Abstract: Background: Stroke remains a leading cause of mortality and long-term disability globally, necessitating effective primary prevention strategies. While machine learning (ML) models offer superior predictive capabilities compared to traditional linear risk scores, their application in clinical practice is often hindered by the "class imbalance" problem, where the rarity of stroke events leads to biased, low-sensitivity models. Furthermore, the literature currently lacks rigorous head-to-head benchmarking of modern boosting algorithms on moderate-sized clinical datasets. This study aimed to identify the optimal predictive model for stroke by systematically benchmarking seven ensemble algorithms and validating their clinical utility using Decision Curve Analysis (DCA).Methods: We analyzed a retrospective multi-center cohort of 5,110 patients, characterized by a severe class imbalance (4.9% stroke incidence). Feature engineering included the encoding of sociodemographic determinants and clinical biomarkers. We conducted a rigorous 10-fold stratified cross-validation tournament to compare seven classifiers: Linear Discriminant Analysis (LDA), Extra Trees, AdaBoost, Gradient Boosting, XGBoost, LightGBM, and CatBoost. Performance was evaluated using the Area Under the Receiver Operating Characteristic Curve (AUC) and Brier Score for calibration. To address clinical safety, decision thresholds were optimized to maximize sensitivity. Clinical utility was assessed using Decision Curve Analysis to quantify net benefit across relevant risk thresholds.Results: The classical Gradient Boosting Classifier emerged as the top-performing model, achieving a mean AUC of 0.842 (95% CI: 0.82–0.86). It statistically outperformed both the linear baseline (LDA, AUC=0.833) and complex modern implementations such as XGBoost (AUC=0.787) and Extra Trees (AUC=0.748). By tuning the decision threshold to 0.01, the champion model achieved a screening Sensitivity of 86.0% and Specificity of 53.6%. SHAP (SHapley Additive exPlanations) analysis identified Age, Average Glucose Level, and BMI as the dominant non-linear predictors. Crucially, Decision Curve Analysis demonstrated that the Gradient Boosting model provided a higher net clinical benefit than "treat-all" or "treat-none" strategies across threshold probabilities of 1% to 40%.Conclusion: Contrary to current trends favoring deep learning or complex boosting implementations, classical Gradient Boosting architectures demonstrated superior generalization on imbalanced tabular clinical data. The developed model combines high discriminatory power with proven clinical utility, supporting its deployment as an automated, high-sensitivity screening tool in primary care settings.

Abstract: Background and Objectives: Studies in hypertension (HTN), migraine (MIG) and HTN associated MIG (HMIG) in women present a link between vascular disorders and migraine. However, there are controversial findings yet for the important factors involved in overweight (OW) women with HTN and HMIG in postmenopause (PMP). Therefore, we planned to investigate the interactive role of body mass index (BMI) based serum levels of interleukin-6 (IL-6) and vitamin D (VitD) in PMP women with HTN, and low frequency episodic MIG and HMIG with aura. Materials and Methods: The subject groups of normal weight normotensives (NW-NTN), OW-NTN, NW-HTN, OW-HTN, NW-MIG, OW-MIG, NW-HMIG and OW-HMIG in PMP women (n:1008) were studied for investigating the BMI based variations and associations of IL-6 and VitD. Age range in each PMP women group (n:126) was 51-60 years. BMI range respectively in NW and OW participants was ≥ 18.5 - ≤ 24.9 and ≥ 25 - ≤29.9 kg/m2. Results: Among groups variations indicated highly significant change in serum IL-6 and VitD. The post hoc Tukey Kramer test for HTN groups indicated significant increased VitD in OW-HTN compared to OW-NTN and NW-HTN, and significantly increased IL-6 in OW-HTN compared to OW-NTN and NW-HTN as well as OW-NTN compared to NW-NTN. Significant increased IL-6 was obtained in OW-MIG compared to NW-MIG and OW-HTN, NW-HMIG compared to NW-NTN, and OW-HMIG compared to OW-MIG, NW-HMIG and OW-NTN. The multiple linear regression indicated collective significant effect among BMI, IL-6, and VitD in OW-HTN, NW-MIG, OW-MIG, NW-HMIG and OW-HMIG. BMI and IL-6 presented significant inverse association with VitD in these groups. The remaining groups presented non-significant effect. Conclusion: Current study shows significant role of serum IL-6 and VitD in HTN and low-frequency episodic MIG and HMIG especially with OW status in PMP women. BMI based significant variation and negative association of IL-6 with vitamin D in HTN, and low-frequency episodic MIG and HMIG with aura in the present report provides evidence of the pathophysiological impact of IL-6 and vitamin D in HTN, and episodic MIG and HMIG.

