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Purpose: Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE), but its etiology is unknown. With functional magnetic resonance imaging (fMRI), we have explored the relationship between brain activation, functional connectivity, and cognitive functioning in a cohort of pediatric patients with FLE and healthy controls.
Methods: Thirty-two children aged 8–13 years with FLE of unknown cause and 41 healthy age-matched controls underwent neuropsychological assessment and structural and functional brain MRI. We investigated to which extent brain regions activated in response to a working memory task and assessed functional connectivity between distant brain regions. Data of patients were compared to controls, and patients were grouped as cognitively impaired or unimpaired.
Key Findings: Children with FLE showed a global decrease in functional brain connectivity compared to healthy controls, whereas brain activation patterns in children with FLE remained relatively intact. Children with FLE complicated by cognitive impairment typically showed a decrease in frontal lobe connectivity. This decreased frontal lobe connectivity comprised both connections within the frontal lobe as well as connections from the frontal lobe to the parietal lobe, temporal lobe, cerebellum, and basal ganglia.
Significance: Decreased functional frontal lobe connectivity is associated with cognitive impairment in pediatric FLE. The importance of impairment of functional integrity within the frontal lobe network, as well as its connections to distant areas, provides new insights in the etiology of the broad-range cognitive impairments in children with FLE.
Frontal lobe epilepsy (FLE) is the second most common type of the localization-related epilepsies and its average age at onset ranges from 4 to 8 years (Manford et al., 1992; Braakman et al., 2011). FLE in children is frequently complicated by cognitive impairment, but this cognitive impairment shows strong interindividual variability (Braakman et al., 2011). Cognitive impairment generally comprises attention deficits and impaired executive functioning. In addition, a decline in intelligence quotient (IQ) scores, language impairment, and memory deficits have been described in children with FLE (Prévost et al., 2006; Braakman et al., 2011). Therefore, FLE does not impact on one specific function but on a broad range of cognitive domains, which frequently results in educational problems and the need for special education (Braakman et al., 2011, 2012). The etiology of cognitive deficits in children with FLE is unknown and correlations with clinical epilepsy characteristics, including age at seizure onset and seizure frequency, remain inconclusive (Braakman et al., 2011, 2012).
With functional MRI (fMRI) techniques, the functional brain organization can be investigated. Functional network changes have been observed in adult patients with localization-related epilepsy of unknown cause complicated by language impairment (Vlooswijk et al., 2010). Because cognitive impairment is already present early in the course of FLE (Prévost et al., 2006), we investigated correlations between cognitive impairment and brain organization in childhood with a focus on the role of the frontal lobe. Recently, we revealed whole-brain resting-state network abnormalities in the same cohort of children with FLE using graph theory (Vaessen et al., 2012). The current research work focuses on the specific role of the frontal lobe during verbal working memory processing. Our research questions were whether fMRI activation and connectivity results differ between children with FLE compared to healthy controls, and, if so, whether these differences relate to the cognitive impairment. In addition, we investigated whether in our patient cohort clinical epilepsy characteristics could be identified that are related to fMRI changes associated with cognitive impairment.
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Appendix S1. Neuropsychological test details.
Appendix S2. Impairment index composition details.
Appendix S3.Flowchart of inclusion.
Appendix S4. Neuropsychological test results.
Appendix S5. Demographical and clinical characteristics of the epilepsy group.
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