Andrei Voustianiouk

A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis.

BackgroundThe cause of neuronal death in amyotrophic lateral sclerosis (ALS) is uncertain but mitochondrial dysfunction may play an important role. Ketones promote mitochondrial energy production and membrane stabilization.ResultsSOD1-G93A transgenic ALS mice were fed a ketogenic diet (KD) based on known formulations for humans. Motor performance, longevity, and motor neuron counts were measured in treated and disease controls. Because mitochondrial dysfunction plays a central role in neuronal cell death in ALS, we also studied the effect that the principal ketone body, D-β-3 hydroxybutyrate (DBH), has on mitochondrial ATP generation and neuroprotection. Blood ketones were > 3.5 times higher in KD fed animals compared to controls. KD fed mice lost 50% of baseline motor performance 25 days later than disease controls. KD animals weighed 4.6 g more than disease control animals at study endpoint; the interaction between diet and change in weight was significant (p = 0.047). In spinal cord sections obtained at the study endpoint, there were more motor neurons in KD fed animals (p = 0.030). DBH prevented rotenone mediated inhibition of mitochondrial complex I but not malonate inhibition of complex II. Rotenone neurotoxicity in SMI-32 immunopositive motor neurons was also inhibited by DBH.ConclusionThis is the first study showing that diet, specifically a KD, alters the progression of the clinical and biological manifestations of the G93A SOD1 transgenic mouse model of ALS. These effects may be due to the ability of ketone bodies to promote ATP synthesis and bypass inhibition of complex I in the mitochondrial respiratory chain.

Norepinephrine Precursor Therapy in Neurogenic Orthostatic Hypotension

Background—In patients with neurogenic orthostatic hypotension (NOH), the availability of the sympathetic neurotransmitter norepinephrine (NE) in the synaptic cleft is insufficient to maintain blood pressure while in the standing posture. Methods and Results—We determined the effect of oral administration of the synthetic amino acid L-threo-3,4-dihydroxyphenylserine (L-DOPS), which is decarboxylated to NE by the enzyme L–aromatic amino acid decarboxylase (L-AADC) in neural and nonneural tissue, on blood pressure and orthostatic tolerance in 19 patients with severe NOH (8 with pure autonomic failure and 11 with multiple-system atrophy). A single-blind dose-titration study determined the most appropriate dose for each patient. Patients were then enrolled in a double-blind, placebo-controlled, crossover trial. L-DOPS significantly raised mean blood pressure both supine (from 101±4 to 141±5 mm Hg) and standing (from 60±4 to 100±6 mm Hg) for several hours and improved orthostatic tolerance in all patients. After L-DOPS, blood pressure increases were closely associated with increases in plasma NE levels. Oral administration of carbidopa, which inhibits L-AADC outside the blood-brain barrier, blunted both the increase in plasma NE and the pressor response to L-DOPS in all patients Conclusions—Acute administration of L-DOPS increases blood pressure and improves orthostatic tolerance in patients with NOH. The pressor effect results from conversion of L-DOPS to NE outside the central nervous system.

Midodrine in neurally mediated syncope: a double-blind, randomized, crossover study.

Neurally mediated syncope is the most frequent cause of syncope in patients without structural heart disease. Its most common trigger is a reduction in venous return to the heart due to excessive venous pooling in the legs. We conducted a double‐blind, randomized, crossover trial to investigate the efficacy of midodrine, a selective α‐1 adrenergic agonist that decreases venous capacitance, in preventing neurally mediated syncope triggered by passive head‐up tilt. Twelve patients with history of recurrent neurally mediated syncope, which was reproduced during head‐up tilt, were randomized to receive a nonpressor dose of midodrine (5mg) or placebo on day 1 and the opposite on day 3. One hour after drug or placebo administration, patients underwent 60‐degree head‐up tilt lasting 40 minutes (unless hypotension or bradycardia developed first). In the supine position, midodrine produced no significant change in blood pressure or heart rate. The responses to head‐up tilt were significantly different on the midodrine and the placebo day: on the placebo day, 67% (8/12) of the subjects suffered neurally mediated syncope, whereas only 17% (2/12) of the subjects developed neurally mediated syncope on the midodrine day (p < 0.02). These results indicate that midodrine significantly improves orthostatic tolerance during head‐up tilt in patients with recurrent neurally mediated syncope.