Abstract: Background :Mas-related G-protein-coupled receptor b4 (Mrgprb4)-lineage neurons in the peripheral nervous system, were a type of C fibers in the hairy skin. Our prior work demonstrated that these neurons respond to both noxious and innocuous mechanical and thermal stimuli. Ablating them eliminates the pleasant sensation elicited by gentle pressure on the mouse nape. However, their potential role in mitigating pain and pain-related negative emotions in response to somatic stimuli remains unclear. Methods:Animal experiments investigated the pivotal role of Mrgprb4-lineage neurons in mediating the analgesic and anxiolytic effects of transcutaneous electrical nerve stimulation (TENS) applied to the Zusanli (ST36) acupoint. In vivo calcium imaging of lumbar 4 dorsal root ganglia (DRG) neurons in Mrgprb4-GCaMP6s transgenic mice characterized neuronal encode of distinct TENS intensities. Mechanical pain thresholds and anxiety-like behaviors were assessed in a CFA-induced mouse model of comorbid chronic pain and anxiety. To simulate TENS, optogenetic stimulation was applied to the ST36 acupoint in Mrgprb4-ChR2 mice; intrathecal viral injection specifically ablated L3-L5 Mrgprb4-lineage neurons, and TENS effects were evaluated with their gain- or loss-of-function manipulation. Results: 0.5 mA TENS on ST36 ameliorated pain and anxiety-like behaviors in model mice and activated Mrgprb4-lineage neurons. Photostimulation on ST36 induced analgesic and anxiolytic effect in comorbidity of chronic pain and anxiety model of Mrgprb4-ChR2 mice. Ablating these neurons attenuated the therapeutic effects of 0.5 mA TENS in model mice. Conclusion:These genetic engineering-assisted findings may deepen our understanding of the analgesic and anxiolytic effect and mechanism of somatic stimulation and further improve the clinical efficacy.

Abstract: Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease with important disability accumulation. Early-onset NMOSD, defined as disease onset before age 50, exhibits distinct clinical characteristics compared to late-onset disease. We present a case series of patients with first symptom onset before age 30. Methods: Retrospective review of 10 patients diagnosed with NMOSD at our center in San Luis Potosí, Mexico, with disease onset before age 30. Clinical presentation, imaging findings, AQP4 antibody status, treatment response, and disability outcomes were analyzed. Results: Mean age at onset was 18.6 years (range 6-30). Area postrema syndrome was the most common presentation (40%), followed by acute myelitis and optic neuritis (30% each). All tested patients were AQP4-positive. Mean EDSS at follow-up was 6.6, indicating severe disability. Most patients received rituximab with variable response rates. Conclusions: Our cohort showed higher disability than reported in other early-onset series, emphasizing the need for prompt diagnosis and aggressive treatment in this population.

