Therapeutic non-invasive brain stimulation in amyotrophic lateral sclerosis: rationale, methods and experience.

The neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) is characterised by increased cortical excitability, thought to reflect pathological changes in the balance of local excitatory and inhibitory neuronal influences. Non-invasive brain stimulation (NIBS) has been shown to modulate cortical activity, with some protocols showing effects that outlast the stimulation by months. NIBS has been suggested as a potential therapeutic approach for disorders associated with changes in cortical neurophysiology, including ALS. This article reviews NIBS methodology, rationale for its application to ALS and progress to date.

Repeated unilateral handgrip contractions alter functional connectivity and improve contralateral limb response times.

In humans, motor learning is underpinned by changes in sensorimotor network functional connectivity (FC). Unilateral contractions increase FC in the ipsilateral primary motor cortex (M1) and supplementary motor area (SMA); areas involved in motor planning and execution of the contralateral hand. Therefore, unilateral contractions are a promising approach to augment motor performance in the contralateral hand. In a within-participant, randomized, cross-over design, 15 right-handed adults had two magnetic resonance imaging (MRI) sessions, where functional-MRI and MR-Spectroscopic Imaging were acquired before and after repeated right-hand contractions at either 5% or 50% maximum voluntary contraction (MVC). Before and after scanning, response times (RTs) were determined in both hands. Nine minutes of 50% MVC contractions resulted in decreased handgrip force in the contracting hand, and decreased RTs and increased handgrip force in the contralateral hand. This improved motor performance in the contralateral hand was supported by significant neural changes: increased FC between SMA-SMA and increased FC between right M1 and right Orbitofrontal Cortex. At a neurochemical level, the degree of GABA decline in left M1, left and right SMA correlated with subsequent behavioural improvements in the left-hand. These results support the use of repeated handgrip contractions as a potential modality for improving motor performance in the contralateral hand.

Limited value of serum neurofilament light chain in diagnosing amyotrophic lateral sclerosis.

A biomarker specific for the diagnosis of amyotrophic lateral sclerosis must be sensitive across a spectrum of clinical heterogeneity. Neurofilament light chain levels in amyotrophic lateral sclerosis correlate with the rate of disability progression. Previous attempts to establish a diagnostic role for neurofilament light chain have been limited to comparison with healthy individuals or controls with alternative diagnoses unlikely to be confused with amyotrophic lateral sclerosis in real-world clinical practice. In a tertiary amyotrophic lateral sclerosis referral clinic, at first visit, serum was taken for neurofilament light chain measurement after prospectively recording the clinical diagnosis as 'amyotrophic lateral sclerosis', 'primary lateral sclerosis', 'alternative' or 'currently uncertain'. Of 133 referrals, 93 patients were diagnosed with amyotrophic lateral sclerosis (median neurofilament light chain 218.1 pg/ml, interquartile range 130.7-311.9), three primary lateral sclerosis (65.6, 51.5-106.9) and 19 alternative diagnoses (45.2, 13.5-71.9) at first visit. Of 18 initially uncertain diagnoses, eight were subsequently diagnosed with amyotrophic lateral sclerosis (98.5, 45.3-300.1). Neurofilament light chain ≥110.9 pg/ml had a positive predictive value of 0.92 for amyotrophic lateral sclerosis; <110.9 pg/ml had a negative predictive value of 0.48. In a specialized clinic, neurofilament light chain is largely confirmatory to clinical judgement in diagnosing amyotrophic lateral sclerosis and has limited ability to exclude alternative diagnoses. The current, important, value of neurofilament light chain is its potential to stratify patients with amyotrophic lateral sclerosis by disease activity and as a biomarker in therapeutic trials.

Multicentre appraisal of amyotrophic lateral sclerosis biofluid biomarkers shows primacy of blood neurofilament light chain.

The routine clinical integration of individualized objective markers of disease activity in those diagnosed with the neurodegenerative disorder amyotrophic lateral sclerosis is a key requirement for therapeutic development. A large, multicentre, clinic-based, longitudinal cohort was used to systematically appraise the leading candidate biofluid biomarkers in the stratification and potential therapeutic assessment of those with amyotrophic lateral sclerosis. Incident patients diagnosed with amyotrophic lateral sclerosis (n = 258), other neurological diseases (n = 80) and healthy control participants (n = 101), were recruited and followed at intervals of 3-6 months for up to 30 months. Cerebrospinal fluid neurofilament light chain and chitotriosidase 1 and blood neurofilament light chain, creatine kinase, ferritin, complement C3 and C4 and C-reactive protein were measured. Blood neurofilament light chain, creatine kinase, serum ferritin, C3 and cerebrospinal fluid neurofilament light chain and chitotriosidase 1 were all significantly elevated in amyotrophic lateral sclerosis patients. First-visit plasma neurofilament light chain level was additionally strongly associated with survival (hazard ratio for one standard deviation increase in log10 plasma neurofilament light chain 2.99, 95% confidence interval 1.65-5.41, P = 0.016) and rate of disability progression, independent of other prognostic factors. A small increase in level was noted within the first 12 months after reported symptom onset (slope 0.031 log10 units per month, 95% confidence interval 0.012-0.049, P = 0.006). Modelling the inclusion of plasma neurofilament light chain as a therapeutic trial outcome measure demonstrated that a significant reduction in sample size and earlier detection of disease-slowing is possible, compared with using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale. This study provides strong evidence that blood neurofilament light chain levels outperform conventional measures of disease activity at the group level. The application of blood neurofilament light chain has the potential to radically reduce the duration and cost of therapeutic trials. It might also offer a first step towards the goal of more personalized objective disease activity monitoring for those living with amyotrophic lateral sclerosis.

A nudge towards better lumbar puncture practice.

BACKGROUND: Despite a body of evidence demonstrating reduced incidence of post-lumbar puncture headache associated with pencil-point (vs bevelled-edge) needles, their use remains variable in the UK. METHODS: A multimodal longitudinal intervention was performed over a 12-month period at a tertiary neurology referral centre. In addition to simulation training using pencil-point needles and an electronic documentation pro forma, a change in the default needles presented in clinical environments was performed. RESULTS: Prior to the intervention, pencil-point needle usage was minimal. Documentation significantly improved throughout the intervention period. Simulation training interventions only resulted in transient, moderate improvements in pencil-point needle usage. However, changing the default produced a marked increase in use that was sustained. No significant changes in operator success rate were found. CONCLUSIONS: In the context of wider literature on the power of default options in driving behavioural choices, changing defaults may be an effective, inexpensive and acceptable intervention to improve lumbar puncture practice.