Search

Objective To characterize the presence and nature of discrete behavioral phenotypes and their correlates in a cohort of youth with new and recent onset focal and generalized epilepsies. Methods The parents of 290 youth (age = 8-18 years) with epilepsy (n = 183) and typically developing participants (n = 107) completed the Child Behavior Checklist for children aged 6-18 from the Achenbach System of Empirically Based Assessment. The eight behavior problem scales were subjected to hierarchical clustering analytics to identify behavioral subgroups. To characterize the external validity and co-occurring comorbidities of the identified subgroups, we examined demographic features (age, gender, handedness), cognition (language, perception, attention, executive function, speed), academic problems (present/absent), clinical epilepsy characteristics (epilepsy syndrome, medications), familial factors (parental intelligence quotient, education, employment), neuroimaging features (cortical thickness), parent-observed day-to-day executive function, and number of lifetime-to-date Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnoses. Results Hierarchical clustering identified three behavioral phenotypes, which included no behavioral complications (Cluster 1, 67% of epilepsy cohort [n = 122]), nonexternalizing problems (Cluster 2, 11% of cohort [n = 21]), and combined internalizing and externalizing problems (Cluster 3, 22% of cohort [n = 40]). These behavioral phenotypes were characterized by orderly differences in personal characteristics, neuropsychological status, history of academic problems, parental status, cortical thickness, daily executive function, and number of lifetime-to-date DSM-IV diagnoses. Cluster 1 was most similar to controls across most metrics, whereas Cluster 3 was the most abnormal compared to controls. Epilepsy syndrome was not a predictor of cluster membership. Significance Youth with new and recent onset epilepsy fall into three distinct behavioral phenotypes associated with a variety of co-occurring features and comorbidities. This approach identifies important phenotypes of behavior problem presentations and their accompanying factors that serve to advance clinical and theoretical understanding of the behavioral complications of children with epilepsy and the complex conditions with which they co-occur.

Objective To identify cognitive phenotypes in temporal lobe epilepsy (TLE) and test their reproducibility in a large, multi-site cohort of patients using both data-driven and clinically driven approaches. Method Four-hundred seven patients with TLE who underwent a comprehensive neuropsychological evaluation at one of four epilepsy centers were included. Scores on tests of verbal memory, naming, fluency, executive function, and psychomotor speed were converted into z-scores based on 151 healthy controls (HCs). For the data-driven method, cluster analysis (k-means) was used to determine the optimal number of clusters. For the clinically driven method, impairment was defined as >1.5 standard deviations below the mean of the HC, and patients were classified into groups based on the pattern of impairment. Results Cluster analysis revealed a three-cluster solution characterized by (a) generalized impairment (29%), (b) language and memory impairment (28%), and (c) no impairment (43%). Based on the clinical criteria, the same broad categories were identified, but with a different distribution: (a) generalized impairment (37%), (b) language and memory impairment (30%), and (c) no impairment (33%). There was a 82.6% concordance rate with good agreement (κ = .716) between the methods. Forty-eight patients classified as having a normal profile based on cluster analysis were classified as having generalized impairment (n = 16) or an isolated language/memory impairment (n = 32) based on the clinical criteria. Patients with generalized impairment had a longer disease duration and patients with no impairment had more years of education. However, patients demonstrating the classic TLE profile (ie, language and memory impairment) were not more likely to have an earlier age at onset or mesial temporal sclerosis. Significance We validate previous findings from single-site studies that have identified three unique cognitive phenotypes in TLE and offer a means of translating the patterns into a clinical diagnostic criteria, representing a novel taxonomy of neuropsychological status in TLE.

Objective The greater resilience of older memories relative to recent memories has primarily been demonstrated in clinical groups, but this phenomenon has been less extensively examined in cognitively intact older adults. Additionally, most studies of person-identity have only examined recognition or familiarity of a famous face or name, and there has been less systematic study of access to more specific person-identity semantic knowledge. The current study examined the effect of both memory age and extent of semantic knowledge on famous name recognition and retrieval of person-identity biographical information in healthy older adults. Method We examined recognition accuracy and response time of famous names at three time epochs (recent fame, transitory fame and enduring fame) in cognitively intact older adults. We also compared access to semantic knowledge that differed on the degree of specificity of biographical information: categorical, associative, and attribute knowledge. Results As predicted, participants recognized transitory famous names more quickly and accurately than recent famous names. Additionally, participants recognized enduring famous names more accurately than transitory famous names and recent names. We also found that categorical semantic knowledge was accessed more quickly and accurately than semantic knowledge for associative and attribute information. Conclusions These findings provide data on the cognitive structure and retrieval of person-identity knowledge and memory age in older cognitively intact individuals.

Objective:The Apolipoprotein (APOE) ε4 allele increases the risk for mild cognitive impairment (MCI) and dementia, but not all carriers develop MCI/dementia. The purpose of this exploratory study was to determine if early and subtle preclinical signs of cognitive dysfunction and medial temporal lobe atrophy are observed in cognitively intact ε4 carriers who subsequently develop MCI.Methods:Twenty-nine healthy, cognitively intact ε4 carriers (ε3/ε4 heterozygotes; ages 65–85) underwent neuropsychological testing and MRI-based measurements of medial temporal volumes over a 5-year follow-up interval; data were converted toz-scores based on a non-carrier group consisting of 17 ε3/ε3 homozygotes.Results:At follow-up, 11 ε4 carriers (38%) converted to a diagnosis of MCI. At study entry, the MCI converters had significantly lower scores on the Mini-Mental State Examination, Rey Auditory Verbal Learning Test (RAVLT) Trials 1–5, and RAVLT Immediate Recall compared to non-converters. MCI converters also had smaller MRI volumes in the left subiculum than non-converters. Follow-up logistic regressions revealed that left subiculum volumes and RAVLT Trials 1–5 scores were significant predictors of MCI conversion.Conclusions:Results from this exploratory study suggest that ε4 carriers who convert to MCI exhibit subtle cognitive and volumetric differences years prior to diagnosis.

