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Parkinson's disease (PD) patients exhibit strong placebo responses in clinical trials. Patient characteristics that affect placebo include patients' expectations of good outcomes, genetic variants, and personality. The presence of motor fluctuation and high baseline UPDRS motor scores predicted placebo response. However, gender, age, duration of PD, religion, or level of education do not correlate with placebo response. PD patients who are preconditioned with active treatment such as apomorphine have more robust placebo effects. Studies that focused on patients with motor fluctuations, surgical intervention, or higher probability of placebo assignment had higher rates of placebo response. Patients view participating in placebo-controlled trials positively. Placebo effect can be measured objectively using neuroimaging and neurophysiological techniques. PET studies show that placebo-induced improvement is associated with dopamine release in the dorsal striatum and that the expectation of receiving the reward, not the reward itself, increased dopamine release in the ventral striatum. Expectations of benefitting from repetitive transcranial magnetic stimulation also induced dopamine release. Expectations of receiving a dopaminergic drug induced changes in fMRI in a reward-learning task. Single cell recordings demonstrate that placebo response is associated with changes of single neuronal activities in the basal ganglia circuit. These studies demonstrate that placebo effects are genuine biological responses to the administration of placebo. In clinical trials, we can use several approaches to minimize placebo responses. In clinical practice, we can use approaches to harness the power of placebo and minimize nocebo effects to improve patients' outcome.

Introduction: 3,4‐diaminopyridine has been used to treat Lambert‐Eaton myasthenia (LEM) for 30 years despite the lack of conclusive evidence of efficacy. Methods: We conducted a randomized double‐blind placebo‐controlled withdrawal study in patients with LEM who had been on stable regimens of 3,4‐diaminopyridine base (3,4‐DAP) for ≥ 3 months. The primary efficacy endpoint was >30% deterioration in triple timed up‐and‐go (3TUG) times during tapered drug withdrawal. The secondary endpoint was self‐assessment of LEM–related weakness (W‐SAS). Results: Thirty‐two participants were randomized to continuous 3,4‐DAP or placebo groups. None of the 14 participants who received continuous 3,4‐DAP had > 30% deterioration in 3TUG time versus 72% of the 18 who tapered to placebo (P

Autonomic reflex ascertains cardiovascular homeostasis during standing. Impaired autonomic reflex could lead to dizziness and falls while standing, this is prevalent in stroke survivors. Pulse rate variability (PRV) has been utilized in the literature in lieu of heart rate variability (HRV) for ambulatory and portable monitoring of autonomic reflex predominantly in young, healthy individuals. Here, we compared the PRV with gold standard HRV for monitoring autonomic reflex in ischemic stroke survivors. Continuous blood pressure and electrocardiography were acquired from ischemic stroke survivors (64 &plusmn, 1 years) and age-matched controls (65 &plusmn, 2 years) during a 10-minute sit-to-stand test. Beat-by-beat heart period (represented by RR and peak-to-peak (PP) intervals), systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse arrival time (PAT), an indicator of arterial stiffness, were derived. Time and frequency domain HRV (from RR intervals) and PRV (from PP intervals) metrics were extracted. PAT was lower (248 &plusmn, 7 ms vs. 270 &plusmn, 8 ms, p &lt, 0.05) suggesting higher arterial stiffness in stroke survivors compared to controls during standing. Further, compared to controls, the agreement between HRV and PRV was impaired in stroke survivors while standing. The study outcomes suggest that caution should be exercised when considering PRV as a surrogate of HRV for monitoring autonomic cardiovascular control while standing in stroke survivors.

Importance Cryptogenic sensory polyneuropathy (CSPN) is a common generalized slowly progressive neuropathy, second in prevalence only to diabetic neuropathy. Most patients with CSPN have significant pain. Many medications have been tried for pain reduction in CSPN, including antiepileptics, antidepressants, and sodium channel blockers. There are no comparative studies that identify the most effective medication for pain reduction in CSPN. Objective To determine which medication (pregabalin, duloxetine, nortriptyline, or mexiletine) is most effective for reducing neuropathic pain and best tolerated in patients with CSPN. Design, Setting, and Participants From December 1, 2014, through October 20, 2017, a bayesian adaptive, open-label randomized clinical comparative effectiveness study of pain in 402 participants with CSPN was conducted at 40 neurology care clinics. The trial included response adaptive randomization. Participants were patients with CSPN who were 30 years or older, with a pain score of 4 or greater on a numerical rating scale (range, 0-10, with higher scores indicating a higher level of pain). Participant allocation to 1 of 4 drug groups used the utility function and treatment’s sample size for response adaptation randomization. At each interim analysis, a decision was made to continue enrolling (up to 400 participants) or stop the whole trial for success (80% power). Patient engagement was maintained throughout the trial, which helped guide the study and identify ways to communicate and disseminate information. Analysis was performed from December 11, 2015, to January 19, 2018. Interventions Participants were randomized to receive nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). Main Outcomes and Measures The primary outcome was a utility function that was a composite of the efficacy (participant reported pain reduction of ≥50% from baseline to week 12) and quit (participants who discontinued medication) rates. Results Among the 402 participants (213 men [53.0%]; mean [SD] age, 60.1 [13.4] years; 343 White [85.3%]), the utility function of nortriptyline was 0.81 (95% bayesian credible interval [CrI], 0.69-0.93; 34 of 134 [25.4%] efficacious; and 51 of 134 [38.1%] quit), of duloxetine was 0.80 (95% CrI, 0.68-0.92; 29 of 126 [23.0%] efficacious; and 47 of 126 [37.3%] quit), pregabalin was 0.69 (95% CrI, 0.55-0.84; 11 of 73 [15.1%] efficacious; and 31 of 73 [42.5%] quit), and mexiletine was 0.58 (95% CrI, 0.42-0.75; 14 of 69 [20.3%] efficacious; and 40 of 69 [58.0%] quit). The probability each medication yielded the highest utility was 0.52 for nortriptyline, 0.43 for duloxetine, 0.05 for pregabalin, and 0.00 for mexiletine. Conclusions and Relevance This study found that, although there was no clearly superior medication, nortriptyline and duloxetine outperformed pregabalin and mexiletine when pain reduction and undesirable adverse effects are combined to a single end point. Trial Registration ClinicalTrials.gov Identifier:NCT02260388

