Ekaterina Andreevna Narodova

Conditions characterized by the predominance of pathological “plus-functions” (paroxysmal seizures, sensory overload, productive psychopathological symptoms) are traditionally considered within distinct nosological categories. Accumulated evidence, however, points to overlapping neurobiological mechanisms involving imbalanced excitation/inhibition, inhibitory interneuron dysfunction, chloride homeostasis disturbances, and disrupted rhythmic activity of brain networks. The aim of this review is to analyze putative common mechanisms underlying conditions with predominant pathological “plus-functions”, drawing primarily on epilepsy as the best-characterized model of paroxysmal network hyperactivity, and to discuss applicability of such concepts to other clinical conditions including migraine, anxiety and depressive disorders, and neurodevelopmental conditions. Data on the role of parvalbumin-expressing interneurons, dysregulation of chloride transporters (KCC2/NKCC1), alterations in gamma-band oscillations, and reduced stability of brain network dynamics are presented. Pathological states are assessed as conditions that may be considered regimes of dynamic instability, characterized by an increased probability of transition to synchronized hyperactivity. A conceptual framework is proposed to facilitate integration of partially overlapping neurobiological mechanisms across these conditions. It is emphasized that this framework is hypothesis-generating and requires further empirical validation. Pharmacological and non-pharmacological approaches to modulate brain network dynamics – including rhythmic stimulation – are discussed as strategies aimed at enhancing the stability of functional states.

Objective: To summarize current evidence on the prevalence, phenomenology, and temporal characteristics of prodromal symptoms and early ictal manifestations (auras) in focal epilepsy, and to clarify their clinical relevance for patient counseling and management. Material and methods. A narrative review of the literature on prodromal symptoms and auras in focal epilepsy was conducted. Publications were identified through searches in PubMed/MEDLINE and by screening reference lists of key articles. Given the heterogeneity in definitions and time frames across studies, findings were analyzed qualitatively without meta-analysis, particularly emphasizing on practical aspects of clinical interviewing and safety recommendations. Results. Prodromal symptoms are reported in a substantial proportion of patients with focal epilepsy; reported prevalence varies depending on assessment methods and diagnostic criteria. Prodromes typically occur minutes to hours (less commonly a day or more) before seizure onset and may include affective, cognitive, and autonomic manifestations. According to the current classification by the International League Against Epilepsy, an aura is defined as a focal aware seizure and represents the ictal phase of the epileptic event. Clinically, auras are characterized by brief, stereotyped subjective experiences occurring seconds to minutes before potential seizure propagation. Patients’ responses to warning symptoms often include cessation of ongoing activities, seeking a safe environment, and alerting others, which may reduce the risk of injury. However, in some individuals, anticipatory anxiety and avoidance behaviors develop, negatively affecting quality of life. Conclusion. In patients with focal epilepsy, routine and systematic inquiry about prodromal symptoms and auras during clinical evaluation is advisable. Clinicians should carefully distinguish between prodromal and early ictal manifestations and help patients adopt proportionate safety measures without reinforcing hypervigilance or unnecessary restrictions in daily activities.

