A longitudinal evaluation of personalized intrinsic network topography and cognitive decline in Parkinson's disease.

Resting state functional magnetic resonance imaging (R-fMRI) offers insight into how synchrony within and between brain networks is altered in disease states. Individual and disease-related variability in intrinsic connectivity networks may influence our interpretation of R-fMRI data. We used a personalized approach designed to account for individual variation in the spatial location of correlation maxima to evaluate R-fMRI differences between Parkinson's disease (PD) patients who showed cognitive decline, those who remained cognitively stable and cognitively stable controls. We compared fMRI data from these participant groups, studied at baseline and 18 months later, using both network-based statistics (NBS) and calculations of mean inter- and intra-network connectivity within pre-defined functional networks. The NBS analysis showed that PD participants who remained cognitively stable showed exclusively (at baseline) or predominantly (at follow-up) increased intra-network connectivity, whereas decliners showed exclusively reduced intra-network and inter- (ventral attention and default mode) connectivity, in comparison with the control group. Evaluation of mean connectivity between all regions of interest (ROIs) within a priori networks showed that decliners had consistently reduced inter-network connectivity for ventral attention, somatomotor, visual and striatal networks and reduced intra-network connectivity for ventral attention network to striatum and cerebellum. These findings suggest that specific functional connectivity covariance patterns differentiate PD cognitive subtypes and may predict cognitive decline. Further, increased intra and inter-network synchrony may support cognitive function in the face of PD-related network disruptions.

Association of neighborhood deprivation with white matter connectome abnormalities in temporal lobe epilepsy.

OBJECTIVE: Social determinants of health, including the effects of neighborhood disadvantage, impact epilepsy prevalence, treatment, and outcomes. This study characterized the association between aberrant white matter connectivity in temporal lobe epilepsy (TLE) and disadvantage using a US census-based neighborhood disadvantage metric, the Area Deprivation Index (ADI), derived from measures of income, education, employment, and housing quality. METHODS: Participants including 74 TLE patients (47 male, mean age = 39.2 years) and 45 healthy controls (27 male, mean age = 31.9 years) from the Epilepsy Connectome Project were classified into ADI-defined low and high disadvantage groups. Graph theoretic metrics were applied to multishell connectome diffusion-weighted imaging (DWI) measurements to derive 162 × 162 structural connectivity matrices (SCMs). The SCMs were harmonized using neuroCombat to account for interscanner differences. Threshold-free network-based statistics were used for analysis, and findings were correlated with ADI quintile metrics. A decrease in cross-sectional area (CSA) indicates reduced white matter integrity. RESULTS: Sex- and age-adjusted CSA in TLE groups was significantly reduced compared to controls regardless of disadvantage status, revealing discrete aberrant white matter tract connectivity abnormalities in addition to apparent differences in graph measures of connectivity and network-based statistics. When comparing broadly defined disadvantaged TLE groups, differences were at trend level. Sensitivity analyses of ADI quintile extremes revealed significantly lower CSA in the most compared to least disadvantaged TLE group. SIGNIFICANCE: Our findings demonstrate (1) the general impact of TLE on DWI connectome status is larger than the association with neighborhood disadvantage; however, (2) neighborhood disadvantage, indexed by ADI, revealed modest relationships with white matter structure and integrity on sensitivity analysis in TLE. Further studies are needed to explore this relationship and determine whether the white matter relationship with ADI is driven by social drift or environmental influences on brain development. Understanding the etiology and course of the disadvantage-brain integrity relationship may serve to inform care, management, and policy for patients.

Application of data harmonization and tract-based spatial statistics reveals white matter structural abnormalities in pediatric patients with focal cortical dysplasia.

Our study assessed diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) in pediatric subjects with epilepsy secondary to Focal Cortical Dysplasia (FCD) to improve our understanding of structural network changes associated with FCD related epilepsy. We utilized a data harmonization (DH) approach to minimize confounding effects induced by MRI protocol differences. We also assessed correlations between DTI metrics and neurocognitive measures of the fluid reasoning index (FRI), verbal comprehension index (VCI), and visuospatial index (VSI). Data (n = 51) from 23 FCD patients and 28 typically developing controls (TD) scanned clinically on either 1.5T, 3T, or 3T-wide-bore MRI were retrospectively analyzed. Tract-based spatial statistics (TBSS) with threshold-free cluster enhancement and permutation testing with 100,000 permutations were used for statistical analysis. To account for imaging protocol differences, we employed non-parametric data harmonization prior to permutation testing. Our analysis demonstrates that DH effectively removed MRI protocol-based differences typical in clinical acquisitions while preserving group differences in DTI metrics between FCD and TD subjects. Furthermore, DH strengthened the association between DTI metrics and neurocognitive indices. Fractional anisotropy, MD, and RD metrics showed stronger correlation with FRI and VSI than VCI. Our results demonstrate that DH is an integral step to reduce the confounding effect of MRI protocol differences during the analysis of white matter tracts and highlights biological differences between FCD and healthy control subjects. Characterization of white matter changes associated with FCD-related epilepsy may better inform prognosis and treatment approaches.

