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Diabetes may impair the capacity for neuroplasticity such that patients experience a slower and poorer recovery after stroke. The current study investigated changes in cortical function in stroke patients with diabetes to determine how this comorbidity may affect poststroke cortical plasticity and thereby functional recovery. From a cohort of 57 participants, threshold-tracking transcranial magnetic stimulation was used to assess cortical function over the ipsilateral and contralesional hemispheres in 7 patients with diabetes after an acute stroke compared with 12 stroke patients without diabetes. Cortical function was also assessed in 8 patients with diabetes without stroke and 30 normal control subjects. After acute stroke, short-interval intracortical inhibition (SICI) was reduced over both motor cortices in stroke patients without diabetes compared with normal control patients, while in stroke patients with diabetes, SICI was only reduced over the contralesional but not the ipsilesional cortex compared with control patients with diabetes. In addition, SICI was significantly reduced in the control patients with diabetes compared with normal control patients. These results have demonstrated the absence of ipsilesional cortical excitability change after diabetic strokes, suggesting impaired capacity for neuroplasticity over this hemisphere as a consequence of a "double-hit" phenomenon because of preexisting alterations in cortical function in nonstroke patients with diabetes. The reliance on reorganization over the contralesional cortex after stroke will likely exert influence on poststroke recovery in patients with diabetes. [ABSTRACT FROM AUTHOR]

Clinical signs of upper motor neuron (UMN) involvement are an important component in supporting the diagnosis of amyotrophic lateral sclerosis (ALS), but are often not easily appreciated in a limb that is concurrently affected by muscle wasting and lower motor neuron degeneration, particularly in the early symptomatic stages of ALS. Whilst recent criteria have been proposed to facilitate improved detection of lower motor neuron impairment through electrophysiological features that have improved diagnostic sensitivity, assessment of upper motor neuron involvement remains essentially clinical. As a result, there is often a significant diagnostic delay that in turn may impact institution of disease-modifying therapy and access to other optimal patient management. Biomarkers of pathological UMN involvement are also required to ensure patients with suspected ALS have timely access to appropriate therapeutic trials. The present review provides an analysis of current and recently developed assessment techniques, including novel imaging and electrophysiological approaches used to study corticomotoneuronal pathology in ALS. [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of fampridine on nerve excitability, the present study utilized peripheral axonal excitability techniques in 18 MS patients receiving treatment with fampridine. Methods Studies were performed at baseline and repeated 3 months after institution of fampridine at standard dosing. Results Following treatment with fampridine there were significant changes in axonal excitability for those parameters associated with fast K + channels that shifted towards normal control values. Specifically, increases were noted in the peak superexcitability of recovery cycle (fampridine, −25.6 ± 1.6%; baseline −22.8 ± 1.7%; p < 0.004), peak depolarizing threshold electrotonus (fampridine, 69.1 ± 1.0%; baseline 67.0 ± 1.4%; p < 0.004), and depolarizing threshold electrotonus between 40 and 60 ms after onset of depolarization (fampridine, 52.8 ± 1.3%; baseline 49.9 ± 1.4%; p = 0.02). Conclusion The present study has established that fampridine at standard doses exerts effects on peripheral nerve function that may be mediated by reduction of fast K + conductances. Significance Modulation of fast K + conductances by fampridine may contribute to the improvement observed in MS symptoms including motor fatigue. [ABSTRACT FROM AUTHOR]

The cerebellum has a vital role in fine motor control of the limbs. Consequently, downstream changes in peripheral axonal function may develop following a cerebellar infarct, in part, to adapt to the resultant impairment. The present study investigated changes in excitability in ipsilateral and contralateral upper limb peripheral motor axons in patients with acute cerebellar infarct to determine whether plastic changes may have functional relevance. Peripheral nerve excitability studies and detailed clinical assessments of functional impairment were undertaken in 13 patients with acute unilateral cerebellar infarct within 1 week of ictus. Changes were followed longitudinally over 1 year at 3, 6 and 12 months with results compared to 15 age-matched control subjects. Immediately following stroke, there were significant alterations in peripheral nerve excitability parameters in the upper limbs of patients compared to controls that were most evident in the more severely impaired group. There were significant correlations between excitability indices and functional scores in the entire cohort that demonstrated greater changes in axonal function associated with more impairment. Peripheral excitability trended towards normal over the study period in the context of clinical improvement. Following an acute cerebellar infarct, changes were observed in peripheral motor axons bilaterally that were more pronounced in patients with severe functional impairment. The peripheral changes may represent a functionally relevant plastic process reflecting altered activity to adapt to the disability of the stroke. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Muscle Nerve, 2013 [ABSTRACT FROM AUTHOR]

