ORCID Profile
0000-0003-0381-917X
Current Organisations
University of Sydney
,
Concord Repatriation General Hospital Neurosciences Department
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Publications
Amyotrophic lateral sclerosis diagnostic index: Toward a personalized diagnosis of ALS.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-01-2019
DOI: 10.1212/WNL.0000000000006876
Abstract: The aim of the study was to assess the utility of a novel amyotrophic lateral sclerosis (ALS) diagnostic index (ALSDI). A prospective multicenter study was undertaken on patients presenting with suspected ALS. The reference standard (Awaji criteria) was applied to all patients at recruitment. Patients were randomly assigned to a training (75%) and a test (25%) cohort. The ALSDI was developed in the training cohort and its diagnostic utility was subsequently assessed in the test cohort. A total of 407 patients were recruited, with 305 patients subsequently diagnosed with ALS and 102 with a non-ALS mimicking disorder. The ALSDI reliably differentiated ALS from neuromuscular disorders in the training cohort (area under the curve 0.92, 95% confidence interval 0.89–0.95), with ALSDI ≥4 exhibiting 81.6% sensitivity, 89.6% specificity, and 83.5% diagnostic accuracy. The ALSDI diagnostic utility was confirmed in the test cohort (area under the curve 0.90, 95% confidence interval 0.84–0.97), with ALSDI ≥4 exhibiting 83.3% sensitivity, 84% specificity, and 83.5% diagnostic accuracy. In addition, the diagnostic utility of the ALSDI was confirmed in patients who were Awaji negative at recruitment and in those exhibiting a predominantly lower motor neuron phenotype. The ALSDI reliably differentiates ALS from mimicking disorders at an early stage in the disease process. This study provides Class I evidence that for patients with suspected ALS, the ALSDI distinguished ALS from neuromuscular mimicking disorders.
Riluzole exerts transient modulating effects on cortical and axonal hyperexcitability in ALS
Publisher: Informa UK Limited
Date: 06-2016
DOI: 10.1080/21678421.2016.1188961
Abstract: 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
TDP-43 proteinopathies: a new wave of neurodegenerative diseases
Publisher: BMJ
Date: 11-11-2020
Abstract: 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.
Imbalance of cortical facilitatory and inhibitory circuits underlies hyperexcitability in ALS
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-10-2018
DOI: 10.1212/WNL.0000000000006438
Abstract: To determine the relative contribution of inhibitory and facilitatory circuits in the development of cortical hyperexcitability in amyotrophic lateral sclerosis (ALS). 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. 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). 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.
Brain functional connectome abnormalities in amyotrophic lateral sclerosis are associated with disability and cortical hyperexcitability
Publisher: Wiley
Date: 07-10-2017
DOI: 10.1111/ENE.13461
Abstract: The present study utilized a multimodal approach encompassing connectome networks combined with brain volume analysis, and assessment of cortical excitability to provide novel insights into amyotrophic lateral sclerosis (ALS) pathogenesis. Magnetic resonance images were acquired using a 3.0-Tesla Signa HDx scanner (GE Healthcare, Milwaukee, WI, USA), using an eight-channel head coil. Magnetic resonance images for the resting-state scan were acquired using an echo-planar imaging magnetic resonance sequence, acquiring 40 contiguous axial/oblique slices. Structural magnetic resonance imaging three-dimensional T1-weighted images were acquired in the sagittal plane using three-dimensional spoiled gradient echo sequences. For structural imaging, a T1-weighted high-resolution (3.0-Tesla) magnetic resonance imaging scan was used. Cortical excitability was assessed by using the threshold-tracking transcranial magnetic stimulation paradigm. Network-based statistics and whole-brain functional topology (using graph theoretical approaches) assessed functional connectivity. Using a global network-based statistical analysis approach, functional connectivity was increased in 12 network edges connecting 14 nodes (P < 0.05) within the frontal, temporal, parietal and subcortical regions. Analysis of local connectedness disclosed dichotomous effects with reduced connectivity in frontal regions and increased connectivity in occipital regions in ALS. Cortical hyperexcitability was evident in patients with ALS, negatively correlated with functional connectivity changes in the pre-central gyrus (P < 0.01). Connectivity changes in the frontal regions were negatively associated with functional disability (P < 0.05). Multimodal assessment of cortical function in patients with ALS identified deficits in functional connectivity associated with cortical hyperexcitability that correlated with patient disability. Novel integration of functional brain assessment further contributes to the understanding of disease pathogenesis in ALS.
