8 research outputs found
Functional Biomarkers for Amyotrophic Lateral Sclerosis
The clinical diagnosis of amyotrophic lateral sclerosis (ALS) relies on determination of progressive dysfunction of both cortical as well as spinal and bulbar motor neurons. However, the variable mix of upper and lower motor neuron signs result in the clinical heterogeneity of patients with ALS, resulting frequently in delay of diagnosis as well as difficulty in monitoring disease progression and treatment outcomes particularly in a clinical trial setting. As such, the present review provides an overview of recently developed novel non-invasive electrophysiological techniques that may serve as biomarkers to assess UMN and LMN dysfunction in ALS patients
Quantifying the neural pathways of amyotrophic lateral sclerosis: a structural and functional approach
The development of amyotrophic lateral sclerosis (ALS) represents a singularly human, progressive neurodegenerative process that mainly affects upper (corticomotor) and lower (spinal cord) motor neurones. The considerable heterogeneity within this motor syndrome has rendered disease mechanisms unclear, and the initial site of disease onset and patterns of spread still remain unanswered. As such, this requires contemporary re-investigation using sensitive measures of disease burden. The aim of the work presented in this thesis was to utilise functional and structural techniques to explore the motor cortex in sporadic ALS patients, and to characterise patterns of central change across each ALS motor phenotypes, linking these findings to clinical and prognostic outcomes. New approaches were developed using threshold tracking transcranial magnetic stimulation (TT-TMS) techniques to probe cortical dysfunction. Both the hand and leg motor regions were analysed, in a novel ‘all-four-limbs’ protocol. A global presence of cortical hyperexcitability was demonstrated across the ALS cohort, which was apparent from both motor regions across each hemisphere. Paralleling these findings, widespread changes of microstructural integrity were also demonstrated using diffusion tensor imaging (DTI), which extended along the length of the CST bilaterally. In addition to the global cortical changes across the ALS brain, focality of cortical dysfunction was also seen in very early disease stages, supporting a discrete point of onset from which progressive motor degeneration may evolve, and rationalising the clinical asymmetrical disease onset site. ‘Inexcitability’ to TMS was also defined for the first time, which revealed a unique clinical profile and reduced survival when present early in disease. These central disease patterns remained relevant across the ALS motor phenotypes, suggesting that these subgroups all exist within one disease continuum, but were significantly worse in the bulbar-onset phenotype. Taken together, the patterns of corticomotoneuronal dysfunction provide cogent neurophysiological grounding for the early presence of cortical dysfunction in the ALS brain, and suggest that differences in cortical disease patterns may be linked to clinical and prognostic outcomes
S151. Assessing lower limb cortical function with threshold tracking transcranial magnetic stimulation
Utility of threshold tracking transcranial magnetic stimulation in ALS
Upper motor neuron [UMN] and lower motor neuron [LMN] dysfunction, in the absence of sensory features, is a pathognomonic feature of amyotrophic lateral sclerosis [ALS]. Although the precise mechanisms have yet to be elucidated, one leading hypothesis is that UMN precede LMN dysfunction, which is induced by anterograde glutamatergic excitotoxicity. Transcranial magnetic stimulation (TMS) is a neurophysiological tool that provides a non-invasive and painless assessment of cortical function. Threshold tracking methodologies have been recently adopted for TMS, whereby changes in threshold rather than motor evoked potential (MEP) amplitude serve as outcome measures. This technique is reliable and provides a rapid assessment of cortical function in ALS. Utilisng the threshold tracking TMS technique, cortical hyperexcitability was demonstrated as an early feature in sporadic ALS preceding the onset of LMN dysfunction and possibly contributing to disease spread. Separately, cortical hyperexcitability was reported to precede the clinical onset of familial ALS. Of further relevance, the threshold tracking TMS technique was proven to reliably distinguish ALS from mimicking disorders, even in the presence of a comparable degree of LMN dysfunction, suggesting a diagnostic utility of TMS. Taken in total, threshold tracking TMS has provided support for a cortical involvement at the earliest detectable stages of ALS, underscoring the utility of the technique for probing the underlying pathophysiology. The present review will discuss the physiological processes underlying TMS parameters, while further evaluating the pathophysiological and diagnostic utility of threshold tracking TMS in ALS. Keywords: Amyotrophic lateral sclerosis, Cortical hyperexcitability, Threshold tracking TM
F147. Absolute and relative reliability of short-interval intracortical inhibition measured by threshold tracking transcranial magnetic stimulation
Inter-session reliability of short-interval intracortical inhibition measured by threshold tracking TMS
Paired-pulse transcranial magnetic stimulation (TMS) using fixed test stimuli suffers from marked variability of the motor evoked potential (MEP) amplitude. Threshold tracking TMS (TT-TMS) was introduced to overcome this problem. The aim of this work was to describe the absolute and relative reliability of short-interval intracortical inhibition (SICI) using TT-TMS. Cortical excitability studies were performed on twenty-six healthy subjects over three sessions (two recordings on the same day and one seven days apart), with MEPs recorded over abductor pollicis brevis. Reliability was established by calculating the standard error of the measurements (SEm), minimal detectable change (MDC) and intraclass correlation coefficient (ICC). Resting motor threshold and averaged SICI presented the lowest SEm and highest ICCs. SICI at 1 ms showed a higher SEm than SICI at 3 ms, suggesting different physiological processes, but averaging SICI over a number of intervals greatly increases the reproducibility. The variability was lower for tests undertaken at the same time of day seven days apart compared to tests performed on the same day, and in both instances the ICC for averaged SICI was >= 0.81. The MDC in averaged SICI was reduced from 6.7% to 2% if the number of subjects was increased from one to eleven. In conclusion, averaged SICI is the most reproducible variable across paired-pulse TT-TMS measures, showing an excellent ICC. It is recommended that, in longitudinal studies, testing be performed at the same time of day and that changes in cortical excitability should be measured and averaged over a number of interstimulus intervals to minimise variability.National Health and Medical Research Council of Australia Program Grant
1037746
International Federation of Clinical Neurophysiology (IFCN) Research Scholarship
Becas-Chile Scholarship (CONICYT)
Clinica Alemana de Santiago
University of Sydney Australian Postgraduate Award
Bill Gole Fellowship from the Motor Neurone Disease Research Institute of Australi