Mental disorders pose a major and growing challenge for health care systems worldwide, marked by persistent treatment gaps and limited access to psychotherapeutic care. Mind-body interventions such as mindfulness and relaxation practices are widely used in clinical contexts as low-threshold strategies to support stress regulation and psychological well-being. Despite their broad application, the mechanisms underlying their acute effects remain insufficiently understood, particularly regarding brain-body interactions. This study protocol describes a prospective multimodal investigation of regulation during brief mindfulness-and relaxation-based interventions in clinical populations (at least n = 15 adults with depression according to SCID-5-CV and at least n = 15 adults with adult ADHD according to SCID-5-CV). Using a standardized within-subject experimental paradigm, magnetoencephalography (MEG) will be combined with electrocardiography (ECG) and respiratory measures to capture fast neural dynamics and autonomic regulation during three randomized auditory conditions: mindfulness (body scan), relaxation (safe place imagery), and an auditory control condition (podcast). Subjective ratings of stress and relaxation will be collected repeatedly across the procedure, complemented by questionnaires characterizing interindividual differences relevant to regulation. Outcome measures will include indices of autonomic regulation derived from cardiac activity and respiration, as well as repeated subjective ratings of stress and relaxation across conditions. Neural measures (MEG) will be used to characterize condition-related brain dynamics and brain-body coupling metrics linking neural oscillations to cardiac and respiratory rhythms. Speech-related measures during auditory guidance and brief speech-production features from post-condition reflections will be included as complementary and exploratory extensions to increase psychotherapy relevance, while accounting for methodological challenges related to overt speech in MEG. By integrating neural, physiological, and subjective measures within a single standardized paradigm, this study protocol aims to advance a mechanistic understanding of brief mind-body interventions in clinically relevant populations. Focusing on dynamic brain- body interactions during stress and regulation, the proposed approach is designed to support transparent and reproducible investigation of regulatory processes that are relevant to psychotherapy-related mind-body approaches, clinical practice, and everyday self-regulation. The findings are expected to inform future translational research and contribute to the development of mechanism-informed and potentially personalized applications of mindfulness-and relaxation-based interventions.

Sudden cardiac arrest (SCA) remains a leading cause of mortality, accounting for 300,000-400,000 deaths annually in the United States. Despite advances in device therapy, current approaches to risk stratification remain limited in both sensitivity and specificity. This reflects a broader challenge in medicine: predicting low-incidence, high-consequence events, where traditional statistical frameworks often fail to achieve meaningful clinical utility. In this review, SCA is examined as a model problem highlighting key conceptual and methodological challenges, including class imbalance, heterogeneity of mechanisms, ambiguity in defining cases and controls, and temporal variability in risk. Electrocardiography (ECG) is emphasized as a scalable modality capable of capturing important components of the substrate-trigger-autonomic triad. However, existing ECG-based markers have not translated into robust clinical tools and recent machine learning approaches have not yet overcome this translational gap. We argue that the central translational gap is not the absence of stronger predictors, but insufficient specification of the clinical decisions, target populations, and performance thresholds against which model utility should be evaluated. Within this framework, ECG feature selection should be matched to the mechanistic target: depolarization markers index structural substrate, repolarization markers capture dynamic electrical instability, and autonomic markers reflect modulatory state, each operating on distinct timescales. Population decomposition into mechanistically coherent subproblems, rather than pursuit of a single overarching prediction model, is likely to accelerate both performance and clinical translation. Lessons learned from SCA may extend broadly to other high-impact, low-frequency conditions in medicine.

