Search Results (105)

Chronic pain, sleep disturbances, and mental health disorders such as anxiety and depression disorders frequently co-occur, forming a self-reinforcing cycle that impairs daily functioning and quality of life. Chronic pain is driven by peripheral and central sensitization, the latter sustained by reciprocal microglial–astrocytic crosstalk and maladaptive neuroplasticity. Poor sleep amplifies pain through inflammation and circadian disruption. Imbalances in serotonin, dopamine, and norepinephrine, together with limbic alterations and HPA axis dysregulation, contribute to comorbid anxiety and depression. Elevated pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α), NF-κB-driven neuroinflammation, and mitochondrial oxidative stress serve as key molecular links. Building on previous evidence, this review presents an updated triadic, mechanism-based framework describing the reciprocal reinforcement among chronic pain, sleep disturbances, and anxiety and depressive disorders. Consequently, therapeutic strategies targeting inflammatory cytokines, microglial and astrocytic activation, neurotransmitter imbalance, and psychological dysfunction may help address these shared neuroimmune and neuroplastic mechanisms underlying these interconnected disorders. Full article

The study investigated the systemic responses concerning oxy-inflammation, hormones, and mood after a ski mountaineering competition. Nine experienced military ski mountaineers (age, 32.37 ± 8.90 years; body mass, 59.37 ± 9.58 kg; BMI, 19.85 ± 1.53 kg/m⁻²) were non-invasively assessed using saliva and urine samples collected at baseline (T0) and immediately after competition (T1). Reactive Oxygen Species (ROS), total antioxidant capacity, lipid peroxidation (8-isoPGF2α), systemic inflammatory responses (IL-6; TNF-α; sICAM), neurobiological markers of stress and mood regulation (cortisol and serotonin), and indicators of metabolic and immune activation (creatinine, neopterin, and uric acid) were obtained. In addition, psychometric, physical, and subjective rating scales were administered. At T1, significant increases in oxy-inflammatory biomarkers were recorded (ROS: +137%; 8-iso: +121%; IL-6: +175%; TNF-α: +45%); stress hormones (cortisol: +241%; serotonin: +141%), associated with changes in urinary creatinine (+60%) and an increase in immune activation (neopterin: +94%). An exploratory analysis suggested a potential quadratic association between race completion time and post-race ROS production rate (R² = 0.552), warranting further investigation in larger cohorts. At T1, Visual Analog Scale (VAS) scores increased by 98% for tiredness, 112% for fatigue, 36% for happiness, and 320% for pain. In conclusion, ski mountaineering competitions place an extremely high physiological burden on athletes, eliciting complex oxidative, inflammatory, metabolic, hormonal, and psychophysiological responses that may reflect the interactions among exercise intensity, cumulative hypoxic exposure, and redox adaptive mechanisms. Full article

Behavioural management strategies used in paediatric dentistry have neurobiological effects. This scoping review aimed to map the existing literature on the neurobiological effects of non-invasive behavioural management strategies used in paediatric dentistry. The study protocol was registered on the Open Science Framework (registration number: OSF.IO/9EZVT). A search was conducted on PubMed, Web of Science, Scopus, Google Scholar, and African Journals Online (AJOL) for studies published up to May 2025. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Studies were included if they assessed non-invasive behavioural strategies in children aged 0–17 years undergoing dental procedures and reported at least one neurobiological or physiological outcome. The data were summarised descriptively, and key findings were thematically synthesised to identify trends in behavioural strategy types and neurobiological outcomes measured. Out of 1720 records retrieved, 35 studies met the inclusion criteria. These included randomised and non-randomised controlled trials and observational studies conducted in 13 countries on five continents involving 2919 children. The behaviour management strategies identified were 18 in number, with distraction (n = 19) and tell–show–do (n = 17) being the most frequently applied. The neurobiological outcomes assessed included anxiety (n = 36), pain perception (n = 8), fear (n = 7), and stress response (n = 1). Their physiological regulation was assessed using heart rate (n = 26), oxygen saturation (n = 10), blood pressure (n = 8), pulse rate (n = 6), cortisol (n = 4), respiratory rate (n = 1), and oxytocin (n = 1). Behavioural assessment tools used were classified into Child-Reported Anxiety and Fear Instruments (n = 23), Pain Perception Instruments (n = 9), Clinician/Observer-Rated Behavioural and Anxiety Scales (n = 18), and Parental and Proxy Reports (n = 2). This review underscores the emerging evidence that non-invasive behavioural strategies may be linked to neurobiology in paediatric dentistry. More studies are needed in new countries to be able to map the possible impact of context and culture on study findings. Full article

