The growing recognition of autonomic nervous system (ANS) dysfunction across a broad spectrum of neurological and systemic diseases calls for structured, multidisciplinary care. This position statement by the European Federation of Autonomic Societies aims to provide guidance on establishing an autonomic unit within a neurology department. A Task Force appointed by the European Federation of Autonomic Societies board in October 2022 proposed staffing and equipment requirements for autonomic units, based on a literature review, survey data from ANS laboratories, and existing diagnostic guidelines. These propositions were integrated into the initial 25 questions and refined using a modified Delphi method to achieve expert consensus. Consensus was predefined as ≥ 80% agreement. Statements that did not reach consensus were revised and reassessed in subsequent rounds. After three rounds of Delphi surveys, expert consensus was achieved on the minimal and optimal requirements for autonomic unit personnel, technical equipment, and the availability of multidisciplinary care. This European Federation of Autonomic Societies position statement presents practical, expert-based recommendations to promote the development of autonomic units across various healthcare systems. By establishing minimum and optimal standards for staffing, equipment, and interdisciplinary collaboration, the document offers a clear framework for standardizing clinical care and supporting collaborative research. This statement serves as a foundational resource for clinicians, administrators, and policymakers committed to strengthening the ANS care infrastructure.
Vagus nerve stimulation (VNS) is a neuromodulatory intervention with antiinflammatory and autonomic regulatory properties. Although its clinical applications have primarily been explored in neurological disorders, its potential role in pulmonary and respiratory outcomes across preclinical and clinical settings remains incompletely characterized and dispersed across different study domains. This scoping review aimed to map the available evidence on the effects of VNS on the pulmonary and respiratory systems, with particular emphasis on inflammatory and autonomic mechanisms. This scoping review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Three reviewers systematically searched PubMed, Web of Science, and the Cochrane Library for studies published between January 2020 and February 2026. Original preclinical and clinical studies investigating invasive or noninvasive VNS and reporting pulmonary, respiratory physiology, autonomic, or inflammatory outcomes were included. A total of 159 records were identified, of which 12 studies met the inclusion criteria. The evidence base was predominantly preclinical. In animal studies, invasive cervical VNS was frequently associated with reductions in pulmonary inflammation, histopathological lung injury, and proinflammatory cytokine expression. Clinical studies were limited and heterogeneous, but generally indicated variable modulation of autonomic function, including changes in parasympathetic activity, as well as heterogeneous effects on systemic inflammatory markers and limited respiratory outcomes. Current evidence suggests that VNS may modulate pulmonary inflammatory responses in preclinical models. However, clinical evidence remains limited and heterogeneous, particularly regarding autonomic and respiratory outcomes. Well-designed clinical trials using standardized stimulation protocols and predefined respiratory end points are needed to clarify its therapeutic potential in respiratory disorders.
Many methods have been developed for the assessment of dysautonomia, but they are often unreliable and not readily applicable to daily practice. Among the available investigation methods, the Ewing battery, which includes five non-invasive cardiovascular reflex tests, have become the reference standard in assessing dysautonomia and have been utilized for more than four decades. This systematic review evaluates the diagnostic thresholds and diagnostic performance of Ewing tests across studies in identifying autonomic nervous system (ANS) disorders. We conducted a comprehensive multi-database literature search, including PubMed, EMBASE, Web of Science, Scopus, and the Cochrane Library, using a pre-defined search strategy, for studies that applied the Ewing tests to assess autonomic dysfunction. We focused on studies that used continuous recordings and those reporting extractable numerical data, including either normative values or diagnostic cutoff thresholds for the Ewing tests. The Ewing parameters that were tested were Valsalva manoeuvre, heart rate variability during deep breathing (E/I ratio), the isometric handgrip, heart rate response to standing (30:15 ratio) and blood pressure response to standing. Our analysis demonstrates good diagnostic performance of the Ewing tests, with sensitivity for individual components reaching up to 91% for Valsalva ratio (VR) in some cohorts. The normative data and respective cutoff points are influenced by age and sex. Optimal diagnostic performance was achieved when the Ewing battery was interpreted using the conventional criterion of ≥ 2/5 abnormal tests particularly when age-adjusted cutoffs were applied. The Ewing battery remains a highly effective tool for diagnosing ANS disorders, especially when age-adjusted normative thresholds are used. To further enhance its diagnostic performance, each laboratory should establish its own normative data reflective of the specific population it serves.