The causal relationship between electrical injury and development of amyotrophic lateral sclerosis (ALS) remains controversial. We describe the case of a 25-year-old man who developed ALS after a severe electrical injury. Cerebral magnetic resonance imaging (MRI) demonstrated hyperintensities involving the corticospinal tract. Functional testing with transcranial magnetic stimulation established that the motor cortex was relatively inexcitable. In addition, there were features of denervation on electromyography and muscle biopsy that supported concomitant lower motor neuron findings and the diagnosis of ALS. Muscle Nerve, 2010 [ABSTRACT FROM AUTHOR]

Spinal and bulbar muscular atrophy (SBMA), or Kennedy’s disease (KD), is a rare hereditary neuromuscular disorder demonstrating commonalities with amyotrophic lateral sclerosis (ALS). The current study aimed to define functional and central nervous system abnormalities associated with SBMA pathology, their interaction, and to identify novel clinical markers for quantifying disease activity. 27 study participants (12 SBMA; 8 ALS; 7 Control) were recruited. SBMA patients underwent comprehensive motor and sensory functional assessments, and neurophysiological testing. All participants underwent whole-brain structural and diffusion MRI. SBMA patients demonstrated marked peripheral motor and sensory abnormalities across clinical assessments. Increased abnormalities on neurological examination were significantly associated with increased disease duration in SBMA patients (R2 = 0.85, p < 0.01). Widespread juxtacortical axonal degeneration of corticospinal white matter tracts were detected in SBMA patients (premotor; motor; somatosensory; p < 0.05), relative to controls. Increased axial diffusivity was significantly correlated with total neuropathy score in SBMA patients across left premotor (R2 = 0.59, p < 0.01), motor (R2 = 0.63, p < 0.01), and somatosensory (R2 = 0.61, p < 0.01) tracts. The present series has identified involvement of motor and sensory brain regions in SBMA, associated with disease duration and increasing severity of peripheral neuropathy. Quantification of annualized brain MRI together with Total Neuropathy Score may represent a novel approach for clinical monitoring. [ABSTRACT FROM AUTHOR]

A normal result on the initial cerebrospinal fluid (CSF) study has been traditionally used to exclude the potential diagnosis of bacterial meningitis. However, there have been a number of case studies of bacterial meningitis confirmed by CSF culture, in which an initial lumbar puncture yielded completely normal parameters. A review of the literature reports the frequency of this scenario to arise in 0.5% to 12% of cases. This might result in the delay of appropriate treatment for this potentially fatal condition. We report a 21-year-old female patient who presented with a clinical picture compatible with bacterial meningitis but with a normal initial CSF result. Neisseria meningitidis was later cultured from her CSF. The medicolegal aspects surrounding such a scenario, and its implications towards clinical practice are discussed. We conclude that an abnormal initial CSF study might indicate a diagnosis of bacterial meningitis but a normal result does not exclude it and should not delay early institution of appropriate antimicrobial therapy. [ABSTRACT FROM AUTHOR]

• Transcranial magnetic stimulation is an objective biomarker of upper motor neuron dysfunction in motor neuron disease (MND). • Cortical hyperexcitability is mediated by cortical disinhibition and increased facilitation. • Neuroimaging biomarkers of upper motor neuron dysfunction in MND exhibit utility. 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. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease typically presenting with bulbar or limb weakness. There is increasing evidence that amyotrophic lateral sclerosis is a multisystem disease with early and frequent impacts on cognition, behaviour, sleep, pain and fatigue. Dysfunction of normal physiological and metabolic processes also appears common. Evidence from pre-symptomatic studies and large epidemiological cohorts examining risk factors for the future development of amyotrophic lateral sclerosis have reported a high prevalence of changes in behaviour and mental health before the emergence of motor weakness. This suggests that changes beyond the motor system are underway at an early stage with dysfunction across brain networks regulating a variety of cognitive, behavioural and other homeostatic processes. The full impact of non-motor dysfunction continues to be established but there is now sufficient evidence that the presence of non-motor symptoms impacts overall survival in amyotrophic lateral sclerosis, and with up to 80% reporting non-motor symptoms, there is an urgent need to develop more robust therapeutic approaches. This review provides a contemporary overview of the pathobiology of non-motor dysfunction, offering readers a practical approach with regard to assessment and management. We review the current evidence for pharmacological and non-pharmacological treatment of non-motor dysfunction in amyotrophic lateral sclerosis and highlight the need to further integrate non-motor dysfunction as an important outcome measure for future clinical trial design. [ABSTRACT FROM AUTHOR]