Objective: Depressive symptoms exist on a continuum in the general population, yet the underlying neurobiological mechanisms, particularly the interplay between resting-state networks and task-evoked social cognitive responses, remain elusive. Methods: Leveraging the Human Connectome Project (HCP) dataset, we included 867 participants. With depression scores as the independent variable and age/sex as covariates, we systematically examined associations with sleep quality, negative emotions, sensory scores, gray matter volume (GMV), fractional amplitude of low-frequency fluctuations (fALFF), multi-seed resting-state functional connectivity (rsFC), as well as brain activation and behavioral performance during working memory, emotion recognition, social cognition, relational reasoning, language comprehension, and gambling tasks. The statistical threshold was set at voxel-level p < 0.001 (uncorrected) combined with cluster-level FWE correction at p < 0.05. Results: (1) Depression scores were positively correlated with sleep disturbances, negative emotions (anger/fear), and pain. (2) In resting-state, depression scores negatively correlated with ventral striatum (VS)–cerebellum/parahippocampal gyrus/fusiform rsFC, yet positively correlated with pregenual anterior cingulate cortex (preACC)–supplementary motor area (SMA) rsFC. (3) In task-fMRI, only the social task showed a positive association with task accuracy and regional activation in bilateral pre/postcentral gyri, superior temporal gyri, left middle frontal gyrus, and SMA/paracentral lobule. Conclusions: Elevated depression scores are linked to a pattern that may reflect relative decoupling between reward and perceptual systems, along with enhanced connectivity in cognitive control circuits. Socially, high scorers exhibit a pattern suggestive of compensatory hypervigilance, accompanied by enhanced behavioral performance. This study provides multidimensional evidence for the dimensional neural representation of depressive symptoms. Full article

Background/Objectives: Irritable bowel syndrome (IBS) is among the most prevalent disorders of gut–brain interaction, yet its implications for spine surgery remain poorly characterized. This narrative review examines how IBS influences symptom presentation and postoperative outcomes in spine surgery patients. Methods: We synthesized the neurobiologic, epidemiologic, and perioperative literature linking IBS with musculoskeletal pain, spine-related symptomatology, and surgical outcomes, drawing on spine-specific data where available and on related surgical and chronic-pain populations where it was not. Results: IBS is characterized by central sensitization, impaired descending inhibition, increased temporal summation, autonomic dysregulation, and a high prevalence of psychiatric comorbidity, which manifest as widespread hyperalgesia and symptom amplification that overlap with pain mechanisms common in spine surgery patients. Epidemiologic studies indicate that patients with IBS undergo musculoskeletal and spinal procedures at disproportionately high rates, reflecting both symptom burden and diagnostic uncertainty from viscerosomatic overlap. These same factors have been associated with greater postoperative pain, elevated opioid requirements, slower functional recovery, and reduced satisfaction after spine surgery, although direct IBS-specific spine data remain limited. IBS may also confound preoperative assessment by mimicking radicular, discogenic, or sacroiliac pain. Conclusions: IBS represents an under-recognized potential modifier of symptom localization, perioperative pain trajectories, and functional recovery in spine surgery. Greater awareness of IBS-related nociplastic and psychosocial mechanisms may improve preoperative evaluation, risk stratification, perioperative management, and the design of future outcome studies. Full article

