Background/Objectives: Sport participation and nutrition are increasingly recognized as key determinants of cognitive function and academic achievement in student populations. However, the biological mechanisms underpinning these associations remain only partially understood. This scoping review aimed to map and synthesize the current evidence on neuroendocrine and autonomic mechanisms linking physical activity, sport participation, and nutrition to cognitive and academic outcomes in students. Methods: A systematic search of electronic databases was performed following PRISMA-ScR guidelines. Studies involving student populations that examined physical activity, sport participation, or dietary patterns in relation to cognitive function and/or academic performance were included. Particular attention was given to studies reporting biological or physiological indicators of underlying mechanisms, including neuroendocrine, autonomic, and brain-based measures. Data were extracted and synthesized qualitatively, with studies categorized according to the type of mechanistic evidence. Results: A total of 76 studies met the inclusion criteria. The available evidence was more extensive for physical activity, sport participation, and fitness-related exposures than for nutrition-related variables or integrated lifestyle models. Cognitive outcomes, particularly executive function, attention, working memory, and memory performance, were assessed more frequently and showed more consistent associations with lifestyle behaviors than academic outcomes, which were less commonly and more heterogeneously evaluated. Mechanistic evidence was unevenly distributed: only a limited subset of studies included direct biological or psychophysiological measures, mainly neuroimaging, brain-derived neurotrophic factors, cortisol-related indices, or heart rate variability. In contrast, inflammatory, metabolic, and gut microbiota-related mechanisms were mostly discussed at a conceptual or indirect level. Overall, the findings indicate a broad associative literature but a relatively small body of studies directly testing biological pathways linking physical activity, nutrition, cognition, and academic performance. Conclusions: Current evidence indicates potential associations between sport participation, nutrition, cognitive outcomes, and multiple biological pathways. However, the scoping nature of the review, the predominance of observational designs, and the limited use of direct mechanistic assessments prevent firm causal conclusions. Future research should prioritize longitudinal and intervention studies integrating behavioral, nutritional, cognitive, academic, and biological measures within the same design.
Asthma is a heterogeneous inflammatory disease driven by complex genetic, immunological, environmental, and neuro-immune interactions. Modern therapeutic strategies increasingly target distinct molecular mechanisms underlying specific asthma endotypes. Emerging evidence highlights the role of psychological stress in modulating the neuro-immune axis, contributing to allergic airway inflammation. Systems biology offers a powerful framework to understand the multi-cellular and cross-organ interactions between lung and brain microenvironments that drive asthma pathogenesis. To develop a molecular systems architecture of asthma using the CytoSolve® systems biology platform and process. This approach enables a multi-layered, systems-level analysis of molecular pathway interactions across thirty-one pulmonary, immune, and neuronal cell types involved in allergic-eosinophilic and non-allergic asthma phenotypes, and identifies potential therapeutic targets. A systematic bioinformatics literature review was conducted using Medical Subject Headings (MeSH) across PubMed, Medline, and Google Scholar, covering peer-reviewed publications from January 2008 to August 2025. Relevant full-length articles were curated and analyzed using the CytoSolve® platform to construct a molecular systems architecture of asthma. The relevant literature was critically analyzed to understand the link between environmental and psychological stress triggers that drive asthma pathogenesis and disease exacerbations. The systems architecture identified biomolecular interactions across thirty-one cell types spanning bronchial, immune, stromal, vascular, endocrine, and neuronal compartments, including airway epithelial cells, T-cells, eosinophils, mast cells, fibroblasts, microglia, hypothalamic and brainstem neurons, vagal sensory neurons, and autonomic airway neurons. Environmental triggers such as pollutants and infections initiate cascades that promote three core pathobiological processes: airway inflammation, hyperresponsiveness, and remodeling. Psychological comorbidities, including anxiety and depression, further amplify airway inflammation through brain-lung cross-talk, contributing to neuronal inflammation and asthma exacerbations. This system architecture generated a multilayered visual map that shows the associations between various triggers and biomolecular interactions across airway and neuronal cell types in the lung and brain microenvironment, respectively. The architecture may be utilized for target identification, discovery of single and combination therapeutics, biomarkers, and clinical strategies to treat asthma endotypes.