Behavioral phenotypes of childhood idiopathic epilepsies.

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.

Network analysis of prospective brain development in youth with benign epilepsy with centrotemporal spikes and its relationship to cognition.

OBJECTIVE: Benign epilepsy with centrotemporal spikes (BECTS) is the most common childhood idiopathic localization-related epilepsy syndrome. BECTS presents normal routine magnetic resonance imaging (MRI); however, quantitative analytic techniques have captured subtle cortical and subcortical magnetic resonance anomalies. Network science, including graph theory (GT) analyses, facilitates understanding of brain covariance patterns, potentially informing in important ways how this common self-limiting epilepsy syndrome may impact normal patterns of brain and cognitive development. METHODS: GT analyses examined the developmental covariance among cortical and subcortical regions in children with new/recent onset BECTS (n = 19) and typically developing healthy controls (n = 22) who underwent high-resolution MRI and cognitive assessment at baseline and 2 years later. Global (transitivity, global efficiency, and modularity index [Q]) and regional measures (local efficiency and hubs) were investigated to characterize network development in each group. Associations between baseline-based GT measures and cognition at both time points addressed the implications of GT analyses for cognition and prospective cognitive development. Furthermore, an individual contribution measure was investigated, reflecting how important for cognition it is for BECTS to resemble the correlation matrices of controls. RESULTS: Groups exhibited similar Q and overall network configuration, with BECTS presenting significantly higher transitivity and both global and local efficiency. Furthermore, both groups presented a similar number of hubs, with BECTS showing a higher number in temporal lobe regions compared to controls. The investigated measures were negatively associated with 2-year cognitive outcomes in BECTS. SIGNIFICANCE: Children with BECTS present a higher-than-normal global developmental configuration compared to controls, along with divergence from normality in terms of regional configuration. Baseline GT measures demonstrate potential as a cognitive biomarker to predict cognitive outcome in BECTS 2 years after diagnosis. Similarities and differences in developmental network configurations and their implications for cognition and behavior across common epilepsy syndromes are of theoretical interest and clinical relevance.

Neuroanatomical correlates of personality traits in temporal lobe epilepsy: Findings from the Epilepsy Connectome Project.

Behavioral and personality disorders in temporal lobe epilepsy (TLE) have been a topic of interest and controversy for decades, with less attention paid to alterations in normal personality structure and traits. In this investigation, core personality traits (the Big 5) and their neurobiological correlates in TLE were explored using the Neuroticism Extraversion Openness-Five Factor Inventory (NEO-FFI) and structural magnetic resonance imaging (MRI) through the Epilepsy Connectome Project (ECP). NEO-FFI scores from 67 individuals with TLE (34.6 ±â€¯9.5 years; 67% women) were compared to 31 healthy controls (32.8 ±â€¯8.9 years; 41% women) to assess differences in the Big 5 traits (agreeableness, openness, conscientiousness, neuroticism, and extraversion). Individuals with TLE showed significantly higher neuroticism, with no significant differences on the other traits. Neural correlates of neuroticism were then determined in participants with TLE including cortical and subcortical volumes. Distributed reductions in cortical gray matter volumes were associated with increased neuroticism. Subcortically, hippocampal and amygdala volumes were negatively associated with neuroticism. These results offer insight into alterations in the Big 5 personality traits in TLE and their brain-related correlates.

Progressive dissociation of cortical and subcortical network development in children with new-onset juvenile myoclonic epilepsy.