Despite substantial increases in pharmacological and psychotherapeutic treatment availability, global rates of psychological distress continue to rise, a pattern existing frameworks, taken individually, cannot fully explain. Current dominant models frequently conceptualize distress primarily as neurochemical dysfunction, emphasizing symptom reduction while leaving broader neurobiological signaling processes insufficiently addressed. For a clinically significant subset of individuals, this contributes to recurring symptom patterns, escalating treatment requirements, and eventual treatment resistance that existing literature has not yet fully accounted for. This paper introduces Adaptive Signal Theory (AST), an integrative evolutionary, ecological, and intergenerational framework proposing that psychological distress must be understood simultaneously across four nested levels: the evolutionary origin of distress signals, the autonomic mechanisms of their expression, the contemporary ecological conditions that chronically sustain them, and the intergenerational pathways through which dysregulation may transmit across generations. Critically, AST argues these levels are not parallel explanations for the same phenomenon; rather, they are nested layers of a single adaptive system, and failure to integrate them may produce predictable and clinically recognizable patterns of treatment limitation. Drawing on Polyvagal Theory (Porges, 2011), allostatic load theory (McEwen and Stellar, 1993), hormesis (Calabrese and Mattson, 2011), somatic trauma theory (Levine, 1997; van der Kolk, 2014), attachment theory (Bowlby, 1969), evolutionary psychiatry (Nesse, 2019; Hollon, 2020), and interpersonal neurobiology (Siegel, 2012), AST advances four central propositions: that psychological distress reflects functional neurobiological signaling; that exclusive symptom suppression may fail to resolve underlying threat-detection processes; that contemporary post-industrial environments may systematically deprive nervous systems of the relational, sensory, and co-regulatory inputs necessary for baseline neuroception of safety; and that chronic disruption of adaptive signal processing in caregivers may contribute to intergenerational consequences for infant neurobiological development. The perinatal period is examined as a clinically significant context in which all four propositions converge simultaneously, with implications for dyadic intervention, maternal regulatory restoration, and co-regulatory treatment approaches. A central clinical implication follows across populations and presentations: treatment effectiveness depends on alignment between the level at which a signal is generated and the level at which intervention is applied. Directions for future empirical investigation and interdisciplinary clinical application are discussed.

Heart rate variability (HRV) is widely used as a non-invasive marker of autonomic regulation and physiological adaptability, with relevance across cardiovascular, metabolic, neuropsychiatric, and stress-related conditions. HRV biofeedback has emerged as a non-pharmacological intervention intended to influence autonomic function through paced breathing, resonance-frequency training, and real-time physiological feedback. Although this approach has shown promise in improving stress regulation, emotional symptoms, autonomic balance, and selected cardiovascular outcomes, its effects are not consistent across individuals or clinical states. The reasons for this variability remain insufficiently conceptualized. In this narrative conceptual review, we propose the concept of autonomic non-responsiveness during HRV biofeedback as a descriptive framework for situations in which expected autonomic engagement is weakened, absent, or fails to translate into meaningful physiological or clinical benefit. We discuss potential contributors to non-response, including reduced autonomic flexibility, impaired baroreflex function, disease burden, fatigue, stress-related overload, dysfunctional breathing, methodological limitations, and cognitive-behavioral constraints. We then consider the clinical implications of recognizing non-response as a potentially informative state rather than a simple negative outcome. Finally, we outline a future research agenda focused on operational definition, candidate biomarkers, temporal characterization, and minimally adaptive closed-loop systems.

Radon balneotherapy, a form of low-dose radiation treatment, has been utilized for decades in managing rheumatologic diseases, particularly in Central Europe and parts of Asia. Despite ongoing debate about its efficacy, developing research suggests that low-dose exposure to radon may exert anti-inflammatory and analgesic effects, with potential implications for musculoskeletal and cardiovascular health. This narrative review aims to synthesize current knowledge on the biological mechanisms underlying radon therapy, evaluate clinical evidence for its efficacy in rheumatologic conditions, and explore its potential impact on cardiovascular health. Risks, controversies, and regulatory restrictions are also addressed. Preclinical studies indicate that radon therapy modulates oxidative stress responses, immune signalling cascades, and pro-inflammatory cytokine profiles, thereby influencing tissue homeostasis and pain perception. Clinically, benefits have been observed in patients with rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis, particularly with respect to pain alleviation, functional improvement, and quality of life. However, heterogeneity in treatment protocols, study quality, and confounding factors such as the use of heat, carbon dioxide, and/or other concurrent modalities limit generalizability and attributability. Evidence regarding cardiovascular safety remains sparse but suggests that low-dose exposure may have neutral or even protective effects under specific physiological conditions. In summary, radon balneotherapy may have a complementary role alongside other modalities like heat and negative air ions. However, the isolated therapeutic efficacy, long-term safety profile, and cardiovascular implications of radon balneotherapy remain insufficiently characterized. Higher quality multi-armed randomized controlled trials and isolated mechanistic investigations are needed to better delineate its biological mechanisms, optimize protocols, and define its clinical niche.