In this article, the author discusses Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder that leads to loss of motor neurons within the motor cortex and bulbospinal regions. Topics discussed include influence of polygenetic, environmental and lifestyle factors on the development of the disease, understanding of geneticâ€environmental interactions, and development of effective novel disease.

• Taxanes produce significant peripheral neuropathy. • Variations in chemotherapy-induced peripheral neuropathy (CIPN) phenotypes associated with taxane-treatment exist. • Understanding the CIPN phenotype may inform treatment decisions. To comprehensively describe patient-reported, functional and neurophysiological outcomes to elucidate the phenotypic profile of taxane-induced neuropathy. Taxane-treated patients (n = 47) completed cross-sectional bilateral clinical and sensory assessments and nerve conduction studies. Patients reported symptom severity via Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx13) questionnaire. Symptoms of neuropathy were reported by 81% of patients. On clinical examination, 62% had 2 or more abnormalities, with 20% indicating significant symptomatic and objective neuropathy. Nerve conduction studies were consistent with a sensory predominant axonal neuropathy. However, features more typical of entrapment neuropathy were also present in > 50%, which were not associated with overall severity of chemotherapy-induced peripheral neuropathy (CIPN) or clinical risk factors. There is considerable variation in CIPN phenotypes associated with taxane-treatment. Understanding their clinical associations may assist in identification of patients at risk of severe neurotoxicity. This would enable treatment modification decisions but also limit early cessation of effective anti-cancer treatment in patients with less severe neurological sequelae. Understanding the CIPN phenotype may inform treatment decisions which could impact clinical and survival outcomes. [ABSTRACT FROM AUTHOR]

Background and Objectives: With the advent of novel neuromodulatory interventions in post-stroke recovery, the evolution of intracortical excitability changes, particularly those over the contralesional hemisphere following stroke, and their relevance to functional recovery requires further clarification. As such, the present study utilized a prospective longitudinal design over an 18-month period from stroke onset, to investigate the evolution of intracortical excitability over both motor cortices and their relation to functional recovery. Methods: A total of thirty-three acute stroke patients and 29 control subjects were recruited in the study. Paired-pulse transcranial magnetic stimulation and comprehensive clinical assessments were undertaken at stroke onset and then repeated at 3-, 6-, 12-, and 18-months follow-up. Results: Immediately after stroke, short-interval intracortical inhibition (SICI) was significantly reduced in both hemispheres compared with controls that correlated with the degree of functional improvement over the first 3-months. Over the follow-up period, ipsilesional SICI remained reduced in all patient groups, whilst SICI over the contralesional hemisphere remained suppressed only in the groups with cortical stroke and more severe baseline functional impairment. Furthermore, contralesional SICI was more reduced in these groups of patients compared to those with subcortical stroke location and milder baseline impairment during the longitudinal assessment period. Clinical scores demonstrated improvement over this period with the most significant changes occurring in the first 3-months. Conclusion: Intracortical disinhibition occurs in both hemispheres immediately following acute stroke that likely represent functionally relevant changes supporting the recovery process in stroke. Whilst changes in the lesioned hemisphere persisted over the period of recovery in all patients, contralesional intracortical hyperexcitability persisted in patients with cortical strokes and those with more severe baseline functional impairment, suggesting that ongoing contralesional network recruitment may be necessary for those patients who have significant disruptions to the integrity of ipsilesional motor pathways. The study has demonstrated that evolution of cortical excitability, particularly over the contralesional hemisphere, may vary between patients with differing baseline stroke and clinical characteristics, and thereby has important implications towards the development of protocols for neuromodulatory brain stimulation in stroke recovery. [Copyright &y& Elsevier]