To assess whether multifocal, high-frequency repetitive transcranial magnetic stimulation (rTMS) of motor and prefrontal cortex benefits motor and mood symptoms in patients with Parkinson disease (PD).Patients with PD and depression were enrolled in this multicenter, double-blind, sham-controlled, parallel-group study of real or realistic (electric) sham rTMS. Patients were randomized to 1 of 4 groups: bilateral M1 ( + sham dorsolateral prefrontal cortex [DLPFC]), DLPFC ( + sham M1), M1 + DLPFC, or double sham. The TMS course consisted of 10 daily sessions of 2,000 stimuli for the left DLPFC and 1,000 stimuli for each M1 (50 × 4-second trains of 40 stimuli at 10 Hz). Patients were evaluated at baseline, at 1 week, and at 1, 3, and 6 months after treatment. Primary endpoints were changes in motor function assessed with the Unified Parkinson's Disease Rating Scale-III and in mood with the Hamilton Depression Rating Scale at 1 month.Of the 160 patients planned for recruitment, 85 were screened, 61 were randomized, and 50 completed all study visits. Real M1 rTMS resulted in greater improvement in motor function than sham at the primary endpoint (p0.05). There was no improvement in mood in the DLPFC group compared to the double-sham group, as well as no benefit to combining M1 and DLPFC stimulation for either motor or mood symptoms.In patients with PD with depression, M1 rTMS is an effective treatment of motor symptoms, while mood benefit after 2 weeks of DLPFC rTMS is not better than sham. Targeting both M1 and DLPFC in each rTMS session showed no evidence of synergistic effects.NCT01080794.This study provides Class I evidence that in patients with PD with depression, M1 rTMS leads to improvement in motor function while DLPFC rTMS does not lead to improvement in depression compared to sham rTMS.

Fatigue is one of the most common and disabling symptoms in Parkinson's disease (PD). Since fatigue was first described as a common feature of PD 20 years ago, little progress has been made in understanding its causes or treatment. Importantly, PD patients attending the 2013 World Parkinson Congress voted fatigue as the leading symptom in need of further research. In response, the Parkinson Disease Foundation and ProjectSpark assembled an international team of experts to create recommendations for clinical research to advance this field. The working group identified several areas in which shared standards would improve research quality and foster progress including terminology, diagnostic criteria, and measurement. Terminology needs to (1) clearly distinguish fatigue from related phenomena (eg, sleepiness, apathy, depression); (2) differentiate subjective fatigue complaints from objective performance fatigability; and (3) specify domains affected by fatigue and causal factors. We propose diagnostic criteria for PD-related fatigue to guide participant selection for clinical trials and add rigor to mechanistic studies. Recommendations are made for measurement of subjective fatigue complaints, performance fatigability, and neurophysiologic changes. We also suggest areas in which future research is needed to address methodological issues and validate or optimize current practices. Many limitations in current PD-related fatigue research may be addressed by improving methodological standards, many of which are already being successfully applied in clinical fatigue research in other medical conditions (eg, cancer, multiple sclerosis). © 2016 International Parkinson and Movement Disorder Society.

BACKGROUND: Diabetic neuropathy (DN), a common complication of diabetes mellitus, results from hyperglycemia, poor microcirculation and attendant nerve damage. Currently available treatments relieve symptoms, but do not modify the neurodegeneration underlying DN. Centella asiatica (CA) triterpenes improved microcirculation in earlier clinical studies, and showed neurotropic effects in preclinical models suggesting a potential disease modifying effect in DN. This 52-week, randomized, double-blind, placebo-controlled trial examined the effects of CAST, a standardized CA extract containing triterpenes, on neuropathy symptoms in Type II diabetic subjects. PATIENTS AND METHODS: The study enrolled patients with a history of Type II diabetes, with evidence of symptomatic symmetrical DN with total symptom score (TSS) ≥4, and stable HbA1c level

Parkinson’s disease (PD) is a neurodegenerative disorder known to affect movement. Approximately seven million people around the world suffer from PD [1]. Tremor in one hand characterizes the onset of PD. Population suffering with PD shows symptoms of slowed movement. Consequently, PD patients struggle to complete a simple task like picking up a book. This slowness of movement is called bradykinesia. Bradykinesia measurement is vital for monitoring the progression of PD. The current method of assessing bradykinesia requires patients to perform certain motor tasks in clinical settings. A Unified Parkinson Disease Rating Scale (UPDRS) score is assigned to each task based on the observation by a physician. However, PD patients do not always show natural symptoms during a clinical visit. Also, subjective bias occurs during such assessment of bradykinesia [2]. To overcome these limitations, several attempts have been made to quantify bradykinesia using wearable sensors [3]. Accelerometer, gyroscope or a combination of both have been employed for acquisition of movement data to evaluate bradykinesia [3]. Time domain parameters derived from sensor signals for characterizing bradykinesia which includes speed, amplitude, hesitations, and halt have been evaluated in previous studies. However, the effect of frequency domain parameters and non-linear features extracted from sensor signals for evaluating the severity of bradykinesia is unknown. Whether or not it leads to an improvement in the assessment of bradykinesia needs to be investigated. It is known that the patients suffering from severe bradykinesia have their movement signal distorted due to unpredictable movement or hesitation. Nonlinear features can characterize the degree of complexity and provide further relevant insights regarding the severity of bradykinesia. In this study, we investigated the efficacy of various frequency-domain and nonlinear parameters to quantify bradykinesia. The objective was to develop a predictive model based on a combination of sophisticated linear (frequency) and non-linear features derived from the sensor signal which has not been previously explored in the literature.

