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INTRODUCTION: Bulbar symptoms are frequent in patients with rapid-onset dystonia-parkinsonism (RDP). RDP is caused by ATP1A3 mutations, with onset typically within 30 days of stressor exposure. Most patients have impairments in speech (dysarthria) and voice (dysphonia). These have not been quantified. We aimed to formally characterize these in RDP subjects as compared to mutation negative family controls. METHODS: We analyzed recordings in 32 RDP subjects (male=21, female=11) and 29 mutation negative controls (male=15, female=14). Three raters, blinded to mutation status, rated speech and vocal quality. Dysarthria was classified by subtype. Dysphonia was rated via the GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) scale. We used general neurological exams and the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) to assess dysarthria, dystonia, and speech/swallowing dysfunction. RESULTS: The presence of dysarthria was more frequent in RDP subjects compared to controls (72% vs. 17%, p< 0.0001). GRBAS voice ratings were worse in the RDP cohort across nearly all categories. Dysarthria in RDP was associated with concordant cranial nerve 9–11 dysfunction (54%, p=0.048), speech/swallowing dysfunction (96%, p=0.0003); and oral dystonia (88%, p=0.001). CONCLUSIONS: Quantitative voice and speech analyses are important in assessing RDP. Subjects frequently experience dysarthria and dysphonia. Dystonia is not the exclusive voice abnormality present in this population. In our analysis, RDP subjects more frequently experienced bulbar symptoms than controls. GRBAS scores are useful in quantifying voice impairment, potentially allowing for better assessments of progression or treatment effects. Future directions include using task-specific diagnostic and perceptual voice evaluation tools to further assess laryngeal dystonia.

Background and objectives Rapid-onset dystonia-parkinsonism (RDP) is caused by mutations in the ATP1A3 gene, which codes for the α-3 subunit of the Na+ /K+ ATPase. It has been characterized by rapid-onset bulbar dysfunction, limb dystonia, bradykinesia, and a rostrocaudal spatial gradient of expression, usually after a physiologic trigger. We reexamined whether these features were in fact characteristic. Methods We characterized phenotypic variation within a cohort of 50 ATP1A3 mutation-positive individuals (carriers) and 44 mutation-negative family members (noncarriers). Potential participants were gathered through referral for clinical suspicion of RDP or alternating hemiplegia of childhood. Inclusion criteria were having a ATP1A3 mutation or being a family member of such an individual. Results We found RDP is underdiagnosed if only "characteristic" patients are tested. Rapid onset and bulbar predominance were not universally present in carriers. Among those with at least mild symptoms of dystonia, rostrocaudal severity gradient was rare (7%). Symptoms began focally but progressed to be generalized (51%) or multifocal (49%). Arm (41%) onset was most common. Arms and voice were typically most severely affected (48% and 44%, respectively). Triggers preceded onset in 77% of the participants. Rapid onset, dystonia, parkinsonism, bulbar symptoms, headaches, seizures, frontal impairment, and a history of mood disorder and a history of psychosis were more common in carriers. Approximately half of the proband mutations occurred de novo (56%). Conclusions Our findings suggest that patients should not be excluded from ATP1A3 testing because of slow onset, limb onset, absent family history, or onset in middle adulthood. RDP should be strongly considered in the differential for any bulbar dystonia. © 2019 International Parkinson and Movement Disorder Society.