Background/Objectives: Insomnia is one of the most prevalent and persistent symptoms among patients with breast cancer, yet it remains under-recognized and undertreated in routine clinical practice. Beyond its impact on sleep quality, insomnia is increasingly understood as a multidimensional condition involving neurobiological, psychological, and behavioral mechanisms, closely intertwined with cancer-related stress and psychiatric comorbidities. This narrative review aims to provide a comprehensive and integrative overview of insomnia in breast cancer, focusing on its epidemiology, pathophysiological underpinnings, neuropsychiatric correlates, and clinical implications, while highlighting gaps in current research and management. Methods: A narrative review of the literature was conducted, including studies published in major medical databases (PubMed, Scopus, and Web of Science) up to 2025. Relevant articles addressing insomnia, sleep disturbances, psychiatric symptoms, and neurobiological mechanisms in breast cancer populations were selected and synthesized. Results: Insomnia affects a substantial proportion of breast cancer patients across the disease trajectory, from diagnosis to survivorship. Its etiology is multifactorial, involving dysregulation of the hypothalamic–pituitary–adrenal axis, inflammatory processes, and circadian rhythm, as well as treatment-related factors such as chemotherapy, endocrine therapy, and menopausal symptoms. Insomnia frequently co-occurs with depression, anxiety, fatigue, and pain, forming symptom clusters that significantly impair quality of life and may influence clinical outcomes. Emerging evidence supports a bidirectional relationship between insomnia and psychiatric vulnerability, suggesting a shared neurobiological substrate within the brain–body stress axis. Conclusions: Insomnia in breast cancer should be conceptualized as a neuropsychiatric condition embedded within a broader stress-related symptom network rather than as an isolated sleep disturbance. Improved screening, interdisciplinary management, and the integration of evidence-based interventions such as cognitive behavioral therapy for insomnia are essential. Research should focus on personalized and mechanistically informed approaches to better address this highly prevalent yet insufficiently managed condition. Full article

The role of the gut–brain axis is crucial in maintaining homeostasis and regulating neural, hormonal, and immunological activity. This study aimed to evaluate the effects of prebiotics or synbiotics on serum markers related to emotional disorders in individuals with morbid obesity in a triple-blind, randomized trial. The sample consisted of 22 subjects (16 women and 6 men) with a mean age of 41.8 ± 8.5 years and a mean BMI of 47.7 ± 6.8 kg/m². Serum BDNF concentrations decreased significantly after 30 days of prebiotic supplementation (p = 0.017). Serum cortisol concentrations increased in all groups between the evaluated time points, with the increase being statistically significant in the synbiotic-supplemented group (p = 0.028). Serum TNF-α concentrations increased significantly after 30 days of prebiotic supplementation when compared to the group’s baseline (p = 0.035); however, this variation did not produce a significant difference between the groups evaluated after 30 days of supplementation. The results suggest that a chronic, low-grade inflammatory state may be related to the neuroendocrine changes present in emotional disorders, but the absence of significant results in the primary outcomes is possibly due to severe underpowering. Findings from additional secondary outcomes are hypothesis-generating only, requiring confirmation in adequately powered trials. Full article

Systemic inflammation plays a pivotal role in the progression of rheumatoid arthritis (RA) and its associated comorbidities, ranging from cardiovascular (CV) disease to neurodegenerative conditions such as Alzheimer’s disease (AD). This narrative review examines the molecular cross-talk linking these pathologies, with a specific focus on the distinction between pentameric C-reactive protein (pCRP) and its proinflammatory monomeric form (mCRP). We discuss evidence suggesting that mCRP is not merely a passive marker but also an active driver of endothelial dysfunction, atherosclerosis, and synovial inflammation. This review further explores the connections among inflammatory biomarkers, blood vessel integrity, and neurodegeneration, detailing how persistent cytokine elevation (IL-6, TNF-α) and vascular injury contribute to cerebral small vessel disease (cSVD) and cognitive decline, with neurofilament light chain (NfL) serving as a key biomarker of neuroaxonal injury. Additionally, we address the neurobiology of pain in RA, highlighting the mechanisms of central sensitization (CS) and neuroimmune signalling that sustain pain-independent joint swelling. This evidence indicates that understanding the dynamic connection between CRP isoforms and neuronal markers should offer new insights for risk stratification and suggests that targeting mCRP may provide a novel therapeutic avenue to mitigate both articular and extra-articular manifestations of RA. Full article