Chronic stress exposure contributes to the onset and maintenance of a wide range of mental and physical disorders. Non-invasive modulation of vagal pathways has received increasing attention as a potential strategy for the prevention and treatment of stress-related conditions, given the central role of the vagus nerve in brain-body communication. By stimulating auricular vagal afferents, transcutaneous auricular vagal nerve stimulation (taVNS) is proposed to engage stress regulatory circuits, with downstream effects that may modulate stress-related physiology. Consistent with this mechanistic rationale, preclinical rodent research has begun investigating the effectiveness of taVNS as a non-invasive approach to mitigate stress-related outcomes. The aim of this narrative review is to summarize this emerging preclinical evidence, focusing on potential mechanisms involving central neural circuits implicated in stress regulation, as well as downstream autonomic function, inflammatory signaling pathways, and gut microbiota composition. Collectively, available studies support taVNS as a multi-system modulator of stress responses acting through interconnected neural, autonomic, immune, and gut-brain pathways. However, preclinical taVNS research remains at an early stage. Major unresolved challenges include the lack of standardized stimulation parameters and insufficient consideration of biological sex as a critical experimental variable. Addressing these limitations will be essential to improve reproducibility and strengthen translational relevance.

This review synthesizes current evidence on autonomic nervous system (ANS) dysfunction in irritable bowel syndrome (IBS). Patients with IBS often exhibit sympathovagal imbalance-reduced vagal tone with relative sympathetic hyperactivity-which correlates with symptom severity and shows subtype specificity. The ANS orchestrates bidirectional brain-gut communication via interactions with psychosocial factors, low-grade neuroinflammation, and the gut microbiota. Key mechanisms include vagal afferent signaling by microbial metabolites, sympathetic regulation of mucosal immunity, stress-induced disruption of autonomic homeostasis, and neuroplastic changes in intestinal and central pain pathways. Emerging evidence supports therapeutic targeting of autonomic circuits through vagus nerve stimulation, pharmacological modulation of serotonin and adrenergic receptors, and microbiome-based interventions. Current challenges include methodological limitations in assessing neural dynamics and insufficient integration of multi-system interactions. Future research should employ multi-omics approaches to elucidate pathway-specific mechanisms and develop precision medicine strategies for this heterogeneous disorder.

Parkinson's disease (PD) exhibits highly heterogeneous clinical trajectories, yet "advanced PD" (aPD) lacks a standardized definition. Current reliance on clinical milestones (e.g., motor fluctuations, cognitive decline) is limited by non-linear progression and the absence of objective measures. Although biomarkers like aggregated α-synuclein, MRI, and PET are under investigation, their correlation with clinical progression remains modest. Robust, reproducible endpoints are urgently needed to evaluate disease-modifying therapies across diverse phenotypes, accounting for genetic background, age of onset, co-pathologies, and motor/autonomic/cognitive domains. Given this complexity, single-target interventions are likely insufficient. We propose a multi-domain therapeutic framework for aPD that integrates: (A) simultaneous targeting of key pathological cascades, including α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, proteostasis imbalance, neuroinflammation, and the gut-brain axis; (B) biology-driven patient stratification using emerging biomarkers to match subgroups with targeted interventions; and (C) systematic management of comorbidities and lifestyle factors, such as cardiovascular health and exercise, to enhance neuroresilience. Finally, advancing aPD care requires addressing systemic determinants, including global healthcare inequities, and prioritizing caregiver well-being. Mechanistically informed, patient-centered strategies that combine multi-target therapies with precision stratification and holistic support will be essential to modify disease progression and improve long-term outcomes.