Abstract: Central cord syndrome (CCS) is the most common incomplete spinal cord injury, producing more severe motor deficits in the upper than lower extremities and impairing sensory and autonomic function. Although transcutaneous spinal cord stimulation (tSCS) has shown benefits in motor and sensory recovery after spinal cord injury, studies have not explicitly documented whether CCS subjects were included. The aim of this study was to assess the effects of tSCS over 12 weeks on motor and sensory outcomes in a subject with CCS. Methods: A 20-year-old male with a C7 injury was evaluated at baseline and after 12 weeks with the American Spinal Cord Injury Impairment scale, Modified Ashworth Scale, Penn and Spasm Frequency Scale, 3-Meter Walk Test, 6-Minute Walk Test, 9-Hole Peg Test, Box and Block Test, hand dynamometry, and lower-limb EMG. tSCS was applied between T9 and L1 at 30 Hz. Results: At 12 weeks, upper-limb motor and sensory scores improved, while spasm frequency and hand spasticity were reduced. Manual dexterity improved bilaterally in the 9-Hole Peg and Box and Block Tests, with a 2 kg gain in right-hand grip strength. In the 6-Minute Walk Test, the distance covered increased from 224.4 m to 295.2 m, and a 1.36 s reduction in 3-Meter walking time was achieved. Conclusions: tSCS improved motor and sensory function and reduced spasticity and spasms. These findings suggest that tSCS may serve as an effective complementary intervention for motor and sensory rehabilitation in individuals with mild cervical injuries, including CCS.

Abstract: National Institute for Health and Care Excellence (NICE) and National Clinical Guideline for Stroke 2023 (NCGFS23) guidelines recommend specialist TIA clinic assessment within 24 hours of symptom onset of suspected TIA. There is limited evaluation of TIA clinic services in the United Kingdom (UK) and Republic of Ireland (ROI). This study aims to assess attendee characteristics, NICE/NCGFS23 adherence, and clinical outcomes across the UK and ROI.DelAys in TIA Evaluation and Service (DATES) is a prospective national audit and service evaluation delivered through an established collaborative (The Neurology and Neurosurgery Interest Group (NANSIG)). All UK and ROI outpatient rapid-access TIA clinics are eligible. All index suspected TIA presentations will be included, irrespective of final diagnosis. Centres will register as an audit/service evaluation without altering routine practice. Data will be collected electronically, with blinded independent validation. The primary outcome is adherence to the NICE/NCGFS23 recommended 24-hour target. Secondary outcomes include presenting symptoms, diagnosis, investigations, treatment, and onward referral.DATES is anticipated to be the largest prospective study presenting in-depth evaluation of UK/ROI TIA clinic attendances. Our results will provide real-world data on TIA pathways and potentially improve existing services.

Abstract: Background/Objectives: Normal pressure hydrocephalus (NPH) is a neurodegenerative disease, a type of communicating hydrocephalus, in which excess cerebrospinal fluid builds up in the ventricles. It is a treatable cause of gait disturbance, cognitive decline and urinary incontinence in older adults. Early recognition and shunt treatment may substantially improve patient outcomes, yet data from Slovenia remain limited. This study aimed to analyze clinical characteristics, postoperative outcomes, and complications in elderly NPH patients treated with ventriculoperitoneal shunt (VPS) implantation at the University Medical Centre Ljubljana. Methods: A retrospective review was conducted in 98 patients aged ≥65 years who underwent VPS implantation for NPH between 2015 and 2025. Demographic data, symptom duration, pre- and postoperative clinical status (including Eide gait grading), comorbidities, and complications were collected from medical records and electronic medical database. Descriptive statistics and Mann-Whitney U tests were used; p < 0.05 was considered significant. Results: Ninety-eight patients (mean age 73.84 ± 5.59; 61.2% male, 38.8% female) were included. Gait disturbance was present in 95.9%, cognitive impairment in 84.2%, and urinary incontinence in 62.2%; 57.1% exhibited the complete Hakim triad. The mean symptom-to-surgery interval was 6.51 months. Postoperatively, the proportion of patients in severe gait stages (Eide 1–2) decreased from 38.3% to 12.0%, and 27.2% reached independent gait (grade 5). Cognitive improvement occurred in 78.8%, and urinary incontinence improved in 61.8%, with the full triad persisting in only 5.4%. Complications included shunt infection (2.0%) and intracerebral hemorrhage (6.1%). Revision surgery was needed in 14.9%, primarily due to overdrainage. Conclusions: VPS implantation led to significant improvement in gait, cognition, and continence in the majority of elderly NPH patients, with a low complication rate. These findings confirm surgical treatment as an effective and relatively safe option in this population and highlight the importance of timely diagnosis and multidisciplinary management.