OBJECTIVE: Structural and functional magnetic resonance imaging (MRI) studies have consistently documented cortical and subcortical abnormalities in patients with juvenile myoclonic epilepsy (JME). However, little is known about how these structural abnormalities emerge from the time of epilepsy onset and how network interactions between and within cortical and subcortical regions may diverge in youth with JME compared to typically developing children. METHODS: We examined prospective covariations of volumetric differences derived from high-resolution structural MRI during the first 2 years of epilepsy diagnosis in a group of youth with JME (n = 21) compared to healthy controls (n = 22). We indexed developmental brain changes using graph theory by computing network metrics based on the correlation of the cortical and subcortical structural covariance near the time of epilepsy and 2 years later. RESULTS: Over 2 years, normally developing children showed modular cortical development and network integration between cortical and subcortical regions. In contrast, children with JME developed a highly correlated and less modular cortical network, which was atypically dissociated from subcortical structures. Furthermore, the JME group also presented higher clustering and lower modularity indices than controls, indicating weaker modules or communities. The local efficiency in JME was higher than controls across the majority of cortical nodes. Regarding network hubs, controls presented a higher number than youth with JME that were spread across the brain with ample representation from the different modules. In contrast, children with JME showed a lower number of hubs that were mainly from one module and comprised mostly subcortical structures. SIGNIFICANCE: Youth with JME prospectively developed a network of highly correlated cortical regions dissociated from subcortical structures during the first 2 years after epilepsy onset. The cortical-subcortical network dissociation provides converging insights into the disparate literature of cortical and subcortical abnormalities found in previous studies.

Brain structure and organization five decades after childhood onset epilepsy.

The purpose of this project was to characterize brain structure and organization in persons with active and remitted childhood onset epilepsy 50 years after diagnosis compared with healthy controls. Participants from a population-based investigation of uncomplicated childhood onset epilepsy were followed up 5 decades later. Forty-one participants had a history of childhood onset epilepsy (mean age of onset = 5.2 years, current chronological age = 56.0 years) and were compared with 48 population-based controls (mean age = 55.9 years). Of the epilepsy participants, 8 had persisting active epilepsy and in 33 the epilepsy had remitted. All participants underwent 3T MRI with subsequent vertex analysis of cortical volume, thickness, surface area and gyral complexity. In addition, cortical and subcortical volumes, including regions of the frontal, parietal, temporal, and occipital lobes, and subcortical structures including amygdala, thalamus, and hippocampus, were analyzed using graph theory techniques. There were modest group differences in traditional vertex-based analyses of cortical volume, thickness, surface area and gyral index, as well as across volumes of subcortical structures, after correction for multiple comparisons. Graph theory analyses revealed suboptimal topological structural organization with enhanced network segregation and reduced global integration in the epilepsy participants compared with controls, these patterns significantly more extreme in the active epilepsy group. Furthermore, both groups with epilepsy presented a greater number of higher Z-score regions in betweenness centrality (BC) than lower Z-score regions compared with controls. Also, contrary to the group with remitted epilepsy, patients with active epilepsy presented most of their high BC Z-score regions in subcortical areas including the amygdala, thalamus, hippocampus, pallidum, and accumbens. Overall, this population-based investigation of long term outcome (5 decades) of childhood onset epilepsy reveals persisting abnormalities, especially when examined by graph theoretical measurements, and provides new insights into the very long-term outcomes of active and remitted epilepsy. Hum Brain Mapp 38:3289-3299, 2017. © 2017 Wiley Periodicals, Inc.

Cognitive phenotypes in childhood idiopathic epilepsies.

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.

Neurodevelopment in new-onset juvenile myoclonic epilepsy over the first 2 years.

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.

Children with epilepsy and anxiety: Subcortical and cortical differences.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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). SIGNIFICANCE: 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.

Cognition and brain development in children with benign epilepsy with centrotemporal spikes.

OBJECTIVE: Benign epilepsy with centrotemporal spikes (BECTS), the most common focal childhood epilepsy, is associated with subtle abnormalities in cognition and possible developmental alterations in brain structure when compared to healthy participants, as indicated by previous cross-sectional studies. To examine the natural history of BECTS, we investigated cognition, cortical thickness, and subcortical volumes in children with new/recent onset BECTS and healthy controls (HC). METHODS: Participants were 8-15 years of age, including 24 children with new-onset BECTS and 41 age- and gender-matched HC. At baseline and 2 years later, all participants completed a cognitive assessment, and a subset (13 BECTS, 24 HC) underwent T1 volumetric magnetic resonance imaging (MRI) scans focusing on cortical thickness and subcortical volumes. RESULTS: Baseline cognitive abnormalities associated with BECTS (object naming, verbal learning, arithmetic computation, and psychomotor speed/dexterity) persisted over 2 years, with the rate of cognitive development paralleling that of HC. Baseline neuroimaging revealed thinner cortex in BECTS compared to controls in frontal, temporal, and occipital regions. Longitudinally, HC showed widespread cortical thinning in both hemispheres, whereas BECTS participants showed sparse regions of both cortical thinning and thickening. Analyses of subcortical volumes showed larger left and right putamens persisting over 2 years in BECTS compared to HC. SIGNIFICANCE: Cognitive and structural brain abnormalities associated with BECTS are present at onset and persist (cognition) and/or evolve (brain structure) over time. Atypical maturation of cortical thickness antecedent to BECTS onset results in early identified abnormalities that continue to develop abnormally over time. However, compared to anatomic development, cognition appears more resistant to further change over time.