Establish the minimally clinically important difference (MCID) for the Orthostatic Hypotension Questionnaire (OHQ). Neurogenic orthostatic hypotension (nOH) causes disabling symptoms that impair daily function and quality of life. The OHQ is a validated patient-reported outcome with a symptom assessment (OHSA) and daily activity scale (OHDAS), widely used in clinical trials, despite the MCID being unestablished. We analyzed data from two phase 3, randomized placebo-controlled trials (SEQUOIA and REDWOOD), evaluating ampreloxetine for symptomatic nOH in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure. Using anchor-based and distribution-based methods, we calculated the MCID for the total OHQ score, OHSA and OHDAS composite subscales, and for the single dizziness/lightheadedness question (OHSA1). The analysis included 184 subjects from SEQUOIA and 128 from REDWOOD. The total OHQ MCID for improvement was a reduction of 0.9-1.2 points and for worsening was an increase of 0.7-1.1 points. The MCID for the OHSA composite ranged from a reduction of 0.9-1.3 points for improvement and an increase of 0.7-1.1 points for worsening. For the single-item OHSA1, the MCID was a reduction of 2.0-3.0 points for improvement and an increase of 1.0 point for worsening. Owing to poor correlation with the symptom-based anchors, a reliable MCID for the OHDAS component was not established. These MCID thresholds for the OHQ, OHSA and OHSA item 1 alone, enhance the interpretability of scores and support their use in evaluating clinical benefit.
Carotid sinus massage (CSM) is essential in evaluating recurrent unexplained reflex syncope, as it uniquely identifies cardioinhibitory forms that other tests may miss. CSM is largely underused in clinical practice outside dedicated syncope facilities and, when performed, its execution varies, as does the interpretation of results. Underuse affects the diagnostic yield of CSM in the syncope evaluation, thereby denying patients mechanism-based personalized treatment. There are several barriers to the proper use of CSM in the work-up of patients with unexplained syncope.To address these important limitations, an international panel of experts in the field of syncope provide herein a consensus document with the aim of offering practical guidance for the indications, contraindications, and methodology for performing carotid sinus massage in general and dedicated syncope facilities and in the emergency department.
To explore the relationship between primary focal hyperhidrosis (PFH) and generalized autonomic dysfunction, we assessed autonomic symptom burden using a comprehensive and validated measure of autonomic symptoms. In this case-control study, we compared 132 patients with PFH with 74 matched healthy controls. Autonomic symptoms were assessed using the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire. Propensity score matching minimized confounding. Mann-Whitney U tests compared COMPASS-31 scores between groups. A sensitivity analysis using multivariate linear regression accounted for specific hyperhidrosis sites and demographic factors. PFH cases demonstrated significantly higher median COMPASS-31 scores compared to controls (18.7 [IQR 7.7-34.8] vs. 11.2 [IQR 3.5-19.3], p < 0.001). Significant differences were observed in orthostatic (2.0 [0-20] vs. 0 [0-12], p = 0.028), vasomotor (0 [0-0] vs. 0 [0-0], p = 0.005; 24.2% vs. 9.5% non-zero scores, respectively), secretomotor (3.2 [2.1-8.6] vs. 0 [0-3.8], p < 0.001), and gastrointestinal (5.4 [1.8-8] vs. 1.8 [0.9-5.4], p = 0.004) domains. Sensitivity analysis confirmed PFH status as a significant predictor of higher COMPASS-31 scores (additional 7.5 points on average, 95% CI 1.6-13.4, p = 0.012) after adjusting for demographic factors and hyperhidrosis sites. Craniofacial and truncal hyperhidrosis were associated with higher autonomic symptom burden. PFH is associated with a broader spectrum of autonomic symptoms beyond localized sweating, establishing a link to more generalized autonomic dysfunction. These findings underscore the need for a comprehensive approach to evaluating and managing patients with PFH.