Vestibular control of sympathetic activity. An otolith-sympathetic reflex in humans

It has been proposed that a vestibular reflex originating in the otolith organs and other body graviceptors modulates sympathetic activity during changes in posture with regard to gravity. To test this hypothesis, we selectively stimulated otolith and body graviceptors sinusoidally along different head axes in the coronal plane with off-vertical axis rotation (OVAR) and recorded sympathetic efferent activity in the peroneal nerve (muscle sympathetic nerve activity, MSNA), blood pressure, heart rate, and respiratory rate. All parameters were entrained during OVAR at the frequency of rotation, with MSNA increasing in nose-up positions during forward linear acceleration and decreasing when nose-down. MSNA was correlated closely with blood pressure when subjects were within ±90° of nose-down positions with a delay of 1.4 s, the normal latency of baroreflex-driven changes in MSNA. Thus, in the nose-down position, MSNA was probably driven by baroreflex afferents. In contrast, when subjects were within ±45° of the nose-up position, i.e., when positive linear acceleration was maximal along the naso-ocipital axis, MSNA was closely related to gravitational acceleration at a latency of 0.4 s. This delay is too short for MSNA changes to be mediated by the baroreflex, but it is compatible with the delay of a response originating in the vestibular system. We postulate that a vestibulosympathetic reflex, probably originating mainly in the otolith organs, contributes to blood pressure maintenance during forward linear acceleration. Because of its short latency, this reflex may be one of the earliest mechanisms to sustain blood pressure upon standing.

Botulinum toxin type A in primary palmar hyperhidrosis Randomized, single-blind, two-dose study

Background: Primary palmar hyperhidrosis is characterized by excessive sweating due to increased sympathetic cholinergic sudomotor nerve traffic to the palmar surface of the hands. Clinical studies suggest that intradermal injections of botulinum toxin are effective in the treatment of palmar hyperhidrosis. Objectives: To establish the effectiveness of intradermal botulinum toxin in reducing hyperhidrosis, to determine the most effective dose of toxin, and to examine its effect on muscle strength. Methods: In a prospective, single blind, randomized trial, 24 patients with severe palmar hyperhidrosis received either a low (50 U) or a high dose (100 U) of botulinum toxin type A (Botox, Allergan) injected intradermally in 20 sites in each palm. Results: Following injection with either dose, iodine starch test revealed a significant decrease in sweating within the first month. Six months after injection, the anhidrotic effect was still evident in two thirds of the patients in both groups. Handgrip strength was not affected with either dose but finger pinch strength, 2 weeks after the injection, decreased 23 ± 27% with 50 U (p < 0.05) and 40 ± 21% with 100 U (p < 0.001). Pinch strength improved gradually but 6 months after treatment it was still 7–11% lower than at baseline. Conclusions: Both 50 and 100 U of botulinum toxin type A, injected intradermally in each hand, decreased sweating in patients with primary hyperhidrosis for at least 2 months in all the patients, and 6 months in most patients. Weakness in the intrinsic muscles of the hand was observed.

Effect of medication and psychotherapy on heart rate variability in panic disorder

Background: Panic disorder (PD) patients have been shown to have reduced heart rate variability (HRV). Low HRV has been associated with elevated risk for cardiovascular disease. Our aim was to investigate the effects of treatment on heart rate (HR) in patients with PD through a hyperventilation challenge. Methods: We studied 54 participants, 43 with Diagnostic and Statistical Manual of Mental Disorders (DSM‐IV) PD and 11 controls. Subjects lay supine with their heads in a plastic canopy chamber, resting for 15 min and then breathing at a rate of 30 breaths per minute for 10 min. HRV was sampled for spectral analysis. Clinical and behavioral measures of anxiety were assessed. Treatment was chosen by patients: either 12 weeks of CBT alone or CBT with sertraline. Results: All patients showed significant decrease on clinical measures from baseline and 31 were treatment responders, 8 dropped out of the study before completion of the 12‐week treatment phase and 4 were deemed nonresponders after 12 weeks of treatment. Although both treatments led to significant clinical improvement, only CBT alone demonstrated a significant reduction in HR and increase in HRV. Conclusions: Our study replicated the finding that increased HR and decreased HRV occur in PD patients. Given the evidence of cardiac risk related to HRV, CBT appears to have additional benefits beyond symptom reduction. The mechanisms of this difference between CBT and sertraline are unclear and require further study. Depression and Anxiety, 2009.