Fibromyalgia represents a complex chronic pain condition in which patients experience widespread pain accompanied by fatigue and a broad range of physical and psychological symptoms. Diagnosis relies on symptom-based diagnostic criteria that lack objectivity, making it difficult to properly diagnose and treat. The etiology of fibromyalgia is thought to be multifactorial, including neurobiological, psychological, environmental, and genetic factors. In addition to pain, many patients experience central nervous system-related symptoms, such as fatigue, sleep disturbances, cognitive impairment, anxiety, and depression. Fibromyalgia has recently been recognized as a nociplastic pain disorder. Alterations in sensory processing and pain thresholds in the central nervous system may result in the perception of widespread pain throughout the body. In a recent study, we divided fibromyalgia patients who reported widespread pain into two subgroups based on their pain threshold: a low pain threshold group and a normal pain threshold group. We comparably analyzed these subgroups by using resting-state functional magnetic resonance imaging. This hypothesis article provides an overview of the pathogenesis of fibromyalgia and discusses these two subgroups of nociplastic pain. Recognizing the various pathophysiologies of fibromyalgia will allow us to better understand patients’ conditions and select appropriate treatment options for each patient. Full article

Background: The plant Griffonia simplicifolia is marketed as a dietary supplement; it is said to have antidepressant and sleep-promoting properties. Its main ingredient, 5-hydroxytryptophan (5-HTP), is the immediate precursor of serotonin and crosses the blood–brain barrier, thereby enhancing central serotonergic neurotransmission. Reduced serotonergic activity has been associated with affective disorders, sleep disturbances, and impaired central pain modulation. Despite this neurobiological rationale, evidence for analgesic efficacy remains limited. This study investigated the effects of Griffonia simplicifolia on peripheral and central sensitization and descending pain inhibition. Methods: In a randomized, double-blind, placebo-controlled crossover trial, 18 healthy volunteers underwent quantitative sensory testing (QST). Participants received 100 mg Griffonia simplicifolia orally once daily for 28 days or matching placebo. Sensory parameters were reassessed, followed by repetitive phasic heat application (RPHA) to induce short-term peripheral and central sensitization. After a 4-week washout period, participants crossed over to the alternate intervention. Results: A total of 17 participants completed the study. Griffonia simplicifolia showed no significant effect on acute pain perception after RPHA (β = −4.17; 95% CI −14.44 to 6.10; p = 0.401). The only significant difference was an increased distance of mechanical allodynia in the verum group (β = 0.82; 95% CI 0.05–1.59; p = 0.038). No differences were observed in thermal detection or pain thresholds, pressure pain thresholds, conditioned pain modulation, wind-up ratio, mechanical pain sensitivity, or flare area. Mild, transient adverse events occurred in two participants (11%) during Griffonia simplicifolia intake. Conclusions: Griffonia simplicifolia demonstrated limited effects on experimentally induced pain mechanisms compared with placebo and was well tolerated. Increased distance of allodynia may reflect serotonergic facilitation of pronociceptive pathways, suggesting an enhanced central and peripheral sensitization. Larger controlled trials are required to clarify its impact on pain perception. Full article