Deep brain stimulation (DBS) and spinal cord stimulation (SCS) are widely used neuromodulation therapies for movement disorders, pain, neuropsychiatric conditions, and other indications. Beyond symptom control, both techniques may modulate neuroendocrine and metabolic pathways, but the available evidence is fragmented across targets, indications, and hormone systems. This review aims to map the existing human and preclinical evidence on hormonal and neuroendocrine changes associated with DBS and SCS across different stimulation targets and clinical indications. We conducted a scoping review following PRISMA guidelines. Experimental and clinical studies, case series, and case reports reporting hormonal, endocrine, or neuropeptide outcomes during or after DBS or SCS were eligible. Data were charted for study design, population (human/animal), indication, stimulation target/level, stimulation type, hormones assessed, direction of hormonal change, associations with clinical outcomes, and side effects. Given heterogeneity of designs and outcomes, results were synthesized narratively and organized by stimulation modality. Eighteen studies were included: thirteen focused on DBS and five on SCS. DBS of the subthalamic nucleus, hypothalamus, nucleus accumbens, bed nucleus of the stria terminalis, medial forebrain bundle, and basolateral amygdala was associated with changes in prolactin, TSH, ACTH, cortisol/corticosterone, testosterone, thyroid hormones, ghrelin, NPY, insulin, leptin, and oxytocin, with some studies linking these changes to weight gain, mood elevation, pain behavior, or OCD symptom trajectories. SCS studies reported modulation of leptin and catecholamines in humans, oxytocin release in analgesia models, and norepinephrine dynamics in cardiac and autonomic contexts. DBS and SCS can modulate multiple endocrine axes in a target- and indication-specific manner, but the literature is sparse, heterogeneous, and largely exploratory, especially for SCS. Systematic hormone monitoring in neuromodulation trials, with standardized reporting of endocrine outcomes, is needed to clarify mechanisms, predict responders, and anticipate metabolic and neuropsychiatric side effects.
While systemic inflammation is the hallmark of Systemic Lupus Erythematosus (SLE) and Sjögren's Syndrome (SS), the failure of endogenous "anti-inflammatory brakes" remains poorly understood. The Hypothalamic-Pituitary-Adrenal (HPA) axis and the Autonomic Nervous System (ANS) constitute the body's primary neuro-immune regulatory circuit. This study investigates whether concurrent dysregulation of these two systems contributes to the persistent inflammatory state in SLE and SS. In this cross-sectional study, we evaluated 40 patients with Systemic Lupus Erythematosus (SLE), 40 with Sjögren's Syndrome (SS), and 32 age- and sex-matched healthy controls. Cardiac autonomic modulation was quantified via Heart Rate Variability (HRV) analysis using short-term (5-minute) ECG recordings. The dynamic activity of the hypothalamic-pituitary-adrenal (HPA) axis was mapped through the Cortisol Awakening Response (CAR), utilizing salivary samples collected at four precise time points (awakening, +30 min, +60 min, and bedtime) and analyzed via ELISA. To ensure protocol reliability, only samples from participants with verified spontaneous awakening were included. Systemic inflammation was assessed through hemogram parameters and serum C-reactive protein (CRP, mg/dL) levels. Our data reveal a distinctive neuroendocrine-immune signature in both disorders. Both SLE and SS patients exhibited a significantly blunted CAR at 60 min (p < 0.05), suggesting a failure in the "anticipatory" stress response. Autonomic profiling showed widespread impairment in SDNN and Total Power (p < 0.05) across both groups. Notably, we identified a phenotypic divergence: SLE patients demonstrated a specific impairment in parasympathetic "vagal tone" (RMSSD and HF), whereas SS patients were characterized by a unique leukocyte and neutrophil depletion (p < 0.05). This suggests that while HPA hyporesponsiveness is a shared trait, the autonomic-immune coupling may follow disease-specific pathways. This study provides compelling evidence of interrelated regulatory alterations in the neuro-immune axis of SLE and SS patients. The combination of diminished cortisol signaling and impaired vagal modulation creates a "permissive environment" for chronic inflammation. By demonstrating that the degree of HPA suppression correlates with autonomic rigidity, we propose a new theoretical framework: systemic autoimmunity is not merely an immune defect but a dysregulation of the neuroendocrine-autonomic homeostatic loop. Targeting this "stress-axis" could provide a novel bio-behavioral window for therapeutic intervention and disease monitoring.