Abstract: Background: Contemporary psychiatry has achieved unprecedented neurobiological precision in understanding symptom-level mechanisms, yet clinical outcomes remain stagnant—depression prevalence unchanged, suicide rates rising, and patients frequently reporting existential emptiness despite achieving symptom remission. This paradox suggests a fundamental theoretical gap: psychiatry lacks a scientific language for meaning.Objective: This paper develops the Neuro-Existential Architecture System (NEAS), integrating five previously disparate theoretical domains—Friston's Free Energy Principle, Melloni's laminar cortical architecture, Tucker's affective criticality, Northoff's spatiotemporal neuroscience, and Frankl's existential psychology—into a unified framework explaining how meaning stabilizes resilience at the neurobiological level.Theoretical Framework: The NEAS proposes that meaning is the highest-order generative model in the brain's hierarchical predictive system. It is not epiphenomenal but thermodynamically necessary: meaning minimizes free energy by providing a stable prior that constrains lower hierarchical levels through downward causation. Three core mechanisms are proposed: (1) Model Shattering and Reconstruction—how trauma destabilizes priors and meaning-centered recovery provides scaffolding for reintegration; (2) Affective Criticality—how meaning maintains the balance between confidence and error-checking that characterizes optimal neural function; (3) Spatiotemporal Coherence—how meaning extends temporal integration windows, preventing dissociation and fragmentation.Clinical and Empirical Implications: The framework generates a three-level intervention model (physiological, narrative, existential) and four falsifiable predictions regarding autocorrelation window extension, infra-slow oscillation strengthening, laminar disruption in trauma, and three-level intervention efficacy.Conclusions: By grounding existential meaning in neurobiological architecture, the NEAS bridges a century-long gap between neuroscience and existential psychology, explaining why meaning is fundamental to resilience and suggesting that psychiatry must become a science of meaning to advance beyond symptom management toward genuine healing.

Abstract: Pituitary neuroendocrine tumors (PitNETs) constitute a significant proportion of primary intracranial neoplasms and were historically differentiated based on clinical hormone excess syndromes and tinctorial properties. The 5th edition of the WHO classification introduces a paradigm shift towards the lineage-based taxonomy based on the cell-specific expression of transcription factors (TFs). This overview focuses on the biological justifications and diagnostic value of the core TFs of PIT1, TPIT and SF1 which signify the somatotroph, lactotroph, thyrotroph, corticotroph and gonadotroph lineages respectively. By focusing on TF expressions instead of hormone immunoreactivity, pathologists can better subtype clinically non-functioning tumors, effectively relegating the previously overutilized, null cell category, to about 1% of cases. The TF-based classification is also essential in discriminating high-risk histotypes of silent corticotroph tumors, sparsely granulated somatotrophs, and immature PIT1-lineage PitNETs, which are linked to a higher invasiveness and recurrence. We suggest a practical, stepwise immunohistochemical diagnostic algorithm with the integration of ancillary markers (e.g. GATA3 and ERα) to refine lineage assignment. New molecular correlates such as GNAS and USP8 mutations also add to this framework and guide the use of individualized treatment involving somatostatin analogs or dopamine agonists. And lastly, we discuss the ongoing issues of diagnosis of triple-negative and multilineage tumors and the growing importance of DNA methylation profiling and artificial intelligence in standardized reporting and improving precision management.