Our previous studies in Parkinson's disease have shown that both levodopa and expectancy of receiving levodopa reduce cortical excitability. We designed this study to evaluate how degree of expectancy and other individual factors modulate placebo response in Parkinson's patients. Twenty-six Parkinson's patients were randomized to 1 of 3 groups: 0%, 50%, and 100% expectancy of receiving levodopa. All subjects received placebo regardless of expectancy group. Subjects completed the NEO-Five Factor Inventory, General Perceived Self-Efficacy Scale, and Perceived Stress Scale. Cortical excitability was measured by the amplitude of motor-evoked potential (MEP) evoked by transcranial magnetic stimulation. Objective physical fatigue of extensor carpi radialis before and after placebo levodopa was also measured. Responders were defined as subjects who responded to the placebo levodopa with a decrease in MEP. Degree of expectancy had a significant effect on MEP response (P < .05). Subjects in the 50% and 100% expectancy groups responded with a decrease in MEP, whereas those in the 0% expectancy group responded with an increase in MEP (P < .05). Responders tended to be more open to experience than nonresponders. There were no significant changes in objective physical fatigue between the expectancy groups or between responders and nonresponders. Expectancy is associated with changes in cortical excitability. Further studies are needed to examine the relationship between personality and placebo effect in Parkinson's patients. © 2013 Movement Disorder Society.

Purpose: This article reviews characteristics of amyotrophic lateral sclerosis (ALS) and appropriate timing of referrals by the nurse practitioner (NP). Data sources: Selected research and clinical articles. Conclusion: Management of patients with ALS by the NP requires anticipation of needed referrals based on symptom assessment and knowledge of the common timeline of ALS progression. Close collaboration with specialists such as neurologists, pulmonologists, and a palliative care team provides patients and families with much needed support and improves outcomes. Implications for practice: Anticipating and initiating appropriate and timely referrals for patients with ALS may improve quality of life for patients with this devastating condition.

OBJECTIVES: The muscles of the pelvic floor closest to the vaginal opening are subject to the greatest degree of stretch during vaginal childbirth. We aim to define normative quantitative EMG (QEMG) parameters for the pubovisceralis (PV) muscle in nulliparous women, and compare them to the external anal sphincter (EAS). METHODS: In 31 asymptomatic nulliparous women, concentric Needle EMG of the PV and the EAS was performed. Multi-motor unit action potential (Multi-MUAP) and interference pattern (IP) algorithms were utilized to obtain QEMG parameters. We used paired t-tests to compare PV and EAS parameters. RESULTS: The motor units for the PV were of greater duration (p < 0.002) and had more turns (p = 0.03) than the paired motor units in the EAS. The EAS demonstrated more turns/second (p = 0.02), greater activity (p = 0.01), and more short segments (p = 0.009) than the PV. CONCLUSIONS: The PV has longer and more complex motor units than the EAS. This knowledge continues to improve our ability to detect neuropathic changes in this vulnerable muscle area following childbirth or in women with pelvic floor dysfunction. In addition, the PV muscle group appears less responsive to requests for increased neuromuscular activity than the EAS. This needs to be further evaluated, as it may be associated with understanding which portion of the muscle functionally shortens to maintain the closure of the levator hiatus.

Fatigue is a common and potentially debilitating symptom of neuromuscular disease (NMD). Studies show that patients with NMD subjectively report increased levels of fatigue. Laboratory testing has demonstrated that patients with NMD show objective physiological signs of increased fatigue, with both central and peripheral components. To date, no treatment has been proven to be truly effective through evidence-based medicine. Thus, the clinician must use a multimodality approach to treating fatigue in patients with NMD. Management interventions are generally based on a sequential approach including treatment of comorbid factors, with the goal of maximizing physical and psychological functioning. This might include low-intensity exercise training, cognitive therapy, treatment of associated depression, correction of risk factors such as obesity, poor nutrition, and inactivity (deconditioning). Optimizing cardiopulmonary function is also critical and measures such as noninvasive, positive pressure ventilation may reduce fatigue in patients with NMD. Novel medications such as modafinil, a nonamphetamine stimulant, may be a helpful pharmacological treatment. Nutraceutical agents, such as creatine monohydrate, coenzyme Q10 (CoQ10), and α-lipoic acid, may also improve neuromuscular function and reduce fatigue.

Background: Fatigue is a major nonmotor symptom in Parkinson disease (PD). It is associated with reduced activity and lower quality of life. Objective: To determine if modafinil improves subjective fatigue and physical fatigability in PD. Methods: Nineteen PD patients who reported significant fatigue in the Multidimensional Fatigue Inventory (MFI) participated in this 8-week study. Subjects took their regular medications and were randomly assigned to the treatment group (9 subjects, modafinil 100-mg capsule BID) or placebo group (10 subjects). We used the MFI to measure subjective fatigue and used finger tapping and intermittent force generation to evaluate physical fatigability. Subjects also completed the Epworth Sleepiness Scale (ESS) and the Center of Epidemiological StudyYDepression Scale. Results: There were no significant differences at baseline and at 1 month in finger tapping and ESS between the modafinil and placebo groups. At 2 months, the modafinil group had a higher tapping frequency (P G 0.05), shorter dwell time (P G 0.05), and less fatigability in finger tapping and tended to have lower ESS scores (P G 0.12) than the placebo group. However, there was no difference between groups over time for any dimension of the MFI. Conclusions: This small study demonstrated that although modafinil may be effective in reducing physical fatigability in PD, it did not improve fatigue symptoms.

