High-Frequency Oscillations and Neuroinflammation: Mechanisms of Pathological Network Synchronization and Epileptogenicity
Department
Department of Biomedical and Translational Sciences
Graduate Level
Doctoral
Graduate Program/Concentration
Eastern Virginia Medical school - Doctor of Medicine
Presentation Type
No Preference
Abstract
Background: High-frequency oscillations (HFOs) are transient electroencephalographic (EEG) events >80 Hz, classified into ripples (80–250 Hz) and fast ripples (>250 Hz). While physiological ripples facilitate memory consolidation through precisely timed excitatory-inhibitory (E/I) interactions, fast ripples are increasingly recognized as pathological markers of network dysfunction, particularly in epileptogenesis. Advances in intracranial EEG and computational modeling have expanded our understanding of HFO dynamics, highlighting their role in seizure onset, propagation, and non-epileptic pathological states such as traumatic brain injury (TBI) and neuroinflammation.
Objective: This review characterizes the mechanistic underpinnings of HFO generation, propagation, and modulation, with an emphasis on synaptic and nonsynaptic coupling, microcircuit disorganization, and inflammatory modulation.
Methods: A comprehensive analysis of intracranial EEG studies, computational models, and experimental research was performed to elucidate HFO mechanisms. Particular focus was placed on inhibitory interneuron dysfunction, gap junction-mediated synchronization, ephaptic coupling, and cytokine-driven hyperexcitability.
Results: Pathological HFOs are preferentially localized within the seizure onset zone (SOZ), with fast ripples exhibiting higher specificity for epileptogenic tissue. Mechanistically, ripples arise from in-phase synchronization of principal neuron firing, modulated by parvalbumin-positive (PV+) interneurons, whereas fast ripples emerge from impaired perisomatic inhibition, out-of-phase neuronal clustering, and conduction velocity mismatches. Gap junction-mediated axonal coupling, ephaptic interactions in gliotic tissue, and network re-entry circuits contribute to the generation and maintenance of pathological HFOs. Neuroinflammatory processes, mediated by IL-1β, TNF-α, and IL-6, exacerbate excitatory drive while disrupting inhibitory synaptic and astrocytic homeostasis, thereby potentiating HFO incidence and amplitude. Anti-proinflammatory mediators such as IL-1 receptor antagonists and TNF-α inhibitors have been shown to reduce HFO incidence in experimental models of epileptogenesis, highlighting a potential therapeutic avenue for seizure prevention. Sleep-stage modulation of HFOs suggests preferential diagnostic utility during non-rapid eye movement (NREM) sleep, where physiological and pathological HFO differentiation is most pronounced. Neuromodulatory techniques such as transcranial magnetic stimulation (TMS) and direct cortical stimulation can invoke HFOs, providing potential avenues for biomarker-based epilepsy interventions. Computational models indicate that HFO propagation follows established epileptogenic pathways, reinforcing their utility in mapping functional networks.
Conclusion: HFOs serve as a robust biomarker of pathological network activity, with implications for epilepsy diagnostics, surgical planning, and therapeutic modulation. Their mechanistic link to microcircuit disorganization and neuroinflammatory modulation underscores their broader relevance in neurological disease. The ability of anti-inflammatory mediators to attenuate HFO generation suggests an emerging role for targeted immunomodulatory strategies in epilepsy treatment. Future research should integrate multimodal neuroimaging, computational modeling, and neuromodulation to refine the diagnostic and therapeutic potential of HFOs.
Keywords: High-frequency oscillations, ripples, fast ripples, epilepsy, neuroinflammation, gap junctions, inhibitory dysfunction, ephaptic coupling, cytokines, neuromodulation, seizure onset zone, computational modeling, astrocytic dysregulation.
Keywords
High-frequency oscillations, Ripples, Fast ripples, Epilepsy, Neuroinflammation, Gap junctions, Inhibitory dysfunction, Ephaptic coupling, Cytokines, Neuromodulation, Seizure onset zone, Computational modeling, Astrocytic dysregulation
High-Frequency Oscillations and Neuroinflammation: Mechanisms of Pathological Network Synchronization and Epileptogenicity
Background: High-frequency oscillations (HFOs) are transient electroencephalographic (EEG) events >80 Hz, classified into ripples (80–250 Hz) and fast ripples (>250 Hz). While physiological ripples facilitate memory consolidation through precisely timed excitatory-inhibitory (E/I) interactions, fast ripples are increasingly recognized as pathological markers of network dysfunction, particularly in epileptogenesis. Advances in intracranial EEG and computational modeling have expanded our understanding of HFO dynamics, highlighting their role in seizure onset, propagation, and non-epileptic pathological states such as traumatic brain injury (TBI) and neuroinflammation.
Objective: This review characterizes the mechanistic underpinnings of HFO generation, propagation, and modulation, with an emphasis on synaptic and nonsynaptic coupling, microcircuit disorganization, and inflammatory modulation.
Methods: A comprehensive analysis of intracranial EEG studies, computational models, and experimental research was performed to elucidate HFO mechanisms. Particular focus was placed on inhibitory interneuron dysfunction, gap junction-mediated synchronization, ephaptic coupling, and cytokine-driven hyperexcitability.
Results: Pathological HFOs are preferentially localized within the seizure onset zone (SOZ), with fast ripples exhibiting higher specificity for epileptogenic tissue. Mechanistically, ripples arise from in-phase synchronization of principal neuron firing, modulated by parvalbumin-positive (PV+) interneurons, whereas fast ripples emerge from impaired perisomatic inhibition, out-of-phase neuronal clustering, and conduction velocity mismatches. Gap junction-mediated axonal coupling, ephaptic interactions in gliotic tissue, and network re-entry circuits contribute to the generation and maintenance of pathological HFOs. Neuroinflammatory processes, mediated by IL-1β, TNF-α, and IL-6, exacerbate excitatory drive while disrupting inhibitory synaptic and astrocytic homeostasis, thereby potentiating HFO incidence and amplitude. Anti-proinflammatory mediators such as IL-1 receptor antagonists and TNF-α inhibitors have been shown to reduce HFO incidence in experimental models of epileptogenesis, highlighting a potential therapeutic avenue for seizure prevention. Sleep-stage modulation of HFOs suggests preferential diagnostic utility during non-rapid eye movement (NREM) sleep, where physiological and pathological HFO differentiation is most pronounced. Neuromodulatory techniques such as transcranial magnetic stimulation (TMS) and direct cortical stimulation can invoke HFOs, providing potential avenues for biomarker-based epilepsy interventions. Computational models indicate that HFO propagation follows established epileptogenic pathways, reinforcing their utility in mapping functional networks.
Conclusion: HFOs serve as a robust biomarker of pathological network activity, with implications for epilepsy diagnostics, surgical planning, and therapeutic modulation. Their mechanistic link to microcircuit disorganization and neuroinflammatory modulation underscores their broader relevance in neurological disease. The ability of anti-inflammatory mediators to attenuate HFO generation suggests an emerging role for targeted immunomodulatory strategies in epilepsy treatment. Future research should integrate multimodal neuroimaging, computational modeling, and neuromodulation to refine the diagnostic and therapeutic potential of HFOs.
Keywords: High-frequency oscillations, ripples, fast ripples, epilepsy, neuroinflammation, gap junctions, inhibitory dysfunction, ephaptic coupling, cytokines, neuromodulation, seizure onset zone, computational modeling, astrocytic dysregulation.