Neurodevelopmental alterations of large-scale structural networks in children with new-onset epilepsy.

Recent neuroimaging and behavioral studies have revealed that children with new onset epilepsy already exhibit brain structural abnormalities and cognitive impairment. How the organization of large-scale brain structural networks is altered near the time of seizure onset and whether network changes are related to cognitive performances remain unclear. Recent studies also suggest that regional brain volume covariance reflects synchronized brain developmental changes. Here, we test the hypothesis that epilepsy during early-life is associated with abnormalities in brain network organization and cognition. We used graph theory to study structural brain networks based on regional volume covariance in 39 children with new-onset seizures and 28 healthy controls. Children with new-onset epilepsy showed a suboptimal topological structural organization with enhanced network segregation and reduced global integration compared with controls. At the regional level, structural reorganization was evident with redistributed nodes from the posterior to more anterior head regions. The epileptic brain network was more vulnerable to targeted but not random attacks. Finally, a subgroup of children with epilepsy, namely those with lower IQ and poorer executive function, had a reduced balance between network segregation and integration. Taken together, the findings suggest that the neurodevelopmental impact of new onset childhood epilepsies alters large-scale brain networks, resulting in greater vulnerability to network failure and cognitive impairment.

The relevance of Spearman's g for epilepsy.

Whilst the concept of a general mental factor known as 'g' has been of longstanding interest, for unknown reasons, it has never been interrogated in epilepsy despite the 100+ year empirical history of the neuropsychology of epilepsy. This investigation seeks to identify g within a comprehensive neuropsychological data set and compare participants with temporal lobe epilepsy to controls, characterize the discriminatory power of g compared with domain-specific cognitive metrics, explore the association of g with clinical epilepsy and sociodemographic variables and identify the structural and network properties associated with g in epilepsy. Participants included 110 temporal lobe epilepsy patients and 79 healthy controls between the ages of 19 and 60. Participants underwent neuropsychological assessment, clinical interview and structural and functional imaging. Cognitive data were subjected to factor analysis to identify g and compare the group of patients with control participants. The relative power of g compared with domain-specific tests was interrogated, clinical and sociodemographic variables were examined for their relationship with g, and structural and functional images were assessed using traditional regional volumetrics, cortical surface features and network analytics. Findings indicate (i) significantly (P < 0.005) lower g in patients compared with controls; (ii) g is at least as powerful as individual cognitive domain-specific metrics and other analytic approaches to discriminating patients from control participants; (iii) lower g was associated with earlier age of onset and medication use, greater number of antiseizure medications and longer epilepsy duration (Ps < 0.04); and lower parental and personal education and greater neighbourhood deprivation (Ps < 0.012); and (iv) amongst patients, lower g was linked to decreased total intracranial volume (P = 0.019), age and intracranial volume adjusted total tissue volume (P = 0.019) and age and intracranial volume adjusted total corpus callosum volume (P = 0.012)-particularly posterior, mid-posterior and anterior (Ps < 0.022) regions. Cortical vertex analyses showed lower g to be associated specifically with decreased gyrification in bilateral medial orbitofrontal regions. Network analysis of resting-state data with focus on the participation coefficient showed g to be associated with the superior parietal network. Spearman's g is reduced in patients, has considerable discriminatory power compared with domain-specific metrics and is linked to a multiplex of factors related to brain (size, connectivity and frontoparietal networks), environment (familial and personal education and neighbourhood disadvantage) and disease (epilepsy onset, treatment and duration). Greater attention to contemporary models of human cognition is warranted in order to advance the neuropsychology of epilepsy.

