IntroductionSeveral 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.MethodsWe 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.ResultstpTMS 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.ConclusionAltogether, 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.
IntroductionHemispheric asymmetries are a core organizational principle of the vertebrate brain, but they are still not fully integrated into the study of preclinical models of neurological disease. Although many rodent models naturally include lateralization through unilateral interventions, hemispheric differences are not consistently examined or systematically reported.MethodsA systematic review was conducted following PRISMA guidelines, combining evidence from 48 studies on hemispheric asymmetries in rodent models of neurological conditions, including mild traumatic brain injury, epilepsy, stroke, Alzheimer’s, and Parkinson’s disease.ResultsAcross these models, disease processes cause strong lateralized effects on behavior, neurochemistry, and regional metabolism. In epilepsy models specifically, hemispheric asymmetries depend on the model: early seizure spread and network excitability can be lateralized, while other paradigms show more symmetric responses, emphasizing the role of baseline circuit asymmetries and genetic background. Similar lateralized effects are seen in stroke and Parkinson’s models, reflecting clinical phenomena such as lesion-side-dependent outcomes and unilateral symptom onset.DiscussionModels focusing on intrinsic hemispheric asymmetry or interhemispheric/bilateral response highlight existing differential sensitivity to experimental manipulations that may predispose the system to asymmetric outcomes. Nonetheless, variability and dynamic shifts in hemispheric organization are rarely taken into account. Incorporating hemispheric analysis systematically into experimental design and data interpretation could enhance the sensitivity, clarity, and clinical relevance of rodent models of neurological disease.
Persistent Afferent Bias (PAB) represents a state-dependent alteration in sensory weighting through which Somatic Disruption influences Autonomic Regulation. While the classical concept of the facilitated spinal segment provided an early neurophysiological explanation for somatic dysfunction, contemporary neuroscience increasingly favors models based on distributed neural networks and dynamic modulation of neural gain. Recent reinterpretations of facilitation as a network-level phenomenon offer a more consistent account of altered sensorimotor processing, yet remain largely confined to musculoskeletal and pain-related mechanisms and do not fully explain the origin and persistence of such bias. The present paper proposes Persistent Afferent Bias as a mechanistic link between Somatic Disruption and Autonomic Dysregulation. Within the Somato-Psychic Pathway (SPP), a theoretical model proposed by the author, PAB represents the previously unarticulated neurophysiological mechanism linking altered somatic input to changes in regulatory state. In this context, disturbances in afferent signaling—arising from Distorted Proprioceptive Information (DPI), nociceptive input, interoceptive imbalance, or other sources—lead to a reorganization of sensory weighting within neural systems. A defining feature of this process is the persistence of altered afferent conditions. Under sustained conditions, this biased processing contributes to a shift in Autonomic Regulation conceptualized as Somato-Psychic Autonomic Dysregulation (SPAD), which may subsequently give rise to broader functional manifestations, including Somato-Psychic Syndrome (SPS). This formulation situates Persistent Afferent Bias within a hierarchical regulatory cascade consistent with Directional Developmental Sequencing (DDS), in which alterations at the level of somatic input propagate to autonomic and higher-order functional domains. In this sense, PAB is not a primary phenomenon, but a secondary expression of underlying disturbances within the somatic regulatory system. Beyond its theoretical significance, this model has direct clinical implications. It supports a shift in clinical reasoning from predominantly symptomatic modulation toward identification and targeted treatment of primary somatic drivers of altered afferent input. This is particularly relevant in patients presenting with Somato-Psychic Syndrome (SPS), in whom conventional approaches focused on higher-order manifestations may fail to address the underlying regulatory disturbance. By providing a mechanistic basis for this shift, Persistent Afferent Bias enables a more etiologically grounded and hierarchically organized approach to intervention within the Somato-Psychic Pathway.