In conventional superconductors, Cooper pairing occurs between electrons of opposite spin. We observe spin-polarized superconductivity in Bernal bilayer graphene when doped to a saddle-point van Hove singularity generated by a large applied perpendicular electric field. We observe a cascade of electrostatic gate-tuned transitions between electronic phases distinguished by their polarization within the isospin space defined by the combination of the spin and momentum-space valley degrees of freedom. Although all of these phases are metallic at zero magnetic field, we observe a transition to a superconducting state at finite magnetic field B‖ ≈ 150 milliteslas applied parallel to the two-dimensional sheet. Superconductivity occurs near a symmetry-breaking transition and exists exclusively above the B‖ limit expected of a paramagnetic superconductor with the observed transition critical temperature TC ≈ 30 millikelvins, consistent with a spin-triplet order parameter. [ABSTRACT FROM AUTHOR]

Enhanced behavioral complexity may be observed when animals are tested in naturalistic environments and engaging in nonforced social interactions. For each of six experimental runs, different groups of five adult Swiss-Webster mice (four ovariectomized females and a single male) were maintained under 12h dark:12h light in a 122 × 122 × 30.5-cm open box containing six peripheral “nestboxes.” On Day 1, females were released into the box first and their nesting behavior was observed. Two days later, each female was injected with estradiol benzoate and the male was introduced into the environment. Females were injected with progesterone (P) 48 h later and the animals were observed for an additional 14 h. Behaviors were recorded with a video camera suspended over the apparatus. Mating occurred only post-P and males always mated preferentially with certain females. The amount of nesting behavior per female on Day 1 correlated significantly with the number of times each female was mated by the male (r = 0.57, P < 0.005). In all but one run, the male ejaculated with the female who performed the most nesting behavior. While 63% of mating was in the open, 56% of nestbox matings resulted in female postmating darting to alternate nestboxes; in 19% of these cases, the female quickly returned to the mating nestbox and was mated there again. Direct approaches by females to the male and behaviors which affect pacing were observed. These behaviors have not been reported previously for mice and may provide additional endpoints for the exploration of hormonal and genetic influences on reproductive behaviors. [Copyright &y& Elsevier]

Individuals who are diagnosed with amyotrophic lateral sclerosis (ALS) today face the same historically intransigent problem that has existed since the initial description of the disease in the 1860s - a lack of effective therapies. In part, the development of new treatments has been hampered by an imperfect understanding of the biological processes that trigger ALS and promote disease progression. Advances in our understanding of these biological processes, including the causative genetic mutations, and of the influence of environmental factors have deepened our appreciation of disease pathophysiology. The consequent identification of pathogenic targets means that the introduction of effective therapies is becoming a realistic prospect. Progress in precision medicine, including genetically targeted therapies, will undoubtedly change the natural history of ALS. The evolution of clinical trial designs combined with improved methods for patient stratification will facilitate the translation of novel therapies into the clinic. In addition, the refinement of emerging biomarkers of therapeutic benefits is critical to the streamlining of care for individuals. In this Review, we synthesize these developments in ALS and discuss the further developments and refinements needed to accelerate the introduction of effective therapeutic approaches. [ABSTRACT FROM AUTHOR]

Introduction: The mechanisms of lead neuropathy remain unexplained. A 48-year-old painter presented after undertaking a 3-week project of paint removal without the use of a protective mask. Two weeks later, he developed fasciculations, weakness, and muscle wasting. Nerve conduction studies demonstrated a motor neuropathy. A high serum lead level was identified, leading to a diagnosis of acute lead neuropathy. Methods: To investigate the pathophysiology, nerve excitability studies were undertaken acutely and in convalescence. Studies were undertaken at baseline and after the induction of limb ischemia. Results: Prominent abnormalities of excitability were noted, including a rightward shift of stimulus-response curves, reduction in depolarizing threshold electrotonus, and increased refractoriness. These changes became more severe with limb ischemia, and there was abolition of the superexcitable period and increased refractoriness. Conclusions: We identified prominent changes in nerve excitability in lead neuropathy. The results suggest that there is impairment of axonal energy-dependent processes in lead neuropathy. Muscle Nerve, 2012 [ABSTRACT FROM AUTHOR]

