Low-to-High Cross-Frequency Coupling in the Electrical Rhythms as Biomarker for Hyperexcitable Neuroglial Networks of the Brain

<italic>Objective</italic>: One of the features used in the study of hyperexcitablility is high-frequency oscillations (HFOs, >80 Hz). HFOs have been reported in the electrical rhythms of the brain’s neuroglial networks under physiological and pathological conditions. Cross-frequency coupling (CFC) of HFOs with low-frequency rhythms was used to identify pathologic HFOs in the epileptogenic zones of epileptic patients and as a biomarker for the severity of seizure-like events in genetically modified rodent models. We describe a model to replicate reported CFC features extracted from recorded local field potentials (LFPs) representing network properties. <italic>Methods </italic>: This study deals with a four-unit neuroglial cellular network model where each unit incorporates pyramidal cells, interneurons, and astrocytes. Three different pathways of hyperexcitability generation—Na<inline-formula> <tex-math notation="LaTeX">$^{+}$</tex-math></inline-formula>-<inline-formula><tex-math notation="LaTeX"> ${\rm K}^{+}$</tex-math></inline-formula> ATPase pump, glial potassium clearance, and potassium afterhyperpolarization channel—were used to generate LFPs. Changes in excitability, average spontaneous electrical discharge (SED) duration, and CFC were then measured and analyzed. <italic>Results</italic>: Each parameter caused an increase in network excitability and the consequent lengthening of the SED duration. Short SEDs showed CFC between HFOs and theta oscillations (4–8 Hz), but in longer SEDs the low frequency changed to the delta range (1–4 Hz). <italic>Conclusion</italic>: Longer duration SEDs exhibit CFC features similar to those reported by our team. <italic>Significance</italic>: First, Identifying the exponential relationship between network excitability and SED durations; second, highlighting the importance of glia in hyperexcitability (as they relate to extracellular potassium); and third, elucidation of the biophysical basis for CFC coupling features.