Abstracts

Rationale: Neuropsychological evaluations predominantly report impaired frontal lobe functions in patients with JME and their unaffected siblings, and abnormal frontal lobe connectivity is also described in patients. Functional magnetic resonance imaging (fMRI) studies identified a hyperactivation of the motor system with increasing cognitive load both in patients and their siblings. The extent to which temporal lobe functions are also affected in JME remains controversial. Long term memory deficits have been detected, and there is preliminary evidence for structural abnormalities encompassing the hippocampus and temporal neocortex. We aimed to characterize temporal lobe functions in JME patients and their siblings employing neuropsychometry and a memory encoding fMRI task.Methods: 30 patients with JME, 12 siblings and 20 healthy controls (HC) underwent a neuropsychological assessment including the Vocabulary, Similarity, Digit Span and Mental Arithmetic subtests of the WAIS-III, List Learning and Design Learning subtests of the Adult Memory and Information Processing Battery, McKenna Graded Naming Test, Trail Making Test, letter and category fluency. The fMRI memory encoding paradigm consisted of 210 items presented inside in a 3T MRI scanner, grouped in 30s blocks of 10 pictures (black and white nameable line-drawn objects), 10 words (single concrete nouns) or 10 faces (unfamiliar photographs), separated by 15s cross-hair fixation. Participants were instructed to actively memorize the items for subsequent out-of-scanner recall, in which the 210 presented items were randomly intermixed with an additional 105 novel items.Results: JME patients performed worse than HC in the Design Learning, McKenna Graded Naming, Trail Making and letter fluency tests (all p<0.05). No differences were detected between siblings and HC. Recall performances for the memory encoding task did not differ across the three groups (p=0.50, 0.44 and 0.29 - words, pictures and faces, respectively). During the memory encoding task, JME patients showed areas of greater activation compared with HC (p<0.05, FWE-corrected) in the left sensory-motor cortex, bilateral supplementary motor areas, superior temporal gyri and rolandic opercula. Areas of increased activations in siblings compared with HC (p<0.001, cluster extent threshold=20 voxels) included the left motor cortex and right temporal gyrus, rolandic operculum, inferior frontal gyrus and orbitofrontal cortex.Conclusions: Cognitive impairment in JME is shown to encompass both frontal and temporal lobe functions, while no such deficits are evident in unaffected siblings. We report fMRI evidence for hyperexcitability of the motor system during a cognitive task in JME patients and their siblings, which expands the results of previous studies and is suggestive of an imaging endophenotype of JME. In the absence of between-group differences in memory performance, we interpret increased activations in the superior temporal gyri and rolandic opercula as a compensatory mechanism for frontal lobe disturbances in both groups.