Introduction: This study explored potential diagnostic markers of nerve ultrasound in differentiating amyotrophic lateral sclerosis (ALS) from mimic disorders.Methods: Ultrasound of the median, ulnar, and tibial nerves was conducted in 53 patients with ALS, 32 patients with ALS-mimic disorders, and 30 controls. Nerve cross-sectional area (CSA) and distal-proximal ratios were calculated.Results: The median nerve CSA in the upper arm was decreased (7.9 ± 1.3 mm2 vs. 9.0 ± 1.4 mm2 , P < 0.05), and the median nerve wrist-upper arm ratio was increased in ALS patients compared with controls (1.3 ± 0.4 vs. 1.1 ± 0.2; P < 0.01). In differentiating ALS from mimic presentations, assessment of median nerve CSA in the upper arm and comparison of a median and ulnar nerve CSA distal-proximal ratio provide diagnostic potential.Discussion: Assessment of nerve CSA combined with calculation of nerve CSA distal-proximal ratio provides a useful marker to aid in the diagnosis of ALS. Muscle Nerve 58:777-783, 2018. [ABSTRACT FROM AUTHOR]

Highlights • Anti-MAG neuropathy is associated with proximal nerve enlargement. • Changes in juxtaparanodal fast potassium channel function may underlie nerve dysfunction. • Potassium channels blockers may hence improve nerve function. Abstract Objective To improve understanding of disease pathophysiology in anti-myelin-associated glycoprotein (anti-MAG) neuropathy to guide further treatment approaches. Methods Anti-MAG neuropathy patients underwent clinical assessments, nerve conduction and excitability studies, and ultrasound assessment. Results Patients demonstrated a distinctive axonal excitability profile characterised by a reduction in superexcitability [MAG: −14.2 ± 1.6% vs healthy controls (HC): −21.8 ± 1.2%; p < 0.01] without alterations in most other excitability parameters. Mathematical modelling of nerve excitability recordings suggested that changes in axonal function could be explained by a 72.5% increase in juxtaparanodal fast potassium channel activation and an accompanying hyperpolarization of resting membrane potential (by 0.3 mV) resulting in a 94.2% reduction in discrepancy between anti-MAG data and the healthy control model. Superexcitability changes correlated strongly with clinical and neurophysiological parameters. Furthermore, structural assessments demonstrated a proximal pattern of nerve enlargement (C6 nerve root cross-sectional area: 15.9 ± 8.1 mm2 vs HC: 9.1 ± 2.3 mm2; p < 0.05). Conclusions The imaging and neurophysiological results support the pathogenicity of anti-MAG IgM. Widening between adjacent loops of paranodal myelin due to antibodies would expand the pathway from the node to the juxtaparanode, increasing activation of juxtaparanodal fast potassium channels, thereby impairing saltatory conduction. Significance Potassium channel blockers may prove beneficial in restoring conduction closer to its normal state and improving nerve function in anti-MAG neuropathy. [ABSTRACT FROM AUTHOR]

Highlights • Fasciculation intensity in patients with amyotrophic lateral sclerosis (ALS) was measured using neuromuscular ultrasound. • Fasciculation frequency appears linked to disease progression. • Assessment of fasciculations is a noninvasive approach that may provide insight into ALS disease pathophysiology. Abstract Objective To investigate the association between the frequency and intensity of fasciculations with clinical measures of disease progression in amyotrophic lateral sclerosis (ALS). Methods Twenty-four consecutive patients with ALS underwent clinical review and neuromuscular ultrasound assessment to detect intensity of fasciculations. Results were correlated with clinical markers of disease severity, as measured by the ALS Functional Rating Scale-revised (ALSFRS-R) and rate of disease progression (ΔFS), in addition to assessment of cortical motor function. Results Disease duration negatively correlated (R = −0.530, p < 0.01) with fasciculation intensity, while the ΔFS positively correlated with the fasciculation number (R = 0.626, p < 0.01). In terms of potential central contributions to ectopic impulse generation, patients were classified into cohorts based on their fasciculation intensity and short interval intracortical inhibition (SICI). ΔFS was significantly higher in patients with established hyperexcitability (low SICI) with high fasciculation intensity compared to those patients with minimal SICI change. Conclusions Fasciculation intensity appears linked to disease progression and separately to markers of cortical dysfunction, specifically the advent of cortical hyperexcitability. Significance Assessment of the intensity of patient fasciculations is a noninvasive approach that may provide further insight disease pathophysiology in ALS. [ABSTRACT FROM AUTHOR]