Abstract: Background/Objectives: Spontaneous intracerebral hemorrhage (sICH) is a severe form of stroke associated with high mortality and disability rates, and reliable prognostic markers remain limited. This study aimed to evaluate the prognostic value of ICH score components, the National Institutes of Health Stroke Scale (NIHSS), and high-sensitivity cardiac troponin I (hs-cTnI) for predicting 30-day mortality in patients with sICH. Methods: In this prospective observational cohort study, 100 consecutive patients with neuroradiologically confirmed sICH were enrolled. Demographic data, clinical parameters, neuroimaging findings, and serum hs-cTnI levels were collected on admission. Subsequently, the ICH score, its individual components, and the NIHSS score were assessed. Results: Patients who died had significantly higher ICH and NIHSS scores, were older, had lower Glasgow Coma Scale (GCS) scores, larger hema-toma volumes, more frequent intraventricular hemorrhage (IVH), and elevated hs-cTnI levels compared with survivors. Serum hs-cTnI concentrations significantly correlated with ICH and NIHSS scores, lower GCS scores, larger hematoma volumes, and the presence of IVH. On univariate logistic regression, ICH score, NIHSS, and hs-cTnI were independent predictors of mortality, whereas multivariate analysis identified GCS score, hematoma volume, and IVH as significant determinants of fatal outcome. Conclusions: ICH score and its components, NIHSS, and serum hs-cTnI levels are valuable prognostic tools in patients with sICH. These markers may help clinicians identify high-risk pa-tients, optimize monitoring, and guide therapeutic decisions. Nevertheless, larger multicenter studies are warranted to further clarify their clinical implications in sICH management.

Abstract: Calcium signaling dysfunction is a central contributor to neuronal hyperexcitability and seizure propagation in epilepsy, yet the intracellular mechanisms underlying the actions of valproic acid (VPA) remain incompletely un-derstood. In this study, we investigated whether VPA modulates calcium homeostasis at the level of the endo-plasmic reticulum (ER) and how this action influences cytosolic calcium dynamics associated with epileptiform activity. ER calcium levels were directly measured using ER-targeted aequorin in HeLa and PC12 cells, while cy-tosolic Ca²⁺ signals were monitored by fura-2 fluorescence imaging in bovine chromaffin cells exposed to veratri-dine, a model of sustained sodium channel activation and calcium oscillations. VPA induced a concentra-tion-dependent release of Ca²⁺ from the ER, with an IC₅₀ of approximately 17 µM. This effect was preserved in permeabilized cells and exhibited activation kinetics comparable to those elicited by inositol 1,4,5-trisphosphate (InsP₃). Pharmacological inhibition of InsP₃ receptors (InsP₃Rs), but not ryanodine receptors or SERCA, abolished VPA-induced ER Ca²⁺ release, supporting a selective InsP₃R-mediated mechanism. Functionally, VPA suppressed the repetitive cytosolic Ca²⁺ oscillations induced by veratridine, while simultaneously producing a sustained ele-vation of cytosolic Ca²⁺ originating from ER stores and facilitating depolarization-evoked catecholamine secretion. Together, these results support the conclusion that VPA acts as a novel functional agonist of InsP₃Rs and identify ER Ca²⁺ mobilization as a previously unrecognized intracellular mechanism contributing to its modulatory effects on calcium signaling and excitability in epilepsy.

Abstract: Background/Objectives: Dynamic movement orthoses (DMO) are elasto-compressive bodysuits used in the rehabilitation of children with motor disabilities and mainly in children with cerebral palsy. Among the DMO, the FLEXA® represents one of the most frequently used orthoses in clinical practice due to its adaptability and flexibility. The purpose of the present case study is to describe the application of FLEXA® in a female child of 18 months of correct age with a choreic form of cerebral palsy. Methods: To evaluate the effect of the dynamic movement orthosis's (FLEXA®), the Move-ment Disorder-Childhood Rating Scale (MD-CRS) 0-3 was administered. The child was eval-uated before the use of the FLEXA® bodysuit and with the bodysuit donned at approxi-mately 30 minutes after its application. Results: The results showed an important change in the severity of the movements ac-cording to the MD-CRS; mainly the child’s movement disorder severity changed from a a grade 5 severity (profoundly affected) performed without the bodysuit to grade 3 (moder-ately affected) with the use of the bodysuit. The evaluation also shows better trunk posture with use of FLEXA®. Conclusions: This case report highlights the potential benefits of dynamic movement orthosis like the FLEXA® in managing movement disorders in chil-dren with choreic form of cerebral palsy. A follow up evaluation is necessary to confirm the beneficial effects of continuous use of the DMO in a short and a long period of time.