While the pain- and stress-reducing effects of music are well investigated, effects of visual art and the combination of both modalities (music and visual art) are much less explored. We tested the (1) pain- and (2) stress-reducing effects of a multimodal (music + visual art) aesthetic experience-expecting stronger effects than single modal aesthetic experiences (music or visual art)-and, in an exploratory manner, (3) investigated underlying mechanisms of aesthetic experience and (4) individual differences. In a repeated-measures design (music, visual art, multimodal aesthetic experience, control), 42 female participants submitted their self-selected movingly beautiful visual artworks and music pieces to the lab, where pain and stress were induced by a cold pressor test. Pain (global pain perception, pain intensity, pain affect, pain tolerance) and stress responses (subjective reports, autonomic [electrocardiography, electrodermal activity, salivary alpha-amylase] and endocrine activity [salivary cortisol]) were measured. Individual differences of the experience, trait empathy and absorption were investigated. Exposure to multimodal art resulted in longer pain tolerance (M = 80.19s; SD = 61.05) compared to visual art (M = 56.63s; SD = 47.86), but not compared to music (M = 81.34s; SD = 64.19; p < .001; η² = .039). Other measures of pain intensity, stress intensity, and pain affect did not differ across the conditions. Exposure to all types of art distracted participants' attention from pain, prompted mind wandering, and elicited greater enjoyment than the control condition. While participants were overall more stressed during the cold pressor test, no differences emerged across the four conditions (p = 0.38; η² = .012). Also, no differences were found regarding cortisol and alpha-amylase. Regarding individual differences, higher trait absorption was associated with longer pain tolerance in the multimodal condition (b = 0.58, SE = 0.29, t(120)=2.02, p = .046) and with lower pain intensity in the music-only condition (b = -0.27, SE = 0.12, t(120)=-2.20, p = .030), compared to the other conditions. In conclusion, exposure to art can influence pain; however, the underlying mechanisms require further research.
Acute ischemic stroke constitutes a significant systemic stress event that initiates a complex cascade of neuroendocrine and autonomic responses. Central to this process is activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system, reflecting the brain's integrated response to acute cerebral injury. These changes are accompanied by widespread alterations in physiological regulation, including endocrine signaling, autonomic balance, circadian organization, and cardiovascular control. Understanding the nature and coordination of these responses is important for gaining insight into the broader pathophysiological impact of acute ischemic stroke beyond focal neuronal damage. This narrative review provides an overview of the mechanisms underlying HPA axis activation, circadian rhythm dysregulation, and autonomic dysfunction in the setting of acute ischemic stroke. Particular emphasis is placed on the interactions between neuroendocrine signaling and cardiovascular regulation, highlighting how disruptions in these systems may reflect the severity of systemic stress and autonomic imbalance. The review also discusses the relevance of neuroendocrine and autonomic biomarkers, including cortisol, melatonin, and ambulatory blood pressure parameters, as integrative indicators of physiological stress, autonomic regulation, and recovery patterns in acute stroke.
Non-motor symptoms, especially autonomic dysfunction, are major contributors to disability and decreased quality of life in Parkinson's disease (PD). Despite being common and having a wide range of clinical facets, exocrine gland dysfunction is still not well recognized and managed. The aim of this narrative review is to present a thorough and integrative synthesis of exocrine gland dysfunction in PD, including an overview of its underlying mechanisms, clinical manifestations, diagnostic techniques, and treatment approaches. We critically reviewed the literature addressing autonomic regulation of exocrine glands, α-synuclein pathology in central and peripheral autonomic networks, and clinical studies of glandular dysfunction across salivary, lacrimal, sebaceous, nasal, sweat, gastric, and pancreatic systems in PD. Exocrine dysfunction in PD is multifaceted and potentially linked to degeneration within central autonomic control regions, peripheral autonomic nerves, and even glandular tissues themselves, often compounded by iatrogenic medication effects. Importantly, certain disturbances may precede motor features, underscoring their potential as prodromal markers. Clinically, such dysfunctions significantly impair different aspects of health and well-being overall. Multidisciplinary approach is needed for management, striking a balance between symptom relief and consideration of treatment-related tradeoffs. Exocrine gland dysfunction represents a prevalent, intricate, and clinically significant range of non-motor symptoms in PD, indicative of extensive autonomic involvement. Early detection may enhance quality of life and symptom management while also offering insights into disease mechanisms, the discovery of biomarkers and therapeutic interventions.
