The Potential of Laminar fMRI for Refining the Understanding of Epilepsy in Humans at the Microcircuit Level

Despite decades of development and clinical application drug-resistant epilepsy occurs in 25–30% of patients. One limiting factor in the success of anti-seizure medications are challenges in mapping the neural effects of epilepsy drugs to seizure mechanisms in humans. Most anti-seizure medications were developed in animal models and primarily target nano-scale structures like ion channels and receptors. However, they exert their effects and are typically measured in humans at the macro-scale using techniques like EEG and conventional fMRI. This disconnect between the molecular mechanisms of pharmaceutical interventions and the clinical management of epilepsy leaves a critical gap in our understanding. This is because all seizures, even those of a generalised nature, appear to initiate in intermediate scale, local microcircuits and then propagate from that initial ictogenic zone. Invasive electrophysiological recordings in both animal models and humans have shown that one such microcircuit, cortical layers, and more specifically deep cortical layers, play a critical role in seizure generation in both generalized and focal epilepsies, serving as the critical link between nano-scale dysfunctions and the macro-scale activity observed in seizures. Laminar fMRI, a technique capable of resolving activity across cortical depths, offers a promising avenue to bridge this gap. By providing a non-invasive measure of laminar response alterations in humans, it could complement animal model and electrophysiological findings, offering novel insights into the layer-specific mechanisms of seizure generation and propagation in humans. This review discusses evidence for this concept, highlighting key findings from animal models and human intracranial recordings in this regard, and details how laminar fMRI may be able to refine our understanding of epilepsy at the microcircuit level. It concludes with a discussion regarding the possible role of laminar fMRI in improving surgical targeting for focal epilepsies, elucidating the mechanistic effects of anti-seizure medications, and ultimately, targeting current and future epilepsy treatments.