AIM: To determine whether the first degree cousins of children with idiopathic focal and genetic generalized epilepsies (cases) show any association across measures of cognition, behavior and brain structure. The presence/absence of associations addresses the question of whether and to what degree first degree cousins may serve as unbiased controls in research addressing the cognitive, psychiatric, and neuroimaging features of pediatric epilepsies. METHODS: Participants were children (age 8 – 18) with epilepsy who had at least one first-degree cousin control enrolled in the study (n=37) and all enrolled cousin controls (n=100). Participants underwent neuropsychological assessment, brain imaging (cortical, subcortical and cerebellar volumes) and parents completed the Child Behavior Checklist (CBCL). Data (42 outcome measures) from cousin controls were regressed on the corresponding epilepsy cognitive, behavioral and imaging measures in a linear mixed model and case – control correlations were examined. RESULTS: Of the 42 uncorrected correlations involving cognitive, behavioral and neuroimaging measures, only 2 were significant (p 0.25). Similar results held for the cognition/behavior and brain imaging measures separately. CONCLUSIONS: Given the lack of association between cases and first degree cousin performances on measures of cognition, behavior and neuroimaging, the results suggest a non-significant genetic influence on control group performance. First -degree cousins appear to be unbiased controls for cognitive, behavioral, and neuroimaging research in pediatric epilepsy.

Intraindividual variability (IIV) in motor performance has been shown to predict future cognitive decline. The apolipoprotein E-epsilon 4 (APOE-ε4) allele is also a well-established risk factor for memory decline. Here, we present novel findings examining the influence of the APOE-ε4 allele on the performance of asymptomatic healthy elders in comparison to individuals with amnestic MCI (aMCI) on a fine motor synchronization, paced finger-tapping task (PFTT).Two Alzheimer's disease (AD) risk groups, individuals with aMCI (n = 24) and cognitively intact APOE-ε4 carriers (n = 41), and a control group consisting of cognitively intact APOE-ε4 noncarriers (n = 65) completed the Rey Auditory Verbal Learning Test and the PFTT, which requires index finger tapping in synchrony with a visual stimulus (interstimulus interval = 333 ms).Motor timing IIV, as reflected by the standard deviation of the intertap interval (ITI), was greater in the aMCI group than in the two groups of cognitively intact elders; in contrast, all three groups had statistically equivalent mean ITI. No significant IIV differences were observed between the asymptomatic APOE-ε4 carriers and noncarriers. Poorer episodic memory performance was associated with greater IIV, particularly in the aMCI group.Results suggest that increased IIV on a fine motor synchronization task is apparent in aMCI. This IIV measure was not sensitive in discriminating older asymptomatic individuals at genetic risk for AD from those without such a genetic risk. In contrast, episodic memory performance, a well-established predictor of cognitive decline in preclinical AD, was able to distinguish between the two cognitively intact groups based on genetic risk.

Objectives: White matter (WM) integrity within the mesial temporal lobe (MTL) is important for episodic memory (EM) functioning. The current study investigated the ability of diffusion tensor imaging (DTI) in MTL WM tracts to predict 3-year changes in EM performance in healthy elders at disproportionately higher genetic risk for Alzheimer’s disease (AD). Methods: Fifty-one cognitively intact elders (52% with family history (FH) of dementia and 33% possessing an Apolipoprotein E ε4 allelle) were administered the Rey Auditory Verbal Learning Test (RAVLT) at study entry and at 3-year follow-up. DTI scanning, conducted at study entry, examined fractional anisotropy and mean, radial and axial diffusion within three MTL WM tracts: uncinate fasciculus (UNC), cingulate-hippocampal (CHG), and fornix-stria terminalis (FxS). Correlations were performed between residualized change scores computed from RAVLT trials 1–5, immediate recall, and delayed recall scores and baseline DTI measures; MTL gray matter (GM) and WM volumes; demographics; and AD genetic and metabolic risk factors. Results: Higher MTL mean and axial diffusivity at baseline significantly predicted 3-year changes in EM, whereas baseline MTL GM and WM volumes, FH, and metabolic risk factors did not. Both ε4 status and DTI correlated with change in immediate recall. Conclusions: Longitudinal EM changes in cognitively intact, healthy elders can be predicted by disruption of the MTL WM microstructure. These results are derived from a sample with a disproportionately higher genetic risk for AD, suggesting that the observed WM disruption in MTL pathways may be related to early neuropathological changes associated with the preclinical stage of AD. (JINS, 2016, 22, 1005–1015)

Objective The objective of this study was to identify cognitive phenotypes in children with new-onset focal and generalized idiopathic epilepsies and determine their relationship with epilepsy syndrome, brain structure, neurodevelopmental history, and family characteristics. Methods One hundred thirty-eight children with new-onset epilepsy and 95 controls (age: 8–18) underwent neuropsychological, clinical, and quantitative MR evaluations. Control participants' neuropsychological data were subjected to confirmatory factor analysis and then resultant factor scores were applied to participants with epilepsy and subjected to latent class analysis. Identified cognitive phenotypes were examined in relation to epilepsy syndrome, quantitative neuroimaging, and familial and neurodevelopmental variables. Results Confirmatory factor analysis identified five cognitive factors (verbal, perceptual, speed, attention, executive), and latent class analysis identified three clusters of participants with epilepsy: 1) average and similar to controls, 2) mild impairment across multiple cognitive domains, and 3) impairment across all domains with severe attentional impairment, representing 44%, 44%, and 12% of the epilepsy sample, respectively. Cognitive phenotype membership was not associated with epilepsy syndrome but was associated with increasing abnormalities in brain structure, parental IQ, and features of early developmental history. Significance Cognitive phenotypes are present in idiopathic childhood epilepsies that are unassociated with traditional epilepsy syndromes but are associated with measures of brain structure, family history, and neurodevelopmental features.

