Sub-optimal protection against past hepatitis B virus infection where subtype mismatch exists between vaccine and circulating viral genotype in northern Australia.

BACKGROUND: In Australia's Northern Territory, the hepatitis B virus (HBV) subgenotype A2 (subtype adw2) vaccine was introduced in 1988 for Indigenous infants. Subsequently, the circulating viral genotype has been identified as subgenotype C4 (subtype ayw3). We assessed HBV vaccine effectiveness (VE) in light of this subtype mismatch. METHODS: Participants of the Aboriginal Birth Cohort (ABC) study were recruited at birth (1987-1990), with HBV serology obtained at follow-up waves 3 (2005-2007) and 4 (2013-2015). Participants were immune if HBV surface antibody levels exceeded 10 IU/L. We determined the VE against any HBV infection (anti-HBc+) and against chronic infection (HBsAg+ or HBV DNA+), comparing non-vaccinated participants with those fulfilling United States Centers for Disease Control and Prevention (CDC) criteria for full HBV immunisation. RESULTS: Of 686 participants in the ABC study, we obtained HBV serology from 388 at wave 4. 181 participants were immune to HBV and 97 had evidence of any infection. Seven participants were chronically infected, of whom five had received three vaccine doses, and anti-HBc seroconversion had occurred subsequent to the three vaccine doses for two of these seven participants. Comparing the 107 participants who had been vaccinated in accordance with CDC recommendations and 127 who had not been vaccinated, VE against any infection was 67% (95%CI, 43-104%). The odds of being anti-HBc+ was 87% lower in participants raised in urban settings compared to those born into families from remote areas (OR, 0.1; 95%CI, 0.03-0.4). CONCLUSIONS: In a setting where there exists a subtype mismatch between vaccine and circulating genotype, the vaccine was largely effective in preventing chronic infection but sub-optimal against any infection. The implications of a high prevalence of anti-HBc seropositivity in this population are unclear and require further study. The fact that anti-HBc seropositivity was strongly associated with remote dwelling suggests ongoing viral exposure in remote settings.

Cardiometabolic health and risk of amyotrophic lateral sclerosis.

INTRODUCTION: Patients diagnosed with amyotrophic lateral sclerosis (ALS) generally have a limited medical history and a normal body mass index, raising the possibility of a premorbid ALS phenotype. METHODS: The prevalence of cardiometabolic factors was analyzed in 58 ALS patients via comprehensive cardiovascular assessments and compared with Australian population norms. RESULTS: ALS patients had good cardiac fitness and no reported cardiovascular events. Average blood pressure, heart rate, PR interval, and corrected QT interval were in the normal range. There were significantly fewer obese women in the ALS cohort (13.6%, P < 0.05) and more men with a normal body mass index than in the general population (47.2%, P < 0.001). The percentage of individuals who had never smoked was greater for the ALS cohort (55.8%, P ≤ 0.001), and the prevalence of dyslipidemia was lower (38.7%) compared with the general population (74.4%, P < 0.001). CONCLUSION: ALS patients had good cardiometabolic health, with evidence of a reduced vascular risk profile. Muscle Nerve 56: 721-725, 2017.

Flecainide in Amyotrophic Lateral Sclerosis as a Neuroprotective Strategy (FANS): A Randomized Placebo-Controlled Trial.

