Memory processes and prefrontal network dysfunction in cryptogenic epilepsy

Purpose: Impaired memory performance is the most frequently reported cognitive problem in patients with chronic epilepsy. To examine memory deficits many studies have focused on the role of the mesiotemporal lobe, mostly with hippocampal abnormalities. However, the role of the prefrontal brain remains unresolved. To investigate the neuronal correlates of working memory dysfunction in patients without structural lesions, a combined study of neurocognitive assessment, hippocampal and cerebral volumetry, and functional magnetic resonance imaging of temporal and frontal memory networks was performed. Methods: Thirty-six patients with cryptogenic localization-related epilepsy and 21 healthy controls underwent neuropsychological assessment of intelligence (IQ) and memory. On T-1-weighted images obtained by 3-Tesla magnetic resonance imaging (MRI), volumetry of the hippocampi and the cerebrum was performed. Functional MRI (fMRI) was performed with a novel picture encoding and Sternberg paradigm that activated different memory-mediating brain regions. Functional connectivity analysis comprised cross-correlation of signal time-series of the most strongly activated regions involved in working memory function. Key Findings: Patients with epilepsy displayed lower IQ values; impaired transient aspects of information processing, as indicated by lower scores on the digit-symbol substitution test (DSST); and decreased short-term memory performance relative to healthy controls, as measured with the Wechsler Adult Intelligence Scale subtests for working memory, and word and figure recognition. This could not be related to any hippocampal volume changes. No group differences were found regarding volumetry or fMRI-derived functional activation. In the Sternberg paradigm, a network involving the anterior cingulate and the middle and inferior frontal gyrus was activated. A reduced strength of four connections in this prefrontal network was associated with the DSST and word recognition performance in the patient group. Significance: Deficits in the processes involved in transient working memory, and to a lesser extent in short-term memory, in patients with localization-related epilepsy of both temporal and extratemporal origin cannot be attributed to hippocampal atrophy or function only, but are also related to reduced functional connectivity in the prefrontal brain. Because patients with symptomatic lesions or mesiotemporal sclerosis were excluded from this study, the results cannot be explained by structural lesions. Therefore, the current findings highlight the influence of epilepsy on the prefrontal network integrity as a possible underlying problem of memory impairment.