Using a hypothesis-driven approach, subcortical and cortical regions implicated in anxiety disorders in the general population were examined in children with recent-onset epilepsy with versus without anxiety compared to controls. This study reports frequency of anxiety disorders while examining familial, clinical, and demographic variables associated with anxiety in children with epilepsy.Participants included 88 children with epilepsy aged 8-18 years: 25 with a current anxiety disorder and 63 children with epilepsy and no current anxiety disorder. Forty-nine controls without anxiety disorders were included. T1 volumetric magnetic resonance imaging (MRI) scans were collected; subcortical volumes and cortical thickness were computed using the FreeSurfer image analysis suite. Analyses focused on adjusted measures of subcortical volumes and cortical thickness.Relative to controls, larger left amygdala volumes were found in the Epilepsy with Anxiety group compared to the Epilepsy without Anxiety group (p = 0.027). In the hippocampus, there were no significant differences between groups. Examination of cortical thickness demonstrated that the Epilepsy with Anxiety group showed thinning in left medial orbitofrontal (p = 0.001), right lateral orbitofrontal (p = 0.017), and right frontal pole (p = 0.009). There were no differences between groups in age, sex, IQ, age of onset, medications, or duration of epilepsy. There were more family members with a history of anxiety disorders in the Epilepsy with Anxiety group compared to the Epilepsy without Anxiety group (p = 0.005).Anxiety is a common psychiatric comorbidity in children with recent-onset epilepsy with volumetric enlargement of the amygdala and thinner cortex in orbital and other regions of prefrontal cortex, suggesting structural abnormalities in brain regions that are part of the dysfunctional networks reported in individuals with anxiety disorders in the general population. These findings are evident early in the course of epilepsy, are not related to chronicity of seizures, and may be linked to a family history of anxiety and depressive disorders.

OBJECTIVE Adults with juvenile myoclonic epilepsy (JME) have subtle brain structural abnormalities in the frontothalamocortical network, poorer cognitive function, and worse long-term social outcomes, even when their seizures are controlled and/or remitted. The natural history of JME and development of abnormalities in brain structure and cognition from epilepsy onset has not been studied. METHODS The maturational trajectories of cognitive and brain development were prospectively compared between 19 children with new-onset JME in the first 2 years after diagnosis and 57 healthy controls. RESULTS Cognitive abilities of children with JME were similar to or worse than healthy controls at baseline but failed to reach the competence level of healthy controls at follow-up across most of the tested cognitive abilities. Abnormal patterns of brain development, as assessed by magnetic resonance imaging studies, were evident in children with JME and included attenuation of age-related decline in cortical volume, thickness, and surface area compared to typically developing children. The altered brain developmental trajectory in the JME group was evident in higher-association frontoparietotemporal brain regions (p < 0.05, corrected for multiple comparisons). INTERPRETATION Children with JME have abnormal structural brain development and impaired cognitive development early in the course of their epilepsy.

Summary Objective Birth weight is an important indicator of prenatal environment, and subtle variations of birth weight within the normal range have been associated with differential risk for cognitive and behavioral problems. Therefore, we aimed to determine if there are differences in birth weight between full-term children with uncomplicated new/recent-onset epilepsies and typically developing healthy controls. We further examined the relationships between birth weight and childhood/adolescent cognition, behavior, and academic achievement. Methods One hundred eight children with new-onset/recent-onset epilepsy and 70 healthy controls underwent neuropsychological assessment. All participants were born full-term (>37 weeks) without birth complications. Parents were interviewed regarding their child's gestation, birth, and neurodevelopmental history. Results Birth weight of children with epilepsy was significantly lower than healthy controls (p = 0.023). Whereas birth weight (covaried with age, sex, handedness, and mother's education) was significantly associated with cognition in controls in multiple domains (intelligence, language, aspects of academic achievement), this relationship was absent in children with epilepsy. Birth weight was not associated with clinical epilepsy variables (age of onset, epilepsy syndrome) and was not predictive of a variety of other academic or psychiatric comorbidities of epilepsy. Significance Although the origin of lower birth weight in children with epilepsy is unknown, these findings raise the possibility that abnormal prenatal environment may affect childhood-onset epilepsy. Furthermore, the positive relationship between birth weight and cognition evident in healthy controls was disrupted in children with epilepsy. However, birth weight was not related to academic and psychiatric comorbidities of childhood epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Summary Introduction Diffusion tensor imaging (DTI) studies have reported white matter abnormalities in childhood-onset epilepsy, but the mechanisms and timing underlying these abnormalities, and their resolution, are not well understood. This study examined white matter integrity in children with active versus remitted epilepsy. Methods Tract-based spatial statistics (TBSS) was used to examine whole-brain DTI indices of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in 20 children with epilepsy 5–6 years after diagnosis, compared to 29 healthy controls. To determine the status of white matter following cessation of seizures, participants with epilepsy were classified as active versus remitted and comparisons included: (1) controls versus all children with epilepsy, (2) controls versus children with remitted seizures, (3) controls versus children with active seizures, and (4) children with active versus remitted epilepsy. Results In the active compared to remitted epilepsy group, significantly higher FA and lower MD, AD and RD values were dispersed in the internal capsule, cingulum, body of the corpus callosum, superior corona radiata and superior fronto-occipital fasciculus. Similar differences were found between the active epilepsy and the control group. There were no significant differences between the remitted epilepsy and control groups. Conclusion Children with active epilepsy differed in white matter integrity compared to children with remitted epilepsy and healthy controls. It remains to be determined whether these findings represent the outcomes of seizure remission versus an initial biomarker for those children who will ultimately have intractable epilepsy.