Post-stroke epilepsy (PSE) is one of the most common long-term neurological complications of stroke and represents a major contributor to disability, reduced quality of life, and increased healthcare burden. Although numerous risk factors and biomarkers have been proposed, many current risk models still emphasize lesion-related predictors and do not fully account for the temporal evolution of post-stroke network excitability. This narrative review aims to examine post-stroke epileptogenesis as a dynamic process of network reconfiguration and to summarize current evidence on biological, neurophysiological, imaging, and clinical biomarkers across different stages following stroke. A structured narrative review of the literature was performed using major biomedical databases. Studies addressing mechanisms of post-stroke epileptogenesis, biomarkers, network dysfunction, neuroinflammation, EEG findings, neuroimaging correlates, and longitudinal monitoring strategies were evaluated and synthesized qualitatively. Evidence suggests that post-stroke epileptogenesis is driven by complex interactions among structural injury, neuroinflammation, blood–brain barrier dysfunction, neurotransmitter imbalance, maladaptive plasticity, and large-scale network reorganization. Importantly, many biomarkers demonstrate substantial temporal variability, and their clinical significance depends on the stage of recovery and the evolving state of brain networks. Emerging data indicate that sleep disturbances, stress, mood disorders, metabolic factors, and other state-dependent influences may further modulate seizure susceptibility after stroke. Post-stroke epileptogenesis may be better conceptualized as a dynamic process of network instability rather than a fixed consequence of focal brain damage. It is proposed that the post-stroke brain can transiently or persistently enter an “irritable brain state”, characterized by increased vulnerability to pathological synchronization under the influence of biological and behavioral modulators. This framework may facilitate the development of longitudinal biomarker strategies and personalized monitoring approaches in future research. However, it should be emphasized that the “irritable brain state” remains a conceptual and hypothesis-generating construct; no validated diagnostic criteria exist, and prospective evidence demonstrating that interventions targeting this state reduce the incidence of post-stroke epilepsy is currently lacking.

Epilepsy is increasingly conceptualized as a disorder of dynamic network instability rather than a static imbalance between excitation and inhibition. However, substantial variability in seizure occurrence, clinical expression, and treatment response remains insufficiently explained by existing models. This narrative review examines how neurotransmitter systems contribute to seizure dynamics within a state-dependent framework, in which factors such as sleep–wake cycles, stress, inflammation, and metabolic conditions modulate network excitability. The review identified four key findings: neurotransmitter function in epilepsy is state-dependent rather than fixed; multiple physiological state modifiers shape seizure susceptibility; seizure termination is an active state-sensitive process; and biomarker performance depends on the prevailing brain state. Evidence from experimental and clinical studies indicates that neurotransmitter function is context-sensitive and interacts with molecular pathways, including ion channel function, synaptic plasticity, and neuromodulatory signaling. These interactions influence key stages of seizure dynamics, including initiation, propagation, and termination, and may differ across etiological categories of epilepsy. This perspective also helps explain the limited performance of static biomarkers, as they do not capture temporal variability in network states. Instead, state-sensitive markers and context-aware interpretations of electrophysiological and clinical data may provide more informative insights. Overall, integrating neurotransmitter mechanisms with dynamic brain states offers a more precise perspective on seizure variability and may support the development of individualized, state-aware approaches to epilepsy management.

Epileptogenesis is commonly defined by the emergence of spontaneous seizures after an initial insult; however, convergent experimental and clinical evidence indicates that the underlying disease process begins well before seizures become clinically detectable. During this pre-seizure phase, persistent molecular cascades remodel synaptic plasticity, circuit architecture, and glial–immune signaling. These processes are associated with trait-like alterations in cognition, affect, and behavior. Despite their clinical relevance, these neurobehavioral signatures remain poorly integrated into molecular models of epileptogenesis and are rarely considered as translational biomarkers of disease progression. This review synthesizes evidence linking core epileptogenic molecular cascades—maladaptive synaptic plasticity, glial–immune signaling, oxidative–metabolic stress, and activity-dependent gene regulation—to reproducible alterations in executive control, cognitive flexibility, emotional regulation, and motivational–social behavior. We outline an integrative framework in which these phenotypes are conceptualized as system-level readouts of progressive network reconfiguration rather than nonspecific “comorbidities” or mere consequences of recurrent seizures. Within this perspective, neurobehavioral markers can complement electrophysiological and molecular measures by capturing disease-relevant changes during windows when anti-epileptogenic interventions would be most effective. To increase mechanistic specificity, we provide representative pathway and gene-level anchors across epileptogenesis stages, a structured molecular-to-neurobehavioral mapping, and an operational biomarker panel specifying confounders and minimal controls. These anchors are included to ground the framework in experimentally documented molecular nodes with stage-dependent relevance; examples are representative rather than exhaustive, and evidence strength is indicated as preclinical mechanistic versus associative human observations. Finally, we discuss methodological requirements for biomarker validity (specificity, temporal anchoring, and cross-model consistency) and outline how integrating molecular and neurobehavioral trajectories may refine target discovery and improve the translation of anti-epileptogenic strategies. Conceptualizing epileptogenesis as a progressive disease process with measurable pre-seizure neurobehavioral signatures may broaden biomarker strategies beyond seizure occurrence and support the development of disease-modifying interventions.