Long COVID is increasingly recognized as a multisystem condition involving persistent inflammation, autonomic dysregulation, and metabolic disturbance. The vagus nerve–mediated cholinergic anti-inflammatory pathway (CAP) provides a biologically plausible link between neural regulation and immune homeostasis, while metabolic pathways involving AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) are closely related to mitochondrial function and energy balance. In this review, we synthesize evidence from neuroscience, immunology, and metabolic research to investigate how electroacupuncture (EA) may modulate vagal-cholinergic signaling and the downstream inflammatory and metabolic processes associated with long COVID. Experimental studies indicate that EA can influence CAP-related mechanisms, including α7 nicotinic acetylcholine receptor (α7nAChR)-mediated inhibition of NF-κB/NLRP3-related inflammatory signaling, and may also regulate AMPK–SIRT1–PGC-1α-associated metabolic pathways. Although clinical evidence is more indirect, it suggests that electroacupuncture may affect autonomic function, inflammatory markers, symptom burden, and neurophysiological regulation. To support a balanced interpretation, we organize the evidence in this review into a framework based on levels of evidence, which distinguishes direct preclinical findings from indirect clinical indicators and associations used to generate hypotheses. This framework highlights the potential convergence of vagal–cholinergic anti-inflammatory regulation and metabolic recovery pathways, while recognizing that several proposed connections—particularly those linking CAP-related signaling to improvements in long COVID symptoms—require further validation. Overall, this review provides a structured basis for future mechanistic studies and phenotype-oriented clinical trials evaluating EA as a neuromodulatory strategy for long COVID and related chronic inflammatory conditions.
Chronic fatigue is widely discussed across clinical and non-clinical contexts, yet its definition and measurement remain heterogeneous and debated. In this fragmented landscape, adopting an efficacy-informed perspective grounded in mitigating interventions offers a reliable pathway to delineate the core features and regulatory mechanisms of chronic fatigue. This Mini Review aims to identify and synthesize interventions shown to be effective in mitigating chronic fatigue. A preliminary screening was conducted using the terms “fatigue” AND (“relief” OR “mitigation” OR “treatment”), thereby inherently focusing on persistent and functionally impairing forms of fatigue. The analysis was then restricted to the most cited evidence to highlight the most consolidated findings. Four classes of behavioral interventions consistently emerged as effective across heterogeneous conditions (stroke, cancer, multiple sclerosis, traumatic brain injury, and non-clinical contexts): cognitive behavioral therapy, mindfulness-based approaches, yoga, and physical activity. Their convergence suggests that chronic fatigue reflects, rather than condition-specific processes, the alteration of shared regulatory mechanisms, likely involving neurophysiological dynamics and associated biological markers, which can be further elucidated by integrating evidence from effective interventions with their neurophysiological and biomarker correlates. The evidence from this Mini Review on the transversal effectiveness of the same interventions supports leveraging their efficacy and the associated neurophysiological and biochemical changes to identify sensitive markers that track treatment response and inform the underlying mechanisms of fatigue. Future research should therefore prioritize standardized measures, shared markers, and personalized interventions, potentially supported by biochemical and neuromodulatory approaches.
Ten years ago, we published a position paper in this journal, criticizing reductionist claims of neurobiology related to mental disorders and important theoretical concepts like free will. Our interdisciplinary group of experts highlighted the need for and the challenges of integrating different approaches and system levels in neuroscience. We argued—and still argue—that such an integrative and multi-perspective approach is an important precondition for progress in the understanding and treatment of neuro-psychiatric disorders. We now review the progress towards an integrative neuroscience during the past decade in five steps: First, we examine the social and institutional context of brain research that has enabled tremendous technical developments and insights. Nevertheless, many research programs remain reductionist and fail to acknowledge differences between different system levels, their complex interactions, and domain-specific languages. We argue that scientific discourse largely lacks any critical account on the very nature of neurobiological explanations and interdisciplinary interfaces. Second, these conceptual weaknesses lead us to highlight the need for establishing an interdisciplinary neurophilosophy which tackles the challenging multiplicity of perspectives and approaches in modern neurosciences. The task is not just a collaboration between philosophers and neuroscientists, but rather the development of a critical philosophical stance within the neurosciences themselves. Third, based on this, we plead for the importance of the emerging science of complex systems, which is particularly helpful to integrate interdisciplinary knowledge and develop new strategies for modeling multi-level relations and phenomena. We suggest the application of systemic approaches in the mind sciences. Fourth, in line with this holistic view, we present an ecological perspective on human beings. The still dominating cephalocentric paradigm in neurosciences is severely limited without understanding the brain as a regulative organ in a situated organism and—in case of humans—an acting person “extended” to tools, technologies, and social structures. Fifth, in our final section, we illustrate our view using the debate about free will. We argue that any position respecting the complexity and irreducibility of mental phenomena will escape inappropriate reductionist and deterministic assumptions while fully acknowledging scientific evidence. We conclude with the demand for stronger efforts towards an institutionalized, interdisciplinary, systems-oriented neurophilosophy.
