The potential of laminar functional MRI in refining the understanding of epilepsy in humans

TY - JOUR

T1 - The potential of laminar functional MRI in refining the understanding of epilepsy in humans

AU - Aitken, Fraser

AU - Winston, Joel S.

AU - O'Muircheartaigh, Jonathan

AU - Carmichael, David W.

N1 - Publisher Copyright: © The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.

PY - 2025/12/4

Y1 - 2025/12/4

N2 - Despite decades of development and clinical application, drug-resistant epilepsy occurs in 25%-30% of patients. One limiting factor in the success of antiseizure medications are challenges in mapping the neural effects of epilepsy drugs to seizure mechanisms in humans. Most antiseizure 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 functional MRI (fMRI). This disconnect between the 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 generalized 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 antiseizure medications, and ultimately, targeting current and future epilepsy treatments.

AB - Despite decades of development and clinical application, drug-resistant epilepsy occurs in 25%-30% of patients. One limiting factor in the success of antiseizure medications are challenges in mapping the neural effects of epilepsy drugs to seizure mechanisms in humans. Most antiseizure 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 functional MRI (fMRI). This disconnect between the 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 generalized 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 antiseizure medications, and ultimately, targeting current and future epilepsy treatments.

KW - cortical layers

KW - electrophysiology

KW - focal seizures

KW - generalized seizures

KW - ultra-high-resolution fMRI

UR - https://www.scopus.com/pages/publications/105024018457

U2 - 10.1093/brain/awaf320

DO - 10.1093/brain/awaf320

M3 - Review article

C2 - 40899261

AN - SCOPUS:105024018457

SN - 0006-8950

VL - 148

SP - 4180

EP - 4197

JO - Brain : a journal of neurology

JF - Brain : a journal of neurology

IS - 12

ER -