting greater utility. SIGNIFICANCE: The split hand index represents could serve as a potential diagnostic biomarker in ALS.

Dependence of cortical neuronal strength-duration properties on TMS pulse shape.

OBJECTIVE: The aim of present study was to explore the effects of different combinations of transcranial magnetic stimulation (TMS) pulse width and pulse shape on cortical strength-duration time constant (SDTC) and rheobase measurements. METHODS: Resting motor thresholds (RMT) at pulse widths (PW) of 30, 45, 60, 90 and 120 µs and M-ratios of 0.2, 0.1 and 0.025 were determined using figure-of-eight coil with initial posterior-to-anterior induced current. The M-ratio indicates the relative phases of the induced current with lower values signifying a more unidirectional stimulus. Strength-duration time constant (SDTC) and rheobase were estimated for each M-ratio and various PW combinations. Simulations of biophysically realistic cortical neuron models assessed underlying neuronal populations and physiological mechanisms mediating pulse shape effects on strength-duration properties. RESULTS: The M-ratio exerted significant effect on SDTC (F(2,44) = 4.386, P = 0.021), which was longer for M-ratio of 0.2 (243.4 ± 61.2 µs) compared to 0.025 (186.7 ± 52.5 µs, P = 0.034). Rheobase was significantly smaller when assessed with M-ratio 0.2 compared to 0.025 (P = 0.026). SDTC and rheobase values were most consistent with pulse width sets of 30/45/60/90/120 µs, 30/60/90/120 µs, and 30/60/120 µs. Simulation studies indicated that isolated pyramidal neurons in layers 2/3, 5, and large basket-cells in layer 4 exhibited SDTCs comparable to experimental results. Further, simulation studies indicated that reducing transient Na+ channel conductance increased SDTC with larger increases for higher M-ratios. CONCLUSIONS: Cortical strength-duration curve properties vary with pulse shape, and the modulating effect of the hyperpolarising pulse phase on cortical axonal transient Na+ conductances could account for these changes, although a shift in the recruited neuronal populations may contribute as well. SIGNIFICANCE: The dependence of the cortical strength-duration curve properties on the TMS pulse shape and pulse width selection underscores the need for consistent measurement methods across studies and the potential to extract information about pathophysiological processes.

Cortical inhibition and facilitation are mediated by distinct physiological processes.

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.

The split-elbow index: A biomarker of the split elbow sign in ALS.

OBJECTIVE: The split elbow sign is a clinical feature of amyotrophic lateral sclerosis (ALS), characterised by preferential weakness of biceps brachii muscle compared to triceps. A novel neurophysiological index, termed the split elbow index (SEI), was developed to quantify the split-elbow sign, and assess its utility in ALS. METHODS: Clinical and neurophysiological assessment was prospectively undertaken on 34 ALS patients and 32 ALS mimics. Compound muscle action potential (CMAP) amplitude was recorded from biceps brachii and triceps muscles from which the SEI was calculated using the following formula: SEI = CMAPamplitudeBICEPSBRACHII CMAPamplitudeTRICEPSBRACHII . RESULTS: The split elbow sign was significantly more common in ALS patients when compared to ALS mimic patients (P < 0.05). The SEI was significantly reduced in ALS patients when compared to ALS mimics (P < 0.01). This reduction was evident in spinal and bulbar onset ALS. A SEI cut-off value of ≤0.62 exhibited a sensitivity of 71% and specificity of 61%. CONCLUSIONS: The split elbow sign is significantly more common in ALS patients, and was supported by a reduction in the SEI. SIGNIFICANCE: The SEI may be utilised as a surrogate biomarker of the split elbow sign in future ALS studies.

Cortical hyperexcitability and plasticity in Alzheimer's disease: developments in understanding and management.

INTRODUCTION: Transcranial magnetic stimulation (TMS) is a non-invasive neurophysiological tool that provides important insights into Alzheimer's Disease (AD). A significant body of work utilizing TMS techniques has explored the pathophysiological relevance of cortical hyperexcitability and plasticity in AD and their modulation in novel therapies. AREAS COVERED: This review examines the technique of TMS, the use of TMS to examine specific features of cortical excitability and the use of TMS techniques to modulate cortical function. A search was performed utilizing the PubMed database to identify key studies utilizing TMS to examine cortical hyperexcitability and plasticity in Alzheimer's dementia. We then translate this understanding to the study of Alzheimer's disease pathophysiology, examining the underlying neurophysiologic links contributing to these twin signatures, cortical hyperexcitability and abnormal plasticity, in the cortical dysfunction characterizing AD. Finally, we examine utilization of TMS excitability to guide targeted therapies and, through the use of repetitive TMS (rTMS), modulate cortical plasticity. EXPERT OPINION: The examination of cortical hyperexcitability and plasticity with TMS has potential to optimize and expand the window of therapeutic interventions in AD, though remains at relatively early stage of development.