Improving quality of life (QoL) is a major goal in ALS palliative care. Previous studies performed on the general ALS population showed no relationship between QoL and disease progression. ALS subjects participating in clinical trials may differ from those in the general ALS population. We explored the relationship between QoL and disease progression in 412 subjects enrolled in a minocycline trial. We examined correlations between Single Item McGill Quality of Life Scale (MQoL-SIS) score and disease duration, ALS Functional Rating Scale Revised (ALSFRS-R) score, FVC, and survival rate. We also analyzed how NIV and PEG affect QoL. Within subjects, MQoL-SIS scores correlated with ALSFRS-R and FVC (p

We aimed to compare our normative data for quantitative interference pattern (IP) analysis of the anal sphincter to previously published data. In 28 nulliparous women, we performed IP analysis during quantitative concentric needle electromyography (QEMG) of the anal sphincter. At each sampling site, a 500-ms epoch was analyzed. The data were log transformed. Linear regression lines (with 95% confidence intervals) were calculated from the log transformed variables "turns-second" and "amplitude-turn." These confidence intervals were then transformed back into the original parameters to yield scatterplots with confidence curves. The mean turns-second were 203 (SD 174). The mean amplitude (mcv)-turn was 266 (SD 87). The regression coefficients for the log-transformed variables are constant = 1.5, slope = 0.3, and resultant cloud of raw data has a convex upper boundary. These appear slightly different than previously published reports, potentially influencing the determination of normal and abnormal studies.

Fatigue is common in patients with Parkinson's disease (PD). It occurs at every stage of PD and affects quality of life. Fatigue severity worsens over time as PD progresses, and it is associated with other non-motor symptoms such as apathy, depression, sleep disorder, and cognitive dysfunction.In this literature review, I discuss the measurement and pathophysiology of fatigue and fatigability. There are no evidence-based treatments for fatigue and fatigability available. I review several pilot studies on the effects of pharmacological agents and exercise on fatigue and fatigability. These studies provide some insights on the design of future larger clinical trials.Fatigue inventories including The Fatigue Severity Scale, the Multidimensional Fatigue Inventory, or theParkinson Fatigue Scale are used to assess the severity of fatigue. Finger tapping and force generation are useful in quantifying physical fatigability. A reaction time paradigm such as the Attention Network Test can be used to measure cognitive fatigability. Physical fatigability is associated with the change in cortical excitability in PD measured by Transcranial Magnetic Stimulation. Cognitive fatigability is most likely associated with the neurotransmitter abnormalities (dopaminergic, cholinergic and noradrenergic) in PD. Levodopa, modafanil, methylphenidate, and rasagiline may be effective in treating fatigue and fatigability. Exercise programs may also be effective.

Fatigue is one of the most common and disabling symptoms in Parkinson's disease (PD). Since fatigue was first described as a common feature of PD 20 years ago, little progress has been made in understanding its causes or treatment. Importantly, PD patients attending the 2013 World Parkinson Congress voted fatigue as the leading symptom in need of further research. In response, the Parkinson Disease Foundation and ProjectSpark assembled an international team of experts to create recommendations for clinical research to advance this field. The working group identified several areas in which shared standards would improve research quality and foster progress including terminology, diagnostic criteria, and measurement. Terminology needs to (1) clearly distinguish fatigue from related phenomena (eg, sleepiness, apathy, depression); (2) differentiate subjective fatigue complaints from objective performance fatigability; and (3) specify domains affected by fatigue and causal factors. We propose diagnostic criteria for PD-related fatigue to guide participant selection for clinical trials and add rigor to mechanistic studies. Recommendations are made for measurement of subjective fatigue complaints, performance fatigability, and neurophysiologic changes. We also suggest areas in which future research is needed to address methodological issues and validate or optimize current practices. Many limitations in current PD-related fatigue research may be addressed by improving methodological standards, many of which are already being successfully applied in clinical fatigue research in other medical conditions (eg, cancer, multiple sclerosis). © 2016 International Parkinson and Movement Disorder Society.

Objective Normative data on transcranial magnetic stimulation (TMS)-derived measures of cortical excitability in the elderly is sparse. Nevertheless, elderly subjects are included as controls in studies utilizing TMS to investigate disease states. Age-associated increased ventricular cerebrospinal fluid CSF (vCSF) and white matter hyperintensity (WMH) MRI volumes have uncertain significance in non-demented elderly. Information regarding cortical excitability in neurologically intact elderly would augment our understanding of the pathophysiology of aging and assist in the interpretation of TMS studies involving elderly subjects. Methods Twenty-four healthy elderly subjects underwent TMS testing to determine outcomes of resting motor threshold (RMT) cortical silent period (cSP) and central motor conduction time for examination in relation to WMH, vCSF, and CNS volumes. Results Increased vCSF and WMH volumes were associated with decreased right and left hemisphere RMT. Smaller CNS volumes were associated with decreased right hemisphere RMT and shorted cSP. Conclusions Commonly observed age-associated MRI changes are associated with findings consistent with increased cortical excitability. Significance Age-related MRI findings likely reflect changes at a cellular level, and may influence cognitive and motor integrity in the elderly. Future TMS studies investigating cortical excitability may wish to consider neuroimaging markers of neurodegeneration prior to enrolling elderly subjects as controls.

During multi-motor unit action potential (MUAP) analysis of the tonically contracted external anal sphincter (EAS), a mild interference pattern often obscures the baseline, affecting the algorithm's ability to determine accurate boundaries of detected MUAPs. To assess the equivalence of methods of editing and selecting candidate MUAPs from the EAS, 17 nulliparous women underwent concentric needle electromyography (EMG) of the EAS using multi-MUAP software. The selected MUAPs either were accepted without question (“automated”), or a subset was deleted due to a noisy baseline (“manual-deletion”) or manually marked (“manual-mark”). A second examiner repeated the analysis. Each examiner found that the two editing methods were equivalent and yielded results that differed from those obtained by automated analysis of unedited data. However, there was a moderate difference in MUAP amplitude when the manual-deletion method was compared between the two examiners. Editing of selected EAS MUAPs during multi-MUAP analysis is required, and development of common protocols is essential to enable meaningful comparisons between similar studies. Muscle Nerve, 2005

(2004). Western ALS Study Group. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders: Vol. 5, No. sup1, pp. 121-124.

