Major depressive disorder (MDD) is a prevalent and disabling psychiatric disorder characterized by persistent mood disturbances, cognitive impairments, and significant systemic consequences. Despite its substantial clinical burden, diagnosis remains challenging because current approaches rely largely on subjective symptom-based assessments and are complicated by marked biological and clinical heterogeneity. In this review, we synthesize findings from neuroimaging, electrophysiology, genetics, and molecular studies to provide an integrated overview of the structural, functional, and neurobiological alterations that underlie MDD. We discuss abnormalities involving large-scale brain networks, neuroplasticity and stress-related pathways, neuroinflammation, oxidative stress, and neurotransmitter systems, together with their implications for biomarker discovery, patient stratification, and treatment response. Collectively, current evidence implicates both molecular dysregulation and large-scale neural network dysfunction in MDD, although direct evidence linking alterations across these biological levels remains limited. Integrating multimodal biological and neuroimaging approaches may improve diagnostic precision, facilitate personalized therapeutic strategies, and advance the development of biologically informed psychiatry.
Moyan Wang, Qi Han, Xin Teng, Dingyu Liu, Zhen Yang, Huiying Li, Yingxia Yu, Wei Zhao, Ke Xiang, Li Sun
This review aims to investigate the potential mechanisms driving the transition from acute vestibular events to chronic dizziness, focusing on the roles of neural sensitization and psychological sensitization in symptom persistence. The evolution of vestibular dizziness is analyzed from the perspectives of vestibular compensation, sensory reweighting, and the fear-avoidance model. After acute vestibular injury, central nervous system function can be partially restored through vestibular compensation, sensory reweighting, and synaptic plasticity. However, this recovery process is often accompanied by increased visual dependence, which provides a foundation for the development of neural sensitization. The abnormal integration of proprioceptive and visual input described by the fear-avoidance model not only contributes to central sensitization but also reveals the core feature of psychological sensitization: perceptual amplification driven by catastrophizing cognition and avoidance behavior. Patients with chronic dizziness exhibit hypersensitivity to visual and proprioceptive stimuli and reduced sensory processing thresholds, which reflects abnormal sensory gain at the level of neural sensitization. Psychological factors, in turn, maintain or exacerbate neural sensitization by modulating proprioceptive processing and limbic system activity. Neural sensitization and psychological sensitization mutually reinforce each other, constituting a critical link in the transition from acute vestibular events to chronic dizziness. Comprehensive interventions targeting sensory reweighting, fear-avoidance behavior, and psychiatric comorbidity may help interrupt this process.
Contemporary neuroscientific theories of consciousness—including Global Neuronal Workspace Theory (GNW), Integrated Information Theory (IIT), and the Predictive Processing/Free Energy Principle (PP/FEP)—have not formalized autonomic and neuromodulatory state as explicit dynamic control parameters within models of conscious integration. This gap constitutes the explanatory niche addressed by the Emergent Flow Theory (EFT). EFT proposes that consciousness-supporting cortical integration is organized across three nested temporal regimes: ΔTᵢ (autonomic-interoceptive, ~50–200 ms), ΔTₚ (conscious access, ~200–500 ms), and ΔTᶠ (phenomenological-narrative, ~500 ms–3 s)—understood as functional approximations of dominant processing epochs rather than discrete neural compartments. The core theoretical claim is that autonomic coherence (γ), operationally indexed by heart rate variability (HRV), functions as a system-level gain parameter modulating the probability and quality of transitions between these regimes. This relationship is formalized in a phenomenological dynamic equation for a latent integrated-complexity state Q, constrained observationally by measures such as the Perturbational Complexity Index (PCI): dQ/dt = κ·γ·Σ(n,k) [αnk · g(ΔTnk)] − βQ + ξ(t) [ Master Equation — Integrated Cortical Complexity Q ( γ denotes the dimensionless, latent effective autonomic gain parameter; γ̂ is its empirical estimator, used for calibration and testing but not written into the equation itself )]. Five empirical predictions (P1–P5), each with explicit adjudication criteria, are derived from this architecture — with P4 comprising a falsifiable existence test (P4a) followed by conditional model discrimination (P4b) — targeting the HRV–PCI covariation profile, transcutaneous vagus nerve stimulation effects on conscious access markers, stress-induced ΔTᶠ disruption, the functional form of the observable γ̂–PCI relationship as an empirical constraint on the latent γ–Q hypothesis, and salience network causal contributions. EFT is offered as a Tier-2 theoretical framework complementary to GNW, IIT, and PP/FEP, situating autonomic coherence as a proposed physiological precondition within which the integrative capacities described by these frameworks may be realized.