Up to 88% of perimenopausal and postmenopausal women in the United States experience hot flashes or night sweats1 and disturbances in mood and sleep.2–4 With hormone therapy use in decline because of safety concerns,5,6 there is a persistent need for effective, safe, and tolerable ways to support symptom reduction. Relaxation-oriented interventions may impact mechanisms of autonomic hyperarousal implicated in hot flashes, and trials of mind-body techniques have shown promise.7 In an early and thoughtfully designed study, paced respiration training was found to confer significant reductions in hot flash frequency during muscle relaxation and α-wave electroencephalography (EEG) biofeedback given as placebo.8 In contrast, a recent study from the MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) Network showed that yoga was not superior to usual care in reducing hot flash frequency or bother and showed only a small improvement in insomnia symptoms.9 A multicomponent strategy—relaxation training to reduce sympathetic arousal combined with cognitive-behavioral techniques to manage stress and negative thoughts—may be needed to reduce the physiological and psychological components of menopausal symptoms.10 Because the brain is the substrate common to physiological and psychological symptoms, an intervention that can facilitate relaxation through the brain itself could theoretically be more efficient and more efficacious than multicomponent approaches. Estrogen is an important modulator of noradrenergic and serotonergic systems; the transition from regular rhythms in estrogen levels to irregular fluctuations and, finally, to an absolute reduction has been described as a prolonged process of “brain resetting” or “brain adaptation” that produces the various symptom clusters of menopause.11,12 High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM) is a noninvasive closed-loop neurotechnology that identifies dominant brain frequencies through high-resolution spectral analysis of noninvasively recorded brain electrical activity. Those dominant frequencies are reflected by translating them into auditory tones of varying pitch and timing, based on mathematical algorithms, which are presented bilaterally, simultaneously, to the recipient through earphones, with a delay of as little as 8 milliseconds. This acoustic stimulation paradigm is intended to allow an opportunity for the brain to relax and to self-optimize (improved capacity for adaptation) and for neural oscillatory patterns to shift, on their own, toward improved balance or reduced hyperarousal. Although an exact mechanism awaits confirmation, there is presumed to be resonance between neural oscillatory frequencies and auditory tones reflected in near real time.13 HIRREM is described as an allostatic (“stability through change”) technology through which an individual tends to self-adjust toward greater hemispheric symmetry and more optimal amplitudes across different frequency ranges of brain electrical activity in recipient-unique ways. HIRREM differs from EEG biofeedback in that there is no intention to learn voluntary control of brain activity, nor does it rely on EEG databases to define normality. In a controlled clinical pilot trial, use of HIRREM was associated with improved sleep and reduced depressive symptoms among individuals with insomnia,13 and a trend for reduced amplitudes in a high-frequency range (23-36 Hz) of brain electrical activity was observed. In the Study of Women’s Health Across the Nation Sleep Study, a relationship between higher-amplitude brain electrical activity in a high-frequency range (16-32 Hz) and menopause status and hot flash frequency was found.14 These studies point to the possible clinical significance of amplitude changes in the high-frequency range of brain electrical activity. Here, we report on changes in menopause-related symptoms and high-frequency brain electrical activity in an open-label cohort of women who undertook HIRREM.

Background Rapid-Onset Dystonia-Parkinsonism (RDP) is caused by mutations in the ATP1A3 gene. This observational study sought to determine if cognitive performance is decreased in patients with RDP compared with mutation-negative controls.

Background Effective interventions are needed for individuals with persisting post-concussion symptoms. High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM®) is an allostatic, closed-loop, acoustic stimulation neurotechnology, designed to facilitate relaxation and self-optimization of neural oscillations. Methods Fifteen athletes (seven females, mean age 18.1 years, SD 2.6) with persisting post-concussion symptoms received 18.7 (SD 6.0) HIRREM sessions over a mean of 29.6 (SD 23.2) days, including 11.3 (SD 4.6) in office days. Pre- and post-HIRREM measures included the Rivermead Post-Concussion Symptoms Questionnaire (RPQ, n = 12), the Insomnia Severity Index (ISI, n = 15), the Center for Epidemiologic Studies Depression Scale (CES-D, n = 10), short-term blood pressure and heart rate recordings for measures of autonomic cardiovascular regulation (n = 15), and reaction time by the drop-stick method (n = 7). All participants were asked about their physical activity level and sports participation status at their post-HIRREM data collection visit and 1 to 3 months afterward. Results At the post-HIRREM visit, subjects reported improvements in all three inventories (RPQ mean change 19.7, SD 11.4, Wilcoxon p = 0.001; ISI mean change −4.1, SD 4.1, Wilcoxon p = 0.003; CES-D mean change −12.0, SD 10.0, Wilcoxon p = 0.004), including statistically significant reductions in 14 of the 16 individual items of the RPQ. There were also statistically significant improvements in baroreflex sensitivity, heart rate variability in the time domain (SDNN), and drop-stick reaction testing (baseline mean distance of 23.8 cm, SD 5.6, decreased to 19.8 cm, SD 4.6, Wilcoxon p = 0.016). Within 3 months of the post-HIRREM data collection, all 15 had returned to full exercise and workouts, and ten had returned to full participation in their athletic activity. Conclusions The use of HIRREM by a series of athletes with persisting post-concussion symptoms was associated with a range of improvements including, for the majority, return to full participation in their sport. The findings do not appear to be consistent with constituents of the placebo effect. A larger controlled trial is warranted.