The neuropsychological and academic substrate of new/recent-onset epilepsies.

OBJECTIVE: To characterize neuropsychological and academic status in children, ages 8-18 years, with new-/recent-onset idiopathic generalized epilepsy (IGE) and idiopathic localization-related epilepsy (ILRE) compared with healthy controls. STUDY DESIGN: Participants underwent neuropsychological assessment, and parents were interviewed regarding their child's academic history. Cognitive scores for children with epilepsy were age- and sex-adjusted and compared with controls across both broad-band (IGE n = 41 and ILRE n = 53) and narrow-band (childhood/juvenile absence, juvenile myoclonic, benign epilepsy with centro-temporal spikes, and focal [temporal/frontal/not otherwise specified]) syndromes. Academic histories were examined, including problems antecedent to epilepsy onset and diagnosis. RESULTS: Children with new/recent-onset epilepsies exhibit considerable cognitive abnormality at baseline, including patterns of shared abnormalities across syndromes (eg, psychomotor slowing) as well as unique syndrome-specific cognitive effects (eg, executive function in IGE and language/verbal memory in ILRE) that are observed and sometimes exacerbated in specific IGE and ILRE syndromes. Academic difficulties are evident in approximately 50% of the children with epilepsy, affecting all syndrome groups to an equal degree. DISCUSSION: Patterns of shared and syndrome-specific cognitive abnormalities and academic problems are present early in the course of virtually all epilepsy syndromes examined here, including syndromes classically viewed as benign. This is the base upon which the effects of recurrent seizures, treatment, and psychosocial effects will be added over time.

Patterns of cortical thickness and the Child Behavior Checklist in childhood 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.

Is lower IQ in children with epilepsy due to lower parental IQ? A controlled comparison study.

AIM: The aim of this study was to determine the relationship between parent and child Full-scale IQ (FSIQ) in children with epilepsy and in typically developing comparison children and to examine parent-child IQ differences by epilepsy characteristics. METHOD: The study participants were 97 children (50 males, 47 females; age range 8-18y; mean age 12y 3mo, SD 3y1mo) with recent-onset epilepsy including idiopathic generalized (n=43) and idiopathic localization-related epilepsies (n=54); 69 healthy comparison children (38 females, 31 males; age range 8-18y; mean age 12y 8mo, SD 3y 2mo), and one biological parent per child. All participants were administered the Wechsler Abbreviated Scale of Intelligence (WASI). FSIQ was compared in children with epilepsy and typically developing children; FSIQ was compared in the parents of typically developing children and the parents of participants with epilepsy; parent-child FSIQ differences were compared between the groups. RESULTS: FSIQ was lower in children with epilepsy than in comparison children (p<0.001). FSIQ of parents of children with epilepsy did not differ from the FSIQ of the parents of typically developing children. Children with epilepsy had significantly lower FSIQ than their parents (p<0.001), whereas comparison children did not. The parent-child IQ difference was significantly higher in the group with epilepsy than the comparison group (p=0.043). Epilepsy characteristics were not related to parent-child IQ difference. INTERPRETATION: Parent-child IQ difference appears to be a marker of epilepsy impact independent of familial IQ, epilepsy syndrome, and clinical seizure features. This marker is evident early in the course of idiopathic epilepsies and can be tracked over time.

The presence, nature and network characteristics of behavioural phenotypes in temporal lobe epilepsy.