Our overarching objective was to determine whether autonomic reflex dysfunction and heightened sensory sensitivity contribute to orthostatic intolerance (OI) in patients with migraine. Adults with migraine (N = 30) underwent autonomic function tests summarized as the Composite Autonomic Severity Score (CASS) and vagal/adrenergic baroreflex sensitivity (BRS-V/A). Postural orthostatic tachycardia syndrome (POTS) and orthostatic hypotension/hypertension were diagnosed during tilt table testing. A cold pressor test (CPT) evaluated sympathetic vasomotor function. Participants completed the Migraine Disability Assessment (MIDAS), the 2011 Fibromyalgia (FM) Survey Criteria, and chronic overlapping pain condition (COPC) screening. The number of headache days per month correlated with CASS (p = 0.001), BRS-V (p < 0.001), and the CPT (p = 0.003) in the expected direction, with increasing autonomic nervous system (ANS) reflex dysfunction correlating with increasing number of headache days. During tilt testing, OI was prevalent (25/30; 83%) and was reported by all patients with chronic migraine. An abnormal cardiovascular response to tilt was present in 63%; POTS was the most common etiology (56.2%). Patients reporting OI during tilt table testing despite a normal cardiovascular response (33%) had higher FM scores (15.8 ± 3.6 vs. 7.5 ± 4.6; p < 0.01) and a greater prevalence of non-headache COPCs (88.8% vs. 20.0%, p = 0.02) than asymptomatic patients. Increased headache frequency correlates with increasing ANS reflex dysfunction. The high prevalence of OI in patients with migraine may be due to both autonomic reflex dysfunction and an abnormal cardiovascular response to tilt (i.e., concordant OI) and heightened sensory sensitivity (i.e., discordant OI).
Paroxysmal sympathetic hyperactivity (PSH) is a severe complication of acquired brain injuries (ABIs), characterized by sudden autonomic surges that exacerbate clinical outcomes. Its pathophysiology remains debated, and early biomarkers are lacking. This study aims to investigate autonomic changes preceding PSH and assess the feasibility of predictive modeling using heart rate variability (HRV). Continuous electrocardiogram (ECG) recordings were obtained from six male patients with disorders of consciousness (DoC), including unresponsive wakefulness syndrome and minimally conscious state. A total of 24 PSH episodes and 24 matched control (noPSH) events were analyzed. HRV metrics, including entropy measures and power spectral density (PSD), were evaluated. A support vector machine (SVM) classifier was implemented to differentiate PSH from control events and to predict PSH onset. PSH events were associated with significant heart rate increases, reduced entropy-based complexity, and decreased PSD in both low-frequency (LF) and high-frequency (HF) bands. An increased very-low-frequency (VLF)/(LF + HF) ratio suggested potential involvement of the renin-angiotensin-aldosterone system (RAAS) in PSH pathogenesis. The SVM classifier achieved perfect classification during the event. In addition, 10 min prior to onset, the model reached 67% sensitivity, 100% specificity, and 83% balanced accuracy. HRV analysis reveals distinct autonomic signatures preceding PSH and suggests, as a working hypothesis, that dysregulation of the RAAS may play a role. However, VLF power is influenced by multiple mechanisms and cannot be considered a specific or exclusive marker of RAAS activity. SVM-based predictive modeling offers a promising tool for PSH detection, providing a basis for investigating autonomic/neuroendocrine regulation, including RAAS.