Stimulation of the subthalamic nucleus increases heart rate in patients with Parkinson disease

Cardiovascular adjustments during movement are achieved by changes in autonomic outflow modulated by feedback from mechano- and chemoreceptors in contracting skeletal muscle,1 and by a feed forward mechanism originating in locomotor brain areas called central command.2 In cats, electrical stimulation of the globus pallidum pars externa (GPe) and the subthalamic nucleus (STN)3 increases heart and respiratory rates, suggesting that the basal ganglia may be part of the neural substrate of central command. Recently, the introduction of high frequency electrical stimulation of the STN in the treatment of patients with PD provided a unique opportunity to examine whether, in awake nonsedated humans, the basal ganglia modulate cardiorespiratory function. We report the acute cardiovascular and respiratory effects of STN stimulation on three men with advanced PD in whom, 6 months before, electrodes had been implanted into the STN—bilateral in two and unilateral in one (Medtronic; Minneapolis, MN). Patients were age 71, 49, and 67, Hoehn and Yahr stage of 4, …

ALSFRS AND APPEL ALS SCORES : DISCORDANCE WITH DISEASE PROGRESSION

Progression of disease and effectiveness of therapy in patients with amyotrophic lateral sclerosis (ALS) are determined by both questionnaire‐ and examination‐based measures. To determine whether both types of measurement tools are equally predictive at all stages of disease, we compared questionnaire‐based ALS Functional Rating Scale (ALSFRS) scores to the examination‐based Appel ALS (AALS) scores at different stages of disease. Same‐day scores were obtained during 174 visits in 62 patients with definite or probable ALS. Using normalized scores, correlation between the scales and predictability were best in mildly affected patients. Predictions of ALSFRS based on AALS scores were less than half as precise in the later stages of disease. Both scales showed significant change with disease progression, but ALSFRS consistently underestimated disease severity defined by AALS (P < 0.001). Questionnaire‐based measurements should be compared against objective scales at all stages of disease severity before they are accepted as primary endpoint measures. Muscle Nerve, 2008

Differential role of dopamine in emotional attention and memory: Evidence from Parkinson's disease

Consistent with the hypothesis that dopamine is implicated in the processing of salient stimuli relevant to the modification of various behavioral responses, Parkinsons disease is associated with emotional blunting. To address the hypothesis that emotional attention and memory are modulated by dopaminergic neurotransmission in Parkinsons disease, we assessed 15 nondemented patients with Parkinsons disease while on and off dopaminergic medication and 15 age‐matched healthy controls. Visual stimuli were presented, and recognition was used to assess emotional memory. Response latency was used as a measure of emotional attention modulation. Stimuli were varied based on valence (pleasant, neutral, and unpleasant) and arousal (high and low) dimensions. Controls had significantly better memory for positive than negative stimuli, whereas patients with Parkinsons disease tested off medication had significantly better memory for negative than positive items. This negativity bias was lost when they were tested while on dopaminergic medication. Reaction times in patients with Parkinsons disease off medication were longer than in healthy controls and, paradoxically, were even longer when on medication. Further, although both healthy controls and patients with Parkinsons disease in the “off” state had arousal‐induced prolongation of reaction time, this effect was not seen in patients with Parkinsons disease on medication. These data indicate that dopaminergic neurotransmission is implicated in emotional memory and attention and suggest that dopamine mediates emotional memory via the valence dimension and emotional attention via arousal. Furthermore, our findings suggest that emotional changes in Parkinsons disease result from the effects of both the disease process and dopaminergic treatment.

Emotional processing affects movement speed.

Emotions can affect various aspects of human behavior. The impact of emotions on behavior is traditionally thought to occur at central, cognitive and motor preparation stages. Using EMG to measure the effects of emotion on movement, we found that emotional stimuli differing in valence and arousal elicited highly specific effects on peripheral movement time. This result has conceptual implications for the emotion–motion link and potentially practical implications for neurorehabilitation and professional environments where fast motor reactions are critical.