BACKGROUND: Abnormalities in membrane excitability and Na(+) channel function are characteristic of amyotrophic lateral sclerosis (ALS). We aimed to examine the neuroprotective potential, safety and tolerability of the Na(+) channel blocker and membrane stabiliser flecainide in ALS. METHODS: A double-blind, placebo-controlled, randomised clinical trial of flecainide (200 mg/day) for 32-weeks with a 12-week lead-in phase was conducted in participants with probable or definite ALS recruited from multiple Australian centres (ANZCT Registry number ACTRN12608000338369). Patients were reviewed by a cardiologist to rule out cardiac contraindications. Participants were randomly assigned (1:1) to flecainide or placebo using stratified permuted blocks by a central pharmacy. The primary outcome measure was the slope of decline of the ALS Functional Rating Scale-revised (ALS FRS-r) during the treatment period. FINDINGS: Between March 11, 2008 and July 1, 2010, 67 patients were screened, 54 of whom were randomly assigned to receive flecainide (26 patients) or placebo (28 patients). Four patients in the flecainide group and three patients in the placebo group withdrew from the study. One patient in the flecainide group died during the study, attributed to disease progression. Flecainide was generally well tolerated, with no serious adverse events reported in either group. There was no significant difference in the rate of decline in the primary outcome measure ALS-FRS-r between placebo and flecainide treated patients (Flecainide 0.65 [95% CI 0.49 to 0.98]; Placebo 0.81 [0.49 to 2.12] P = 0.50). However, the rate of decline of the neurophysiological index was significantly reduced in the flecainide group (Flecainide 0.06 [0.01 to 0.11]; Placebo 0.14 [0.09 to 0.19], P = 0.02). Placebo-treated patients demonstrated greater CMAP amplitude reduction during the course of the study in the subset of patients with a reduced baseline CMAP amplitude (Flecainide: - 15 ± 12%; Placebo - 59 ± 12%; P = 0.03). Flecainide-treated patients maintained stabilized peripheral axonal excitability over the study compared to placebo. INTERPRETATION: This pilot study indicated that flecainide was safe and potentially biologically effective in ALS. There was evidence that flecainide stabilized peripheral axonal membrane function in ALS. While the study was not powered to detect evidence of benefit of flecainide on ALS-FRS-r decline, further studies may demonstrate clinical efficacy of flecainide in ALS.

Online prostate cancer screening decision aid for at-risk men: a randomized trial.

OBJECTIVE: This study examines the efficacy of an online screening decision aid (DA) for men with a family history of prostate cancer. METHODS: Unaffected Australian men (40-79 years) with at least one affected relative completed the first online questionnaire, were randomized to read either the tailored DA (intervention) or nontailored information about prostate cancer screening (control), then completed a questionnaire postreading and 12 months later. The primary outcome was decisional conflict regarding prostate specific antigen (PSA) testing. The impact of the DA on longitudinal outcomes was analyzed by using random intercept mixed effects models. Logistic and linear regressions were used to analyze the impact of the DA on screening behavior and decision regret. Stage of decision-making was tested as a moderator for decisional conflict and decision regret. The frequency of online material access was recorded. RESULTS: The DA had no effect on decisional conflict, knowledge, inclination toward PSA testing, accuracy of perceived risk, or screening behavior. However, among men considering PSA testing, those who read the DA had lower decision regret compared with men who read the control materials, ß = 0.34, p < .001, 95% confidence interval (CI) = [.22, .53]. CONCLUSIONS: This is the first study to our knowledge to evaluate the uptake and efficacy of an online screening DA among men with a family history of prostate cancer. Men who were undecided about screening at baseline benefitted from the DA, experiencing less regret 12 months later. In relation to decisional conflict, the control materials may have operated as a less complex and equally informative DA.

The acceptability, feasibility, and efficacy (phase I/II study) of the OVERcome (Olive Oil, Vaginal Exercise, and MoisturizeR) intervention to improve dyspareunia and alleviate sexual problems in women with breast cancer.

INTRODUCTION: Almost half of breast cancer survivors experience chronic sexual problems. Despite the negative effects of dyspareunia on physical and overall quality of life, sexual dysfunction remains underreported and undertreated in clinical practice. This is likely due to the paucity of evidence-based interventions to improve sexual functioning. AIM: The study aims to prospectively evaluate the acceptability, feasibility, and efficacy of a novel intervention (Olive Oil, Vaginal Exercise, and MoisturizeR [OVERcome]) to improve sexual problems following breast cancer treatment. MAIN OUTCOME MEASURES: Dyspareunia, sexual functioning, quality of life, distress, and pelvic floor muscles (PFMs) functioning were evaluated. METHODS: Twenty-five women with dyspareunia were instructed to perform pelvic floor muscle (PFM) relaxation exercises twice/day to prevent/manage PFM overactivity, apply a polycarbophil-based vaginal moisturizer three times/week to alleviate vaginal dryness, use olive oil as a lubricant during intercourse, and complete a weekly compliance diary. PFM relaxation training was administered by a physiotherapist at weeks 0 and 4, with follow-up at weeks 12 and 26. At each visit, women completed validated self-report questionnaires and the physiotherapist recorded objective measures of PFM functioning. RESULTS: OVERcome resulted in significant improvements in dyspareunia, sexual function, and quality of life over time (all P<0.001). PFM relaxation training was reported to be effective (P≤0.001). Maximum benefits were observed at week 12. Most women rated PFM relaxation exercises (92%), vaginal moisturizer (88%), and olive oil (73%) as helpful, indicating that the intervention was acceptable. Unexpectedly, six cases (11%) of vaginal stenosis were noted during initial screening. CONCLUSIONS: This novel intervention is acceptable to patients with demonstrated efficacy in improving dyspareunia and sexual function following breast cancer. Delivery of the OVERcome intervention appears feasible in a clinical setting, providing a potential treatment for this important clinical issue. The unexpected number of observed cases of stenosis further highlights the underreporting of sexual problems in this population, deserving further exploration.