Hormonal dysregulation is increasingly reported in ME/CFS and Long COVID, yet the broader role of neuroendocrine disruption in these conditions remains underexplored. While changes in steroid, peptide, and neuropeptide hormones have been identified, these findings are often considered in isolation and without attention to their timing or integration within broader physiological systems. The hypothalamic-pituitary axes regulate endocrine, immune, autonomic, nervous, and metabolic functions, systems commonly affected in both conditions, yet their circadian and menstrual dynamics are rarely investigated. In this review, we examine the evidence for neuroendocrine dysfunction in ME/CFS and Long COVID, focusing on hormone output, functional assays, receptor expression, and the coordination of endocrine biorhythms. Sex hormone signalling emerges as a key area of vulnerability, particularly given the female predominance in both conditions and the complexity of reproductive hormone regulation. We argue that accurate hormone measurement and time-structured sampling, including circadian and menstrual rhythms, are essential for detecting meaningful biological differences. By embedding chronobiology-aware, dense-sampling strategies and integrating multi-omic analyses into multi-system study designs, we outline a framework for investigating dynamic endocrine mechanisms underlying symptom variability and multisystem dysfunction, which may ultimately support the development of more targeted, personalised interventions.
Unconscious/implicit processes are increasingly conceptualized as biologically instantiated, multisystem regulatory functions rather than purely psychological constructs. This review examines whether an integrative framework linking psychoneuroimmuneendocrine (PINE) regulation, epigenetic mechanisms, and principles of morphogenetic organization can help organize evidence relevant to "unconscious ontogenesis." To systematically review empirical evidence on PINE-related regulation and epigenetic modifications associated with unconscious/implicit processing, and to evaluate developmental morphogenetic principles as an organizing conceptual template (distinct from direct evidence of adult unconscious processing). We searched PubMed/MEDLINE, Web of Science, and Scopus (1990-2024), plus gray literature sources, for experimental and observational studies, systematic reviews/meta-analyses, and a limited set of theoretical/historical works used only for conceptual context. Unconscious/implicit processing was operationalized as outcomes measured with implicit or non-conscious paradigms (behavioral tasks) and/or biological proxies of automatic regulation (e.g., autonomic, endocrine, immune, epigenetic, or neuroimaging markers) when the study design or authors' framework explicitly linked these measures to implicit/unconscious processing. Risk of bias was assessed with RoB 2, ROBINS-I, Newcastle-Ottawa Scale, and GRADE as appropriate; theoretical works were excluded from quantitative synthesis and bias assessment. No language restrictions were applied at the search stage; non-English studies were screened via available abstracts and full texts were used when accessible. From 1,245 records identified, 58 studies met inclusion criteria; 30 contributed to the quantitative synthesis. Evidence most consistently supported associations between PINE-system dysregulation and stress-adaptive behavioral/physiological outcomes, as well as between environmental exposures and epigenetic modifications relevant to neurodevelopment and stress regulation. In contrast, morphogenetic fields and morphogen-gradient principles were supported as established developmental biology mechanisms but did not provide direct quantitative evidence for adult unconscious processes, and were therefore treated exclusively as a conceptual organizational layer. Available evidence supports PINE regulation and epigenetic mechanisms as empirically grounded contributors to multisystem integration relevant to unconscious/implicit regulation. Morphogenetic principles are best interpreted as a developmental organizing template rather than as empirically supported mechanisms of unconscious processing, generating testable hypotheses for future prospective and mechanistic studies. https://www.crd.york.ac.uk/prospero/, identifier [CRD42024594352].
We are seeing an exploding expansion of antisemitic attacks worldwide, raising concerns about their potential impact on biological stress regulation and health. Antisemitism is a historically persistent and structurally embedded form of social exclusion that may contribute to chronic psychosocial stress exposure. Building on research into intergenerational trauma, including neuroendocrine alterations in Holocaust survivors and their descendants, this commentary integrates psychometric, empirical, and conceptual approaches to propose a biologically grounded framework linking antisemitism to endocrine and cardiometabolic processes. Preliminary findings from a pilot study using a Checklist of Antisemitic Perception instrument, in combination with established psychometric measures, indicate an increased psychological burden associated with antisemitic experiences, with clinically relevant symptom levels observed across groups. Mechanistically, chronic stress is mediated by neuroendocrine pathways involving the hypothalamic-pituitary-adrenal axis, autonomic nervous system, and immune regulation, contributing to allostatic load and cardiometabolic risk. Emerging evidence suggests that stress responses are heterogeneous and influenced by individual coping styles, with distinct allostatic set-points and associated neurobiological adaptations, including alterations in striatal glutamatergic signaling. Institutional and discursive contexts may further modulate exposure to antisemitic stressors, as reflected in heterogeneous professional engagement and variations in thematic emphasis within medical discourse. Taken together, these observations support the conceptualization of antisemitism as a chronic stressor with potential biological consequences and highlight the importance of integrating psychometric and biological approaches in future research.