Objectives : To measure exercise induced changes in cortico-motoneuron excitability in Parkinson's disease (PD) before and after levodopa. Methods : Transcranial magnetic stimulation was delivered at 10% above resting motor threshold in 9 PD and 8 control subjects. Each subject performed repetitive isometric wrist extension at 50% of the baseline maximal voluntary contraction (MVC) for 30s with 3s rest between extensions until fatigued, defined as the inability to generate force at more than 25% of the baseline MVC. We recorded motor evoked potentials (MEPs) from the resting extensor carpi radialis muscle before (baseline), during, and after fatiguing exercise. Baseline electromyographic activity was closely monitored. We compared absolute MEP amplitudes between PD and controls, before and after levodopa, during baseline, exercise, and recovery periods. We correlated absolute MEP amplitudes with an objective measure of fatigability. Results : PD subjects in the "off" state had increased absolute MEP amplitudes compared with controls. The effect was present in all 3 exercise periods. These differences disappeared after levodopa. Post-exercise facilitation was clear for PD subjects before and after levodopa, but post-exercise depression was not significant. Absolute MEP amplitude showed negative correlation with objective fatigability for PD subjects before levodopa. Conclusions : Levodopa normalized the increased cortico-motoneuron excitability in PD patients before, during, and after fatiguing exercise. Significance : This study demonstrated the abnormal cortico-motoneuron excitability associated with motor fatigue in PD.

Summary Background Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with few therapeutic options. Mild obesity is associated with greater survival in patients with the disease, and calorie-dense diets increased survival in a mouse model. We aimed to assess the safety and tolerability of two hypercaloric diets in patients with amyotrophic lateral sclerosis receiving enteral nutrition. Methods In this double-blind, placebo-controlled, randomised phase 2 clinical trial, we enrolled adults with amyotrophic lateral sclerosis from participating centres in the USA. Eligible participants were aged 18 years or older with no history of diabetes or liver or cardiovascular disease, and who were already receiving percutaneous enteral nutrition. We randomly assigned participants (1:1:1) using a computer-generated list of random numbers to one of three dietary interventions: replacement calories using an isocaloric tube-fed diet (control), a high-carbohydrate hypercaloric tube-fed diet (HC/HC), or a high-fat hypercaloric tube-fed diet (HF/HC). Participants received the intervention diets for 4 months and were followed up for 5 months. The primary outcomes were safety and tolerability, analysed in all patients who began their study diet. This trial is registered with ClinicalTrials.gov, number NCT00983983. Findings Between Dec 14, 2009, and Nov 2, 2012, we enrolled 24 participants, of whom 20 started their study diet (six in the control group, eight in the HC/HC group, and six in the HF/HC group). One patient in the control group, one in the HC/HC group, and two in the HF/HC group withdrew consent before receiving the intervention. Participants who received the HC/HC diet had a smaller total number of adverse events than did those in the other groups (23 in the HC/HC group vs 42 in the control group vs 48 in the HF/HC group; overall, p=0·06; HC/HC vs control, p=0·06) and significantly fewer serious adverse events than did those on the control diet (none vs nine; p=0·0005). Fewer patients in the HC/HC group discontinued their study diet due to adverse events (none [0%] of eight in the HC/HC group vs three [50%] of six in the control group). During the 5 month follow-up, no deaths occurred in the nine patients assigned to the HC/HC diet compared with three deaths (43%) in the seven patients assigned to the control diet (log-rank p=0·03). Adverse events, tolerability, deaths, and disease progression did not differ significantly between the HF/HC group and the control group. Interpretation Our results provide preliminary evidence that hypercaloric enteral nutrition is safe and tolerable in patients with amyotrophic lateral sclerosis, and support the study of nutritional interventions in larger randomised controlled trials at earlier stages of the disease. Funding Muscular Dystrophy Association, National Center for Research Resources, National Institutes of Health, and Harvard NeuroDiscovery Center.

OBJECTIVE: To characterize fatigue in Parkinson's disease (PD). BACKGROUND: Fatigue is a recognized problem in PD. Fatigue can be in the physical realm or in the mental realm. Fatigue has not been characterized in PD. METHODS: We characterized fatigue in 39 PD patients and 32 age-matched normal controls using five questionnaires: A. The Multidimensional Fatigue Inventory (MFI), which measures five dimensions of fatigue independently including general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue. B. The Fatigue Severity Inventory (FSI), which quantifies fatigue in general. C. The Profile of Mood States (POMS), which assesses six subjective subscales: tension-anxiety, depression-dejection, anger-hostility, fatigue-inertia, vigor-activity, and confusion-bewilderment. D. Center for Epidemiological Studies-Depression Scale (CES-D). E. Visual Analog linear scale of energy (VA-E). RESULTS: PD patients scored higher in all of the five dimensions of fatigue in the MFI including general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue (P < 0.001 except for mental fatigue P = 0.005). The severity of physical fatigue did not correlate with that of mental fatigue. PD patients scored higher on the FSI, POMS, CES-D, and scored lower on the VA-E. The scores in the FSI correlated with general fatigue, physical fatigue, reduced activity, and reduced motivation but not with mental fatigue in the MFI. Depression correlated with all dimensions of fatigue except physical fatigue in the MFI. Disease severity, as measured by Modified Hoehn and Yahr staging, did not correlate with any of the measures. CONCLUSIONS: PD patients have increased physical fatigue and mental fatigue compared to normals. Physical fatigue and mental fatigue are independent symptoms in PD that need to be assessed and treated separately. © 2001 Movement Disorder Society.