Riluzole exerts central and peripheral modulating effects in amyotrophic lateral sclerosis.

Riluzole, a benzothiazole derivative, has been shown to be effective in prolonging survival in amyotrophic lateral sclerosis. The mechanisms by which riluzole exerts neuroprotective effects in amyotrophic lateral sclerosis remains to be fully elucidated, although inhibition of glutamatergic transmission and modulation of Na+ channel function have been proposed. In an attempt to determine the mechanisms by which riluzole exerts neuroprotective effects, in particular to dissect the relative contributions of inhibition of glutamatergic transmission and Na+ channel modulation, the present study utilized a combination of cortical and peripheral axonal excitability approaches to monitor changes in excitability and function in patients with amyotrophic lateral sclerosis. Cortical assessment was undertaken by utilising the threshold tracking transcranial magnetic stimulation (TMS) technique and combined with peripheral axonal excitability studies in 25 patients with amyotrophic lateral sclerosis. Studies were performed at baseline and repeated when patients were receiving riluzole 100 mg/day. At the time of second testing all patients were tolerating the medication well. Motor evoked potential and compound muscle action potential responses were recorded over the abductor pollicis brevis muscle. At baseline, features of cortical hyperexcitability were evident in patients with amyotrophic lateral sclerosis, indicated by marked reduction in short interval intracortical inhibition (P < 0.001) and cortical silent period duration (P < 0.001), as well as an increase in the motor evoked potential amplitude (P < 0.01). Riluzole therapy partially normalized cortical excitability by significantly increasing short interval intracortical inhibition (short interval intracortical inhibitionbaseline 0.5 ± 1.8%; short interval intracortical inhibitionON riluzole 7.9 ± 1.7%, P < 0.01). In contrast, riluzole did not exert any modulating effect on cortical silent period duration (P = 0.45) or motor evoked potential amplitude (P = 0.31). In terms of peripheral nerve function, axonal excitability studies established that, relative to control subjects, patients with amyotrophic lateral sclerosis had significant increases in depolarizing threshold electrotonus [amyotrophic lateral sclerosisbaseline TEd (90-100 ms) 49.1 ± 1.8%; controlsTEd (90-100 ms) 45.2 ± 0.6%, P < 0.01] and superexcitability (amyotrophic lateral sclerosisbaseline 30.1 ± 2.3%; control subjects 23.4 ± 1.0%, P < 0.01) at baseline. Following institution of riluzole therapy there was a significant reduction in superexcitability (amyotrophic lateral sclerosisbaseline 30.1 ± 2.3%; amyotrophic lateral sclerosisON riluzole 27.3 ± 2.3%, P < 0.05) and refractoriness at 2 ms (amyotrophic lateral sclerosisbaseline 98.7 ± 10.7%; amyotrophic lateral sclerosisON riluzole 67.8 ± 9.3%, P < 0.001). In conclusion, the present study has established that riluzole exerts effects on both central and peripheral nerve function, interpreted as partial normalization of cortical hyperexcitability and reduction of transient Na+ conductances. Taken together, these findings suggest that the neuroprotective effects of riluzole in amyotrophic lateral sclerosis are complex, with evidence of independent effects across both compartments of the nervous system.

Progressive axonal dysfunction and clinical impairment in amyotrophic lateral sclerosis.

