Children with epilepsy can experience significant cognitive dysfunction that can lead to academic underachievement. Traditionally believed to be primarily due to the effects of factors such as the chronicity of epilepsy, medication effects, or the location of the primary epileptogenic lesion;, recent evidence has indicated that disruption of cognition-specific distributed neural networks may play a significant role as well. Specifically, over the last decade, researchers have begun to characterize the mechanisms underlying disrupted cognitive substrates by evaluating neural network abnormalities observed during specific cognitive tasks, using task-based functional magnetic resonance imaging (fMRI). This targeted review assesses the current literature investigating the relationship between neural network abnormalities and cognitive deficits in pediatric epilepsy. The findings indicate that there are indeed neural network abnormalities associated with deficits in executive function, language, processing speed, and memory. Overall, cognitive dysfunction in pediatric epilepsy is associated with a decrease in neural network activation/deactivation as well as increased recruitment of brain regions not typically related to the specific cognitive task under investigation. The research to date has focused primarily on children with focal epilepsy syndromes with small sample sizes and differing research protocols. More extensive research in children with a wider representation of epilepsy syndromes (including generalized epilepsy syndromes) is necessary to fully understand these relationships and begin to identify underlying cognitive phenotypes that may account for the variability observed across children with epilepsy. Furthermore, more uniformity in fMRI protocols and neuropsychological tasks would be ideal to advance this literature.

We investigated the existence of the "winner effect" (winning an aggressive encounter following previous victories) and an associated rise in testosterone (T) in the white-footed mouse (Peromyscus leucopus) which generally display low levels of aggression and territoriality. We compared the effect of previously winning three, two, one, or zero resident-intruder encounters on the likelihood of winning a subsequent aggressive encounter. Although 50% of males were removed during training because of peaceful encounters, the winner effect was weak and not significant. We hypothesize that territoriality/aggression may be associated with the strength of the winner effect and discuss whether the slight winner effect exhibited by P. leucopus may become significant when population densities increase and males become more territorial. There was also no associated change in T with winning; however, corticosterone (Cort) changed with experience as winners had low Cort levels compared to losers and controls. Furthermore, low Cort levels in winners were associated with quicker attack latencies. These results contrast with findings of a significant winner effect and increase in T in males of the highly territorial and aggressive California mouse (Peromyscus californicus) using an identical methodology. California mice also attacked their opponents at more caudal regions of the body compared to white-footed mice that attacked their opponents at more rostral regions of the body, possibly related to different levels/types of aggression expressed by the two species.

The 'winner effect' has been studied in a variety of species, but only rarely in mammals. We compared effects of winning three, two, one, or zero resident-intruder encounters on the likelihood of winning a subsequent aggressive encounter in the California mouse (Peromyscus californicus). During the training phase, we ensured that resident males won all encounters by staging contests with mildly sedated, smaller intruders. During the test phase, the resident male encountered an unfamiliar, more evenly matched intruder that had experience winning an encounter and was larger than the resident. Testosterone (T) plasma levels significantly increased after the final test when they had experienced two prior winning encounters, and the probability of winning a future encounter increased significantly after three prior wins independent of intrinsic fighting ability. We hypothesize a 'winner-challenge' effect in which increased T levels serve to reinforce the winner effect in male California mice.

The processes through which salient social experiences influence future behavior are not well understood. Winning fights, for example, can increase the odds of future victory, yet little is known about the internal mechanisms that underlie such winner effects. Here, we use the territorial California mouse (Peromyscus californicus) to investigate how the effects of postvictory testosterone (T) release and winning experience individually mediate positive changes in future winning ability and antagonistic behavior. Male mice were castrated and implanted with T capsules to maintain basal levels of this hormone. We found that males form a robust winner effect if they win three separate territorial disputes and experience a single T surge roughly 45 min after each encounter. Meanwhile, males exhibit only an intermediate winner effect if they either 1) acquire three previous wins but do not experience a change in postvictory T or 2) acquire no previous wins but experience three separate T pulses. The results indicate that the effect of postvictory T must be coupled with that of winning experience to trigger the maximum positive shift in winning ability, which highlights the importance of social context in the development of the winner effect. At the same time, however, postvictory T and winning experience are each capable of increasing future winning ability independently, and this finding suggests that these two factors drive plasticity in antagonistic behavior via distinct mechanistic channels. More broadly, our data offer insight into the possible ways in which various species might be able to adjust their behavioral repertoire in response to social interactions through mechanisms that are unlinked from the effects of gonadal steroid action.

