Multiscale Circuit Architecture Associated With Memory Dysfunction in Temporal Lobe Epilepsy

ABSTRACT Memory impairment is a major source of disability in temporal lobe epilepsy (TLE), yet how focal pathology relates to distributed circuit alterations underlying memory dysfunction remains unclear. We performed an integrative multiscale circuit‐level analysis in 250 patients with TLE to characterize memory dysfunction across focal structural damage, white matter disconnection, and distributed metabolic network organization, and to estimate individualized deviations in relation to memory performance. Auditory memory impairment was associated with damage to medial temporal structures centered on the hippocampus and parahippocampal cortex, as well as disruption of a key hippocampo‐cingulate white matter pathway. Memory deficits were linked to abnormal metabolic organization within a limbic‐centered network, with greater metabolic deviation associated with more severe global memory impairment. Spatial correspondence analyses showed that memory‐related hypometabolism aligns with serotonergic, GABAergic, and synaptic receptor distributions, with additional associations observed for inhibitory interneuron and mitochondrial signatures. Together, these findings delineate a multiscale circuit architecture underlying memory dysfunction. This framework provides a biologically grounded basis for understanding cognitive vulnerability and may inform individualized risk assessment in epilepsy surgery.