Parkinson's disease is the most common basal ganglia disorder that is caused by the degeneration of dopaminergic neurons in the substantia nigra. This article reviews the normal physiology of the basal ganglia in the normal state, as well as the pathophysiology of Parkinson's disease (PD) and other movement disorders associated with the basal ganglia. Also discussed is the pathophysiological basis for the surgical treatment of PD.

Few studies have addressed the rehabilitation of hand function in persons with severe impairment following stroke, and few therapeutic options are available for treatment. We investigated whether an intervention of robot-assisted movement and muscle vibration could reduce impairment and enable hand-opening to a greater extent when combined with torque biofeedback or electromyographic (EMG) biofeedback.Forty-three participants with severe hand impairment due to chronic stroke (≥1 year poststroke) were randomized to 1 of 2 treatment groups receiving assisted movement and muscle vibration combined with either torque or EMG biofeedback. Each participant received 30 sessions (30 minutes duration per session) directed at the impaired hand over 10 to 12 weeks. Outcomes were assessed using the Upper Extremity Fugl-Meyer Assessment (UE-FMA), Stroke Impact Scale, and Box-and-Block Test scores.Twenty-eight of 43 participants had no baseline finger extension; the remainder had an average of 23 ± 26 mm extension in the most active finger. Assisted movement and muscle vibration were associated with a significant increase in all outcome measures across both treatment groups, and for the UE-FMA and Stroke Impact Scale within treatment groups, with no significant difference between groups. Based on the Box-and-Block Test scores, the assisted movement and muscle vibration intervention did not restore functional hand-opening to participants with baseline UE-FMA scores less than 17/66, regardless of the form of biofeedback.Assisted movement and muscle vibration, combined with either EMG or torque biofeedback, appears to reduce upper limb impairment, improve volitional activation of the hand muscles, and restore a modicum of hand function in some persons with severe hand impairment due to chronic stroke.Video Abstract available (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A64) for more insights from the authors.

The objective of this study was to determine whether AMES (Assisted Movement with Enhanced Sensation), a novel therapeutic intervention that addresses impairments, rather than function, can reduce impairment and restore lost function in persons with a severely disabled hand. Forty-three participants with stroke (>1 yr post-injury) were provided with thirty 30-min AMES treatments over 10 weeks. Of these participants, 24 had no baseline active extension of any finger of the affected hand. Participants were randomized to 1 of 2 treatment groups differentiated by the kind of biofeedback (active torque or EMG) associated with the AMES intervention. During treatment, a robotic device cyclically opened and closed the hand (5 deg/s, ±15 deg) while the participant assisted this movement using visual biofeedback, and while vibration (60 pulses/s, 2 mm) was applied to the lengthening muscles. Participants were evaluated twice, before and after the treatment period, with the Fugl-Meyer Assessment (FMA-UE), Stroke Impact Scale (SIS), and Box-and-Block Test. In addition, during each treatment session, the AMES robot tested each participant’s strength of thumb-and-finger flexion and extension. Both torque and EMG were recorded during this Strength Test in participants assigned to the EMG-biofeedback group. The results showed overall a significant increase in the FMA-UE score (t-test, p

We studied the effects of altered sensory information on standing balance in 25 patients with cortical cerebellar atrophy (CCA), nine patients with olivoponto-cerebellar atrophy (OPCA), and 10 normal subjects. The total sway path and its components, the anteroposterior (AP) sway path and the lateral sway path, were measured under six conditions: (1) standing on a fixed platform with the eyes open and visual surroundings fixed, (2) standing on a fixed platform with the eyes closed, (3) standing on a fixed platform with the eyes open and visual surroundings AP sway referenced, (4) standing on an AP sway-referenced platform with the eyes open and visual surroundings fixed, (5) standing on an AP sway-referenced platform with the eyes closed, and (6) standing on an AP sway-referenced platform with the eyes open and visual surroundings AP sway referenced. Patients swayed more than normal subjects during normal stance (condition 1), when the visual information was absent (condition 2) or distorted (condition 3), and when the proprioceptive information from the ankles was distorted (condition 4). Patients swayed much more than normal, and most fell, when two sensory modalities were affected under condition 5 (proprioceptive information distorted and visual information absent) and condition 6 (both proprioceptive information and visual information distorted). When the patients' sway was normalized to that of the first condition, however, only their lateral sway was greater than the sway in normal subjects. Unlike in normal subjects, the patients' lateral sway varied with the AP sway to approximately the same degree in each condition for conditions 1-5. Clinical ratings of gait and balance were highly correlated with the sway measures. Quantitative testing of standing balance with altered sensory information has better sensitivity than normal stance testing.

Our previous studies in Parkinson's disease have shown that both levodopa and expectancy of receiving levodopa reduce cortical excitability. We designed this study to evaluate how degree of expectancy and other individual factors modulate placebo response in Parkinson's patients. Twenty-six Parkinson's patients were randomized to 1 of 3 groups: 0%, 50%, and 100% expectancy of receiving levodopa. All subjects received placebo regardless of expectancy group. Subjects completed the NEO-Five Factor Inventory, General Perceived Self-Efficacy Scale, and Perceived Stress Scale. Cortical excitability was measured by the amplitude of motor-evoked potential (MEP) evoked by transcranial magnetic stimulation. Objective physical fatigue of extensor carpi radialis before and after placebo levodopa was also measured. Responders were defined as subjects who responded to the placebo levodopa with a decrease in MEP. Degree of expectancy had a significant effect on MEP response (P .05). Subjects in the 50% and 100% expectancy groups responded with a decrease in MEP, whereas those in the 0% expectancy group responded with an increase in MEP (P .05). Responders tended to be more open to experience than nonresponders. There were no significant changes in objective physical fatigue between the expectancy groups or between responders and nonresponders. Expectancy is associated with changes in cortical excitability. Further studies are needed to examine the relationship between personality and placebo effect in Parkinson's patients. © 2013 Movement Disorder Society.