A 21-year old male presented with ataxia and dysarthria that had appeared over a period of months. Exome sequencing identified a de novo missense variant in ATP1A3, the gene encoding the α3 subunit of Na,K-ATPase. Several lines of evidence suggest that the variant is causative. ATP1A3 mutations can cause rapid-onset dystonia-parkinsonism (RDP) with a similar age and speed of onset, as well as severe diseases of infancy. The patient’s ATP1A3 p.Gly316Ser mutation was validated in the laboratory by the impaired ability of the expressed protein to support the growth of cultured cells. In a crystal structure of Na,K-ATPase, the mutated amino acid was directly apposed to a different amino acid mutated in RDP. Clinical evaluation showed that the patient had many characteristics of RDP, however he had minimal fixed dystonia, a defining symptom of RDP. Successive magnetic resonance imaging (MRI) revealed progressive cerebellar atrophy, explaining the ataxia. The absence of dystonia in the presence of other RDP symptoms corroborates other evidence that the cerebellum contributes importantly to dystonia pathophysiology. We discuss the possibility that a second de novo variant, in ubiquilin 4 (UBQLN4), a ubiquitin pathway component, contributed to the cerebellar neurodegenerative phenotype and differentiated the disease from other manifestations of ATP1A3 mutations. We also show that a homozygous variant in GPRIN1 (G protein-regulated inducer of neurite outgrowth 1) deletes a motif with multiple copies and is unlikely to be causative.

Objective: Rapid-onset dystonia-parkinsonism (RDP) is caused by a variety of missense mutations in the ATP1A3 gene. Psychiatric comorbidity has been reported, although systematic examination of psychiatric disease in individuals with RDP is lacking. This study examines psychiatric morbidity for 23 patients with RDP in 10 families with family member control subjects and in 3 unrelated patients with RDP, totaling 56 individuals. Methods: Twenty-nine ATP1A3 mutation–positive individuals were examined; 26 exhibited motor symptoms (motor manifesting carrier [MMC]) and 3 did not (nonmotor manifesting carriers [NMC]). Twenty-seven ATP1A3 mutation-negative participants (noncarriers [NC]) were included. Rates of psychiatric illness for patients with RDP and related asymptomatic gene mutation carriers were compared with those for related nonmutation carriers. Outcome measures included the Unified Parkinson9s Disease Rating Scale, Burke-Fahn-Marsden Dystonia Rating Scale, Instrumental Activities of Daily Living, Composite International Diagnostic Interview, Structured Clinical Interview for DSM-IV , Hamilton Depression Scale, Hamilton Anxiety Scale, and Yale-Brown Obsessive-Compulsive Scale. Results: NMC participants did not report any history of psychiatric disorder. Findings in MMC and NC groups included anxiety (MMC 48, NC 41%), mood (MMC 50%, NC 22%), psychotic (MMC 19%, NC 0%), and substance abuse/dependence (MMC 38%, NC 27%). Conclusions: ATP1A3 mutations cause a wide spectrum of motor and nonmotor features. Psychotic symptoms tended to emerge before or concurrent with motor symptom onset, suggesting that this could be another expression of the ATP1A3 gene mutation.

Objective: Elevated rates of psychiatric disease and cognitive dysfunction have been found in primary dystonias. These features have not been studied in Rapid-Onset Dystonia-Parkinsonism (RDP), DYT12. Data are presented for 47 individuals (with or without gene mutation). Background RDP is a rare form of dystonia caused by mutation of the gene encoding the alpha-3 subunit of Na+/K+-ATPase ( ATP1A3 ). RDP is characterized by abrupt onset of dystonic symptoms with features of Parkinsonism and subsequent stabilization without recovery. Psychiatric and cognitive symptoms have not been systematically studied in RDP. Design/Methods: The SCID-I and CIDI-I were administered to 47 individuals, including 27 mutation carriers (24 motor-manifesting, 3 non-motor-manifesting) and 20 family members without ATP1A3 mutation. Discrepancies in diagnoses were adjudicated by a psychiatrist blinded to mutation status, who rendered final diagnoses. Cognitive data were obtained on 43 individuals, including 23 motor-manifesting carriers, 3 non-motor-manifesting carriers, and 17 non-carrier relatives. Results: Mood disorders appear more prevalent among carriers (44%) compared to non-carriers (25%). Anxiety (44% vs. 50%) and substance use (33% vs. 32%) were similar across groups. Five individuals from three families with ATP1A3 mutation (19%) exhibited psychotic disorder. Psychotic disorder was not present among non-carriers. One non-carrier exhibited evidence of visual memory dysfunction. Gene carriers exhibited visual (17%) and verbal (22%) memory deficits. More gene carriers exhibited impairment compared to non-carriers on Trail Making B (54% vs. 12%) and Trail Making A (42% vs. 29%). Self reported rates of childhood learning difficulties (post-RDP onset) were higher among gene carriers (69% vs. 24%). Conclusions: Anxiety disorders and substance use/abuse did not differ among individuals with and without ATP1A3 mutation. Increased mood and psychotic disorders for gene carriers illustrate comorbid mental illness. Impaired memory and executive functioning is consistent with findings in other dystonias. Higher prevalence of childhood learning difficulties in gene carriers suggests non-motor manifestations prior to motor onset. Supported by: NINDS 5R01NS058949-03. Disclosure: Dr. Brashear has received personal compensation for activities with Allergan, Inc., Merz Pharma, Ipsen as a consultant. Dr. Brashear has received personal compensation in an editorial capacity for the American Academy of Neurology. Dr. Brashear will receive future royalty payments for editing a book on spasticity. Dr. Brasher has received research support from Allergan, Inc., Merz Pharma, and Ipsen. Dr. Cook has nothing to disclose. Dr. Amponsah has nothing to disclose. Dr. Hill has nothing to disclose. Dr. Snively has nothing to disclose. Dr. Light has nothing to disclose. Dr. Suerken has nothing to disclose. Dr. McCall has received personal compensation for activities with Sepracor, Inc. Dr. Boggs has nothing to disclose. Dr. Stacy has received personal compensation for activities with Allergan, Inc., Biogen Idec, General Electric, Novartis, Osmotica, Teva Neuroscience, and Synosia. Dr. Stacy has received research support from Ceregene, Impax, Neuraltus, Novartis, Schering-Plough, and the Parkinson Study Group. Dr. Ozelius has nothing to disclose. Dr. Sweadner has nothing to disclose.