The relationship between temporal lobe epilepsy and psychopathology has had a long and contentious history with diverse views regarding the presence, nature and severity of emotional-behavioural problems in this patient population. To address these controversies, we take a new person-centred approach through the application of unsupervised machine learning techniques to identify underlying latent groups or behavioural phenotypes. Addressed are the distinct psychopathological profiles, their linked frequency, patterns and severity and the disruptions in morphological and network properties that underlie the identified latent groups. A total of 114 patients and 83 controls from the Epilepsy Connectome Project were administered the Achenbach System of Empirically Based Assessment inventory from which six Diagnostic and Statistical Manual of Mental Disorders-oriented scales were analysed by unsupervised machine learning analytics to identify latent patient groups. Identified clusters were contrasted to controls as well as to each other in order to characterize their association with sociodemographic, clinical epilepsy and morphological and functional imaging network features. The concurrent validity of the behavioural phenotypes was examined through other measures of behaviour and quality of life. Patients overall exhibited significantly higher (abnormal) scores compared with controls. However, cluster analysis identified three latent groups: (i) unaffected, with no scale elevations compared with controls (Cluster 1, 37%); (ii) mild symptomatology characterized by significant elevations across several Diagnostic and Statistical Manual of Mental Disorders-oriented scales compared with controls (Cluster 2, 42%); and (iii) severe symptomatology with significant elevations across all scales compared with controls and the other temporal lobe epilepsy behaviour phenotype groups (Cluster 3, 21%). Concurrent validity of the behavioural phenotype grouping was demonstrated through identical stepwise links to abnormalities on independent measures including the National Institutes of Health Toolbox Emotion Battery and quality of life metrics. There were significant associations between cluster membership and sociodemographic (handedness and education), cognition (processing speed), clinical epilepsy (presence and lifetime number of tonic-clonic seizures) and neuroimaging characteristics (cortical volume and thickness and global graph theory metrics of morphology and resting-state functional MRI). Increasingly dispersed volumetric abnormalities and widespread disruptions in underlying network properties were associated with the most abnormal behavioural phenotype. Psychopathology in these patients is characterized by a series of discrete latent groups that harbour accompanying sociodemographic, clinical and neuroimaging correlates. The underlying neurobiological patterns suggest that the degree of psychopathology is linked to increasingly dispersed abnormal brain networks. Similar to cognition, machine learning approaches support a novel developing taxonomy of the comorbidities of epilepsy.

Cerebral cortical thickness and cognitive decline in Parkinson's disease.

In Parkinson's disease (PD), reduced cerebral cortical thickness may reflect network-based degeneration. This study performed cognitive assessment and brain MRI in 30 PD participants and 41 controls at baseline and 18 months later. We hypothesized that cerebral cortical thickness and volume, as well as change in these metrics, would differ between PD participants who remained cognitively stable and those who experienced cognitive decline. Dividing the participant sample into PD-stable, PD-decline, and control-stable groups, we compared mean cortical thickness and volume within segments that comprise the prefrontal cognitive-control, memory, dorsal spatial, and ventral object-based networks at baseline. We then compared the rate of change in cortical thickness and volume between the same groups using a vertex-wise approach. We found that the PD-decline group had lower cortical thickness within all 4 cognitive networks in comparison with controls, as well as lower cortical thickness within the prefrontal and medial temporal networks in comparison with the PD-stable group. The PD-decline group also experienced a greater rate of volume loss in the lateral temporal cortices in comparison with the control group. This study suggests that lower thickness and volume in prefrontal, medial, and lateral temporal regions may portend cognitive decline in PD.

Prevalence and localization of nocturnal epileptiform discharges in mild cognitive impairment.

Recent evidence shows that identifying and treating epileptiform abnormalities in patients with Alzheimer's disease could represent a potential avenue to improve clinical outcome. Specifically, animal and human studies have revealed that in the early phase of Alzheimer's disease, there is an increased risk of seizures. It has also been demonstrated that the administration of anti-seizure medications can slow the functional progression of the disease only in patients with EEG signs of cortical hyperexcitability. In addition, although it is not known at what disease stage hyperexcitability emerges, there remains no consensus regarding the imaging and diagnostic methods best able to detect interictal events to further distinguish different phenotypes of Alzheimer's disease. In this exploratory work, we studied 13 subjects with amnestic mild cognitive impairment and 20 healthy controls using overnight high-density EEG with 256 channels. All participants also underwent MRI and neuropsychological assessment. Electronic source reconstruction was also used to better select and localize spikes. We found spikes in six of 13 (46%) amnestic mild cognitive impairment compared with two of 20 (10%) healthy control participants (P = 0.035), representing a spike prevalence similar to that detected in previous studies of patients with early-stage Alzheimer's disease. The interictal events were low-amplitude temporal spikes more prevalent during non-rapid eye movement sleep. No statistically significant differences were found in cognitive performance between amnestic mild cognitive impairment patients with and without spikes, but a trend in immediate and delayed memory was observed. Moreover, no imaging findings of cortical and subcortical atrophy were found between amnestic mild cognitive impairment participants with and without epileptiform spikes. In summary, our exploratory study shows that patients with amnestic mild cognitive impairment reveal EEG signs of hyperexcitability early in the disease course, while no other significant differences in neuropsychological or imaging features were observed among the subgroups. If confirmed with longitudinal data, these exploratory findings could represent one of the first signatures of a preclinical epileptiform phenotype of amnestic mild cognitive impairment and its progression.