Methods The stability of CAST was monitored throughout the study using reversed phase high performance liquid chromatography. CAST or placebo capsules were administered to 33 DN subjects, in a randomized double-blind, placebocontrolled study. The dose of CAST was escalated from 60 mg to 240 mg/day over the first 12 weeks, followed by a stable dose of 240 mg/day for the remaining 40 weeks. The primary outcome was total symptom score (TSS), while secondary outcomes were nerve conduction studies, neurological disability score (NDS) and qualitative sensory testing (QST).

Fatigue is common in neuromuscular disease and it may affect quality of life; however, it has not been adequately studied. We can approach fatigue in neuromuscular diseases systematically. Questionnaires are used to assess subjective or experienced fatigue, and with the wide availability of the Internet, many patients can fill out questionnaires through Web-based surveys. Researchers can use force-generation protocols to evaluate physical fatigability and attention protocols to evaluate mental fatigability. Using these techniques to further understand the mechanisms of subjective and physiologic fatigue will help physicians to develop more effective treatments for fatigue and improve patients' quality of life.

In 4 patients with familial olivopontocerebellar atrophy (OPCA) we have recently described an abnormal movement of facial muscles characterized by rhythmic muscle twitching during voluntary activation (facial action myoclonus). In the present article, we present the results of a neurophysiologicel study of brainstem reflexes in those 4 patients, in 4 other patients with OPCA but without facial action myoclonus, in 3 patients with pure cerebellar cortical atrophy, and in 6 normal volunteers used as control subjects. All patients had similar clinical features, but only the patients with facial action myoclonus and only one of the other patients with OPCA had brainstem atrophy detected on magnetic resonance imaging. Electrophysiological abnormalities were found in all patients with facial action myoclonus and consisted of myokymia in perioral muscles at rest, spread of spontaneous and reflex blinking to the orbicularis oris, and enhanced long-latency facial reflex responses to stimuli applied to the facial or trigeminal nerve. Other relevant electrophysiological abnormalities were the absence of jaw jerk in 2 patients, the absence of an R1 response of the blink reflex in 1 patient, and a markedly reduced compound muscle action potential of the facial nerve in another patient. Comparable electrophysiological abnormalities were found in only 1 of the patients with OPCA but without facial action myoclonus, and in none of the patients with pure cerebellar cortical atrophy. Facial action myoclonus is a clinical manifestation of a global brainstem functional derangement that may characterize a subgroup of patients with OPCA or constitute a distinctive step in the natural evolution of some forms of the disease. © 1994 John Wiley & Sons, Inc.

OBJECTIVES: The muscles of the pelvic floor closest to the vaginal opening are subject to the greatest degree of stretch during vaginal childbirth. We aim to define normative quantitative EMG (QEMG) parameters for the pubovisceralis (PV) muscle in nulliparous women, and compare them to the external anal sphincter (EAS). METHODS: In 31 asymptomatic nulliparous women, concentric Needle EMG of the PV and the EAS was performed. Multi-motor unit action potential (Multi-MUAP) and interference pattern (IP) algorithms were utilized to obtain QEMG parameters. We used paired t-tests to compare PV and EAS parameters. RESULTS: The motor units for the PV were of greater duration (p0.002) and had more turns (p = 0.03) than the paired motor units in the EAS. The EAS demonstrated more turns/second (p = 0.02), greater activity (p = 0.01), and more short segments (p = 0.009) than the PV. CONCLUSIONS: The PV has longer and more complex motor units than the EAS. This knowledge continues to improve our ability to detect neuropathic changes in this vulnerable muscle area following childbirth or in women with pelvic floor dysfunction. In addition, the PV muscle group appears less responsive to requests for increased neuromuscular activity than the EAS. This needs to be further evaluated, as it may be associated with understanding which portion of the muscle functionally shortens to maintain the closure of the levator hiatus.

The supplementary motor area is thought to contribute to the generation of anticipatory postural adjustments (which act to stabilize supporting body segments prior to movement), but its precise role remains unclear. In addition, participants with Parkinson’s disease (PD) exhibit impaired function of the supplementary motor area as well as decreased amplitudes and altered timing of the anticipatory postural adjustment during step initiation, but the contribution of the supplementary motor area to these impairments also remains unclear. To determine how the supplementary motor area contributes to generating the anticipatory postural adjustment and to the impaired anticipatory postural adjustments of participants with PD, we examined the voluntary steps of 8 participants with PD and 8 participants without PD, before and after disrupting the supplementary motor area and dorsolateral premotor cortex, in separate sessions, with 1-Hz repetitive transcranial magnetic stimulation. Both groups exhibited decreased durations of their anticipatory postural adjustments after repetitive transcranial magnetic stimulation over the supplementary motor area but not over the dorsolateral premotor cortex. Peak amplitudes of the anticipatory postural adjustments were unaffected by repetitive transcranial magnetic stimulation to either site. The symptom severity of the participants with PD positively correlated with the extent that repetitive transcranial magnetic stimulation over the supplementary motor area affected the durations of their anticipatory postural adjustments. The results suggest that the supplementary motor area contributes to the timing of the anticipatory postural adjustment and that participants with PD exhibit impaired timing of their anticipatory postural adjustments, in part, due to progressive dysfunction of circuits associated with the supplementary motor area.