Fibromyalgia, a syndrome characterized by hyperalgesia and ‘negative emotionality’, and major depressive disorder (MDD) demonstrate substantial overlaps in clinical, neurobiological, and therapeutic domains. Currently, treatment options for fibromyalgia remain limited; however, the epidemiology of this syndrome continues to grow worldwide. The use of animal models is indispensable for developing new treatment strategies for fibromyalgia. Meanwhile, the choice of animal paradigms is limited. Here, we used the ultrasound exposure of emotional stress on CBA, BALB/c, and C57BL/6 mouse strains to model this condition and to identify new molecular targets of fibromyalgia treatment. We exposed young male mice of three common strains to a three-week ultrasound stress (US) comprising emotionally negative and neutral frequencies of 20–25 kHz and 25–45 kHz, resulting in the development of altered pain sensitivity and signs of ‘negative emotionality’. Specifically, mice were studied for timid-like/aggressive behaviors and the tail flick response. Serum levels of corticosterone, cortisol, β-Endorphin, and brain-derived neurotrophic factor (BDNF), as well as brain gene expression of interleukin-33 (Il-33), Bdnf, and its receptor Trkb were investigated. Among the stressed mouse strains, C57BL/6 mice displayed augmented pain sensitivity, allodynia, and suppressed dominant behavior, whereas CBA and BALB/c mice demonstrated opposing changes. Glucocorticoid levels were increased in all stressed groups. Stressed C57BL/6 mice showed downregulated gene and protein expression of functionally inter-related BDNF and IL-33 molecules in the hippocampus, amygdala, and striatum, significantly correlating with behavioral outcomes, as well as lowered blood levels of β-Endorphin and elevated cortisol concentrations. Altogether, our study identified the BDNF/IL-33 regulatory pathway as a molecular correlate of fibromyalgia, and the use of US-exposed young C57BL/6 mice as a potential model that recapitulates this syndrome. Full article

Background: Migraine in older adults represents an increasingly relevant yet underrecognized clinical challenge in aging societies, where multimorbidity, frailty, and polypharmacy complicate both diagnosis and management. Although traditionally considered a disorder of younger individuals, migraine frequently persists or presents after the age of 60 with atypical features, contributing to diagnostic uncertainty. Methods: This narrative review, conducted in accordance with the SANRA principles, aims to provide a comprehensive overview of the epidemiology, clinical presentation, pathophysiology, and management of migraine in older adults, with particular emphasis on age-related complexities, therapeutic challenges, and unmet clinical needs. Results: Migraine in this population often presents with atypical or misleading features, such as aura without headache, vestibular symptoms, or overlap with cerebrovascular conditions, leading to delayed or incorrect diagnoses. The burden of disease is substantial, affecting physical function, mobility, cognition, emotional well-being, and social participation, and is further amplified by comorbid conditions including cardiovascular and metabolic disorders, mood disturbances, and chronic pain syndromes. Aging-related neurobiological changes, such as impaired pain modulation, endothelial dysfunction, and neuroinflammation, may influence disease expression and treatment response. Therapeutic management is challenged by contraindications, increased susceptibility to adverse drug effects, and the complexity of polypharmacy, highlighting the importance of individualized and non-pharmacological approaches. Conclusions: Migraine in older adults is a significant but often overlooked contributor to disability and reduced quality of life. Improved recognition of its unique clinical features and age-specific vulnerabilities is essential to optimize patient-centered care. Future research should prioritize the inclusion of older populations and the development of tailored, safe, and effective management strategies. Full article

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent urological disorder characterized by persistent pelvic pain, urinary symptoms, and significant impact on quality of life. In addition to its clinical symptoms, CP/CPPS is frequently associated with psychiatric comorbidities, such as anxiety and depression, indicating complex neurobiological mechanisms. This review explores the mechanisms linking CP/CPPS with affective disorders, emphasizing central nervous system alterations, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, and neuroimmune interactions. Evidence in-dicates that central sensitization, microglial and astrocytic activation, and elevated proinflammatory cytokines (IL-1β, IL-6, TNF-α) contribute to maladaptive painemotion network interactions. Additionally, dysregulation of hormones and neurotransmitters may exacerbate both pain perception and mood disorders. Psychosocial factors, including stress, coping strategies, and cognitive-emotional processes, further modulate symptom severity and treatment outcomes, highlighting the importance of a biopsychosocial approach. Gaining a deeper understanding of the neurobiological and psychosocial mechanisms behind anxiety and depression in CP/CPPS can lead to more effective, multidimensional management strategies and enhance patient-centered care. Full article