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This study aimed to investigate autonomic alterations associated with periodic limb movements during sleep (PLMS) by comparing linear and non-linear heart rate variability (HRV) parameters across whole-night recordings and stage N2 non-rapid eye movement (NREM) sleep (N2). From 8082 polysomnographic (PSG) recordings, we identified 21 patients with PLMS and 28 age- and sex-matched controls. Linear and non-linear HRV indices were analyzed for whole-night recordings and the longest N2 segment. Periodic limb movement (PLM) indices and arousal-related parameters were also evaluated. Compared with controls, patients with PLMS showed significantly higher standard deviation of normal-to-normal intervals (SDNN) and root mean square of successive differences (RMSSD), increased low-frequency (LF) power, and reduced approximate entropy (ApEn) and sample entropy (SampEn) across the whole night, together with a lower Stress Index (SI). No significant group differences were observed in high-frequency (HF) power or in the composite sympathetic/parasympathetic nervous system (SNS/PNS) indices. During stage N2, the PLM group exhibited significantly greater SDNN, Poincaré plot long-axis standard deviation (SD2), detrended fluctuation analysis alpha-1 exponent (DFA α1), and very-low-frequency (VLF) power, along with lower ApEn values. A significant increase in the SD2/SD1 ratio was also observed specifically during N2, whereas the LF/HF ratio showed only a non-significant upward trend. PLMS counts, indices, and arousal-related parameters were markedly elevated during stage N2. PLMS are characterized by increased autonomic variability (SDNN, SD2, DFA α1) but reduced complexity (ApEn, SampEn), particularly during stage N2. Stage-specific HRV assessment may provide novel insights into the cardiovascular implications of PLMS.
This study investigated the relationship between short-term blood pressure variability (BPV), autonomic function measured by heart rate variability (HRV), and the prevalence of complex arrhythmias in hypertensive patients. We retrospectively analyzed 198 middle-aged and elderly patients with primary hypertension, stratified by tertiles of 24-h systolic BPV. Simultaneous 24-h ambulatory blood pressure and Holter monitoring were performed. Echocardiography was performed within 72 h of monitoring. HRV was analyzed in time and frequency domains, and a composite autonomic score was derived via principal component analysis. Complex arrhythmia was defined as Lown grade ≥ 3 or Kleiger grade ≥ 3.  The high-BPV group showed significantly reduced HRV across all indices and a higher incidence of complex arrhythmias (71.2% versus 40.9% in low-BPV group). BPV was inversely correlated with all HRV parameters, most strongly with SDNN. Multivariate analysis confirmed BPV as an independent negative predictor of the composite autonomic score. Logistic regression adjusted for medication use identified higher BPV, older age, and larger left atrial diameter as independent predictors of complex arrhythmias. Increased short-term BPV is independently associated with impaired cardiac autonomic function and is a significant predictor of complex arrhythmias in hypertension. Assessment of BPV may improve autonomic and arrhythmic risk stratification in this population.
Postural orthostatic tachycardia syndrome (POTS) is a condition defined by symptoms of orthostatic intolerance and a sustained heart rate (HR) increment of ≥ 30 beats per minute (bpm) upon postural change to the upright position in the absence of orthostatic hypotension, defined as a sustained decrease in systolic blood pressure (SBP) of ≥ 20 mmHg or a decrease in diastolic blood pressure (DBP) of ≥ 10 mmHg within 3 min of standing. In children, a sustained HR increment of at least 40 bpm is required for diagnosis of POTS. POTS is a common condition in adults and children suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In daily clinical practice, therapeutic recommendations are rare and evidence is missing. The objective of this review is to present the current knowledge on non-pharmacological and pharmacological approaches in POTS with a special focus on POTS therapy in children and people with ME/CFS. Of 3853 studies, 45 studies were included in the systematic review. Evidence on therapy in POTS is rare and large randomized controlled trials (RCT) on single interventions are needed. Non-pharmacological approaches such as the use of compression garments, physical training, salt supplementation and transdermal vagal nerve stimulation could be possible treatment options in POTS because they are easy to implement as first-line therapeutic measures in clinical practice. For pharmaceuticals, several studies showed significant effects following therapy with ivabradine and β-adrenergic blocking agents. There are single studies which imply that midodrine (hydrochloride) and pyridostigmine seem to have a beneficial effect on hemodynamics in POTS.