The purpose of this investigation was to characterize the neuroanatomical correlates (cortical thickness) of variations in parent-reported Child Behavior Checklist (CBCL) scores. Ninety children with epilepsy (aged 8-18) underwent brain MRI, and their parents completed the CBCL. FreeSurfer-derived measures of cortical thickness were examined in relation to the CBCL broad and narrow band competence and behavioral problem scales, as well as the newer DSM-oriented scales. Parent reports of higher (better) social competence skills were associated with increased cortical thickness, especially in frontal regions. Parent reports of behavioral problems were associated with patterns of decreased cortical thickness that varied as a function of the specific behavioral issue under investigation. Congruence of patterns of cortical thinning between the DSM-oriented scales and conceptually related specific problem scales (e.g., ADHD Problems and Attention Problems) was generally weak. The parent-report version of the CBCL is associated with variations in cortical thickness among children with epilepsy. Anatomic abnormalities specific to selected competence and behavioral problem scales can be identified, with more reliable and robust patterns of thinning across scales assessing externalizing behaviors, with generally less prominent findings on scales assessing internalizing behaviors.

Summary Cognitive and psychomotor slowing is a complication of epilepsy and is less often a focus of investigation relative to other cognitive domains (e.g., memory). A diversity of tasks has been used to examine psychomotor slowing in epilepsy, but it remains unknown whether the degree of epilepsy-related slowing is fixed or is exacerbated with increasing task demand. Also unknown is to what degree age related slowing is accelerated in epilepsy. Participants with temporal lobe epilepsy ( n =50) were compared to healthy controls ( n =69) across three tasks of psychomotor speed with varied complexity. Performance was examined as a function of group (epilepsy, controls), task complexity (simple, intermediate, complex), and chronological age. The results showed that speed of performance declined across the epilepsy and control participants as a function of task complexity. Epilepsy participants were significantly slower than controls across the three tasks, and there was a significant three-way interaction (group by task complexity by age). These results demonstrate that psychomotor slowing is related to task complexity in both epilepsy and healthy control participants, always greater in epilepsy participants, and there is a significant age acceleration of psychomotor slowing in the epilepsy group that is magnified by complex tasks.

Background: Engagement in cognitively stimulating activities (CA) and leisure time physical activity (PA) have been associated with maintaining cognitive performance and reducing the likelihood of cognitive decline in older adults. However, neural mechanisms underlying protective effects of these lifestyle behaviors are largely unknown. In the current study, we investigated the effect of self-reported PA and CA on hippocampal volume and semantic processing activation during a fame discrimination task, as measured by functional magnetic resonance imaging (fMRI). We also examined whether possession of the apolipoprotein E (APOE) ?4 allele could moderate the effect of PA or CA on hippocampal structure or function. Methods: Seventy-eight healthy, cognitively intact older adults underwent baseline neuropsychological assessment, hippocampal volume measurement via manually-traced structural MRI, and task-activated fMRI. Results: After 18 months, 27 participants declined by one standard deviation or more on follow-up neuropsychological testing. Logistic regression analyses revealed that CA alone or in combination with baseline hippocampal structure or functional activity did not predict the probability of cognitive decline. In contrast, PA interacted with APOE 4 status such that engagement in PA reduced the risk of cognitive decline in APOE 4 carriers only. Furthermore, the benefits of PA appeared to diminish with reduced functional activity or volume in the hippocampus. Conclusions: Our findings suggest that increased leisure time PA is associated with reduced probability of cognitive decline in persons who are at high risk for AD. The beneficial effects of PA in this group may be related to enhancement of the functional and structural integrity of the hippocampus.

SUMMARY Purpose: To characterize differences in brain structure and their patterns of age-related change in individuals with chronic childhood/adolescent onset temporal lobe epilepsy compared with healthy controls. Methods: Subjects included participants with chronic temporal lobe epilepsy (n = 55) of mean childhood/adolescent onset and healthy controls (n = 53), age 14–60 years. Brain magnetic resonance imaging (MRI) studies (1.5 T) were processed using FreeSurfer to obtain measures of lobar thickness, area, and volume as well as volumes of diverse subcortical structures and cerebellum. Group differences were explored followed by cross-sectional lifespan modeling as a function of age. Key Findings: Anatomic abnormalities were extensive in participants with chronic temporal lobe epilepsy including distributed subcortical structures (hippocampus, thalamus, caudate, and pallidum), cerebellar gray and white matter, total cerebral gray and white matter; and measures of cortical gray matter thickness, area, or volume in temporal (medial, lateral) and extratemporal lobes (frontal, parietal). Increasing chronologic age was associated with progressive changes in diverse cortical, subcortical, and cerebellar regions for both participants with epilepsy and controls. Age-accelerated changes in epilepsy participants were seen in selected areas (third and lateral ventricles), with largely comparable patterns of age-related change across other regions of interest. Significance: Extensive cortical, subcortical, and cerebellar abnormalities are present in participants with mean chronic childhood/adolescent onset temporal lobe epilepsy implicating a significant neurodevelopmental impact on brain structure. With increasing chronologic age, the brain changes occurring in epilepsy appear to proceed in a largely age-appropriate fashion compared to healthy controls, the primary exception being age-accelerated ventricular expansion (lateral and third ventricles). These cumulative structural abnormalities appear to represent a significant anatomic burden for persons with epilepsy, the consequences of which remain to be determined as they progress into elder years.