OBJECTIVE: To elucidate longitudinal changes in axonal function in amyotrophic lateral sclerosis (ALS) patients, and to relate such changes with motor unit loss and functional impairment. METHODS: 37 ALS patients (age, 53.7 ± 1.7 years; 22 males) were studied using axonal excitability techniques at baseline and 12 weeks follow-up. RESULTS: Longitudinal measurements across excitability parameters suggested increasing K(+) channel dysfunction, with further increases in depolarising threshold electrotonus (90-100 ms, baseline, 46.8 ± 1.0%; follow-up, 48.7 ± 0.8%; P=0.02) and superexcitability (baseline, -24.0 ± 1.2%; 12 weeks, -26.0 ± 1.2%; P=0.04). Patients with preserved compound muscle action potential (CMAP) amplitude at follow-up developed more severe changes in axonal excitability than those in whom CMAP decreased from baseline, suggesting that the most pronounced disease effects were on motor axons immediately prior to axonal loss in ALS patients. Fine motor decline was associated with more severe changes in axonal excitability, suggesting that functional impairment was related to axonal dysfunction. CONCLUSIONS: Longitudinal changes in axonal excitability in ALS patients suggest increasing K(+) channel dysfunction in motor axons. SIGNIFICANCE: Axonal excitability studies enable investigation of longitudinal changes in axonal ion channel dysfunction, and thereby the processes that potentially contribute to axonal degeneration in ALS.

Maladaptation of cortical circuits underlies fatigue and weakness in ALS.

Although fatigue is frequently reported in amyotrophic lateral sclerosis (ALS), the underlying mechanisms remain to be elucidated. Cortical excitability studies were utilized to determine the contribution of central mechanisms to development of fatigue and weakness in ALS. Threshold-tracking transcranial magnetic stimulation (TMS) studies were undertaken in 16 ALS patients and 22 normal controls using a 90-mm circular coil. TMS studies were performed at baseline, immediately after a voluntary contraction (VC) period of 120 s duration (three VC periods), and at 5, 10 and 20 min after last VC. At baseline, there was a significant reduction of short-interval intracortical inhibition (SICI) at interstimulus interval of 1 ms (ALS 2.3 ± 2.3%; controls 9.5 ± 2.5%, p < 0.01) and 3 ms (ALS5.1 ± 3.4%; controls 16.8 ± 1.7%, p < 0.01) in ALS patients. Although there was a significant reduction of SICI post-VC in controls at ISI 1 ms (p < 0.05) and ISI 3 ms (p < 0.05), there was no significant change in ALS patients at ISI 1 ms (p = 0.15) or 3 ms (p = 0.31). The changes in cortical excitability correlated with fatigue (R = 0.59, p < 0.05). In conclusion, maladaptation of cortical processes related to degeneration of inhibitory GABAergic intracortical circuits, is a feature of ALS that significantly correlates with development of fatigue and weakness.

Cortical excitability distinguishes ALS from mimic disorders.

OBJECTIVE: The diagnosis of amyotrophic lateral sclerosis (ALS) relies on stringent clinical criteria, resulting in diagnostic delay and inevitably the institution of appropriate therapy. Cortical hyperexcitability, as assessed by the novel threshold tracking transcranial magnetic stimulation (TTTMS) technique, appears as an early feature of ALS. Consequently, the present study assessed the diagnostic utility of threshold tracking TMS and developed algorithms to aid the diagnosis of ALS. METHODS: Prospective studies were undertaken on a cohort of 156 consecutive patients with neuromuscular symptoms (104 ALS and 52 lower motor neuron syndrome, non-ALS syndrome, NALS) and 62 healthy controls. RESULTS: Short-interval intracortical inhibition (SICI) was significantly reduced in ALS patients (2.4 ± 0.9%) compared to NALS (8.7 ± 0.8%, P<0.0001) and controls (10.6 ± 0.8%, P < 0.0001). The MEP amplitude and intracortical facilitation were increased, while the cortical silent period duration was reduced in ALS, all indicative of cortical hyperexcitability. Analysis of receiver operating characteristic curves suggested that threshold tracking TMS distinguished ALS from NALS, with averaged (area under curve 0.76, P < 0.0001) and peak SICI 3 ms (area under curve 0.73, P<0.0001) being the most robust diagnostic markers. CONCLUSIONS: The presence of cortical hyperexcitability distinguishes ALS from mimic disorders. SIGNIFICANCE: The threshold tracking TMS techniques may prove useful as a diagnostic investigation for ALS.

Amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal neurodegenerative disease of the human motor system. In this Seminar, we summarise current concepts about the origin of the disease, what predisposes patients to develop the disorder, and discuss why all cases of ALS are not the same. In the 150 years since Charcot originally described ALS, painfully slow progress has been made towards answering these questions. We focus on what is known about ALS and where research is heading-from the small steps of extending longevity, improving therapies, undertaking clinical trials, and compiling population registries to the overarching goals of establishing the measures that guard against onset and finding the triggers for this neurodegenerative disorder.

Neurophysiological index as a biomarker for ALS progression: validity of mixed effects models.

Our objective was to evaluate the neurophysiological index (NI) as a biomarker for amyotrophic lateral sclerosis (ALS) and to assess the validity of linear mixed effects models for describing longitudinal changes. Functional assessment and nerve conduction studies were undertaken in 58 ALS patients. Neurophysiological data were collected on four occasions over 12 weeks (baseline, weeks 4, 8 and 12). The NI was calculated for the abductor digiti minimi and ulnar nerve at the wrist. NI declined at a rate of 0.04 per week (S.E. 0.006, p < 0.0001). Patients with bulbar-onset disease had 0.88 greater NI than patients with upper limb-onset disease over the follow-up period (S.E. 0.39, p = 0.03). There were no differences in the rates of decline among patients with different disease phenotypes. Rates of change in NI and functional impairment were weakly correlated (Spearman's p = 0.29, p = 0.03). Linear mixed effects models were appropriate for detailing the longitudinal changes in NI. The present findings support incorporation of NI as an outcome measure for ALS clinical trials conducted over short time periods.

Dissecting the mechanisms underlying short-interval intracortical inhibition using exercise.

Recently, 2 physiologically distinct phases of short-interval intracortical inhibition (SICI) have been identified, a larger phase at interstimulus interval (ISI) 3 ms and a smaller phase at ISI 1 ms. While the former is mediated by synaptic processes, the mechanisms underlying the first phase of SICI remain a matter of debate. Separately, it is known that fatiguing hand exercise reduces SICI, a measure of cortical excitability. Consequently, the present study assessed effects of fatiguing hand exercise on the 2 SICI phases, using threshold tracking transcranial magnetic stimulation techniques, to yield further information on underlying mechanisms. Studies were undertaken on 22 subjects, with SICI assessed at baseline, after each voluntary contraction (VC) period of 120 s and 5, 10, and 20 min after last VC, with responses recorded over abductor pollicis brevis. Exercise resulted in significant reduction of SICI at ISI 1 ms (SICI(baseline) 9.5 ± 2.7%; SICI(MAXIMUM REDUCTION) 2.5 ± 2.5%, P < 0.05) and 3 ms (SICI(baseline) 16.8 ± 1.7%; SICI(MAXIMUM REDUCTION) 11.6 ± 2.1%, P < 0.05), with the time course of reduction being different for the 2 phases. Taken together, findings from the present study suggest that synaptic processes were the predominant mechanism underlying the different phases of SICI.

Dexpramipexole, the R(+) enantiomer of pramipexole, for the potential treatment of amyotrophic lateral sclerosis.

Dexpramipexole (KNS-760704), the R(+) enantiomer of pramipexole, is under development by Knopp Neurosciences and Biogen Idec as a potential neuroprotective therapy for amyotrophic lateral sclerosis (ALS), a universally fatal neurodegenerative disease. Pramipexole, exclusively the S(-) enantiomer, is a non-ergot dopaminergic autoreceptor agonist that is currently marketed for use in the treatment of Parkinson's disease and restless legs syndrome. Pramipexole has been proposed to exert a broad spectrum of neuroprotective properties, primarily through antioxidant effects, inhibiting apoptotic enzymes and preserving mitochondrial structure and activity. More recent work has suggested that pramipexole possesses anti-excitotoxic properties, raising the possibility of beneficial effects in patients with ALS. However, pramipexole has high intrinsic dopaminergic receptor activity and, consequently, dose-limiting side effects, including orthostatic hypotension and hallucination, are frequent. Dexpramipexole exhibits significantly lower affinity for dopaminergic receptors, thereby making it unlikely to be associated with dopaminergic side effects. In clinical trials to date, dexpramipexole has been safe and well tolerated at doses up to 67-fold higher than the maximum recommended daily dose of pramipexole in patients with Parkinson's disease, and has demonstrated signs of neuroprotective benefit. This report summarizes the chemical and pharmacological properties of dexpramipexole and describes the potential utility of the drug in the pharmaceutical development pipeline.