Rapid-onset dystonia-parkinsonism (RDP) is a movement disorder associated with mutations in the ATP1A3 gene. Signs and symptoms of RDP commonly occur in adolescence or early adulthood and can be triggered by physical or psychological stress. Mutations in ATP1A3 are also associated with alternating hemiplegia of childhood (AHC). The neuropathologic substrate of these conditions is unknown. The central nervous system of four siblings, three affected by RDP and one asymptomatic, all carrying the I758S mutation in the ATP1A3 gene, was analyzed. This neuropathologic study is the first carried out in ATP1A3 mutation carriers, whether affected by RDP or AHC. Symptoms began in the third decade of life for two subjects and in the fifth for another. The present investigation aimed at identifying, in mutation carriers, anatomical areas potentially affected and contributing to RDP pathogenesis. Comorbid conditions, including cerebrovascular disease and Alzheimer disease, were evident in all subjects. We evaluated areas that may be relevant to RDP separately from those affected by the comorbid conditions. Anatomical areas identified as potential targets of I758S mutation were globus pallidus, subthalamic nucleus, red nucleus, inferior olivary nucleus, cerebellar Purkinje and granule cell layers, and dentate nucleus. Involvement of subcortical white matter tracts was also evident. Furthermore, in the spinal cord, a loss of dorsal column fibers was noted. This study has identified RDP-associated pathology in neuronal populations, which are part of complex motor and sensory loops. Their involvement would cause an interruption of cerebral and cerebellar connections which are essential for maintenance of motor control. Electronic supplementary material The online version of this article (doi:10.1007/s00401-014-1279-x) contains supplementary material, which is available to authorized users.

Autonomic dysregulation and heterogeneous symptoms characterize postural orthostatic tachycardia syndrome (POTS). This study evaluated the effect of high-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM®), a noninvasive, allostatic neurotechnology for relaxation and auto-calibration of neural oscillations, on heart rate variability, brain asymmetry, and autonomic symptoms, in adolescents with POTS. Seven subjects with POTS (three males, ages 15–18) underwent a median of 14 (10–16) HIRREM sessions over 13 (8–17) days. Autonomic function was assessed from 10-min continuous heart rate and blood pressure recordings, pre- and post-HIRREM. One-minute epochs of temporal high-frequency (23–36 Hz) brain electrical activity data (T3 and T4, eyes closed) were analyzed from baseline HIRREM assessment and subsequent sessions. Subjects rated autonomic symptoms before and after HIRREM. Four of seven were on fludrocortisone, which was stopped before or during their sessions. Heart rate variability in the time domain (standard deviation of the beat-to-beat interval) increased post-HIRREM (mean increase 51 %, range 10–143, p = 0.03), as did baroreflex sensitivity (mean increase in high-frequency alpha 65 %, range −6 to 180, p = 0.05). Baseline temporal electrical asymmetry negatively correlated with change in asymmetry from assessment to the final HIRREM session (p = 0.01). Summed high-frequency amplitudes at left and right temporal lobes decreased a median of 3.8 μV (p = 0.02). There was a trend for improvements in self-reported symptoms related to the autonomic nervous system. Use of HIRREM was associated with reduced sympathetic bias in autonomic cardiovascular regulation, greater symmetry and reduced amplitudes in temporal lobe high-frequency electrical activity, and a trend for reduced autonomic symptoms. Data suggest the potential for allostatic neurotechnology to facilitate increased flexibility in autonomic cardiovascular regulation, possibly through more balanced activity at regions of the neocortex responsible for autonomic management. Clinical trial registry “Tilt Table with Suspected postural orthostatic tachycardia syndrome (POTS) Subjects,” Protocol Record: WFUBAHA01.