Extensive research efforts have been directed toward strategies for predicting risk of developing Alzheimer's disease (AD) prior to the appearance of observable symptoms. Existing approaches for early detection of AD vary in terms of their efficacy, invasiveness, and ease of implementation. Several non-invasive magnetic resonance imaging strategies have been developed for predicting decline in cognitively healthy older adults. This review will survey a number of studies, beginning with the development of a famous name discrimination task used to identify neural regions that participate in semantic memory retrieval and to test predictions of several key theories of the role of the hippocampus in memory. This task has revealed medial temporal and neocortical contributions to recent and remote memory retrieval, and it has been used to demonstrate compensatory neural recruitment in older adults, apolipoprotein E ε4 carriers, and amnestic mild cognitive impairment patients. Recently, we have also found that the famous name discrimination task provides predictive value for forecasting episodic memory decline among asymptomatic older adults. Other studies investigating the predictive value of semantic memory tasks will also be presented. We suggest several advantages associated with the use of semantic processing tasks, particularly those based on person identification, in comparison to episodic memory tasks to study AD risk. Future directions for research and potential clinical uses of semantic memory paradigms are also discussed. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

Summary Purpose: Benign epilepsy with centrotemporal spikes (BECTS), the most common childhood epilepsy syndrome, is a neurodevelopmental disorder with a genetic influence. Despite its signature electroencephalographic pattern and distinct focal motor seizure semiology, little is known about the underlying brain anatomic alteration and the corresponding cognitive consequences. Given the motor manifestations of seizures in BECTS, we hypothesize that anatomic networks in BECTS involve a distributed corticostriatal circuit. Methods: We investigated volumetric differences and shape deformities of caudate, putamen, pallidum, and thalamus in a group of children with new- and recent-onset BECTS (N = 13) compared to healthy controls (N = 54). We correlated specific subcortical volumes in BECTS that were significantly different from those in healthy controls with performances in executive function. Key Findings: Children with BECTS demonstrated significantly hypertrophied putamen, which was selective among the subcortical regions examined. Shape analysis showed dorsoventral elongation of the left caudate and bilateral putamen, with subnuclei expansion in ventral and dorsal striatum. Larger putamen volumes were linked to better cognitive performances on two complementary executive function tests. Significance: Children with BECTS showed aberrant volume and shape in subcortical regions that are critical for both motor processing and executive function. It is of importance to note that the hypertrophy appears to be cognitively adaptive, as enlargement was associated with improved cognitive performances. The anatomic abnormalities and their cognitive effects are evident in a group of children with new- and recent-onset epilepsy, suggesting that the structural brain anomalies occurred before the diagnosis of epilepsy.

Abnormal expansion of the ventricular system has been observed in many neurologic and psychiatric disorders, including dementia (Carmichael et al., 2007), multiple sclerosis (Dalton et al., 2006) and autism spectrum disorder (Palmen et al., 2005). The natural history of ventricular enlargement and its consequences have been increasingly investigated, and in some disorders such as schizophrenia, enlargement is present at the onset of the disorder (Sowell et al., 2000; Vita et al., 2006) and progresses over time (Kempton et al., 2010). In the literature on aging, age-accelerated ventricular enlargement may herald the cognitive decline associated with the onset and progression of Alzheimer’s disease (Nestor et al., 2008). In 1917, Thom was the first to note ventricle enlargement in individuals with epilepsy; he reported lateral ventricle dilation following postmortem examinations of patients with idiopathic epilepsy (Thom, 1917). But over the decades, interest in the ventricular system has never matched that seen in other disorders. Recently, Kalnin et al. (2008) used a qualitative magnetic resonance imaging (MRI) scoring system to identify brain abnormalities in children with new-onset epilepsies. Interestingly, enlarged ventricles were the most common finding among those with imaging abnormalities (seen in 51% of abnormal scans), a potentially clinically significant finding as mild generalized cognitive impairment is present in new-onset pediatric epilepsy (Oostrom et al., 2003; Hermann et al., 2006; Fastenau et al., 2009). Herein we examine volumes of the third, fourth, and lateral ventricles in children with new/recent-onset idiopathic generalized (IGE) and idiopathic localization-related epilepsy (ILRE) and healthy controls (HCs). Shape analysis was subsequently used to determine whether identified volumetric abnormalities were diffuse or localized. A consecutive subset of children were seen 2 years later to facilitate examination of whether ventricle enlargement was progressive in nature or reflected a static neurodevelopmental abnormality.

Epilepsy is a prevalent childhood neurological disorder, but there are few prospective quantitative magnetic resonance imaging studies examining patterns of brain development compared to healthy controls. Controlled prospective investigations initiated at or near epilepsy onset would best characterize the nature, timing and course of neuroimaging abnormalities in paediatric epilepsy. In this study, we report the results of a deformation-based morphometry technique to examine baseline and 2-year prospective neurodevelopmental brain changes in children with new and recent onset localization-related epilepsies ( n = 24) and idiopathic generalized epilepsies ( n = 20) compared to healthy controls ( n = 36). Children with epilepsy demonstrated differences from controls in baseline grey and white matter volumes suggesting antecedent anomalies in brain development, as well as abnormal patterns of prospective brain development that involved not only slowed white matter expansion, but also abnormalities of cortical grey matter development involving both greater and lesser volume changes compared to controls. Furthermore, abnormal neurodevelopmental changes extended outside the cortex affecting several subcortical structures including thalamus, cerebellum, brainstem and pons. Finally, there were significant differences between the epilepsy syndromes (localization-related epilepsies and idiopathic generalized epilepsies) with the idiopathic generalized epilepsies group showing a more disrupted pattern of brain structure both at baseline and over the 2-year interval. * Abbreviations : IGE : idiopathic generalized epilepsies LRE : localization-related epilepsies

Summary 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.

SUMMARY Purpose: To characterize prospective neurodevelopmental changes in brain structure in children with new and recent-onset epilepsy compared to healthy controls. Methods: Thirty-four healthy controls (mean age 12.9 years) and 38 children with new/recent-onset idiopathic epilepsy (mean age 12.9 years) underwent 1.5 T magnetic resonance imaging (MRI) at baseline and 2 years later. Prospective changes in total cerebral and lobar gray and white matter volumes were compared within and between groups. Results: Prospective changes in gray matter volume were comparable for the epilepsy and control groups, with significant (p 0.06). The group by white matter volume change interactions were significant for total cerebrum (p = 0.04) and frontal lobe (p = 0.04). Discussion: Children with new and recent-onset epilepsy exhibit an altered pattern of brain development characterized by delayed age-appropriate increase in white matter volume. These findings may affect cognitive development through reduced brain connectivity and may also be related to the impairments in executive function commonly reported in this population.