Abstract: Background: Engagement of the NF-κB signaling pathway is crucial for controlling im-mune and inflammatory gene expression within the central nervous system (CNS). Naringenin, a flavonoid derived from citrus fruits, is known for its anti-inflammatory and antioxidant effects; however, its impact on LPS-induced neuroinflammation in HMC3 (human microglial) and SH-SY5Y (neuronal) cell lines has not been thoroughly studied. Objectives: To ascertain the neuroprotective role of Naringenin on LPS-induced neuroin-flammation in microglia and neuronal cell lines with focus on modulation of NF-κB sig-naling pathway. Methods: LPS treatment was given to HMC3 cells to induce an inflam-matory response and secretome of HMC3 cells to SH-SY5Y cells with the administration of Naringenin. The cell viability assay, ROS levels, Western blotting, immunocytochemis-try were employed to quantify and localize NF-κB and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β). Nuclear and cytosolic fractions of NF-κB were analyzed to screen its activation and translocation. Results: Naringenin treatment led to a dose-dependent de-crease in LPS-induced reactive oxygen species (ROS) production. It significantly reduced the expression of pro-inflammatory cytokines and inhibited NF-κB activation in HMC3 cells. The nuclear translocation of NF-κB was notably diminished after treatment, as demonstrated by both western blot and immunocytochemistry. These results suggest that Naringenin exerts an anti-inflammatory effect by suppressing the NF-κB signaling path-way. Conclusion: The findings suggest the potential therapeutic role of Naringenin using in vitro models in mitigating neuroinflammation through modulation of NF-κB signaling pathway.

Abstract: Autism spectrum disorder (ASD) is a prevalent and largely idiopathic developmental disorder with relatively widespread etiology. Currently there are no validated diagnostic or screening biomarkers for ASD, besides addressing the associated comorbidities. ASD is primarily diagnosed based on behavioral motor and cognitive characteristics. Until recently, the cerebellum had been particularly implicated in motor control, and under-researched for its potential role in the development of ASD. However, cerebellar circuitry is altered in ASD, impacting its brain interconnections, affecting brain development, and social and behavioral outcomes associated with ASD. We review the potential role of the cerebellum in ASD, how its dysfunction during development or its early postnatal injury may impact the maturation of other connected circuits, and play a role in the development of core ASD symptoms. We address cerebellar changes that may alter synaptic pruning, immune cells’ function, neurotransmitters, blood brain barrier permeability, and potential signaling pathways involved in ASD and how all these changes interplay may contribute to ASD pathophysiology. Understanding of these interactions, may provide novel therapeutic options specifically targeted to the cerebellum.

Abstract: We present the case of a women in her 30’s with treatment-resistant epilepsy (TRE), psychogenic non-epileptic seizures, intellectual disability, psychosis, and a maternally inherited balanced t(14;X)(q32.3;p11.2) translocation. Despite multiple antiepileptic drugs, vagus nerve stimulation, and deep brain stimulation (DBS) of the anterior thalamic nuclei, she continues to experience daily seizures. DBS implantation led to partial seizure reduction but was complicated by worsening behavioral disturbances, consistent with reported psychiatric side effects and the phenomenon of forced normalization. This case highlights the complex interplay between epilepsy, psychiatric comorbidities, and neurostimulation, as well as the potential genetic underpinnings of TRE. The association of balanced X-autosome translocations with intellectual disability and epilepsy suggests pathogenic disruption of neurodevelopmental genes influencing inhibitory signalling. Awareness of psychiatric risks in DBS recipients and consideration of genetic etiologies are essential for optimizing management strategies in refractory epilepsy.