Postural orthostatic tachycardia syndrome (POTS) is a common autonomic disorder characterized by orthostatic intolerance and excessive tachycardia upon standing. Despite its prevalence, POTS is often underdiagnosed or diagnosed late, largely due to limited access to autonomic specialists and testing. This study aimed to evaluate the performance of machine learning (ML) models in diagnosing POTS using validated symptom surveys and physiological measurements. We retrospectively analyzed data from patients evaluated at the Autonomic Laboratory at Brigham and Women's Faulkner Hospital (2017-2025), with POTS diagnoses confirmed by autonomic testing. ML models based on a multilayer perceptron were trained using patient-reported surveys (Survey of Autonomic Symptoms [SAS], COMPASS-31) and autonomic testing data. Importantly, no orthostatic heart rate criteria for the POTS diagnosis were provided to the models. A total of 3210 patients were included, of whom 810 had confirmed POTS. All patients completed SAS; 1337 also completed COMPASS-31 (334 with POTS). Models incorporating heart rate data achieved the highest diagnostic accuracy (PyTorch/LightGBM: AUC 0.98/0.99; precision 0.94/0.93; F1 score 0.88/0.93; sensitivity 83%/92%; specificity 98%/98%). In contrast, models trained solely on SAS (AUC 0.68/0.63) or COMPASS-31 (AUC 0.66/0.62) performed poorly. ML models accurately diagnosed POTS when incorporating heart rate data alongside survey responses, with heart rate data being the strongest predictor. These findings suggest ML could assist in POTS diagnosis. The study also highlights the importance of heart rate measures in POTS diagnosis.
Orthostatic hypotension (OH), defined as a sustained reduction of ≥ 20 mmHg in systolic or ≥ 10 mmHg in diastolic blood pressure within 3 minutes of standing, represents one of the most clinically significant manifestations of autonomic failure. Beyond its hemodynamic definition, OH is associated with disabling symptoms, falls, syncope, reduced quality of life, increased healthcare utilization, and excess mortality. In clinical practice, management often requires balancing objective blood pressure measurements with the patient's lived experience of orthostatic intolerance. This viewpoint argues that symptoms represent an appropriate and clinically meaningful target for screening and management of OH. Three central assumptions support this perspective. First, patients are reliable reporters of orthostatic symptoms and clinicians are capable interpreters of these reports. Validated patient-reported outcome measures, such as the Orthostatic Hypotension Questionnaire (OHQ), demonstrate that symptom burden and functional impairment can be reproducibly quantified and that clinically meaningful changes can be detected. Second, although the relationship between orthostatic blood pressure changes and symptoms is not absolute, evidence supports a clinically relevant association, with symptomatic individuals often experiencing greater cerebral hypoperfusion when upright. Third, symptoms serve as a practical proxy for meaningful OH-related outcomes, including functional independence, fall risk, and quality of life, and have been accepted as primary endpoints in pivotal clinical trials. A symptom-centered framework complements objective hemodynamic assessment by contextualizing physiological findings within patients' functional experience. Integrating symptom reporting with orthostatic measurements provides a pragmatic, patient-centered approach to screening, treatment decisions, and evaluation of therapeutic response in OH.