Objective To evaluate the excitability of sensory axons in patients with amyotrophic lateral sclerosis (ALS). Methods Comprehensive sensory nerve excitability studies were prospectively performed on 28 sporadic ALS patients, compared to age-matched controls. Sensory nerve action potentials were recorded from digit 2 following median nerve stimulation at the wrist. Disease severity was measured using motor unit number estimation (MUNE), the revised ALS Functional Rating Scale (ALSFRS-R) and the MRC scale. Results There were no significant differences in standard and extended measures of nerve excitability between ALS patients and controls. These unchanged excitability measures included accommodation to long-lasting hyperpolarization and the threshold changes after two supramaximal stimuli during the recovery cycle. Excitability parameters did not correlate with MUNE, ALSFRS-R, APB MRC scale or disease duration. Conclusions This cross-sectional study has identified normal axonal membrane properties in myelinated sensory axons of ALS patients. Previously described sensory abnormalities could be the result of axonal fallout, possibly due to a ganglionopathy, or to involvement of central sensory pathways rostral to gracile and cuneate nuclei. Significance These results demonstrate the absence of generalized dysfunction of the membrane properties of sensory axons in ALS in the face of substantial deficits in motor function. [ABSTRACT FROM AUTHOR]

Objective: The provision of written information is a low-cost and readily available intervention that has been found to reduce pain and anxiety in a variety of clinical settings. The current study was undertaken to determine if information provision may improve patients’ experience during conventional electrodiagnostic studies. Methods: 128 participants were recruited from a tertiary teaching hospital who were referred for electrodiagnostic studies. They were randomized into 2 groups where the intervention group was provided with written information about the electrodiagnostic testing. Patients were invited to complete a questionnaire that included pain and anxiety using a visual analogue scale (VAS) following the testing. All participants underwent nerve conduction studies (NCS) whilst a subset also underwent subsequent needle electromyography (EMG). Results: Those who received information had a statistically significant lower perception of anxiety during NCS, whilst only females who received information had a statistically significant lower perception of pain to both NCS and EMG. Conclusions: The provision of written information can reduce the degree of pain and anxiety experienced during electrodiagnostic testing. Significance: Improving patient comfort and tolerability during electrodiagnostic testing may have practical implications towards more reliable and accurate results obtained from such investigations that may in turn improve patient diagnosis and management. [ABSTRACT FROM AUTHOR]

Objective To elucidate differences in the distribution and firing frequency of fasciculations between peripheral nerve hyperexcitability syndromes and amyotrophic lateral sclerosis (ALS) and to explore the generator site of fasciculations. Methods Ultrasound of 14 preselected muscles was performed in patients with peripheral hyperexcitability and ALS. The distribution and firing frequency of fasciculations were calculated. Cortical excitability assessment was also done by threshold tracking transcranial magnetic stimulation. Results In total, 518 muscles from 37 peripheral hyperexcitability patients and 756 muscles from 54 ALS patients were examined. Regarding the detection rate, 74% of muscles in ALS patients demonstrated fasciculations, compared with 34% of muscles in peripheral hyperexcitability patients ( P  < 0.001). The number of unique repeating focal muscle fasciculation movements per muscle and firing frequency of individual fasciculations in ALS were both significantly higher than those in peripheral hyperexcitability ( P  < 0.001). Furthermore, cortical silent period duration negatively correlated with the number and firing frequency of fasciculations in ALS ( P  < 0.05). A similar relationship was not evident in peripheral hyperexcitability. Conclusions In ALS patients, fasciculations were more widespread, greater in number and higher in firing frequency than in peripheral hyperexcitability patients. Significance A significant proportion of fasciculations in ALS may be influenced by changes in central excitability. [ABSTRACT FROM AUTHOR]

Introduction: This study seeks to elucidate the optimal scan time to detect fasciculations by using ultrasound in the diagnosis of amyotrophic lateral sclerosis (ALS).Methods: The intervals between fasciculations were recorded from tongue, abdominal, and limb muscles in ALS patients, incorporating assessment of the cumulative probability of 2 fasciculations occurring.Results: From prospective studies of 228 muscles from 19 ALS patients, fasciculations were detectable in 68% of patients. The longest interfasciculation interval recorded was 81.4 s in the hand muscle. The cumulative probability of 2 fasciculations occurring was calculated as ≥0.9 in all muscles during a period of 60 s.Discussion: A definition of 2 or more fasciculations occurring during a scan time of 60 s reliably allowed detection of fasciculations in ALS. Muscle Nerve, 2017. [ABSTRACT FROM AUTHOR]