Utility of Transcranial Magnetic Simulation in Studying Upper Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is characterised by progressive dysfunction of the upper and lower motor neurons. The disease can evolve over time from focal limb or bulbar onset to involvement of other regions. There is some clinical heterogeneity in ALS with various phenotypes of the disease described, from primary lateral sclerosis, progressive muscular atrophy and flail arm/leg phenotypes. Whilst the majority of ALS patients are sporadic in nature, recent advances have highlighted genetic forms of the disease. Given the close relationship between ALS and frontotemporal dementia, the importance of cortical dysfunction has gained prominence. Transcranial magnetic stimulation (TMS) is a noninvasive neurophysiological tool to explore the function of the motor cortex and thereby cortical excitability. In this review, we highlight the utility of TMS and explore cortical excitability in ALS diagnosis, pathogenesis and insights gained from genetic and variant forms of the disease.

Split-hand index: A diagnostic and prognostic marker in amyotrophic lateral sclerosis across varying regions of onset.

OBJECTIVE: The split-hand index (SI), a reliable diagnostic marker of amyotrophic lateral sclerosis (ALS), was prospectively assessed for differences across ALS subtypes and between the onset side of clinical symptoms or the dominant and contralateral sides. In addition, the prognostic utility of the SI was longitudinally assessed. METHODS: Two hundred and forty-five ALS patients underwent measurement of SI on both sides compared with 126 neuromuscular mimic disorders (NMD). A subset of patients (N = 45) underwent longitudinal assessment of SI. RESULTS: The SI was significantly reduced (SI RIGHT ALS 5.47(4.2), SINMD 9.0 (5.0); P < 0.001; SILEFT ALS 5.5 (4.1), SI NMD 9.4 (5.0), P < 0.001) on both sides in all ALS patients with prominent reduction on the onset side in upper limb onset ALS (SI RIGHT P < 0.001; SI LEFT P < 0.05) and in Awaji definite/probable diagnostic category (SI RIGHT P < 0.05; SI LEFT P < 0.05). Longitudinal studies disclosed that the rate of SI decline correlated with the decline in ALSFRS-R (r = 0.21, P < 0.05). CONCLUSION: The SI is reduced in all ALS subtypes most prominently in upper limb onset disease, on the side of clinical onset, and in patients with Awaji definite/probable diagnostic category. SIGNIFICANCE: The split-hand index is a reliable diagnostic and outcome biomarker across ALS subtypes and may have potential utility in a clinical trial setting, although further multicenter studies are required to confirm this.

Association of Cortical Hyperexcitability and Cognitive Impairment in Patients With Amyotrophic Lateral Sclerosis.

OBJECTIVE: To determine whether cortical hyperexcitability was more prominent in cognitively impaired patients with amyotrophic lateral sclerosis (ALS). METHODS: Threshold tracking transcranial magnetic stimulation (TMS) was used to assess cortical excitability and cognitive function was determined by the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Cognitive impairment was defined by ECAS < 105. Patients with ALS, defined by the Awaji criteria, were prospectively recruited. Patients unable to undergo TMS, or in whom TMS indices were compromised by coexistent medical conditions, were excluded. Cortical hyperexcitability was defined by reduced short interval intracortical inhibition (SICI) and increased short interval intracortical facilitation (SICF), index of excitability (IE), and motor evoked potential (MEP) amplitude. Student t test determined differences between groups and multivariable regression modeling was used to assess association among cognitive, clinical, and TMS measures. TMS results were compared with those of 42 controls. RESULTS: Cognitive impairment was evident in 36% of the 40 patients with ALS (23 male, mean age 62.1 years). Cortical hyperexcitability was more prominent in cognitively impaired patients as indicated by an increase in SICF (ECAS≥105 -15.3 ± 1.7%, ECAS<105 -20.6 ± 1.2%; p < 0.01), IE (ECAS ≥105 80.9 ± 7.8, ECAS <105 95.0 ± 4.5; p < 0.01), and MEP amplitude (ECAS≥105 28.7 ± 3.3%, ECAS<105 43.1 ± 5.9%; p < 0.05). SICF was independently associated with the ECAS score (ß = 2.410; p < 0.05). Reduced SICI was evident in ALS, being more prominent in patients with reduced executive score (ECASexecutive score>33 6.2 ± 1.3%, ECASexecutive score<33 1.5 ± 2.1%; p < 0.01). CONCLUSION: Cortical hyperexcitability was more prominent in cognitively impaired patients with ALS than in controls. Given that ECAS is a valid predictor of TDP-43 pathology, the increase in cortical hyperexcitability may be associated with TDP-43 accumulation.

Diagnostic Utility of Gold Coast Criteria in Amyotrophic Lateral Sclerosis.