Low-level laser therapy (LLLT; ≤ 0.5 W) is guideline-recommended in the United States for shallow-tissue oral mucositis and other superficial pathologies but has generally failed in trials for deeper tissue conditions due to limited penetration and subtherapeutic dosing. By contrast, Class IV high-intensity laser therapy (HILT; ≥ 0.5–80 W), typically at ∼100-fold higher power, has proven successful for many of these deeper tissue indications. We systematically searched PubMed, Google Scholar, and the Cochrane Database for Class IV HILT trials published from 2018 to April 2026, classifying interventions as effective when they showed large effect sizes (Cohen’s d > 0.8). Across 105 included studies ( n = 2,710 HILT; n = 2,925 controls), no serious adverse events were reported. HILT reduced pain in all randomized trials of knee ( k = 27), spine/neuromuscular ( k = 20), shoulder/arm ( k = 20), and wounds ( k = 2), with > 90% showing large effect sizes. Additional benefits were observed in disorders of the feet ( k = 13), hand/wrist ( k = 8), face/jaw ( k = 7), osteoporosis ( k = 2), endometriosis, coronary artery disease, cognitive impairment, fibromyalgia, COVID-19, and obesity. HILT yielded durable analgesia, with large VAS pain reductions at end of treatment, < 3-month, and ≥ 3-month follow-ups (SMD -0.98, -1.18, and -1.01; k = 50, 19, and 21, respectively). Functional outcomes improved consistently, including range of motion (92%; k = 26), functional performance (84%; k = 57), and quality of life (85%; k = 25). Structural and physiological changes were observed, including increased knee cartilage thickness, reduced rotator cuff tear size, weight loss, and improved nerve conduction. Comparative trials showed HILT produced greater pain reduction than LLLT in 13/13 studies, all with large effect sizes. Mean HILT power was 9.3 W (median 10.0; range 0.5–30), and mean power density was 19.5 W/cm 2 (median 10; range 0.1–52.5). Class IV high-intensity laser therapy appears effective and safe for durable pain reduction across deep-tissue musculoskeletal pathologies, supporting its recognition in clinical practice and coverage by payers as a valuable therapeutic option. Further multicenter trials are needed to refine treatment protocols. https://www.crd.york.ac.uk/PROSPERO/view/CRD420251021772 , identifier CRD420251021772.
Sergio Delle Monache, Gianluca Paolocci, Michela Gamberini, Francesco Scalici, Iole Indovina, Patrizia Fattori, Claudio Galletti, Francesco Lacquaniti, Gianfranco Bosco
Several cortical regions have been implicated in the control of interceptive actions, such as area MT/V5, posterior parietal areas, a vestibular area in the temporo-parietal junction (TPJ) involved in an internal representation of gravity, and premotor areas. Here, we assessed the potential contributions of visual areas V6 and V6A and of another premotor region in the inferior frontal gyrus associated to the vestibular network (IFG), which could potentially contribute based on their connectivity and known functional properties, and compared them with those of MT/V5. We applied triple-pulse transcranial magnetic stimulation (tpTMS) during interception of ballistic trajectories, either congruent with natural gravity (1g) or perturbed with constant-velocity profiles (0g). Trajectories were either fully visible or occluded prior to landing. tpTMS was applied on each cortical site right after the trajectory perturbations or occlusions. tpTMS of MT/V5 produced robust changes in the interceptive performance with both visible and occluded trajectories, by modulating central processing delays with continuously available visual information, while contributing to visual extrapolation with occluded motion. V6 stimulation produced significant effects only with visible trajectories by modulating the central processing delays downstream of MT/V5. IFG showed distinct contributions to the spatial and temporal aspects of the interceptive action with respect to the integration of predictive signals based on visual information and on internalized gravity information. V6A stimulation was seemingly ineffective. Altogether, the functional dissociations emerging among these cortical areas support a complex, parallel distributed organization of the cortical network involved in the interception of projectile motion.