To elucidate the pathophysiology of the carotid sinus reflex in a large cohort of patients with suspected reflex syncope. We reviewed an electronic database of patients with suspected reflex syncope who underwent carotid sinus massage. The diagnostic protocol included both right and left massage, in supine and upright positions, followed by tilt testing. The cohort included 2249 patients (52% male), median age 73 years. The conventional abnormality threshold of a maximum RR interval ≥ 3000 ms was present in 14.7% of patients and of a systolic blood pressure fall > 50 mmHg in 14.3% of patients. Abnormal responses occurred more frequently on the right side than the left side, and more during upright than supine testing. A second abnormal test occurred more often ipsilaterally. The extent of the maximum RR interval elicited by massage was independent of the baseline RR interval, whereas the difference in systolic blood pressure fall increased markedly with higher baseline values. The occurrence and severity of cardioinhibition and vasodepression increased with age, beginning at 40 years. Abnormal RR intervals and blood pressure drops were observed more frequently in men than in women. Additionally, there was only a limited correlation between positive responses to carotid massage and tilt testing concerning asystole and blood pressure reduction. Age, sex and initial systolic blood pressure strongly influence response to carotid sinus massage. Abnormal responses did not correlate with positive tilt test results, possibly as a result of opposing effects of age and sex on carotid sinus hypersensitivity and vasovagal syncope.
Postural tachycardia syndrome (POTS) is a chronic disorder marked by excessive orthostatic tachycardia, without clear structural/organic (e.g., cardiovascular) etiology. Recent evidence suggests that persistent autonomic symptoms may be driven by threat-induced and central nervous system-maintained dysregulation, similar to centralized chronic pain disorders. This study describes the rationale and development process of a brain-body intervention-POts Reprocessing Therapy (PORT)-aimed at reducing orthostatic symptomatology by taking advantage of the brain's plasticity. PORT was adapted from pain reprocessing therapy (PRT), an evidence-based mind-body approach for treating centralized chronic pain. The initial protocol was developed through consultations with multidisciplinary experts, including the developers of PRT. To refine the protocol, a focus group was conducted with five women participants with POTS who underwent an early version of PORT. Rapid qualitative analysis was conducted to identify themes and inform intervention improvements. The intervention consists of a medical evaluation followed by eight weekly treatment sessions. Intervention components include psychoeducation, safety learning-based exposure to symptoms, somatic inquiry, and emotional processing. Focus group participants identified reduced fear about symptoms, greater understanding of their condition, and improved functioning. Participants provided suggestions around language and content, and some shared emotional challenges of the treatment, underscoring the need for sensitive provider communication and implementation. This study introduces a novel therapeutic treatment for POTS that targets centrally mediated processes hypothesized to underlie persistent autonomic dysregulation. Trials are underway to formally assess feasibility, acceptability, and efficacy.
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by autonomic dysfunction, parkinsonism, and cerebellar impairment. Understanding the physiological correlates of disease severity and survival remains challenging due to heterogeneity in disease progression. Heart rate variability (HRV) is a noninvasive measure of autonomic nervous system function. However, the role of nonlinear HRV in MSA remains incompletely understood. This study investigated the association between HRV features, clinical severity, and survival in MSA (n = 214). Regression models were used to examine relationships between HRV and disease severity assessed by the Unified MSA Rating Scale (UMSARS), as well as time to death. Survival analyses evaluated the contribution of HRV features to risk stratification, and mediation analysis explored the relationships among HRV, UMSARS, and survival. HRV features were negatively associated with disease severity, consistent with progressive autonomic dysfunction. While individual HRV features showed limited associations with UMSARS, their combination demonstrated a stronger relationship. Models incorporating HRV features showed associations with time to death comparable to those based on UMSARS, and the combined inclusion of HRV and UMSARS was associated with improved accuracy. Mediation analyses suggested that HRV captures physiological information related to survival that is not fully reflected by clinical severity scores. HRV features are associated with disease severity and survival in MSA and provide complementary physiological information beyond established clinical scales. These findings support the relevance of HRV as an exploratory modeling tool for autonomic dysfunction in MSA and highlight candidate features for future longitudinal and validation studies, rather than establishing a validated prognostic model.