OBJECTIVE: The diagnosis of amyotrophic lateral sclerosis (ALS) remains problematic, with current diagnostic criteria (revised El Escorial [rEEC] and Awaji) being complex and prone to error. Consequently, the diagnostic utility of the recently proposed Gold Coast criteria was determined in ALS. METHODS: We retrospectively reviewed 506 patients (302 males, 204 females) to compare the diagnostic accuracy of the Gold Coast criteria to that of the Awaji and rEEC criteria (defined by the proportion of patients categorized as definite, probable, or possible ALS) in accordance with standards of reporting of diagnostic accuracy criteria. RESULTS: The sensitivity of Gold Coast criteria (92%, 95% confidence interval [CI] = 88.7-94.6%) was comparable to that of Awaji (90.3%, 95% CI = 86.69-93.2%) and rEEC (88.6, 95% CI = 84.8-91.7%) criteria. Additionally, the Gold Coast criteria sensitivity was maintained across different subgroups, defined by site of onset, disease duration, and functional disability. In atypical ALS phenotypes, the Gold Coast criteria exhibited greater sensitivity and specificity. INTERPRETATION: The present study established the diagnostic utility of the Gold Coast criteria in ALS, with benefits evident in bulbar and limb onset disease patients, as well as atypical phenotypes. The Gold Coast criteria should be considered in clinical practice and therapeutic trials. ANN NEUROL 2021;89:979-986.

Pathophysiological associations of transcallosal dysfunction in ALS.

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.

TDP-43 proteinopathies: a new wave of neurodegenerative diseases.

Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (~45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the TDP-43 gene coding (TARDBP) and unrelated genes (eg, C9orf72). While TDP-43 is an essential RNA/DNA binding protein critical for RNA-related metabolism, determining the pathophysiological mechanisms through which TDP-43 mediates neurodegeneration appears complex, and unravelling these molecular processes seems critical for the development of effective therapies. This review highlights the key physiological functions of the TDP-43 protein, while considering an expanding spectrum of neurodegenerative diseases associated with pathogenic TDP-43 deposition, and dissecting key molecular pathways through which TDP-43 may mediate neurodegeneration.

Cortical hyperexcitability evolves with disease progression in ALS.

OBJECTIVE: Cortical hyperexcitability has been established as an early feature of amyotrophic lateral sclerosis (ALS). The evolution of cortical hyperexcitability with ALS progression remains to be fully elucidated. This study aims to investigate changes in cortical function in ALS with disease progression. METHODS: Cortical function assessed by threshold tracking transcranial magnetic stimulation (TMS) along with clinical phenotyping was prospectively undertaken on 444 patients presenting with suspected ALS (345 ALS; 99 neuromuscular mimics). Disease stage was defined as follows: (1) King's clinical staging system and (2) proportion of disease duration statistically categorized into tertials. RESULTS: Cortical hyperexcitability was evident across all ALS stages, being more prominent in later stages of ALS as indicated by increased motor-evoked potential amplitude (P < 0.05), as well as longer disease duration as reflected by reduced short-interval intracortical inhibition (P < 0.05). Prolonged central motor conduction time was evident with disease progression. These changes were accompanied by reduction in neurophysiological index (P < 0.001) and compound muscle action potential amplitude (P < 0.01), progressive muscle weakness (P < 0.001), and decline in the ALS functional rating scale (P < 0.001). INTERPRETATION: This study established an increase in cortical hyperexcitability with increased disease duration in ALS, mediated by cortical disinhibition and direct increase in corticomotoneuronal excitability.

Interneuronal networks mediate cortical inhibition and facilitation.

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.

Reproducibility of motor unit number index and MScanFit motor unit number estimation across intrinsic hand muscles.

INTRODUCTION: We sought to evaluate the reproducibility of the motor unit number index (MUNIX) and MScanFit motor unit number estimation (MScan) when recording was performed over intrinsic hand muscles. METHODS: The compound muscle action potential (CMAP) amplitude, MUNIX, and MScan were measured from the abductor pollicis brevis (APB), first dorsal interosseous (FDI), and abductor digit minimi (ADM) muscles from 15 healthy volunteers on three different occasions. RESULTS: The reproducibility of CMAP amplitudes was excellent, with intraclass correlation coefficients (ICC) of 0.86 (APB), 0.90 (FDI), and 0.96 (ADM). Motor unit number index (ICCAPB 0.73, ICCFDI 0.85, ICCADM 0.85) and MScan (ICCAPB 0.86, ICCFDI 0.83, ICCADM 0.81) were highly reproducible across the three muscles. There were no significant correlations between MUNIX and MScan coefficients of variation (CV) and CMAP amplitude CVs. DISCUSSION: Reproducibility of MUNIX and MScan was not significantly different across the intrinsic hand muscles and was independent of CMAP amplitude variability.