Consciousness remains one of the central challenges in contemporary neuroscience, in part due to the absence of an explicit framework describing the temporal constraints required for integrative processing. While influential models such as Integrated Information Theory and the Free Energy Principle characterize structural and functional aspects of conscious systems, they remain largely agnostic regarding the minimum temporal windows necessary for information to become phenomenologically accessible. We propose that temporal integration constitutes a biologically invariant constraint operating across multiple organizational scales. Drawing on recent experimental evidence of memory formation in non-neuronal cells, we introduce the concept of a minimal bioelectrical/biochemical temporal window (ΔT_b) governing cellular information consolidation. We propose that this foundational temporal constraint may contribute to organismic basal coherence (γ) through bioelectric and autonomic mechanisms, which in turn modulate higher-order perceptual and phenomenological integration. Within the Emergent Flow Theory framework, classical findings from the Libet paradigm are reinterpreted not as evidence against agency, but as reflecting necessary delays associated with multilevel temporal integration. By linking cellular memory, bioelectric signaling, vagal–autonomic regulation, and cortical dynamics, this work outlines a unified temporal architecture of conscious processing that is biologically grounded, mechanistically plausible, and empirically testable using multimodal neurophysiological protocols. The proposed pathway linking cellular temporal integration (ΔT_b) to organismic autonomic coherence (γ) is classified as mechanistically plausible, requiring empirical validation within the EFT framework.
ObjectiveTo explore the mediating role of serum uric acid (SUA) in the relationship between the acclimatization/adaptation index (AAI) and the transition probability of electroencephalographic (EEG) Microstate D within cognitive control networks under hypoxic conditions at 3,650 m.MethodsA total of 173 high-altitude residents in Lhasa were recruited. Their peripheral oxygen saturation (SpO₂), hematocrit (HCT), and SUA levels were measured, and resting-state EEG data were recorded. AAI was calculated, and the transition probability of Microstate D was analyzed. Correlation analyses and bootstrap methods were employed to examine the mediating effect of SUA.ResultsAAI was significantly negatively correlated with SUA, and the maladaptive group exhibited significantly higher SUA levels. SUA mediated the relationship between AAI and the outward transition probabilities from Microstate D to Microstates A and C, but no significant mediating effect was found for inward transition probabilities.ConclusionUnder high-altitude hypoxic environments, SUA serves as a key mediator through which AAI modulates the outward transitions of Microstate D. Regulating SUA levels and enhancing AAI may play a crucial role in preserving cognitive control network function in high-altitude populations.
IntroductionPeripheral nerve injury (PNI) imposes significant burdens, requiring therapies targeting both mechanical compression and inflammatory pathophysiology. While neurolysis addresses extrinsic compression and methylcobalamin promotes intrinsic nerve repair, their combined potential is underexplored. This study compared the efficacy of neurolysis monotherapy, methylcobalamin monotherapy, and combination therapy across functional, electrophysiological, and inflammatory outcomes in PNI.MethodsNinety PNI patients were randomized to three groups (n = 30/group): neurolysis alone, methylcobalamin alone (0.5 mg tid), or combination therapy. Outcomes at 60 days comprised functional recovery (Carroll Scale), nerve conduction velocities (MCV, SCV, AMP, LAT), joint mobility (AROM/PROM), pain severity (Global Pain Scale), and serum cytokines (NF-κB, TNF-α, IL-6 via ELISA).ResultsThe combination group demonstrated significantly higher total therapeutic efficacy (86.67%) compared to neurolysis alone (50.00%) and methylcobalamin alone (53.33%; P < 0.05). All groups showed significant post-treatment improvements in nerve conduction velocities, joint mobility parameters, pain scores, and inflammatory cytokine levels (P < 0.05). However, combination therapy yielded superior outcomes: it produced the greatest improvements in active and passive range of motion, the most significant reductions in pain scores across all assessed domains, and the lowest post-treatment levels of inflammatory cytokines (NF-κB, TNF-α, IL-6; P < 0.05 versus either monotherapy).DiscussionThe combination of neurolysis and methylcobalamin synergistically enhances functional recovery, nerve conduction, joint mobility, pain relief, and anti-inflammatory effects in PNI, demonstrating superior clinical efficacy compared to either treatment administered alone.
