Electrophysiological Mechanisms in Human Epilepsy

Epileptic seizures arise from aberrant electrical activity within neuronal networks, characterised by excessive synchronisation and hyperexcitability. At the cellular level, paroxysmal depolarisation shifts and interictal spikes reflect transient bursts of synchronous firing, while high-frequency oscillations mark pathological network synchrony. Disruption of the balance between excitatory glutamatergic and inhibitory GABAergic signalling underlies seizure initiation and propagation, with alterations in synaptic structure and receptor function contributing to epileptogenesis. Laminar microelectrode recordings in human cortex and hippocampus have revealed depth-dependent current sinks and sources that evolve during seizure spread, informing frameworks for localising seizure onset zones. Insights from human tissue studies complement animal and in vitro models, advancing neuromodulation strategies, surgical targeting and the development of novel pharmacotherapies to reduce or prevent seizure generation.

Research from Nature Portfolio

Recent studies using laminar microelectrode arrays in human neocortical resections have demonstrated that ictal discharges within the seizure onset zone are confined to infra-granular and granular layers, whereas propagation involves superficial layers, with current sinks and sources shifting depth as seizures evolve. These findings underpin a new cortical–cortical dynamics framework for improved seizure localisation and targeted neuromodulation. Complementary work in human in vitro models shows that interictal-like discharges are initiated by intrinsically bursting pyramidal cells, with excitatory neurons leading and inhibitory interneurons contributing to termination. This delineation of cell-specific burstiness and network interactions refines understanding of hypersynchrony and may guide cell-targeted interventions.

Electrophysiological Mechanisms in Human Epilepsy publication trend

The graph below shows the total number of articles in electrophysiological mechanisms in human epilepsy across all publications each year (not limited to Nature Index journals).

Technical terms

Paroxysmal depolarisation shift (PDS): A prolonged neuronal membrane depolarisation reflecting the cellular correlate of interictal spikes.

Local field potential (LFP): The summed extracellular voltage fluctuations generated by synchronised synaptic activity of local neuronal populations.

Interictal spike: A transient, hypersynchronous discharge recorded between seizures, indicative of network instability.

High-frequency oscillations (HFOs): Rapid rhythmic electrical activity (>80 Hz) associated with epileptogenic regions.

Laminar microelectrode array: A linear series of recording contacts spanning cortical layers to resolve depth-specific electrical events.

References

1. Differential cortical layer engagement during seizure initiation and spread in humans. Nature Communications (2024).
2. Of the Mechanisms of Paroxysmal Depolarization Shifts: Generation and Maintenance of Bicuculline-Induced Paroxysmal Activity in Rat Hippocampal Cell Cultures. International Journal of Molecular Sciences (2023).
3. Synaptic alterations and neuronal firing in human epileptic neocortical excitatory networks. Frontiers in Synaptic Neuroscience (2023).
4. The Paroxysmal Depolarization Shift: Reconsidering Its Role in Epilepsy, Epileptogenesis and Beyond. International Journal of Molecular Sciences (2019).
5. Inhibition and oscillations in the human brain tissue in vitro. Neurobiology of Disease (2019).
6. Bursting of excitatory cells is linked to interictal epileptic discharge generation in humans. Scientific Reports (2022).
7. Limitations of animal epilepsy research models: Can epileptic human tissue provide translational benefit?. ALTEX (2021).