Short-range internal timing supports coordinated movement, attention, and physiological regulation, yet distortions of time experience are frequently reported across clinical and high-arousal states. Patients with anxiety or acute stress often describe an apparent acceleration of time, whereas depressive states are more commonly associated with a slowing of subjective time. Neurological conditions, including Parkinson’s disease and epilepsy, further demonstrate alterations in temporal processing that cannot be reduced to a single mechanism. This narrative review synthesizes evidence from experimental timing paradigms, subjective passage-of-time judgments, and chronobiological approaches to examine how internal timing varies across biological states. In this study, we highlight the distinction between experiential time distortion and performance-based interval timing and discuss how task characteristics, arousal level, and neural context contribute to heterogeneous findings. Historical and methodological foundations are reviewed, including early chronobiological work linking subjective time estimation to biological rhythms. The reviewed evidence suggests that many timing distortions observed in stress-related, affective, and neurological conditions reflect state-dependent reconfiguration rather than irreversible dysfunction. Framing timing variability as a potential marker of internal state may help reconcile inconsistent results across paradigms and inform future clinical and translational research on temporal processing.

Background: Rhythmic sensory stimulation, including structured musical interventions, has gained renewed interest as a non-pharmacological strategy that may modulate cortical excitability and network stability in focal epilepsy. Although several small studies have reported changes in seizure frequency or epileptiform activity during rhythmic or music exposure, the underlying mechanisms and translational relevance remain insufficiently synthesized. Objective: This narrative review summarizes clinical evidence on music-based and rhythmic sensory interventions in focal epilepsy, outlines plausible neurophysiological mechanisms related to neural entrainment and large-scale network regulation, and discusses emerging opportunities for digital delivery of rhythmic protocols in everyday self-management. Methods: A structured search of recent clinical, neurophysiological, and rehabilitation literature was performed with emphasis on rhythmic auditory, tactile, and multimodal stimulation in epilepsy or related conditions. Additional theoretical and translational sources addressing oscillatory dynamics, entrainment, timing networks, and patient-centered digital tools were reviewed to establish a mechanistic framework. Results: Existing studies—although limited by small cohorts and heterogeneous methodology—suggest that certain rhythmic structures, including specific musical compositions, may transiently modulate cortical synchronization, reduce epileptiform discharges, or alleviate seizure-related symptoms in selected patients. Evidence from neurologic music therapy and rhythmic stimulation in other neurological disorders further supports the concept that externally delivered rhythms can influence timing networks, attentional control, and interhemispheric coordination. Advances in mobile health platforms enable structured rhythmic exercises to be delivered and monitored in real-world settings. Conclusions: Music-based and rhythmic sensory interventions represent a promising but underexplored adjunctive approach for focal epilepsy. Their effectiveness likely depends on individual network characteristics and on the structure of the applied rhythm. Digital integration may enhance personalization and adherence. Rigorous clinical trials and mechanistic studies are required to define optimal parameters, identify responders, and clarify the role of rhythmic stimulation within modern epilepsy care.