The nucleus tractus solitarii (NTS) is a highly conserved brainstem structure that has served as a principal hub for visceral sensory integration across vertebrate evolution. While the NTS has long been described as a relay for cardiovascular and respiratory reflexes, recent work increasingly frames it as an integrative node that transforms diverse afferent signals into adaptive, context-sensitive responses. In this review, we synthesize evidence on the developmental origins of the NTS (including contributions from the dorsal alar plate and epibranchial placodes) and its comparative organization across vertebrate taxa. We argue that many interspecies differences are more plausibly interpreted as functional reweighting within a conserved circuit framework-shaped by species-specific respiratory-feeding strategies and ecological demands-rather than as wholesale rewiring of the core network. Within this comparative context, the extensive supranuclear modulation observed in humans is discussed not as biological "superiority," but as layered control that has become particularly prominent in response to human-specific anatomical constraints and behavioral demands, including those associated with speech and complex social interaction. Clinically, we revisit dysphagia, cough hypersensitivity, and nausea/vomiting as manifestations of network-level dysregulation and gating failure rather than isolated breakdowns of single reflex arcs. Finally, we suggest that neuromodulation strategies, including vagus nerve stimulation, may be best conceptualized as delivering patterned afferent input capable of shaping NTS network plasticity, rather than as non-specific electrical activation.
The Somato-Psychic Pathway (SPP) is proposed as a universal ontogenetic developmental trajectory through which somatic structural-functional integrity and autonomic regulation shape the emergence and stability of the mind under both physiological and pathological conditions. Integrating insights from developmental neuroscience, evolutionary biology, and clinical neurodevelopment, SPP conceptualizes mental functions as interpretive extensions of bodily and autonomic states rather than as their primary generators. The framework delineates a developmentally constrained directional sequence beginning with somatic organization, proceeding through proprioceptive and interoceptive accuracy, and culminating in autonomic regulation, emotional stability, and cognitive-social maturation. Disruption of this trajectory-most prominently through axial dysfunction, distorted joint-muscle-fascial proprioception, persistent low-grade nociceptive drive, or direct mechanical influences on peripheral autonomic structures-is proposed to lead to Somato-Psychic Autonomic Dysregulation (SPAD), a state characterized by chronically reduced autonomic flexibility and heightened threat responsivity. Prolonged operation of the pathway in this pathological mode gives rise to the clinical phenotype termed Somato-Psychic Syndrome (SPS). The SPP framework emerged from longitudinal clinical observation of disrupted and restituted developmental trajectories, providing a unique ontogenetic perspective on the directionality of neurodevelopmental regulation. By integrating the somatic, autonomic, emotional, and cognitive domains into a single regulatory continuum, SPP offers a biologically grounded model with implications for understanding childhood neurodevelopmental disorders and guiding future therapeutic strategies.
Brain damage (BD) caused by stroke, traumatic brain injury (TBI), or neurodegenerative conditions often results in persistent cognitive, motor, and emotional impairments. Music-based interventions (MI) have been explored as adjunctive rehabilitation strategies; however, the evidence remains fragmented. This systematic review and meta-analysis synthesize available research on the effects of MI on functional recovery following BD, due to acquired brain injury (ABI), including both TBI and non-TBI. From a total of 868 publications screened in PubMed, Embase, Scopus, Cochrane Library, Web of Science, and ClinicalTrials.gov, 90 were included, of which 41 met the criteria for quantitative evaluation and meta-analysis, to assess the state-of-the-art of research on music and BD in the fields of neuropsychology and cognitive sciences. The reviewed studies span a range of methodologies, including randomized controlled trials and qualitative research, and incorporate diverse MI strategies, such as active music-making, structured listening, and improvisational techniques. The findings indicate that music supports recovery across motor, cognitive, and, albeit to a lesser extent, communicative and psychosocial domains. The findings suggest beneficial effects of MI, particularly in gait function (z = 3.46, P < 0.01), upper extremity function (z = 6.11, P < 0.01; UEF), communication (z = 3.21, P < 0.01), cognitive rehabilitation (z = 3.29, P < 0.01), and emotional, behavioral, and social outcomes (z = 2.35, P = 0.02); notably, these effects were often supported by consistent statistical significance across multiple subgroup analyses (e.g., gait, UEF). This study highlights the therapeutic potential of music in neurorehabilitation and supports its integration into multidisciplinary treatment programs. Despite these promising findings, methodological heterogeneity, small sample sizes, and short intervention durations limit the generalizability of results. The evidence suggests that music may modulate key neurobiological pathways in BD, supporting its integration into evidence-based neurorehabilitation programs.