Corticomotoneuronal function and hyperexcitability in acquired neuromyotonia.

Acquired neuromyotonia encompasses a group of inflammatory disorders characterized by symptoms reflecting peripheral nerve hyperexcitability, which may be clinically confused in the early stages with amyotrophic lateral sclerosis. Despite a clear peripheral nerve focus, it remains unclear whether the ectopic activity in acquired neuromyotonia receives a central contribution. To clarify whether cortical hyperexcitability contributes to development of clinical features of acquired neuromyotonia, the present study investigated whether threshold tracking transcranial magnetic stimulation could detect cortical hyperexcitability in acquired neuromyotonia, and whether this technique could differentiate acquired neuromyotonia from amyotrophic lateral sclerosis. Cortical excitability studies were undertaken in 18 patients with acquired neuromyotonia and 104 patients with amyotrophic lateral sclerosis, with results compared to 62 normal controls. Short-interval intracortical inhibition in patients with acquired neuromyotonia was significantly different when compared to patients with amyotrophic lateral sclerosis (averaged short interval intracortical inhibition acquired neuromyotonia 11.3 +/- 1.9%; amyotrophic lateral sclerosis 2.6 +/- 0.9%, P < 0.001). In addition, the motor evoked potential amplitudes (acquired neuromyotonia 21.0 +/- 3.1%; amyotrophic lateral sclerosis 38.1 +/- 2.2%, P < 0.0001), intracortical facilitation (acquired neuromyotonia -0.9 +/- 1.3%; amyotrophic lateral sclerosis -2.3 +/- 0.6%, P < 0.0001), resting motor thresholds (acquired neuromyotonia 62.2 +/- 1.6%; amyotrophic lateral sclerosis 57.2 +/- 0.9%, P < 0.05) and cortical silent period durations (acquired neuromyotonia 212.8 +/- 6.9 ms; amyotrophic lateral sclerosis 181.1 +/- 4.3 ms, P < 0.0001) were significantly different between patients with acquired neuromyotonia and amyotrophic lateral sclerosis. Threshold tracking transcranial magnetic stimulation established corticomotoneuronal integrity in acquired neuromyotonia, arguing against a contribution of central processes to the development of nerve hyperexcitability in acquired neuromyotonia.

Corticospinal tract dysfunction and development of amyotrophic lateral sclerosis following electrical injury.

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.

Neurophysiological methodologies: diagnosis of peripheral nerve disease and assessment of pharmacological agents.

Recent developments in the field of neurophysiology have led to the refinement of neurophysiological techniques, enabling clinical investigators to assess neuropathy patients with greater precision. In addition to conventional nerve conduction studies and electromyography, novel axonal excitability techniques and quantitative sensory testing may be used to improve diagnosis and to characterize and serially monitor peripheral nerve disorders. A significant expansion in the number of clinical trials being conducted for neurological indications has increased the impetus to further develop neurophysiological measures that reflect the responsiveness to drug therapies. Measures such as motor unit number estimation and the neurophysiological index may facilitate the advancement of compounds in the drug discovery pipeline. This review summarizes several electrodiagnostic and neurophysiological techniques, both conventional and novel, highlighting recent advances that are relevant to disease diagnosis and the assessment of patient response to treatment strategies.

INSPIRATIonAL--INSPIRAtory muscle training in amyotrophic lateral sclerosis.

