Functional connectivity linking the hippocampus, retrosplenial, and orbitofrontal cortex correlates with increased...

Temporal lobe epilepsy (TLE) is a highly prevalent neurological disorder characterized by severe seizures and altered consciousness. Seizures in TLE often originate in the hippocampus (HIP) but can spread to widespread brain regions, including the retrosplenial cortex (RSC) and orbitofrontal cortex (ORB). The RSC is a highly interconnected cortical region implicated in seizure onset and propagation, yet its role in epilepsy remains poorly understood. We induced seizures (n = 48) in behaving adult male Sprague-Dawley rats (n = 5) via unilateral electrical stimulation of the right ventral hippocampus (targeting the dentate gyrus) using square biphasic pulses (1 ms per phase) at 60 Hz for 2 s. Stimulation began at 50 μA and was increased in 25 μA steps if no seizure was evoked, up to a maximum of 500 μA or until the animals exhibited up to five seizure episodes, to investigate the dynamic changes in the RSC during seizures of varying severity and their temporal coordination with other brain regions. Seizures were categorized based on the presence of fast poly-spike activity (7-15 Hz) and slow-wave activity (1-2 Hz) and their spread to the HIP and ORB. Spectral power density changes across the three regions correlated with seizure severity. Coherence patterns transitioned from adaptive (flexible and localized), RSC-ORB and HIP-RSC coupling to maladaptive, persistent hypersynchronization involving the HIP-RSC and HIP-ORB hypersynchronization as severity increased. The RSC acts as a key hub for integrating and transmitting information between distant brain regions, particularly during low-severity seizures. In contrast, it predominantly receives input from both upstream and downstream sources during high-severity seizures. Our findings provide critical insights into the relationship between seizure severity and brain network dynamics, highlighting the RSC as a potential therapeutic target for epilepsy.