Split-hand index: A diagnostic and prognostic marker in amyotrophic lateral sclerosis across varying regions of onset
Publisher: Elsevier BV
Date: 09-2021
Cortical hyperexcitability and disease spread in amyotrophic lateral sclerosis
Publisher: Wiley
Date: 24-04-2017
DOI: 10.1111/ENE.13295
Abstract: Amyotrophic lateral sclerosis (ALS) is characterized by focal disease onset with a predominantly contiguous pattern of disease spread. The pathophysiological mechanisms underlying disease progression in ALS have not been elucidated. Given that cortical hyperexcitability has been identified as an important pathogenic mechanism in ALS, the aim of the present study was to determine whether changes in cortical function could mediate disease spread in ALS. Threshold-tracking transcranial magnetic stimulation was undertaken in 50 patients with sporadic ALS with recording of responses over both abductor pollicis brevis muscles, with results matched to clinical assessments and concurrent neurophysiological investigation of lower motor neuron function. Subsequently, patients were followed longitudinally to map patterns of clinical disease progression. Cortical dysfunction was evident over both motor cortices, with hyperexcitability more prominent over the dominant motor cortex, contralateral to the site of disease onset, with reduction of resting motor threshold (F = 3.83, P < 0.05), short-interval intracortical inhibition (F = 15.0, P < 0.0001) and cortical silent-period duration (F = 8.01, P < 0.01), along with an increase in motor evoked potential litude (F = 5.66, P < 0.01). In addition, patterns of cortical change were consistent with a contiguous pattern of disease progression. Cortical hyperexcitability appears to be more prominent over the dominant motor cortex, contralateral to the side of symptom onset, and contributes to a contiguous pattern of spread in sporadic ALS.
Reproducibility of motor unit number index and MScanFit motor unit number estimation across intrinsic hand muscles
Publisher: Wiley
Date: 28-02-2020
DOI: 10.1002/MUS.26839
19. Cortical hyperexcitability in ALS: A heterogeneous process
Publisher: Elsevier BV
Date: 03-2016
Pathophysiological associations of transcallosal dysfunction in ALS
Publisher: Wiley
Date: 05-12-2020
DOI: 10.1111/ENE.14653
Abstract: 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. 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. 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). 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.
Theta Burst Stimulation in the Rehabilitation of the Upper Limb
Publisher: SAGE Publications
Date: 12-03-2012
Abstract: Background. Noninvasive cortical stimulation could represent an add-on treatment to enhance motor recovery after stroke. However, its clinical value, including anticipated size and duration of the treatment effects, remains largely unknown. Objective. The authors designed a small semi-randomized clinical trial to explore whether long-lasting clinically important gains can be achieved by adding theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation (TMS), to a rehabilitation program for the hand. Methods. A total of 41 chronic stroke patients received excitatory TBS to the ipsilesional hemisphere or inhibitory TBS to the contralesional hemisphere in 2 centers each active group was compared with a group receiving sham TBS. TBS was followed by physical therapy for 10 working days. Patients and therapists were blinded to the type of TBS. Primary outcome measures (9-hole Peg Test [9HPT], Jebsen Taylor Test [JTT], and grip and pinch-grip dynamometry) were assessed 4, 30, and 90 days post treatment. The clinically important difference was defined as 10% of the maximum score. Results. There were no differences between the active treatment and sham groups in any of the outcome measures. All patients achieved small sustainable improvements—9HPT, 5% of maximum (confidence interval [CI] = 3%-7%) JTT, 5.7% (CI = 3%-8%) and grip strength, 6% (CI = 2%-10%)—all below the defined clinically important level. Conclusions. Cortical stimulation did not augment the gains from a late rehabilitation program. The effect size anticipated by the authors was overestimated. These results can improve the design of future work on therapeutic uses of TMS.