Abstract:

Cadherin-8 (CDH8) is a type II cadherin that plays crucial roles in various aspects of neural development and disease. Although anti-CDH8 monoclonal antibodies (mAbs) are available for Western blotting and immunohistochemistry (IHC), anti-CDH8 mAbs suitable for flow cytometry have not been reported. In this study, we developed novel anti-human CDH8 mAbs (named Ca₈Mabs) using a flow cytometry-based high-throughput screening method. Among these, a clone called Ca₈Mab-4 (IgG₁, κ) specifically recognized CDH8-overexpressing Chinese hamster ovary-K1 (CHO/CDH8) cells, with no detectable cross-reactivity toward 21 other cadherins, including both type I and type II, by flow cytometry. Additionally, Ca₈Mab-4 detected endogenous CDH8 in the human esophageal squamous cell carcinoma cell line TE5. The dissociation constant (K_D) values for Ca₈Mab-4 binding to CHO/CDH8 and TE5 were estimated to be 3.8 × 10⁻⁹ M and 4.9 × 10⁻¹⁰ M, respectively. Furthermore, Ca₈Mab-4 was effective in Western blotting and IHC. Overall, these findings suggest that Ca₈Mab-4 is a versatile tool for basic research and holds potential for tumor diagnosis and therapy.

Abstract: Contemporary psychotherapy faces a profound paradox: while empirical evidence confirms the clinical significance of spirituality for resilience, established theoretical frameworks often lack a process-based mechanism to integrate this dimension beyond narrative content or cultural coping. This article addresses this gap by introducing a "spiritual self-pattern" into the Resonance-Inference Model (RIM), conceptualizing it not as a metaphysical construct, but as a fundamental neurocognitive imperative for biological self-organization.Drawing on the Free Energy Principle and spatiotemporal neuroscience, we define the spiritual self-pattern as the system’s highest-order regulator, instantiated within the brain’s slowest Intrinsic Neural Timescales (INTs). These deep temporal structures function as "long-term priors," integrating sensory and emotional data over vast durations—akin to the psychic "climate" that contextualizes the "weather" of momentary affect. We posit that this pattern maintains mental health by modulating the E-I balance (Excitatory-Inhibitory criticality) between predictive confidence (elation) and corrective sensitivity (anxiety) via top-down precision weighting.Within this framework, "meaning" is redefined as the successful integration of sensory chaos into these long-term temporal models, preserving the functional integrity of consciousness against existential entropy. We distinguish spiritual resonance—a state of "Bayesian binding" characterized by metastable synchronization—from spiritual dissonance, where pathological precision leads to the "frozen priors" seen in fanaticism or the systemic collapse of existential despair. By shifting the focus to mechanisms of temporal integration, this model offers a precise grammar for spiritually integrated psychotherapy, framing the therapist as a "criticality manager" dedicated to restoring the client's capacity for global self-organization.

Abstract: Background/Objectives: Parkinson’s disease (PD) involves motor and non-motor im-pairments, including visual dysfunction related to retinal dopamine deficiency and mi-crovascular changes. Photobiomodulation (PBM) and aerobic exercise (AE) may offer neuroprotective and vascular benefits. This brief report presents findings from a ran-domised pilot trial comparing PBM, AE, and their combination on visual function, ocular health, and patient-reported outcomes in PD. Methods: Twenty participants with idio-pathic PD (mean age 76.1 ± 8.8 years; Hoehn & Yahr I–III) completed four 8-week in-terventions (PBM, AE, PBM + AE, sham), separated by 4-week washouts. PBM was ap-plied to the head, neck, and abdomen; AE followed a modified forced-rate protocol. Changes in ocular measures, including visual acuity (VA), contrast sensitivity, retinal nerve fibre layer (RNFL) thickness, choroidal thickness, retinal vascular perfusion, and questionnaires: 12-item Short Form Survey (SF-12), 39-item Parkinson’s Disease Ques-tionnaire (PDQ-39), and Falls Efficacy Scale–International (FES-I), were assessed pre- and post- intervention. Results: Seventeen participants completed all measurements. Non-pharmacological interventions resulted in improved VA (0.10 ± 0.02 to 0.02 ± 0.03, p = 0.01) and increased central retinal vascular perfusion (16.7 ± 1.4 % to 20.5 ± 1.6 %, p < 0.01) from pre- to post-study interventions. RNFL and choroidal thickness did not change significantly. Fear of falling decreased significantly (28.5 ± 2.4 to 22.7 ± 1.8, p < 0.01), while PDQ-39 and SF-12 scores were unchanged. Conclusions: PBM, alone or combined with AE, improved vision and retinal microvascular function and reduced fear of falling in individuals with PD, warranting larger-scale trials to further delineate independent and synergistic effects.