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 1–7 ms) 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. [ABSTRACT FROM AUTHOR]

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 3 ms ( 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 3 ms ( 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

We quantified intraneural blood flow (INBF) using perfusion measurement software (PixelFlux), and compared it with the qualitative method of counting blood vessels (vessel score) in a cohort of carpal tunnel syndrome (CTS) patients.Methods: Forty-seven patients (67 wrists) with a clinical and electrophysiological diagnosis of CTS, and 20 healthy controls (40 wrists) were enrolled. Median nerve ultrasound (US) was performed at the carpal tunnel inlet to measure the cross-sectional area (CSA) and vessel score. Power Doppler sonograms from nerves with detectable INBF were processed with PixelFlux to obtain the maximum perfusion intensity (MPI).Results: Forty-nine percent of CTS patients had detectable INBF compared with none in the control group (P < 0.0001). MPI correlated significantly with vessel score (r = 0.945, P < 0.0001), CSA (r = 0.613, P < 0.0001), and electrophysiological severity (r = 0.440, P < 0.0001). MPI had higher intra- or interobserver reliability compared with vessel score (0.95 vs. 0.47).Conclusion: MPI is a better method for quantification of INBF. Muscle Nerve, 2016 Muscle Nerve 55: 77-83, 2017. [ABSTRACT FROM AUTHOR]

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 83 years (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. [ABSTRACT FROM AUTHOR]

Objective: The Motor Neuron Disease Behavioural Scale (MiND-B) is a clinically validated tool that was developed to detect behavioural dysfunction in patients with amyotrophic lateral sclerosis (ALS). The current study aimed to evaluate behavioural impairment using MiND-B, as well as cognitive dysfunction in ALS patients, and to determine their prognostic implications.Method: Patients with a clinical diagnosis of ALS were prospectively recruited from a specialised multidisciplinary ALS clinic. Patients underwent behavioural assessment with the Motor Neuron Disease Behavioural Scale (MiND-B) and cognitive evaluation using the Addenbrooke's Cognitive Examination (ACE). Primary outcome measure was selected as survival time, defined by time from assessment to time of death or censor date. Univariate assessment of survival effect was carried out using Kaplan-Meier survival analysis followed by cox regression analysis to assess the effect of MiND-B and ACE scores on survival time.Results: A total of 134 patients were included in the study. MiND-B testing determined that 59% were classified as having behavioural dysfunction, with deficits associated with a significantly shorter survival time (HR 2.53, p = 0.003, 95% CI 1.3-4.6). Furthermore, regression analysis demonstrated that for every 1-point reduction in the MiND-B score, risk of death increased by 3%. ACE testing established that 33% of the cohort had evidence of cognitive dysfunction. Patients with cognitive dysfunction on ACE testing had a significantly shorter survival time than patients without cognitive impairment (HR 2.0, p = 0.042, 95% CI 1.04-3.3).Conclusion: The presence of behavioural and cognitive impairments in ALS patients was associated with poor survival. The MiND-B and ACE inventories are simple and efficient clinical tools that can be administered in the multidisciplinary ALS clinic, that aid in the prognostication of this patient population. [ABSTRACT FROM AUTHOR]