Adolescents who engage in nonsuicidal self-injury (NSSI) show a high sensitivity to ostracism, and its effects may be amplified by dysregulated stress-system function. However, ecologically grounded experimental studies examining multilevel stress responses in adolescent mental health remain scarce. We used a novel, ecologically valid in-person ostracism paradigm to assess subjective, autonomic, and endocrine responses in adolescents with recent NSSI and to characterize stress trajectories. Fifty adolescents with recent NSSI (mean age = 16.40 years, 76% female) were randomized (1:1) to live social inclusion or exclusion in a face-to-face ball-toss task based on the Cyberball paradigm. Salivary cortisol was sampled at five points from pre-task to 40 min post-task. Heart rate (HR) and heart rate variability (HRV) were recorded at baseline and during the interaction. Subjective stress, tension, and NSSI urges were assessed before and after the task. Perceived exclusion and psychological need threat were also assessed. We found clear ostracism effects on perceived exclusion and basic psychological need threat. Cortisol declined across the paradigm in both conditions (inclusion/exclusion), but the decline was flatter after exclusion, indicating attenuated hypothalamic-pituitary-adrenal axis downregulation. HR decreased modestly over time across conditions, and HRV diverged by condition: it decreased during exclusion and increased during inclusion. There were no condition-related changes in self-reported stress, tension, or NSSI urges. These findings suggest a decoupling between subjective and psychobiological stress systems in adolescents with NSSI in response to ostracism, characterized by rapid parasympathetic withdrawal and a blunted HPA axis downregulation. This pattern may reflect heightened physiological sensitivity to social threat despite limited conscious distress. This study has been registered at the German Clinical Trials Register (ID: DRKS00025905, https://drks.de/search/en/trial/DRKS00025905).
Resilience is assumed to shape how individuals respond and adapt to stress, potentially through mechanisms such as habituation to repeated exposure. However, few studies have tested links between self-reported resilience and biological stress regulation in a multisystem framework. Here, we tested whether resilience predicts stress reactivity and habituation across endocrine, autonomic, and subjective domains, and cumulative HPA-axis output. Healthy adults (N = 120) underwent the Trier Social Stress Test (TSST) twice, one week apart. Stress reactivity and habituation were assessed repeatedly via salivary cortisol, salivary alpha-amylase (sAA), cardiovascular measures, and self-reports. Hair cortisol and cortisone were measured once to index cumulative HPA-axis output. Resilience was assessed using the Connor-Davidson Resilience Scale 25, Resilience Scale 25, and the State and Trait Assessment of Resilience Scale. The TSST reliably induced stress across all markers. HPA-axis and cardiovascular markers showed reduced responses on Day 2, consistent with habituation, whereas sAA showed no habituation. Trait resilience scales consistently predicted nominally significant reductions in subjective stress reactivity on Day 1 but were not significantly associated with habituation or cumulative HPA-axis output. State resilience remained stable across sessions and was unrelated to stress markers. Despite interindividual variability in stress reactivity and habituation, we found no evidence that self-reported resilience is associated with biological stress measures. While higher resilience may buffer subjective stress responses to novel psychosocial challenges, no corresponding associations with biological stress adaptation were observed. This pattern challenges assumptions about the relationship between resilience and physiological stress adaptation, underscoring conceptual and methodological challenges when delineating the biological correlates of resilience.
