Electric fields are now considered a major mechanism of epileptiform activity. However, it is not clear if another electrophysiological phenomenon, burst suppression, utilizes the same mechanism for its bursting phase. Thus, the purpose of this study was to compare the role of ephaptic coupling—the recruitment of neighboring cells via electric fields—in generating bursts in epilepsy and burst suppression. We used local injections of the GABA-antagonist picrotoxin to elicit epileptic activity and a general anesthetic, sevoflurane, to elicit burst suppression in rabbits. Then, we applied an established computational model of pyramidal cells to simulate neuronal activity in a 3-dimensional grid, with an additional parameter to trigger a suppression phase based on extra-cellular calcium dynamics. We discovered that coupling via electric fields was sufficient to produce bursting in scenarios where inhibitory control of excitatory neurons was sufficiently low. Under anesthesia conditions, bursting occurs with lower neuronal recruitment in comparison to seizures. Our model predicts that due to the effect of electric fields, the magnitude of bursts during seizures should be roughly 2–3 times the magnitude of bursts that occur during burst suppression, which is consistent with our in vivo experimental results. The resulting difference in magnitude between bursts during anesthesia and epileptiform bursts reflects the strength of the electric field effect, which suggests that burst suppression and epilepsy share the same ephaptic coupling mechanism.

The functional deficiency of the inhibitory system typically appears during development and can progress to psychiatric disorders or epilepsy, depending on its severity, in later years. It is known that interneurons, the major source of GABAergic inhibition in the cerebral cortex, can make direct connections with arterioles and participate in the regulation of vasomotion. The goal of this study was to mimic the functional deficiency of interneurons through the use of localized microinjections of the GABA antagonist, picrotoxin, in such a concentration that it did not elicit epileptiform neuronal activity. First, we recorded the dynamics of resting-state neuronal activity in response to picrotoxin injections in the somatosensory cortex of an awake rabbit; second, we assessed the altered neuronal and hemodynamic responses to whisker stimulation using BOLD fMRI and electrophysiology recordings; third, we evaluated brain tissue oxygen levels before and after picrotoxin injection. Our results showed that neuronal activity typically increased after picrotoxin administration, the BOLD responses to stimulation became negative, and the oxygen response was nearly abolished. Vasoconstriction during the resting baseline was not observed. These results indicate that picrotoxin provoked imbalanced hemodynamics either due to increased neuronal activity, decreased vascular response, or a combination of both.

Glutamate provides the principal excitatory drive in the cortex, so reducing ionotropic glutamatergic transmission is expected to suppress neuronal activity. We asked whether reducing ongoing glutamatergic excitation can reveal a previously unrecognized form of neuronal activity: a local population timing mechanism. Combining two established single-neuron constraints (near-threshold susceptibility and spike-history-dependent loss of excitability) we proposed an availability reservoir: a local population can generate a burst only when enough neurons are both susceptible and recovered. This hypothesis predicted a counterintuitive result: local glutamate-receptor antagonism should not simply silence the awake cortex, but should allow the eligible pool to refill and reveal recurrent burst-quiescence. In the awake rabbit cortex, local glutamate-receptor antagonism produced stereotyped local-field-potential and multi-unit population bursts separated by quiescence. Increasing GABAergic inhibition progressively reduced burst size and recurrence before abolishing the pacemaker regime, whereas reducing GABAergic inhibition under baseline conditions produced epileptiform activity with different timing and intra-burst structure. Thus, glutamatergic excitation can mask a recovery-dependent cortical population pacemaker regime. The same framework distinguishes recovery-dependent burst-quiescence from disinhibited epileptiform bursting, providing an operational separation between visually similar but mechanistically different brain states.