Eye Movement Desensitization and Reprocessing (EMDR) is an established therapeutic intervention for post-traumatic stress disorder and related conditions, yet its neurobiological mechanisms remain incompletely understood. While prevailing models emphasize cognitive processes such as working memory taxation and memory reconsolidation, these accounts may not fully explain the durability and generalization of therapeutic effects. Here, we propose a hypothesis in which bilateral rhythmic stimulation associated with EMDR modulates neuroimmune interactions through state-dependent changes in autonomic balance and meningeal lymphatic dynamics. Within this framework, regulatory T cells are conceptualized as contributors to baseline neuroimmune tone, influencing microglial activation states, synaptic stability, and network-level regulation. By integrating findings from autonomic physiology, lymphatic biology, and neuroimmunology, this hypothesis generates testable predictions linking behavioral interventions to sustained neural and behavioral outcomes. The model is intended to guide future experimental investigation rather than assert definitive causal pathways.
Introduction Anticipatory postural adjustments (APAs) stabilize the body before voluntary movement. Although present early in life, their refinement continues into adolescence, especially during complex balance tasks.Aim This study examined developmental differences in APA control between typically developing children (9-12 years) and young adults (19-25 years) during a self-initiated Can Placement Task (CPT).Methods Thirty children and twenty-two adults performed the CPT while standing on one leg. The task was divided into five phases (quiet stance, stooping, can transfer, straightening up, stabilization). Center of pressure (COP) displacement and velocity in anteroposterior (AP) and mediolateral (ML) directions and vertical ground reaction force (GRF) on the can were measured using dual force platforms. Both discrete outcomes and Statistical Parametric Mapping (SPM) were analyzed.Results No differences were observed in static balance (Phase I). In dynamic phases, adults showed larger backward COP shifts during stooping, higher normalized COP velocity, and reduced reliance on the can for support compared with children. Children exhibited slower COP adjustments and higher GRF on the can, indicating greater use of external support. SPM revealed group differences mainly during stooping and straightening phases. Adults' faster COP control likely reflects efficient feedforward strategies, while children adopted more conservative, stability-oriented approaches.Conclusion Children aged 9-12 years can generate APAs but remain less efficient in adapting them to task demands. Phase-specific and SPM analyses revealed subtle developmental differences not evident in static balance. The CPT provides a sensitive framework for assessing postural control and may guide age-appropriate clinical interventions.
IntroductionPhotobiomodulation (PBM) stands out as a promising therapeutic alternative for the management of chronic pain, but there is still controversy regarding its efficacy and safety, given the diversity of protocols and populations evaluated.ObjectivesTo critically review the available literature on the use of PBM in adults with chronic pain conditions, synthesizing the evidence on analgesic and functional effects, impact on quality of life, and safety profile. Methods: A systematic search was conducted in PubMed, Embase, Scopus, LILACS, and MEDLINE, including articles published between September 2015 and September 2025. Randomized clinical trials that compared PBM protocols to placebo, sham, or conventional care were selected. The outcomes investigated included pain intensity (primary), function, quality of life, and occurrence of adverse events (secondary).ResultsFourteen studies were included, covering populations with fibromyalgia, peripheral neuropathies, orofacial pain, and musculoskeletal pain. Most trials demonstrated significant pain reduction with PBM, particularly in fibromyalgia and neuropathy. In some studies, functional gains and improved quality of life were observed. The incidence of adverse events was low, reinforcing the method’s safety, although the heterogeneity of technical parameters compromises the standardization of results.ConclusionPBM has analgesic potential and a safe profile for managing chronic pain, especially in cases difficult to control with conventional therapies. However, the variability of clinical parameters and limited follow-up still hinder more comprehensive recommendations. Additional multicenter studies with standardized protocols are needed to consolidate clinical guidelines.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420251140711, Identifier: CRD420251140711.