Chronic temporal lobe epilepsy (TLE) is characterized by the presence of extra-hippocampal brain abnormality and cognitive impairment in both memory and nonmemory domains. However, the link between structural integrity and cognition has not frequently been studied. Forty-six patients with TLE and 61 age-matched controls were studied to determine the predictive relationship between baseline thalamic volume and performance on measures of executive functioning evaluated 4 years later. As expected, the TLE group had lower baseline thalamic volumes than controls and also performed more poorly on measures of executive functioning. Total thalamic volume significantly predicted subsequent performance on all three measures of executive functioning. These findings were maintained when both hippocampal volume and frontal lobe volume were taken into account. These findings add to a growing literature demonstrating a link between extra-hippocampal volume abnormalities and cognitive functioning in TLE.

Person recognition can be accomplished through several modalities (face, name, voice). Lesion, neurophysiology and neuroimaging studies have been conducted in an attempt to determine the similarities and differences in the neural networks associated with person identity via different modality inputs. The current study used event-related functional-MRI in 17 healthy participants to directly compare activation in response to randomly presented famous and non-famous names and faces (25 stimuli in each of the four categories). Findings indicated distinct areas of activation that differed for faces and names in regions typically associated with pre-semantic perceptual processes. In contrast, overlapping brain regions were activated in areas associated with the retrieval of biographical knowledge and associated social affective features. Specifically, activation for famous faces was primarily right lateralized and famous names were left lateralized. However, for both stimuli, similar areas of bilateral activity were observed in the early phases of perceptual processing. Activation for fame, irrespective of stimulus modality, activated an extensive left hemisphere network, with bilateral activity observed in the hippocampi, posterior cingulate, and middle temporal gyri. Findings are discussed within the framework of recent proposals concerning the neural network of person identification.

The purpose of this investigation was to examine the diffusion properties of cerebral white matter in children with recent onset epilepsy (n=19) compared to healthy controls (n=11). Subjects underwent DTI with quantification of mean diffusion (MD), fractional anisotropy (FA), axial diffusivity (D(ax)) and radial diffusivity (D(rad)) for regions of interest including anterior and posterior corpus callosum, fornix, cingulum, and internal and external capsules. Quantitative volumetrics were also performed for the corpus callosum and its subregions (anterior, midbody and posterior) and total lobar white and gray matter for the frontal, parietal, temporal and occipital lobes. The results demonstrated no group differences in total lobar gray or white matter volumes or volume of the corpus callosum and its subregions, but did show reduced FA and increased D(rad) in the posterior corpus callosum and cingulum. These results provide the earliest indication of microstructural abnormality in cerebral white matter among children with idiopathic epilepsies. This abnormality occurs in the context of normal volumetrics and suggests disruption in myelination processes.

Objective Previous research characterized three cognitive phenotypes in temporal lobe epilepsy, each associated with a different profile of clinical seizure and demographic characteristics, total cerebral (gray, white, cerebrospinal fluid) and hippocampal volumes, and prospective cognitive trajectories. The objective of this investigation was to characterize in detail the specific neuroanatomical abnormalities associated with each cognitive phenotype. Methods High-resolution MRI scans of healthy controls (n = 53) and patients with temporal lobe epilepsy (n = 55), grouped by cognitive phenotype (minimally impaired; memory impaired; memory, executive function, and speed impaired), were examined with respect to patterns of gray matter thickness throughout the cortical mantle, as well as volumes of subcortical structures, corpus callosum, and regions of the cerebellum. Results Increasing abnormalities in temporal and extratemporal cortical thickness, volumes of subcortical structures (hippocampus, thalamus, basal ganglia), all regions of the corpus callosum, and bilateral cerebellar gray matter distinguish the cognitive phenotypes in a generally stepwise fashion. The most intact anatomy is observed in the minimally impaired epilepsy group and the most abnormal anatomy is evident in the epilepsy group with impairments in memory, executive function, and speed. Conclusion Empirically derived cognitive phenotypes are associated with the presence, severity, and distribution of anatomic abnormalities in widely distributed cortical, subcortical, callosal, and cerebellar networks.

Cognitively intact older individuals at risk for developing Alzheimer's disease frequently show increased functional magnetic resonance imaging (fMRI) brain activation presumably associated with compensatory recruitment, whereas mild cognitive impairment (MCI) patients tend not to show increased activation presumably due to reduced neural reserve. Previous studies, however, have typically used episodic memory activation tasks, placing MCI participants at a performance disadvantage relative to healthy elders. In this event-related fMRI study, we employed a low effort, high accuracy semantic memory task to determine if increased activation of memory circuits is preserved in amnestic MCI when task performance is controlled. Fifty-seven participants, aged 65-85 years, comprised three groups (n = 19 each): amnestic MCI patients; cognitively intact older participants at risk for developing Alzheimer's disease based on having at least one ApoE epsilon4 allele and a positive family history of Alzheimer's disease (At Risk); and cognitively intact participants without Alzheimer's disease risk factors (Control). fMRI was conducted on a 3T MR scanner while participants performed a famous name discrimination task. Participants also underwent neuropsychological testing outside the scanner; whole brain and hippocampal atrophy were assessed from anatomical MRI scans. The three groups did not differ on demographic variables or on fame discrimination performance (>87% correct for all groups). As expected, the amnestic MCI participants demonstrated reduced episodic memory performance. Spatial extent of activation (Fame--Unfamiliar subtraction) differentiated the three groups (Control = 0 ml, At Risk = 9.7 ml, MCI = 34.7 ml). The MCI and At Risk groups showed significantly greater per cent signal change than Control participants in 8 of 14 functionally defined regions, including the medial temporal lobe, temporoparietal junction, and posterior cingulate/precuneus. MCI participants also showed greater activation than Controls in two frontal regions. At Risk, but not MCI, participants showed increased activity in the left hippocampal complex; MCI participants, however, evidenced increased activity in this region when hippocampal atrophy was controlled. When performance is equated, MCI patients demonstrate functional compensation in brain regions subserving semantic memory systems that generally equals or exceeds that observed in cognitively intact individuals at risk for Alzheimer's disease. This hyperactivation profile in MCI is even observed in the left hippocampal complex, but only when the extent of hippocampal atrophy is taken into consideration.