Cortical hyperexcitability evolves with disease progression in ALS
Publisher: Wiley
Date: 18-04-2020
DOI: 10.1002/ACN3.51039
Interneuronal networks mediate cortical inhibition and facilitation
Publisher: Elsevier BV
Date: 05-2020
Reproducibility of motor unit number index and multiple point stimulation motor unit number estimation in controls
Publisher: Wiley
Date: 15-10-2018
DOI: 10.1002/MUS.26339
Abstract: Reproducibility of the multiple point stimulation motor unit number estimation (MPS-MUNE) technique was compared with the recently developed motor unit number index (MUNIX) technique. MPS-MUNE and MUNIX were performed on 15 healthy subjects at 3 different time-points by the same examiner. Reproducibility was analyzed using intraclass correlation coefficient (ICC) and coefficient of variation (CV). ICC values for MUNIX and MPS-MUNE were excellent across 3 tests (0.80 and 0.77, respectively), although CV values were significantly lower for MUNIX than MPS-MUNE (P < 0.01). In addition, test-retest reproducibility was better for MUNIX, a finding largely attributable to poor reproducibility of the single motor unit action potential area. MUNIX (R = -0.48, P < 0.05) and MPS-MUNE (R = -0.53, P < 0.05) were significantly correlated with age. MUNIX demonstrated better intrarater reproducibility and may be a more reliable neurophysiological biomarker than MPS-MUNE. Muscle Nerve 58: 660-664, 2018.
Physiological Processes Underlying Short Interval Intracortical Facilitation in the Human Motor Cortex
Publisher: Frontiers Media SA
Date: 11-04-2018
Physiological processes influencing motor-evoked potential duration with voluntary contraction
Publisher: American Physiological Society
Date: 03-2017
Abstract: Voluntary contraction leads to facilitation of motor-evoked potentials (MEPs) producing greater litude, 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 litude 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 litude. 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 litude. 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 litude 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 litude. Whereas the increase in MEP duration was linear, the litude 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 litude, cortical mechanisms appear to contribute to MEP duration changes.
Utility of Transcranial Magnetic Simulation in Studying Upper Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis
Publisher: MDPI AG
Date: 09-07-2021
Abstract: 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.
Writer's cramp in an Australian pedigree with DYT1 dystonia.
Publisher: Elsevier BV
Date: 06-2004
Association of Cortical Hyperexcitability and Cognitive Impairment in Patients With Amyotrophic Lateral Sclerosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-04-2021
DOI: 10.1212/WNL.0000000000011798
Abstract: To determine whether cortical hyperexcitability was more prominent in cognitively impaired patients with amyotrophic lateral sclerosis (ALS). 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) litude. 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. 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 –20.6 ± 1.2% p 0.01), IE (ECAS ≥105 80.9 ± 7.8, ECAS 95.0 ± 4.5 p 0.01), and MEP litude (ECAS ≥105 28.7 ± 3.3%, ECAS 43.1 ± 5.9% p 0.05). SICF was independently associated with the ECAS score ( β = 2.410 p 0.05). Reduced SICI was evident in ALS, being more prominent in patients with reduced executive score (ECAS executive score 6.2 ± 1.3%, ECAS executive score 1.5 ± 2.1% p 0.01). 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
Publisher: Wiley
Date: 24-02-2021
DOI: 10.1002/ANA.26045
Abstract: 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. 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. 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. 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 :979–986
Motor neuron disease with malignancy: Clinical and pathophysiological insights
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.CLINPH.2019.05.026
Abstract: While some regard an association between motor neuron disease (MND) and malignancy as co-incidental, others have argued that it could represent a distinct clinical entity. The present study undertook in depth phenotyping along with assessment of cortical function to further explore disease pathophysiology in MND with malignancy (MND-M) patients. Clinical features along with assessment of peripheral and cortical function was undertaken in 13 MND-M and results were compared to sporadic and familial MND cohorts. From a cohort 13 patients (10 males aged 65.2 ± 2.0 years), 38.5% were diagnosed with a haematological malignancy. The lower motor neuron phenotype predominated in the in the MND-M patients (χ The present study suggests that MND-M falls within the spectrum of MND. The concept of a co-incidental association between MND and malignancy is supported through the present study by the presence of cortical dysfunction, combined with clinical findings that can be explained within the spectrum of abnormality evident in classical MND phenotypes.