Epilepsy is increasingly conceptualized as a disorder of large-scale network instability, involving impairments in interhemispheric connectivity, prefrontal inhibitory control, and slow-frequency temporal processing. Rhythmic sensory stimulation—auditory, vibrotactile, or multisensory—can entrain neuronal oscillations and modulate attentional and sensorimotor networks, yet its mechanistic relevance to epileptic network physiology remains insufficiently explored. This conceptual and mechanistic article integrates empirical findings from entrainment research, prefrontal timing theories, multisensory integration, and network-based models of seizure dynamics and uses them to formulate a hypothesis-driven framework for multisensory exogenous rhythmic stimulation (ERS) in focal epilepsy. Rather than presenting a tested intervention, we propose a set of speculative mechanistic pathways through which low-frequency rhythmic cues might serve as an external temporal reference, engage fronto-parietal control systems, facilitate multisensory-driven sensorimotor coupling, and potentially modulate interhemispheric frontal coherence. These putative mechanisms are illustrated by exploratory neurophysiological observations, including a small pilot study reporting frontal coherence changes during mobile ERS exposure, but they have not yet been validated in controlled experimental settings. The framework does not imply therapeutic benefit; instead, it identifies theoretical pathways through which rhythmic sensory cues may transiently interact with epileptic networks. The proposed model is intended as a conceptual foundation for future neurophysiological validation, computational simulations, and early feasibility research in the emerging field of digital neuromodulation, rather than as evidence of clinical efficacy. This Hypothesis article formulates explicitly testable predictions regarding how multisensory ERS may transiently modulate candidate physiological markers of prefrontal network stability in focal epilepsy.

Background/Objectives: Medication non-adherence and incomplete seizure documentation remain major challenges in epilepsy care, particularly in drug-resistant forms. Digital health tools may improve self-management by integrating seizure tracking, adherence support, and patient–clinician communication. This narrative review summarizes current mobile applications for seizure monitoring and adherence and outlines opportunities and gaps in clinical translation. Methods: A narrative synthesis (PubMed, Scopus, Google Scholar; 2019–2025; English) summarized functionality, usability, clinical validation, and limitations of epilepsy-focused mobile/wearable applications; no systematic methods or meta-analysis were applied. Results: Existing tools cluster into seizure diary apps, smartwatch-based monitoring systems, and adherence-focused applications. While they improve documentation and treatment regularity, most lack adaptive personalization, language localization and therapeutically active components. Comprehensive platforms combining tracking, adherence analytics and telehealth remain unevenly validated. Validated wearable detectors for generalized tonic–clonic seizures typically report sensitivity in the 80–95% range in real-world or simulated-real-world studies, alongside variable specificity and false-alarm rates, underscoring the need for individualized deployment and calibration. Conclusions: Mobile and wearable applications are promising adjuncts to routine epilepsy care. The field is gradually shifting from passive monitoring toward integrated, user-centered platforms that blend monitoring, predictive analytics and neuromodulation. This review also briefly outlines a conceptual example of an integrated mobile platform that combines seizure documentation, adherence support and patient-initiated rhythmic cueing; this example is presented at a purely exploratory level and requires further clinical validation.

Background: Drug-resistant epilepsy remains a major therapeutic challenge, especially in preventing the progression of focal seizures to bilateral tonic-clonic seizures (BTCS). Previous studies demonstrated that exogenous rhythmic stimulation at 1.13 Hz syn-chronized with wrist tapping enhances prefrontal cortex activity in epilepsy patients. Methods: We conducted a randomized controlled study involving 60 adult patients with drug-resistant structural focal epilepsy (SFE). Participants were assigned to either an in-tervention group (n = 30), using the EpiTapp™ smartphone application during aura and/or focal onset of BTCS in out-of-hospital settings, or a control group (n = 30) receiving standard care. The study lasted six months. Primary outcomes were BTCS frequency and quality of life measured by the QOLIE-31 scale. Results: Use of EpiTapp™ significantly reduced BTCS frequency by interrupting seizure progression at the focal onset stage. Additionally, 22.6% of patients in the intervention group reported improved quality of life after six months. Conclusions: Exogenous rhythmic stimulation via the EpiTapp™ ap-plication is a promising non-invasive intervention for preventing seizure generalization in patients with drug-resistant structural focal epilepsy. Larger-scale studies are warranted to confirm these findings.