Line bisection performance in children has been hypothesized to be a measure of corpus callosum maturation. Several previous studies have shown that normal prepubescent children bisect lines to the right of true center with their right hand and to the left with their left hand (symmetrical neglect). In contrast, children entering puberty reportedly bisect lines to the left with both the right and left hands (pseudoneglect). The shift from symmetrical to pseudoneglect has been hypothesized to reflect corpus callosum maturation and its involvement in the transfer of attention-based visuospatial processes. In the current study, line bisection performance and MR quantitative corpus callosum volumes were examined in 46 healthy children ages 8–18 years. A linear relationship between corpus callosum volume and age was found. However, the expected age-contingent line bisection performance pattern was not observed. In addition to the expected two patterns of line bisection bias, pseudoneglect and symmetric neglect, two additional distinct patterns of line bisection were identified. These findings, and other findings in the literature, raise important questions about the reliability and validity of the line bisection test. No relationship was found between corpus callosum volume and amount or direction of line bisection deviation. Our findings do not support previous hypotheses regarding line bisection-corpus callosum relationship.

This paper addresses the issue of cognitive morbidity and abnormalities in quantitative MR volumetric in children with new and recent onset idiopathic epilepsy. The available literature suggests that mild diffuse cognitive problems are evident in children with new onset epilepsy in the context of intact whole brain and lobar volumetrics. Subsets of children can be identified with salient academic and volumetric abnormalities. These findings represent the baseline upon which any subsequent effects of chronic epilepsy may accrue.

Few studies have examined the relative degree of brain volume loss in both the hippocampi and subcortical structures in unilateral temporal lobe epilepsy (TLE) and their association with clinical seizure correlates. In this study, quantitative MRI volumes were measured in the hippocampus, thalamus, caudate, putamen, and corpus callosum in 48 patients with unilateral TLE (26 right, and 22 left) and compared with the volumes of 29 healthy controls. The ipsilateral hippocampus, corpus callosum, and bilateral thalami exhibited the greatest volume loss, reflected by large to moderate effect size differences compared with controls. Bilaterally, the putamen showed the next highest volume reduction. The contralateral hippocampus and bilateral caudate nuclei showed the least volume reduction, characterized by small effect sizes. Furthermore, clinical seizure characteristics (e.g., duration of epilepsy) exhibited different patterns of association with the volume reductions observed across these structures. Findings suggest that distinct neurodevelopmental features may play a role in the volume abnormality observed in these regions.

The temporally graded memory impairment seen in many neurobehavioral disorders implies different neuroanatomical pathways and/or cognitive mechanisms involved in storage and retrieval of memories of different ages. A dynamic interaction between medial-temporal and neocortical brain regions has been proposed to account for memory's greater permanence with time. Despite considerable debate concerning its time-dependent role in memory retrieval, medial-temporal lobe activity has been well studied. However, the relative participation of neocortical regions in recent and remote memory retrieval has received much less attention. Using functional magnetic resonance imaging, we demonstrate robust, temporally graded signal differences in posterior cingulate, right middle frontal, right fusiform, and left middle temporal regions in healthy older adults during famous name identification from two disparate time epochs. Importantly, no neocortical regions demonstrated greater response to older than to recent stimuli. Our results suggest a possible role of these neocortical regions in temporally dating items in memory and in establishing and maintaining memory traces throughout the lifespan. Theoretical implications of these findings for the two dominant models of remote memory functioning (Consolidation Theory and Multiple Trace Theory) are discussed.

It is well known that neuropsychological impairment can be associated with chronic epilepsy. This review suggests that a broad lifespan perspective of cognition in epilepsy should include consideration of: a) neurobiological factors that antedate the first seizure and influence cognition, b) epilepsy-related factors that influence brain growth and cognitive development after epilepsy is diagnosed and treated, c) clinical epilepsy and other risk factors associated with poor cognitive prognosis in the context of chronic pharmacoresistant epilepsy, and d) the modifiable and non-modifiable risk factors that influence cognitive aging in the general population.

Patients with epilepsy frequently report dissatisfaction with their quality of life (QOL), and there is considerable interest in understanding the factors and mechanisms associated with this perception. To date, investigation has focused on the potential contribution of seizure variables (e.g., seizure control) and psychiatric conditions to QOL, but there has not been an examination of the potential role of comorbid medical conditions. Information was gathered concerning current medical and psychiatric conditions for 93 patients with temporal lobe epilepsy, and their relationship with QOL was examined. The numbers of medical and psychiatric conditions were distinct and significant predictors of QOL satisfaction, and both were stronger correlates than seizure-related factors and demographic variables. The implications of these findings for the treatment and management of patients with epilepsy are discussed.

Recent neuroimaging research shows that older adults exhibit recruitment, or increased activation on various cognitive tasks. The current study evaluated whether a similar pattern also occurs in semantic memory by evaluating age-related differences during recognition of Recent (since the 1990s) and Enduring (1950s to present) famous names. Fifteen healthy older and 15 healthy younger adults performed the name recognition task with a high and comparable degree of accuracy, although older adults had slower reaction time in response to Recent famous names. Event-related functional MRI showed extensive networks of activation in the two groups including posterior cingulate, right hippocampus, temporal lobe and left prefrontal regions. The Recent condition produced more extensive activation than the Enduring condition. Older adults had more extensive and greater magnitude of activation in 15 of 20 regions, particularly for the Recent condition (15 of 15; 7 of 15 also differed for Enduring); young adults did not show greater activation magnitude in any region. There were no group differences for non-famous names, indicating that age differences are task-specific. The results support and extend the existing literature to semantic memory tasks, indicating that older adult brains use functional recruitment to support task performance, even when task performance accuracy is high.