Cardiovascular autonomic symptoms, particularly orthostatic intolerance, are frequent in fibromyalgia syndrome (FMS) and markedly contribute to disability, yet their underlying mechanisms remain unclear. Small fiber pathology (SFP), detected in 30-50% of patients with FMS, may also involve postganglionic sympathetic fibers. This study examined the contribution of SFP to autonomic dysfunction and cardiovascular autonomic symptoms in FMS. We prospectively enrolled 43 patients with FMS reporting orthostatic intolerance and 20 age- and sex-matched healthy controls. All participants underwent comprehensive cardiovascular autonomic testing, including head-up tilt, Valsalva maneuver, deep breathing, and spectral analysis of heart rate variability (HRV). Skin biopsies quantified intraepidermal (IENFD) and autonomic small-fiber densities, and patients were stratified into FMS with or without SFP. Compared with healthy controls, patients with FMS showed reduced HRV, diminished parasympathetic modulation, and increased sympathetic predominance, together with impaired dynamic sympathetic recruitment during tilt. Although these abnormalities were present across the FMS cohort, patients with SFP displayed greater impairment across autonomic parameters, with more pronounced tachycardic responses and more severe orthostatic symptoms during tilt. Small fiber damage also correlated with indices of sympathetic hyperactivity, while no associations were observed between autonomic parameters and pain severity. Cardiovascular autonomic dysfunction in FMS reflects alterations in central autonomic networks, partially modulated by peripheral small fiber damage. Identifying SFP as a contributor to autonomic disturbances in FMS may aid patient stratification and support targeted therapeutic strategies.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and bone destruction, accompanied by gut microbiota dysbiosis, neuroimmune dysfunction, and systemic inflammatory amplification. Increasing evidence from the gut-joint axis indicates that microbial dysbiosis disrupts intestinal barrier integrity, enhances permeability, and promotes the translocation of microbial products and antigens, thereby triggering systemic inflammation and autoimmune responses. Meanwhile, alterations in microbial metabolites, including short-chain fatty acids, bile acids, and tryptophan derivatives, drive disease progression by regulating mucosal homeostasis, inflammatory resolution, and the Th17 cells/Tr cells balance. Persistent dysbiosis further activates peripheral immunity and promotes the recruitment of pro-inflammatory cells and mediators to the synovium, resulting in synovial hyperplasia, cartilage degradation, and bone erosion. Concurrently, gut-derived metabolic signals, vagal afferents, and immune mediators modulate central nervous system function and neuroinflammation, whereas brain-derived stress responses regulate intestinal barrier function, microbial composition, and gut immune homeostasis via the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system, collectively exacerbating systemic inflammation. Thus, a dynamic cross-system network linking the gut, brain, and joints is established, involving neural pathway coupling, immune cell migration and recruitment, endocrine regulation, and metabolic messenger- and inflammatory axis-mediated interactions. Microbiota-directed strategies restore microbial homeostasis and barrier integrity to reduce the initiation of inflammation; metabolic interventions rebalance immune and bone homeostasis through key signaling pathways, e.g., tryptophan and short-chain fatty acid pathways; neuroimmune regulation attenuates inflammatory amplification via the cholinergic anti-inflammatory pathway and HPA axis modulation; and multi-target approaches integrate the advantages of microbiota, metabolism, neural, and local inflammatory control to improve therapeutic efficacy. This review elucidates RA from the integrated perspective of the gut-brain-joint axis, providing mechanistic insights into systemic inflammation and supporting the development of novel therapeutic strategies. 类风湿关节炎（RA）是一种慢性自身免疫病，其发生发展除关节局部炎症和骨破坏外，还与肠道微生态失衡、神经免疫异常及全身炎症放大密切相关。近年来，肠-关节轴相关研究表明，肠道微生态失衡可破坏肠屏障完整性，增加肠道通透性，促进微生物产物和抗原易位入血，诱发系统性炎症和自身免疫反应;短链脂肪酸、胆汁酸和色氨酸等微生物代谢产物异常又可通过影响黏膜稳态、炎症消退及辅助性T细胞17/调节性T细胞平衡推动疾病进展;持续的菌群失调进一步激活外周免疫系统，促进分泌促炎性细胞的免疫细胞向滑膜募集，最终导致滑膜增生、软骨侵蚀和骨破坏。同时，肠源性代谢信号、迷走神经传入及免疫介质共同参与中枢神经系统功能和神经炎症调控，而脑源性应激又可经下丘脑-垂体-肾上腺轴（HPA轴）及自主神经系统下行作用于肠屏障、菌群组成和肠道免疫环境，进一步放大全身炎症反应。肠、脑与关节之间形成涉及神经通路联动、免疫细胞迁移和募集、内分泌调控，以及代谢信使和炎症轴介导的动态交互网络。针对该轴关键环节，菌群导向策略可通过重塑微生态和修复肠屏障降低炎症起点，代谢干预可通过调控色氨酸和短链脂肪酸等关键信号恢复免疫和骨代谢稳态，神经免疫调节可通过增强胆碱能抗炎反射及调控HPA轴相关通路缓解炎症放大，多靶点协同防治则有望整合菌群、代谢、神经和局部炎症控制的优势，提高综合干预效果。本综述从肠-脑-关节轴视角认识RA，有助于深化对其系统性炎症机制的理解，并为相关干预策略的研究和临床转化提供参考。.