Pathophysiology and Diagnosis of ALS: Insights from Advances in Neurophysiological Techniques
Publisher: MDPI AG
Date: 10-06-2019
DOI: 10.3390/IJMS20112818
Abstract: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder of the motor neurons, characterized by focal onset of muscle weakness and incessant disease progression. While the presence of concomitant upper and lower motor neuron signs has been recognized as a pathognomonic feature of ALS, the pathogenic importance of upper motor neuron dysfunction has only been recently described. Specifically, transcranial magnetic stimulation (TMS) techniques have established cortical hyperexcitability as an important pathogenic mechanism in ALS, correlating with neurodegeneration and disease spread. Separately, ALS exhibits a heterogeneous clinical phenotype that may lead to misdiagnosis, particularly in the early stages of the disease process. Cortical hyperexcitability was shown to be a robust diagnostic biomarker if ALS, reliably differentiating ALS from neuromuscular mimicking disorders. The present review will provide an overview of key advances in the understanding of ALS pathophysiology and diagnosis, focusing on the importance of cortical hyperexcitability and its relationship to advances in genetic and molecular processes implicated in ALS pathogenesis.
Motor ‘surround inhibition’ is not correlated with activity in surround muscles
Publisher: Wiley
Date: 10-05-2014
DOI: 10.1111/EJN.12613
Abstract: Surround inhibition (SI) is a neural process that has been extensively investigated in the sensory system and has been recently probed in the motor system. Muscle-specific modulation of corticospinal excitability at the onset of an isolated finger movement has been assumed to reflect the presence of SI in the motor system. This study attempted to characterise this phenomenon in a large cohort of normal volunteers and investigate its relationship with muscle activity in the hand. Corticospinal excitability of the pathways projecting to three hand muscles [first dorsal interosseus (FDI), abductor pollicis brevis (APB) and abductor digiti minimi (ADM)] and electromyographic (EMG) activity of the same muscles were assessed in 31 healthy volunteers during an isolated index finger movement. In the agonist FDI muscle both corticospinal excitability and EMG activity were found to be increased at the onset of the movement (P < 0.001 and P < 0.001, respectively). On the contrary, in the surround ADM, there was dissociation between the corticospinal excitability (decreased: P < 0.001) and EMG activity (increased: P < 0.001). Cross-correlation analysis of the EMG activity showed that neuronal signals driving the agonist and surround muscles are not synchronised when SI is present. The results suggest a distinctive origin of the neuronal signals driving the agonist and surround muscles. In addition, they indicate that cortical output might be simultaneously modulated by voluntary and non-voluntary activity, generated in cortical and subcortical structures, respectively.
Utility of threshold tracking transcranial magnetic stimulation in ALS
Publisher: Elsevier BV
Date: 2018
Related Organisations
University College London
Location: United Kingdom of Great Britain and Northern Ireland
Concord Repatriation General Hospital Neurosciences Department
Location: Australia
Related Funding Activities
No related grants have been discovered for Mehdi van den Bos.