The ability to recognize, name, and provide information about famous persons is deficient in patients with temporal lobe epilepsy (TLE), although the neural basis for these deficits is not well understood. We examined the relationship of resting metabolism of the temporal poles, as determined by [18F] fluorodeoxyglucose positron emission tomography, to performance on a task of famous face recognition, naming, and generation of semantic information in 12 patients with TLE. Correlations between metabolic measures of the temporal poles and performance on the Famous Faces Task revealed strong relationships between all aspects of the Famous Faces Task and the left temporal pole, whereas Famous Faces Task correlations with the right temporal pole were not significant. These findings indicate that the left temporal pole is associated with lexical and semantic retrieval of knowledge of famous persons in patients with TLE. Further study appears warranted to elucidate the networks involved in semantic knowledge for famous faces.

Objective First, to determine whether patients with chronic temporal lobe epilepsy have a different cognitive trajectory compared to control subjects over a prospective 4-year interval; second, to determine the proportion of patients who exhibit abnormal cognitive change and their profile of demographic, clinical epilepsy, and baseline quantitative magnetic resonance imaging characteristics; and third, to determine the most vulnerable cognitive domains. Methods Participants with chronic temporal lobe epilepsy (n = 46) attending a tertiary referral clinic and healthy control subjects (n = 65) underwent neuropsychological assessment and reevaluation 4 years later. Analysis of test–retest patterns identified individual patients with adverse cognition outcomes. Results The prospective cognitive trajectory of patients with chronic temporal lobe epilepsy differs from age- and sex-matched healthy control subjects. Lack of practice effects is common, but frank adverse cognitive outcomes are observed in a subset of patients (20–25%), particularly in vulnerable cognitive domains that include memory. Cognitive declines are associated with a profile of abnormalities in baseline quantitative magnetic resonance volumetrics, lower baseline intellectual capacity, as well as longer duration of epilepsy and older chronological age. Interpretation Cognitive prognosis is poor for a subset of patients characterized by chronicity of epilepsy, older age, lower intellectual ability, and more baseline abnormalities in quantitative magnetic resonance volumetrics. Ann Neurol 2006;60:80–87

Summary: Purpose: To determine the relation between neuropsychological morbidity, quantitative magnetic resonance imaging (MRI) measures of whole brain structure, and clinical seizure factors reflecting epilepsy cause, course, and treatment. Methods: Quantitative MRI measurements of total (whole brain) cerebrospinal fluid (CSF) and gray- and white-matter volumes and clinical seizure features were examined in relation to summary indices of cognitive morbidity in 96 patients with temporal lobe epilepsy. MRI volumes were adjusted for intracranial volume (ICV), and cognitive scores were adjusted for age, education, and gender, based on a sample of 82 healthy controls. Results: Whole-brain volumes (gray, white, and CSF) were abnormal in chronic temporal lobe epilepsy patients compared with controls and were related significantly to neuropsychological morbidity, especially total CSF. Statistical modeling demonstrated that markers of total atrophy (CSF) was the primary mediator of the relation between clinical seizure variables and neuropsychological morbidity. Conclusions: Quantitative measurements of overall brain abnormality (atrophy) in temporal lobe epilepsy are clinically meaningful markers that are associated with increased cognitive morbidity. These biomarkers appear to mediate the adverse effects of some clinical seizure variables on cognition.

Summary: Purpose: To assess the presence, extent, and clinical correlates of quantitative MR volumetric abnormalities in ipsilateral and contralateral hippocampus, and temporal and extratemporal lobe regions in unilateral temporal lobe epilepsy (TLE). Methods: In total, 34 subjects with unilateral left (n = 15) or right (n = 19) TLE were compared with 65 healthy controls. Regions of interest included the ipsilateral and contralateral hippocampus as well as temporal, frontal, parietal, and occipital lobe gray and white matter. Clinical markers of neurodevelopmental insult (initial precipitating insult, early age of recurrent seizures) and chronicity of epilepsy (epilepsy duration, estimated number of lifetime generalized seizures) were related to magnetic resonance (MR) volume abnormalities. Results: Quantitative MR abnormalities extend beyond the ipsilateral hippocampus and temporal lobe with extratemporal (frontal and parietal lobe) reductions in cerebral white matter, especially ipsilateral but also contralateral to the side of seizure onset. Volumetric abnormalities in ipsilateral hippocampus and bilateral cerebral white matter are associated with factors related to both the onset and the chronicity of the patients’ epilepsy. Conclusions: These cross-sectional findings support the view that volumetric abnormalities in chronic TLE are associated with a combination of neurodevelopmental and progressive effects, characterized by a prominent disruption in ipsilateral hippocampus and neural connectivity (i.e., white matter volume loss) that extends beyond the temporal lobe, affecting both ipsilateral and contralateral hemispheres. Ke yW ords: Temporal lobe epilepsy—Quantitative MRI.

Prior studies of temporal lobe epilepsy (TLE) patients showed that MRI volumes and resting PET scan measures of temporal lobe structures were related to memory. Weintrob and colleagues [Ann. Neurol. 2002;51:442-7] reported that PET glucose uptake in the left perirhinal cortex predicted verbal paired associate (PA) learning, whereas MRI volume of the left hippocampus did not. We investigated whether MRI volumes could account for memory functioning if both PET and volumes were from the same region in 18 TLE patients. Volumes and glucose uptake of the hippocampus and parahippocampal gyrus (PHG) were compared with WMS-III performance. Significant correlations were observed between hippocampal volumes and PA and Logical Memory (LM) Percent Retention, but not between memory and PHG volumes or any PET measures. Multiple regression revealed that hippocampal volumes, but not PHG volumes or PET, significantly predicted PA and LM retention scores. These findings suggest that hippocampal volumes provide unique information regarding memory.