Respiratory impairment, due to respiratory muscle weakness, is a major cause of morbidity and mortality in patients with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). Threshold loading may strengthen the inspiratory muscles and thereby improve patient prognosis. A phase II, double-blind, randomized-controlled trial was undertaken to determine whether a 12-week inspiratory muscle training programme attenuated the decline in respiratory function and inspiratory muscle strength in patients with ALS/MND. Nine patients were randomized to inspiratory muscle training and 10 to sham training. Primary endpoints were respiratory function (forced vital capacity, vital capacity), lung volumes and inspiratory muscle strength. Patients were assessed before, during and immediately after a 12-week training period, and at eight weeks follow-up. While improvements in inspiratory muscle strength were observed in both treatment arms, there was a non-significant increase in maximum inspiratory pressure of 6.1% in the experimental group compared to controls (standard error of mean, 6.93%; 95% confidence interval -8.58 -20.79; p=0.39). The gains in inspiratory muscle strength were partially reversed during a period of training cessation. In conclusion, inspiratory muscle training may potentially strengthen the inspiratory muscles and slow the decline in respiratory function in patients with ALS/MND.

Defining the mechanisms that underlie cortical hyperexcitability in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis [ALS] is a rapidly progressive neurodegenerative disorder of motor neurons, heralded by the development of cortical hyperexcitability. Reduction of short interval intracortical inhibition [SICI] in ALS, a feature linked to the development of cortical hyperexcitability, may be mediated by degeneration of inhibitory circuits or alternatively activation of high threshold excitatory circuits. As such, determining the mechanisms of SICI reduction in ALS has clear diagnostic and therapeutic significance. Consequently, the present study utilized a novel threshold tracking paired-pulse paradigm to determine whether SICI reduction in ALS represented reduced inhibition or excessive excitation. Using a 90 mm circular coil, SICI was assessed at three different conditioning stimulus intensities: 40%, 70% and 90% of resting motor threshold [RMT]. Motor evoked potential responses were recorded over the abductor pollicis brevis muscle. Short interval intracortical inhibition was uniformly reduced across all three levels of conditioning intensities in ALS [40% RMT, ALS -0.6+/-0.7%, controls 2.0+/-0.6%, P<0.01; 70% RMT, ALS 0.6+/-2.7%, controls 12.8+/-2%, P<0.001; 90% RMT, ALS -15.9+/-1.3%, controls 2.2+/-4.1%, P<0.01]. In addition, the resting motor threshold was reduced, while the motor evoked potential amplitude was increased in ALS patients, in keeping with cortical hyperexcitability. These findings establish that SICI reduction in ALS represents degeneration of inhibitory cortical circuits, combined with excessive excitation of high threshold excitatory pathways. Neuroprotective strategies aimed at preserving the integrity of intracortical inhibitory circuits, in addition to antagonizing excitatory cortical circuits, may provide novel therapeutic targets in ALS.

The effects of alterations in conditioning stimulus intensity on short interval intracortical inhibition.

Short interval intracortical inhibition [SICI] is mediated by cortical inhibitory interneurons, with two physiologically distinct phases at interstimulus interval [ISI]<1 ms and 2.5-3 ms. The second phase of SICI is mediated by synaptic mechanisms, while the first phase has been attributed to axonal refractoriness, synaptic mechanisms or both. In the present study, threshold-tracking transcranial magnetic stimulation was used to explore mechanisms underlying SICI. SICI was studied in 10 normal subjects at three different conditioning stimulus [CS] intensities [40%, 70% and 90% of resting motor threshold, RMT, defined as the threshold for a MEP of approximately 0.2 mV]. Motor responses were recorded from abductor pollicis brevis. Maximal SICI developed with CS set to 70% RMT [SICI(70%)], with two phases evident, at ISI 1 ms [12.7+/-3.4%] and ISI 2.5 ms [19.3+/-2.9%]. With CS set to 40% RMT, SICI occurred between 1 ms and 5 ms, peaking at 2.5 ms and was reduced [1.9+/-1.4%, P<0.0001] compared to peak SICI(70%). The small SICI peak at 1 ms was absent. With CS at 90% RMT, SICI developed between 2 and 5 ms, peaking at 4 ms [11.2+/-7.8%]. Facilitation was evident at 1 ms. The findings from the present study suggest that inhibitory circuits with different thresholds underlie the phases of SICI, with synaptic mechanisms also critical to the development of SICI at 1 ms.