Fatigue is one of the most common non-motor complaints of Parkinson's disease (PD) patients and is associated with reduced activity and poorer quality of life. Fatigue can be experienced as a state of being tired or weary (subjective fatigue) or as a process of becoming tired or fatigued (fatigability). Subjective mental and physical fatigue are evaluated using self-report questionnaires such as the Multidimensional Fatigue Inventory. Physical fatigability is studied in a laboratory setting using physical exercise protocols and transcranial magnetic stimulation. Mental fatigability is evaluated by measuring attention over time using a reaction-time paradigm called the Attention Network Test (ANT). PD patients report more subjective physical and mental fatigue than controls on a variety of fatigue questionnaires. PD patients have increased physical fatigability in force generation and finger tapping. Levodopa and modafinil improve physical fatigability in PD subjects. Methylphenidate is useful for treating subjective physical fatigue. PD subjects have greater mental fatigability than control subjects and display abnormal performance in all three attention networks in the ANT. Therapies targeting the neurotransmitter systems involved in attention may be helpful for treating mental fatigability. Future fatigue research should focus on developing gold standards for fatigue measurement and developing treatments for fatigue and fatigability in PD.

Deep brain stimulation (DBS) and ablation (thalamotomy) of the motor thalamus reduce tremor and improve function of the contralateral hand in patients with essential tremor (ET). Neuroimaging and electrophysiological evidence suggest that unlike a focal lesion, high frequency stimulation affects widespread neural networks that include those involved in motor timing. The purpose of this pilot study was to compare the effects of thalamic stimulation and lesion on the timing of simple, self-paced finger movements in patients with ET. Twenty-one subjects with advanced ET were randomized to unilateral thalamotomy or DBS. Nine healthy controls were also enrolled. Index finger tapping was performed on both hands before and 6 months after surgery. Prior to surgery, timing of simple, repetitive index finger taps was abnormal in both TH and DBS subjects on the contralateral hand. After surgery, regularity was improved by both stimulation and thalamotomy with significantly more improvement in the TH group. On the ipsilateral (non-targeted) hand, timing of index finger taps was improved by stimulation. These results suggest that temporal processing is differentially affected by stimulating and lesioning thalamocortical fibers. That timing regularity is improved ipsilateral to the stimulated thalamus provides evidence that DBS influences a widespread neural network involved in timing of simple repetitive movements.

Combining agents with different mechanisms of action may be necessary for meaningful results in treating ALS. The combinations of minocycline-creatine and celecoxib-creatine have additive effects in the murine model. New trial designs are needed to efficiently screen the growing number of potential neuroprotective agents. Our objective was to assess two drug combinations in ALS using a novel phase II trial design. We conducted a randomized, double-blind selection trial in sequential pools of 60 patients. Participants received minocycline (100 mg)-creatine (10 g) twice daily or celecoxib (400 mg)-creatine (10 g) twice daily for six months. The primary objective was treatment selection based on which combination best slowed deterioration in the ALS Functional Rating Scale-Revised (ALSFRS-R); the trial could be stopped after one pool if the difference between the two arms was adequately large. At trial conclusion, each arm was compared to a historical control group in a futility analysis. Safety measures were also examined. After the first patient pool, the mean six-month decline in ALSFRS-R was 5.27 (SD=5.54) in the celecoxib-creatine group and 6.47 (SD=9.14) in the minocycline-creatine group. The corresponding decline was 5.82 (SD=6.77) in the historical controls. The difference between the two sample means exceeded the stopping criterion. The null hypothesis of superiority was not rejected in the futility analysis. Skin rash occurred more frequently in the celecoxib-creatine group. In conclusion, the celecoxib-creatine combination was selected as preferable to the minocycline-creatine combination for further evaluation. This phase II design was efficient, leading to treatment selection after just 60 patients, and can be used in other phase II trials to assess different agents.

Fatigue is a common and potentially debilitating symptom of amyotrophic lateral sclerosis (ALS). Questionnaire studies show that ALS subjects have increased subjective fatigue. Physiologic studies demonstrate that ALS subjects have increased physical fatigue, both central and peripheral in origin. No treatment has been proved effective through evidence-based medicine; however, modafinil (Provigil) may be a helpful pharmacologic treatment. Palliative care measures, such as noninvasive ventilation and high-frequency chest wall oscillation, may also reduce fatigue.

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND). It is currently incurable and treatment is largely limited to supportive care. Family history is associated with an increased risk of ALS, and many Mendelian causes have been discovered. However, most forms of the disease are not obviously familial. Recent advances in human genetics have enabled genome-wide analyses of single nucleotide polymorphisms (SNPs) that make it possible to study complex genetic contributions to human disease. Genome-wide SNP analyses require a large sample size and thus depend upon collaborative efforts to collect and manage the biological samples and corresponding data. Public availability of biological samples (such as DNA), phenotypic and genotypic data further enhances research endeavors. Here we discuss a large collaboration among academic investigators, government, and non-government organizations which has created a public repository of human DNA, immortalized cell lines, and clinical data to further gene discovery in ALS. This resource currently maintains samples and associated phenotypic data from 2332 MND subjects and 4692 controls. This resource should facilitate genetic discoveries which we anticipate will ultimately provide a better understanding of the biological mechanisms of neurodegeneration in ALS.

Objective The precision grip-and-lift task (PGLT) has been used to measure hand motor coordination in PD. We designed this study to investigate if the PGLT outcome variables correlate with the UPDRS motor scores and if all PGLT outcome variables are “responsive” to levodopa. Methods We used PGLT to assess hand motor coordination in 10 PD and 10 normal controls before and after levodopa. Results Factor analysis showed that the six PGLT parameters were reduced to two factors, a levodopa-responsive factor and a dopa-resistant factor that explained 74% of the total variance. The levodopa-responsive factor, which correlated significantly with “off” UPDRS motor scores, includes load preparation time, maximum vertical acceleration, maximum grip velocity and maximum grip force. The levodopa-resistant factor, which did not correlate with “off” UPDRS motor scores, included maximum negative load force and tremor during lift. Both dopa-responsive and dopa-resistant factors were altered in PD compared to controls before levodopa. Levodopa improved dopa-responsive, but not dopa-resistant factor in PD. Conclusions PGLT can measure two aspects of fine motor performance, both affected by PD but differentially affected by levodopa. Significance PGLT can be useful in characterizing the response of motor abnormality in PD therapeutic trials.