Many skills necessary to perform activities of daily living require individuals to think and move at the same time; otherwise known as cognitive-motor integration (CMI). An upper extremity CMI task has shown how CMI performance changes with age, neurotrauma, and sport experience; however, the majority of movements required for activities of daily living extend beyond the upper extremity. Therefore, the purpose of this pilot study was to compare a full-body balance-related CMI task with the validated upper extremity task. Twenty-nine young healthy adults [24.3 ± 5.1 years (SD); 12 females] completed 2 CMI tasks to assess upper extremity CMI and full-body CMI. In general, both CMI tasks varied in difficulty, ranging from congruent interactions with targets, to incongruent interactions which included visual feedback reversal (requiring increased CMI). Performance in both tasks were quantified using reaction time (RT), movement time (MT), and normalized path length (nPL). An interaction effect of task and condition was found for MT [F (1,28) = 9.344, p = 0.005] and nPL [F (1,28) = 12.766, p = 0.001], with larger increases across conditions in the full-body task compared to the upper extremity task. For the upper extremity task, sex predicted RT, where males had quicker RTs than females (unstandardized B = -78.968, p = 0.038). For the full-body task, MT and nPL were predicted by age and sport experience, respectively; where younger age resulted in faster MTs (unstandardized B = 235.546, p = 0.009), and more sport experience led to less variable nPLs (unstandardized B = -3.802, p = 0.005). Lastly, the full-body task found that sport experience was moderated by sex (unstandardized B = 203.650, p = 0.014), where only females saw decreases in MT with increasing sport experience. The full-body CMI task provides a more comprehensive analysis of sensory, motor, and cognitive contributions to coordination tasks. An isolated upper extremity task may be limited in its ability to extract meaningful information that could contribute to difficulties in performing activities of daily living. Future work could utilize this task in clinical populations with the potential to uncover differences that might not be apparent in standard assessment protocols.
BackgroundChronic stress is known to impair emotional regulation and adaptive behavioral responses through neuroinflammatory activation, oxidative imbalance, and dysregulation of neuroplasticity-related genes. Kiperin Mind Focus, a nootropic nutraceutical containing L-theanine, citicoline, phosphatidylserine, Rhodiola rosea, Ginkgo biloba, caffeine, and Lion’s Mane mushroom extract has been formulated to support stress resilience, mood regulation and neural health. This study aimed to investigate the neuroprotective and neuroregulatory effects of the combined formulation on behavioral, biochemical, histopathological, and molecular parameters in rats exposed to chronic unpredictable mild stress (CUMS).MethodsThirty-two adult male Wistar rats were randomized into four groups (n = 8): Control, Stress, Kiperin Mind Focus (MF), and Stress + Mind Focus (SMF). CUMS was applied for 45 days, and the combined formulation was administered by oral gavage (130 mg/kg/day). Behavioral outcomes were evaluated using the sucrose preference (SPT), open field (OFT), elevated plus maze (EPM), and forced swim (FST) tests. Serum and tissue cytokine levels (IL-1β, IL-6, IL-10, TNF-α) and oxidative stress index (TOS/TAS ratio) were measured. Hippocampal and prefrontal gene expression of FOS, DBH, NMB, BDNF, CREB1, GRIN2A, and GABRB1 was assessed via qPCR, and histopathological changes were semi-quantitatively scored.ResultsChronic stress induced anhedonia, anxiety-like behavior, and behavioral despair, accompanied by elevated proinflammatory cytokines, oxidative imbalance, and neuronal degeneration in the hippocampus and prefrontal cortex. The supplementation significantly improved SPT, OFT, EPM, and FST performance, normalized cytokine and oxidative parameters, and reduced neuronal injury scores. At the molecular level, supplementation attenuated stress-induced upregulation of FOS, DBH, and NMB while maintaining neurotrophic (BDNF, CREB1) and GABAergic (GABRB1) expression near control levels.ConclusionKiperin Mind Focus exerted robust neuroprotective, anti-inflammatory, and antioxidant effects under chronic stress, restoring molecular homeostasis and stabilizing stress-related behavioral outcomes. These findings support its role as a stress-buffering and mood-stabilizing supplement, that promotes emotional regulation and adaptive exploratory behavior under prolonged stress conditions.