Despite the central role of exercise in treating postural orthostatic tachycardia syndrome (POTS) there have been no studies on the subjective experience of exercise interventions and/or recommendations among this patient population. The purpose of this mixed-methods study was to provide greater understanding of the perceived barriers, preferences, perceptions of exercise, and experiences implementing exercise recommendations for adults with POTS in order to optimize treatment recommendations and intervention design. This study consisted of a series of focus groups (n = 29) and an online survey of adults with POTS (n = 255) focusing on exercise engagement, beliefs, barriers, and facilitators. Qualitative data were analyzed using an iterative inductive-deductive approach, informed by social cognitive theory, which resulted in a conceptual framework and a series of themes. Survey results showed that participants reported a wide range of exercise frequency prior to the onset of POTS symptoms, and overall lower exercise engagement post-POTS. In both survey results and qualitative findings, participants reported believing that exercise is important in managing POTS, but identified barriers to exercise training, including most saliently, their symptom burden. Participants also identified important needs and facilitating factors that could support them in engaging in regular exercise to help manage their condition. These findings shed light on the patient experience of exercise in POTS, which can inform both the tailoring of exercise recommendations and the design of interventions to support exercise engagement specific to the POTS population.
The Unified Multiple System Atrophy Rating Scale (UMSARS) is widely used as an outcome measure in MSA trials, but it has limitations for clinical trial use. To address these, we developed the Multiple System Atrophy Combined Outcome Assessment (MuSyCA), a comprehensive multimodal tool for disease-modifying MSA trials. The purpose of this manuscript is to describe the development and validation plan for MuSyCA, with emphasis on its structure, intended use, and assessment of reliability, validity, and sensitivity in tracking disease progression. The development of MuSyCA followed a multistep process. Candidate outcome assessments were identified through systematic literature review and analysis of longitudinal data from large MSA cohorts. Content was refined through multiple Delphi-like consensus rounds involving MSA experts, patient advocacy groups representatives, and industry stakeholders. Cognitive interviews conducted in 20  patients with MSA evaluated the clarity and clinical relevance of patient- and clinician-reported outcomes; feedback was incorporated into a subsequent version of the MuSyCA. Validation is ongoing and includes assessment of construct validity, internal consistency, test-retest reliability, and responsiveness. Longitudinal analyses to determine sensitivity to change over time are ongoing. MuSyCA combines patient- and clinician-reported outcomes, biomarkers (neurofilament light chain, neuroimaging), and performance-based measures to capture subjective and objective aspects of MSA progression, enhancing its utility  to detect treatment effects in clinical trials. MuSyCa is not intended to be used in clinical practice. MuSyCA offers a multidimensional approach to MSA assessment, supporting precise, disease-relevant evaluations in trials of putative disease-modifying therapies. Its validation will provide a standardized multimodal outcome measure, advancing MSA therapeutic development.
Increased adiposity is associated with the development of cardiometabolic disturbances, with sympathetic dysregulation playing a crucial role in the early phase. Both adiposity and chronic sympathetic activation may impair cerebral function, increasing the risk of neurodegenerative diseases. However, whether adiposity and sympathetic activity are associated with brain dynamics in the healthy state is not fully understood. We performed magnetoencephalography in 29 healthy participants (12 males and 17 females; age 19-72 years; body fat percentage 7-45.3%) to record brain dynamics as neural activity index and functional connectivity. Adiposity was assessed using body fat percentage and microneurography was used to assess muscle sympathetic nerve activity. Individuals with higher fat percentage had higher muscle sympathetic nerve activity. Group comparison showed lower activity in the left posterior cingulate gyrus (delta and theta bands) and left precuneus (delta band) in individuals with higher fat percentage. Stronger connectivity between the right superior frontal gyrus and left temporal pole (delta band) was also seen in this group. Neural activity index in the right caudate (theta and low-gamma bands) correlated positively with muscle sympathetic nerve activity while correlating negatively with body fat percentage. We have shown that resting-state brain activity and functional connectivity are associated with adiposity and sympathetic activity even in healthy individuals with no manifest cardiometabolic diseases. Thus, the findings highlight that understanding central pathways associated with the healthy state may help to uncover the pathophysiology of obesity and associated metabolic disorders.