Abstract: Traumatic brain injury (TBI) is increasingly recognized as a major risk factor for chronic neurodegenerative disease, including chronic traumatic encephalopathy (CTE) and Alzheimer’s disease (AD). Biomechanical forces during head trauma, particularly rota-tional acceleration and angular deformation, produce diffuse axonal injury (DAI) and widespread white matter damage that trigger persistent neurobiological cascades. These include axonal transport failure, blood-brain barrier (BBB) disruption, neuroinflamma-tion, neurovascular and mitochondrial dysfunction, and pathological protein aggrega-tion, closely paralleling core features of AD. Epidemiological data support a dose-response relationship between TBI severity or repetition and subsequent dementia risk, moderated by genetic factors such as apolipoprotein E4 (ApoE4). Converging ex-perimental and early clinical studies have begun to target shared injury and neuro-degenerative pathways through acute neuroprotection, stem cell-based strategies for BBB restoration and neural repair, transcriptional and hormonal modulation, mitochondrial stabilization, and immunomodulation of chronic inflammation. This review systemati-cally synthesizes evidence linking biomechanical injury to molecular and neurovascular pathways of neurodegeneration, and summarizes emerging temporally targeted inter-ventions. By integrating mechanistic and therapeutic perspectives, we aim to narrow the translational gap between TBI and AD, refine identification of at-risk populations, and inform priorities for prevention and development of disease-modifying therapies.

Abstract: Background: Epilepsy is network disorder and network-based approaches to its diagnostics and therapies attract growing attention. Identification of prognostic markers of epilepsy, allowing selecting patients with risk of epilepsy development, is urgent unresolved problem. We examined whether intracortical connectivity patterns reflect early epileptogenic changes in the cortex. Methods: We used audiogenic kindling model, in which cortical epileptogenesis is initiated by repetition of reflex subcortically-driven seizures. Two measures of functional connectivity - mutual information and mean phase coherence – were applied to electrocorticographic recordings obtained from homotopical sites of parietal cortex in awake rats during interictal and immediate postictal periods. Interhemispheric connectivity and synchrony in non-kindled and slightly kindled rats were compared. Cortical spreading depolarization (SD), the first manifestation of growing cortical excitability in the model, was used as electrographic marker of earliest kindling stage. Results: In kindled animals, baseline levels of hemispheric connectivity and gamma band synchrony were significantly lower compared to seizure-naive rats. Before kindling, subcortical seizures were followed by mild postictal depression of cortical gamma oscillations without changes in interhemispheric functional connectivity. Early in kindling, seizures produced wideband depression of cortical activity and striking drop of hemispheric connectivity. Conclusion: Thus, primary network alterations during epileptogenesis are reduced synchronization and decoupling of hemispheres, both sustained (between seizures) and transient (postictal). Breakdown of long-range communication may reflect homeostatic plastic changes and active attempt to restrict epileptogenic reorganization of neural networks early in epileptogenesis. We think that resting-state hemispheric disconnection may be used as an early marker of epileptogenesis. Seizure-induced SD contributes to generation of postictal events.