Background/Objectives: Fibromyalgia is increasingly viewed as a disorder of central sensitization, involving altered nociceptive processing and dysregulated stress and affective neural systems. Evidence supports shared neurobiological mechanisms linking chronic pain, emotional distress, and affect regulation, including corticolimbic and hypothalamic–pituitary–adrenal axis alterations. However, predictive models evaluating psychological distress as markers of these brain-based processes remain scarce. This study aimed to internally validate a preliminary model of fibromyalgia diagnosis using self-reported distress indicators as proxies of central dysregulation. Methods: A case-control design study with 180 participants was performed. Medically diagnosed fibromyalgia cases were recruited via a pain facility or referrals, alongside geographically matched controls from the general population. Psychological variables were conceptualized as neurobehavioral indicators reflecting central sensitization and stress-system dysregulation. Predictors were selected using LASSO penalized regression with 10-fold cross-validation. Retained variables were re-estimated using logistic regression. Model performance was evaluated through Nagelkerke’s pseudo-$R^2$, a likelihood ratio test, and area under the curve (AUC). Internal validation was conducted via 1000-bootstrap resampling with calibration-slope-based shrinkage. Results: The final model included global psychological distress, positive affect, sex, and age ($R^2=0.359$, with good discrimination [AUC = 0.81; optimism-corrected AUC ≈ 0.79]). Higher distress and age were associated with increased odds of fibromyalgia. Conclusions: Self-reported psychological distress, particularly global distress and reduced positive affect, combined with sex and age, showed internal validity in predicting fibromyalgia diagnosis. These findings support the hypothesis that behavioral markers of emotional dysregulation may reflect underlying central sensitization and stress-system alterations implicated in chronic pain. Future research integrating psychological measures with neuroimaging and neuroendocrine markers may further clarify the neural mechanisms linking affective dysregulation and chronic pain vulnerability. Full article

Background/Objectives: Postoperative pain pharmacology is complex. We investigated the sensitivity of analgesic-like effects induced by morphine, ibuprofen, and their combination to peripheral opioid antagonism in a mouse laparotomy model. Methods: Mechanical hypersensitivity was assessed using von Frey filaments, and ongoing pain (abdominal licking and facial expressions) was evaluated using artificial intelligence algorithms. We tested the sensitivity of the analgesic treatments to the opioid antagonist naloxone or its peripherally restricted analog, naloxone methiodide. We also tested the effects of neutrophil depletion using an anti-Ly6G antibody. Gastrointestinal transit and pupillary diameter were measured to assess non-analgesic opioid effects. Results: Morphine reversed all pain-related behaviors; its effect on mechanical hypersensitivity was reversed by peripheral opioid antagonism, whereas its effects on ongoing pain were not. Ibuprofen reduced mechanical hypersensitivity and facial expressions but failed to alter licking. Interestingly, the ibuprofen effect on mechanical hypersensitivity depended on peripheral opioid receptors and neutrophils at the injury site. The morphine–ibuprofen combination produced synergistic analgesia across all endpoints without enhancing opioid-induced gastrointestinal inhibition or mydriasis. Peripheral opioid antagonism reversed the effect of the combination on mechanical hypersensitivity and facial expressions but not on licking. Conclusions: Our results replicate the key clinical phenomena relevant to the postoperative pain context, including the potentiation of morphine analgesia by ibuprofen without the exacerbation of adverse effects. Our results suggest that drug effects on different postoperative pain measures rely on distinct neurobiological mechanisms and are not interchangeable. Therefore, the use of a battery of complementary pain endpoints in preclinical pharmacology studies is advisable. Full article