Objectives

Children with temporal lobe epilepsy (TLE) exhibit executive dysfunction on traditional neuropsychological tests. There is limited evidence of different functional network alterations associated with this clinical executive dysfunction. This study investigates working memory deficits in children with TLE by assessing deactivation of the default mode network (DMN) on functional Magnetic Resonance Imaging (fMRI) and the relationship of DMN deactivation with fMRI behavioral findings and neuropsychological test performance.

Experimental design

fMRI was conducted on 15 children with TLE and 15 healthy controls (age: 8-16 years) while performing the N-back task in order to assess deactivation of the DMN. N-back accuracy, N-back reaction time, and neuropsychological tests of executive function (Delis-Kaplan Executive Function System [D-KEFS] Color-Word Interference and Card Sort tests) were also assessed.

Principal observations

During the N-back task, children with TLE exhibited significantly less deactivation of the DMN, primarily in the precuneus/posterior cingulate cortex compared with controls. These alterations significantly correlated with N-back behavioral findings and D-KEFS results.

Conclusions

Children with TLE exhibit executive dysfunction which correlates with DMN alterations. These findings suggest that the level of deactivation of specific functional networks may contribute to cognitive impairment in children with TLE. The findings also indicate that children with TLE have network alterations in extratemporal lobe brain regions.

PURPOSE: Research indicates that patients with chronic temporal lobe epilepsy (TLE) exhibit cerebellar atrophy compared to healthy controls, but the degree to which specific regions of the cerebellum are affected remains unclear. The purpose of this study was to characterize the extent and lateralization of atrophy in individual cerebellar lobes and subregions in unilateral TLE using advanced quantitative magnetic resonance imaging (MRI) techniques. METHODS: Study participants were 46 persons with TLE and 31 age- and gender- matched healthy controls. All participants underwent high-resolution MRI with manual tracing of the cerebellum yielding gray and white matter volumes of the right and left anterior lobes, superior posterior lobes, inferior posterior lobes, and corpus medullare. The degree to which asymmetric versus generalized abnormalities was evident in unilateral chronic TLE was determined and related to selected clinical seizure features (age of onset, duration of disorder). KEY FINDINGS: There were no lateralized abnormalities in cerebellar gray matter or white matter in patients with right or left TLE (all p's > 0.2). Compared with controls, unilateral TLE was associated with significant bilateral reductions in the superior (p = 0.032) and inferior (p = 0.023) posterior lobes, whereas volume was significantly increased in the anterior lobes (p = 0.002), especially in patients with early onset TLE, and not significantly different in the corpus medullare (p = 0.71). Total superior cerebellar tissue volumes were reduced in association with increasing duration of epilepsy. SIGNIFICANCE: Patients with unilateral TLE exhibit a pattern of bilateral cerebellar pathology characterized by atrophy of the superior and inferior posterior lobes, hypertrophy of the anterior lobe, and no effect on the corpus medullare. Cross-sectional analyses show that specific aspects of cerebellar pathology are associated with neurodevelopmental (anterior lobe) or chronicity-related (superior posterior lobe) features of the disorder.

Background

Accumulating evidence suggests that considerable cognitive and psychiatric comorbidity is associated with juvenile myoclonic epilepsy, for which the etiology remains controversial. Our goal was to comprehensively characterize the status of multiple neurobehavioral comorbidities in youth with new- or recent-onset juvenile myoclonic epilepsy, before effects of chronic seizures and medications.

Methods

A total of 111 children aged eight to 18 years (41 new- or recent-onset juvenile myoclonic epilepsy and 70 first-degree cousin controls) underwent neuropsychological assessment (attention, executive, verbal, perceptual, speed), structured review of need for supportive academic services, parent reports of behavior and executive function (Child Behavior Checklist and Behavior Rating Inventory of Executive Function), and formal structured psychiatric interview and diagnosis (Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version).

Results

Children with juvenile myoclonic epilepsy performed worse than controls across all tested cognitive domains (F(1,105) = 3.85, P < 0.01), utilized more academic services (47% versus 19%, P = 0.002), had more parent-reported behavioral problems and dysexecutive function with lower competence (P < 0.001), and had a higher prevalence of current Axis I diagnoses (attention-deficit/hyperactivity disorder, depression, and anxiety; 54% versus 23%, P = 0.001). Academic and psychiatric problems occurred antecedent to epilepsy onset compared with comparable timeline in controls.

Conclusion

Comprehensive assessment of cognitive, academic, behavioral, and psychiatric comorbidities in youth with new- or recent-onset juvenile myoclonic epilepsy reveals a pattern of significantly increased neurobehavioral comorbidities across a broad spectrum of areas. These early evident comorbidities are of clear clinical importance with worrisome implications for future cognitive, behavioral, and social function. It is important for health care providers to avoid delays in intervention by assessing potential comorbidities early in the course of the disorder to optimize their patients' social, academic and behavioral progress.