Background Morvan’s syndrome is a rare disorder, characterized by peripheral nerve hyperexcitability, dysautonomia and encephalopathy with marked insomnia. About three quarters of patients have voltage gated potassium channel (VGKC) antibodies. A significant proportion of patients have associated tumours and the majority of these are thymomas. Introduction A 53 year-old man presented with a history of pain, cramps and twitching of the muscles of the chest and limbs, insomnia, hyperhidrosis, hypersalivation and cognitive impairment with hallucinations. Examination revealed fasciculations of the proximal upper limbs, piloerection of the forearms and mild postural hypotension. Investigations The patient underwent a number of electrophysiological studies: (1) EMG demonstrated spontaneous and frequent irregularly occurring neuromyotonic activity as doublet, triplet and multiplet single motor unit discharges firing at a high intraburst frequency (133–200 Hz), consistent with peripheral nerve hyperexcitability. (2) Paired-pulse transcranial magnetic stimulation revealed reduction in the short-interval intracortical inhibition (SICI) suggestive of central hyperexcitability. (3) EEG demonstrated left temporal slowing on an otherwise normal background. (4) autonomic testing showed a generalized sudomotor impairment consistent with autonomic dysfunction. Neuroimaging of the brain with PET demonstrated bilateral temporal lobe hypometabolism. Whole body PET revealed a hypermetabolic thyroid lesion, which was subsequently confirmed histologically to be a multifocal papillary thyroid carcinoma. Discussion The clinical and electrophysiological presentation was consistent with a diagnosis of Morvan’s syndrome in the context of a paraneoplastic phenomenon secondary to papillary thyroid cancer. The patient underwent a thyroidectomy and adjuvant radiotherapy. In addition, monthly intravenous methylprednisolone and intravenous immunoglobulin was instituted. Subsequently, the patient experienced significant symptomatic improvement with resolution of muscle fasciculations and cramps, hyperhidrosis and visual hallucinations. Insomnia and pain although improved did not completely resolve. Conclusion This case reviews the clinical and neurophysiological findings of Morvan’s syndrome. The case adds to the small number of non-thymomatous tumours associated with this syndrome and highlights the importance of a thorough search for malignancy in this clinical context. [ABSTRACT FROM AUTHOR]

Objective Motor neuronal hyperexcitability potentially contributes to motor neuron death in amyotrophic lateral sclerosis (ALS). We aimed to reveal pathomechanisms of motor neuron hyperexcitability in ALS. Methods Threshold tracking transcranial magnetic stimulation and multiple excitability measurements were performed in 130 healthy controls (HC), 83 sporadic ALS (sALS) patients, 11 patients with superoxide dismutase-1 ( SOD-1 ) mutations, 16 C9orf72 hexanucleotide repeat expansions and 2 FUS mutations. Results Compared to HC, in peripheral nerve excitability sALS had greater strength-duration time constant ( p < 0.05), depolarizing threshold electrotonus ( p < 0.0001) and superexcitability ( p < 0.05) and smaller late subexcitability ( p < 0.05). In cortical excitability, sALS had reduced short interval intracortical inhibition ( p < 0.0001). These indices were not significantly different in SOD-1 and C9orf72 , compared to sALS. Conclusion These findings suggest both sALS and familial ALS have increased sodium currents, decreased potassium currents, rendering to peripheral nerve hyperexcitability. In addition, all ALS patients demonstrated decreased intracortical inhibition. Significance Motor neuronal hyperexcitability may be a common feature in both sALS and familial ALS associated with different pathological bases. [ABSTRACT FROM AUTHOR]

Introduction According to AANEM guidelines, an initial step in the electrodiagnostic study for carpal tunnel syndrome (CTS) is the recording of median sensory response across the wrist. Although any median nerve innervated digit can be studied, digit 2 is most common. Objective The current prospective study was undertaken to determine differences between median nerve sensory parameters following stimulation of digit 2 and 3 in patients presenting with clinical CTS. Methods We prospectively studied 211 wrists in 158 patients with clinically definite CTS defined as nocturnal and/or activity-related sensory symptoms, sensory deficits in the median nerve distribution, or weakness and/or atrophy of median-innervated thenar muscles. Electrophysiological studies were conducted using standard techniques based on the AANEM practice parameters. Specifically, orthodromic sensory studies were performed following stimulation of both digit 2 and 3. Comparison sensory studies with the radial nerve were performed with stimulation at digit 1. Median motor studies were also performed. A cohort of normal patients were also recruited and studied. Results Sensory conduction velocity (SCV) following digit 3 stimulation (32.3 ± 14.5 m/s) was significantly slower ( P < 0.001) when compared to digit 2 (35.1 ± 14.1 m/s) in all severity groups, although the difference was most pronounced in patients with mild compared to those with severe CTS ( p = 0.005). 5% of the total cohort had normal digit 2 SCV, but abnormal digit 3 SCV. In our cohort of normal wrists, there was no significant difference between digits 2 and 3 SCV and sensory amplitude. Conclusion Orthodromic median nerve sensory studies following digit 3 stimulation are significantly more abnormal compared to digit 2 stimulation in patients with CTS, and may be more sensitive for the diagnosis of CTS, particularly in mild cases. [ABSTRACT FROM AUTHOR]