Perinatal asphyxia (PA) remains a major cause of neonatal mortality and long-term neurodevelopmental disability worldwide. Although hypoxic–ischemic brain injury has traditionally been attributed to oxygen deprivation, excitotoxicity, and oxidative stress, accumulating evidence indicates that neurological outcomes are determined by complex interactions among metabolic, mitochondrial, neuroimmune, and neuroendocrine mechanisms. Following hypoxic–ischemic injury, primary energy failure rapidly triggers excitotoxicity, mitochondrial dysfunction, calcium dysregulation, and oxidative damage, leading to activation of microglia and astrocytes, release of pro-inflammatory cytokines, disruption of blood–brain barrier integrity, and recruitment of peripheral immune cells. These events contribute to the development of secondary energy failure and persistent neuroinflammation. Simultaneously, activation of hypoxia-responsive pathways, including hypoxia-inducible factor-1 (HIF-1), heat shock protein 70 (HSP70), glutathione-dependent antioxidant defenses, and neuroendocrine stress responses involving the hypothalamic–pituitary–adrenal axis, promote endogenous adaptation and neuroprotection. Nitric oxide signaling further links mitochondrial dysfunction, oxidative and nitrosative stress, inflammatory activation, and neuronal injury. Together, these mechanisms form an integrated neuroimmune-endocrine network that influences both injury progression and tissue repair. In this review, we propose Brain Energy Failure as a unifying conceptual framework linking mitochondrial dysfunction, oxidative and nitrosative stress, neuroinflammation, endocrine adaptation, and endogenous neuroprotective responses following perinatal hypoxia. We further discuss the role of biomarkers associated with neuro-immuno-endocrine dysfunction, including inflammatory mediators, oxidative stress markers, endocrine factors, and indicators of neuronal and glial injury. Recent evidence has highlighted the therapeutic potential of multimodal neuroprotective approaches, including endogenous lipid mediators such as palmitoylethanolamide (PEA), which exert anti-inflammatory, antioxidant, and mitoprotective effects. We also review current and emerging neuroprotective strategies targeting mitochondrial dysfunction, oxidative stress, inflammatory signaling, and bioenergetic instability, and discuss their translational implications. Understanding the interactions among these interconnected pathways may facilitate biomarker-guided diagnosis, personalized neuroprotection, and the development of more effective therapies aimed at improving long-term neurological outcomes following perinatal asphyxia.
Upper-limb motor impairment after stroke is compounded by a disrupted sensorimotor cascade linking visual attention, cortical motor preparation, and peripheral muscle activation. Whether these stages are temporally dissociated in subacute stroke, and whether their timing carries information about the preparation and execution of a reaching action, remains unclear. Thirty subacute stroke survivors and 30 healthy controls performed a full-plane nine-grid reaching task while eye-tracking, electroencephalography (EEG), and surface electromyography (EMG) were recorded synchronously. Three neurophysiological latencies were extracted: first fixation on the target, stimulus-locked lateralized readiness potential (s-LRP) onset, and peripheral muscle activation onset. Compared with controls, patients showed a stepwise delay across the cascade, with delayed visual engagement (616.73 ms vs. 367.86 ms) and delayed peripheral muscle activation (1,080 ms vs. 605 ms) bracketing a cortical preparation window. A random-forest classifier was trained on window-level gaze-timing features, computed separately for each target-presentation and inter-target interval of the task. Under participant-level leave-one-subject-out cross-validation, it achieved an area under the receiver operating characteristic curve (AUC) of 0.973 (95% CI 0.958–0.984) and an accuracy of 0.918, numerically the highest among the five classifiers compared. These findings describe a quantifiable temporal organization of the sensorimotor cascade in the subacute stage of stroke and indicate that gaze timing carries discriminative information about the occurrence of an instructed reaching action. They establish a descriptive, testable framework rather than a demonstrated clinical benefit. Validation in chronic stroke and across independent samples is further required.
BackgroundDietary restriction, encompassing intermittent fasting and caloric restriction, represents a prominent non-pharmacological approach to modulating brain aging and neuronal resilience. Emerging evidence links metabolism to long-term neural plasticity through epigenetic mechanisms, yet findings remain fragmented. This review integrates preclinical evidence on how dietary restriction alters brain epigenetic regulation and links these changes to neurocognitive outcomes.MethodsThe review followed PRISMA 2020 and the Synthesis Without Meta-analysis (SWiM) reporting guideline. PubMed and SciSpace were searched from inception to December 2025. Eligible studies assessed DNA methylation, histone modifications, non-coding RNA, or epigenetic regulators in brain tissue of animal or human subjects undergoing dietary restriction. Risk of bias was appraised with the SYRCLE tool, and a qualitative narrative synthesis was undertaken given methodological heterogeneity.ResultsNine preclinical animal studies met the inclusion criteria; no human study qualified. Dietary restriction significantly affected DNA methylation, histone modifications, and non-coding RNA expression, exerting a recalibrating influence that attenuated age-associated epigenetic drift and restored homeostatic regulation. Sirtuin-1/CREB signalling, BDNF/TrkB signalling, metabolic signalling (mTOR, AMPK, FOXO), and neuroinflammatory modulation were the principal pathways implicated. Intermittent fasting and caloric restriction showed overlapping and distinct mechanisms, with ketone-induced histone deacetylase inhibition linked to fasting. Cognitive benefit, particularly in hippocampal-dependent memory, accompanied the epigenetic changes, although persistent epigenetic memory of dietary restriction was less clear. Risk of bias was high in seven studies and moderate in two, reflecting incomplete reporting of randomisation, blinding, and protocols.ConclusionDietary restriction alters brain epigenetics through multiple interconnected pathways that strengthen neural circuits and improve cognitive function. The preclinical evidence is consistent across several layers of epigenetic regulation, but the absence of human studies, small sample sizes, and limited causal evidence constrain translation. Multi-omics approaches and epigenome editing are required to establish causality and the therapeutic potential of dietary restriction.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD420251035303.
IntroductionMental health conditions present a particular challenge to categorical nosology. We propose that such conditions are better understood as Dynamical Disorders, defined not only by symptom cluster profiles but by underlying disrupted patterns of coordination across bio-psycho-social scales. We present an exemplary case study of Complex Emotional Needs (CEN) presentations. Its transdiagnostic scope, process-defined clinical presentation, and 40–60% non-remission rates under current protocols reflect a mismatch between categorical nosology and the dynamic, multi-scale psycho-neurobiological processes underlying these conditions.MethodsDrawing on affective neuroscience and synchronization dynamics, we propose reconceptualizing CEN as disorders of flexible functional synchronization across nested bio-psycho-social scales.ResultsWe derive four dynamical phenotypes from the parameter space governing multi-scale synchronization and specify how to operationalize them empirically. They exhibit characteristic dynamical-landscape topologies, quantified by basin curvature, energy barrier heights, and stability exponents. Simulations of the master equation generate dynamical landscape topologies and phenotype-specific parameter regimes.DiscussionThis approach yields pragmatic, testable predictions of clinical dynamics and corresponding treatments. We consider the algorithmic selection of phenotype-matched modular interventions targeting specific coordination failures, along with a validation program that AI agents can eventually augment. We present falsifiable predictions for comparative trials between phenotype-matched and treatment-as-usual approaches. This framework offers a principled path toward evidence-based mental health care grounded in human synchronization dynamics.