Tumor neuron hijack is a malignant adaptive program whereby tumor cells recruit, physically engage and functionally reprogram the peripheral and central nervous system within the local microenvironment and host macroenvironment; this process not only exploits neuro-immune regulatory machineries, neural endocrine signaling, and nutrient supply for sustaining tumor growth, invasion, metastasis, immune escape and treatment resistance, but also closely involves the induction and amplification of cancer-associated pain, a common and debilitating manifestation of the host's pathological response to tumor-neural crosstalk, which further perturbs the host macroenvironment and facilitates tumor progression. Neoplastic cells employ context-dependent strategies: central nervous system tumors (e.g., gliomas) integrate into existing neuronal circuits via synaptogenesis and metabolic coupling, while peripheral solid tumors induce de novo innervation via neurotrophic factors, axon guidance cues regulating angiogenesis, and perineural invasion. Sympathetic, parasympathetic, and sensory nerves modulate tumor behavior via neurotransmitters or neuropeptides, with autonomic nerves also regulating endocrine glands to reprogram tumor metabolism. Pivotal to this regulation is the tripartite crosstalk among nerves, immune cells, and tumor cells, which establishes an immunosuppressive tumor microenvironment and drives progression from immune equilibrium to escape. These mechanisms have spurred therapeutic avenues such as neurotrophic agent repurposing, synaptic blockade, and neural-signal reprogramming, particularly in combination with immunotherapy, with promising preclinical and translational potential for precision oncology and cancer pain management.
Post-viral syndromes are heterogeneous multisystem diseases without a uniform etiology that occur as a result of acute viral infections. During the COVID-19 pandemic, the number of patients increased dramatically due to infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This is known as post-acute sequelae of COVID-19 (PASC), with many cases also meeting the criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), the most severe form of a post-viral disease, characterized by severe fatigue, post-exertional malaise (PEM), unrefreshing sleep, neurocognitive impairment, and autonomic and immune dysregulation. Orexin (OX) neuropeptides, which regulate arousal, metabolism, and neuroendocrine functions, may serve as a central link between stress, immune activation, and metabolic changes in these syndromes. Notable phenotypic similarities between OX system dysfunction and core features of PASC and ME/CFS, including fatigue, sleep issues, impaired glucose metabolism, and neuropsychiatric symptoms, support a mechanistic model in which impaired OX signaling contributes to post-viral endocrine and metabolic dysfunction. This review examines the role of OX in regulating glucose metabolism, HPA axis activity, and systemic homeostasis, with a specific focus on sexually dimorphic expression and function in relation to post-viral syndromes. We also highlight the effect of glucagon-like peptide-1 (GLP-1), another key player in metabolism, which also has neuroprotective, anti-inflammatory, vasoprotective, and immunomodulatory effects. We further emphasize emerging therapeutic strategies, such as GLP-1 receptor agonists (GLP-1RAs) and drugs targeting the OX system. Together, these insights provide an integrated framework for understanding and targeting the neuroendocrine-metabolic underpinnings of PASC, ME/CFS, and other post-viral syndromes.
Dysregulation of physiological stress systems, including the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS), is considered the pathway that links child maltreatment with psychopathology. However, how child maltreatment is linked with the coordination of the HPA axis and ANS stress responses remains unclear, particularly during the critical developmental period such as adolescence. This study investigated the association between the HPA axis indexed by cortisol and the ANS indexed by cardiovascular stress responses among adolescents with and without child maltreatment. The Childhood Trauma Questionnaire was administered to 116 adolescents (59 in the child maltreatment group and 57 in the comparison group), who took part in the Trier Social Stress Test during which their cortisol, heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) reactivity were collected. Results showed that after controlling for age, sex, body mass index, and socioeconomic status, a symmetry between the HPA axis and ANS stress response marked by significantly positive relationships between cortisol reactivity and SBP and DBP reactivity was found in the comparison group, while an asymmetry between the HPA axis and ANS stress response marked by a negative association between cortisol reactivity and DBP reactivity and a null association between cortisol reactivity and SBP reactivity was observed in the child maltreatment group. These findings suggest that child maltreatment disrupts the symmetry between the HPA axis and ANS stress response in adolescents.
Migraine is a very common chronic neurological disorder associated with severe disability and significant social burden worldwide. Beyond recurrent headache attacks, increasing evidence indicates that migraine often coexists with a broad range of systemic disorders, forming complex and often bidirectional relationships. These overlapping conditions complicate clinical management and suggest the presence of shared pathophysiological mechanisms extending beyond the central nervous system. Epidemiological studies have consistently shown strong associations between migraine and multiple comorbidities, including epilepsy, psychiatric disorders, sleep disturbances, cardio-cerebrovascular diseases, multiple sclerosis, asthma, other chronic pain syndromes, gastrointestinal disorders, and metabolic‒endocrine abnormalities. The presence of these conditions is generally associated with increased disease severity, higher rates of migraine chronification, poorer treatment responses, and increased healthcare utilization. Emerging mechanistic evidence indicates that migraine and its comorbidities share common biological pathways, including dysregulation of neurovascular signaling, neuroinflammation, central sensitization, alteration in autonomic nervous system and brain function, and disturbances in immune and metabolic homeostasis. Importantly, the presence of comorbid conditions may affect the efficacy, tolerance and safety of treatment, highlighting the limitations of symptom-oriented treatment strategies that fail to address these shared mechanisms. This review synthesizes current evidence on the epidemiological associations, shared pathophysiological mechanisms, and clinical implications of migraine and its common comorbidities. By elucidating these interrelated pathways, we aim to inform the development of comprehensive, personalized management strategies that transcend symptom-oriented treatment towards mechanism-based, comorbidity-informed approaches. Future research should prioritize the identification of biomarkers and the refinement of patient stratification tools to facilitate precision medicine in migraine and its associated conditions.
Vagus nerve stimulation (VNS) is an established neuromodulatory therapy approved for epilepsy, depression, obesity, stroke rehabilitation, rheumatoid arthritis, migraine, and cluster headaches. Its therapeutic potential has expanded dramatically, with growing evidence supporting its efficacy across a wide spectrum of neurological, psychiatric, cardiovascular, immunological, metabolic, and gastrointestinal disorders. Despite this progress, the field has lacked a comprehensive synthesis that unifies mechanistic insights with translational applications across organ systems. This review addresses that gap by systematically integrating current knowledge in the multifactorial mechanisms through which VNS modulates central and peripheral functions, including neuromodulator release, synaptic plasticity, autonomic regulation, neuroimmune control, and endocrine integration. In addition, this review identifies key limitations of VNS, including biological heterogeneity, technical constraints, and methodological variability, and proposes future innovations such as selective fiber targeting, closed-loop systems, and artificial intelligence-guided personalization. By providing a rigorous, system-level overview of VNS mechanisms and their translational relevance, this article serves as a foundational resource for advancing the science and clinical deployment and helping illustrate future directions for precision neuromodulation and bioelectronic medicine.
Chronic stress is a time-dependent condition characterized by sustained dysregulation across neural, autonomic, and endocrine systems, with important consequences for both health and socioeconomic outcomes. Unlike acute stress, which is typically characterized by short-lived physiological activation, chronic stress reflects an accumulated allostatic load and a longer-term recalibration of stress response systems. Recent advances in physiological sensing and artificial intelligence (AI) have supported the development of computational approaches for chronic stress detection using electroencephalography (EEG), heart rate variability (HRV), photoplethysmography (PPG), electrodermal activity (EDA), and wearable multimodal platforms. This narrative review examines current AI-based studies through three main inferential paradigms: resting baseline dysregulation, longitudinal physiological monitoring, and reactivity-based inference. Across modalities, classical machine learning (ML) methods, particularly support vector machines (SVMs) and tree-based ensembles, remain the most commonly used approaches, largely because available datasets are small and most pipelines still depend on engineered features. Deep learning (DL) methods are beginning to emerge, but their use remains constrained by the lack of large, standardized, longitudinal datasets specifically designed for chronic stress research. Major challenges include ambiguity in stress labeling, limited longitudinal validation, circadian confounding, inter-individual variability, and small cohort sizes. Future progress will depend on standardized datasets, biologically grounded multimodal integration, hybrid baseline-reactivity modeling, adaptive personalization, and more interpretable AI systems. Greater emphasis is also needed on clinical relevance and generalizability if AI-based chronic stress monitoring is to move beyond experimental settings.