Understanding the multidimensional neurodevelopmental outcomes in children after congenital Zika virus exposure.

Since 2016, international research groups have focused on assessing outcomes of children with in utero Zika virus (ZIKV) exposure. While the more severe outcomes of congenital Zika syndrome (CZS) occur in up to 10% of children with antenatal exposure, early findings among ZIKV-exposed children without CZS ages 0-5 years suggest that they may also have differences in multiple domains of neurodevelopment. Thus, longitudinal follow-up of all children with antenatal ZIKV exposure has been recommended. This review presents a summary of neurodevelopmental phenotypes of infants and children following antenatal ZIKV exposure. We present a multidimensional framework to understand child neurodevelopment from an interdisciplinary and whole-child perspective (International Classification of Functioning, Disability and Health model) and multi-domain ZIKV Outcome Toolboxes. The toolboxes are for clinicians, researchers, child educators, and others to implement longitudinal multi-domain neurodevelopmental assessments between ages 0-12 years. Recent innovations in telehealth and neuroimaging can help evaluate outcomes in ZIKV exposed children. The objective is to describe the multiple facets of neurodevelopmental focused care that can support the health, function, and well-being of children with antenatal ZIKV exposure. The research and clinical follow-up strategies are applicable to ZIKV and other congenital infectious or environmental exposures that can impact child neurodevelopment. IMPACT: International longitudinal cohort studies have revealed a range of differences in neurodevelopment among children with antenatal Zika virus (ZIKV) exposure. A multidimensional and whole-child framework is necessary to understand the neurodevelopment of children with antenatal ZIKV exposure in relation to family life, community participation, and environment. Multi-domain toolboxes that utilize parent questionnaires and child evaluations are presented. These toolboxes can be used internationally alongside telehealth, brain imaging, and other innovations to improve understanding of child outcomes.

Clinical Validation of Selected NIH Cognitive Toolbox Tasks in Pediatric Epilepsy.

The NIH Toolbox Cognition Battery (NIHTB-CB) is designed to assess cognitive functioning across the lifespan. We aimed to evaluate the clinical validity of two NIHTB-CB tasks as cognitive screening tools in pediatric epilepsy by comparing them to standard neuropsychological measures and their association with epilepsy characteristics. Forty-seven patients with epilepsy ages 5-18, including ten repeat evaluations, were assessed. Correlational analyses and agreement statistics were conducted to validate NIHTB-CB tasks (Flanker Inhibitory Control and Attention test (Flanker) and Pattern Comparison Processing Speed test (Pattern Comparison)) with standard clinical measures. We also examined if performance was related to epilepsy characteristics, including polytherapy, age of seizure onset, seizure type, and history of Electrical Status Epilepticus in Sleep (ESES). The NIHTB-CB tests had moderate to strong correlations with neuropsychological measures of executive functioning, processing speed, and intelligence. Agreement statistics indicated better sensitivity than specificity. Polytherapy and later age of seizure onset were associated with lower performance on Pattern Comparison. ESES patients did not significantly differ in performance on the tests compared to non-ESES patients. Pilot data from a subset of repeated measures indicated a good range of change scores. These two NIHTB tasks are feasible as a screening tool in a clinic given their correlation with clinical measures that assess executive function, processing speed, and IQ. This study supports the use of these tasks as brief, easily accessible screener tools to identify cognitive dysfunction in domains commonly impacted in patients with epilepsy and potential use for monitoring over time.

Neurodevelopmental assessments used to measure preschoolers' cognitive development in Latin America: a systematic review.

OBJECTIVE: The objective of this study was to systematically review the standardized neurodevelopmental assessments used to study preschool-aged children's cognitive development in Spanish-speaking Latin America. METHODS: The authors systematically searched PubMed, PsycINFO, and ERIC databases for peer-reviewed articles from Spanish-speaking Latin American countries. Articles were included if they measured cognitive development among children aged 2-6 years using at least one standardized assessment tool; 97 articles were included and reviewed in accordance with PRISMA guidelines to assess their use of these tools. RESULTS: Ninety-seven studies across 13 countries used a total of 41 assessments to measure cognitive development; most widely used were the Wechsler intelligence scales (n = 46/97), particularly the Wechsler Preschool and Primary Scale of Intelligence and Wechsler Intelligence Scale for Children (n = 23 and 29, respectively). Other common assessments included the McCarthy Scales of Children's Abilities (n = 9), Raven's Progressive Matrices (n = 9), Child Neuropsychological Assessment (n = 8), and Peabody Picture Vocabulary Test (n = 7). In regions where normative data for a given assessment were unpublished, authors commonly used norms from the United States, Mexico, or Spain or did not report standard scores in their analyses. CONCLUSIONS: The wide range of tools used in these studies presents a challenge for generalizing results when measuring the neurodevelopment of Latin American preschool-aged children. The low availability of normative data for specific regions reveals concerns if some tools are culturally and linguistically appropriate even when Spanish is a common language, particularly in low-resource settings. Future work to forge greater consistency in the use of validated measures, clarity in reporting research methods, and publication of regional normative data would benefit the field.

Comparison of psychosocial screeners in an epilepsy clinic.

Screenings are recommended for co-occurring conditions in pediatric epilepsy. However, there is limited research regarding which screener to implement in the clinic. This study aimed to compare different screening measures for attention-deficit/hyperactivity disorder (ADHD) and emotional concerns in a pediatric epilepsy population during a routine neurology clinic visit. Fifty (22%) of 226 contacted parents of children with epilepsy ages 5-17 years old agreed to participate. Screening measures included the Strengths and Difficulties Questionnaire (SDQ; Hyperactivity/Inattention (ADHD), Emotional Problems (E) subscales), the Pediatric Quality of Life Inventory Epilepsy Module (PedsQL-EM; Executive Functioning (EF), Mood/Behavior (M/B) subscales), and the ADHD Rating Scale (ADHD-RS). Analyses comparing measures included Chi Square, Pearson's correlation, and agreement statistics (Cohen's kappa, overall agreement). Consistent with prior literature, positive screening rates ranged from 40% to 72% for ADHD concerns and 38% to 46% for emotional concerns. Agreement between measures ranged from fair to substantial, with the highest agreement (85%; κ = 0.70) between the SDQ-E and PedsQL-EM-M/B. Although all measures rendered positive screens within expected rates, there are differences among the measures that inform screening measure selection.

One right can make a left: sentence processing in the right hemisphere after perinatal stroke.

When brain regions that are critical for a cognitive function in adulthood are irreversibly damaged at birth, what patterns of plasticity support the successful development of that function in an alternative location? Here we investigate the consistency of language organization in the right hemisphere (RH) after a left hemisphere (LH) perinatal stroke. We analyzed fMRI data collected during an auditory sentence comprehension task on 14 people with large cortical LH perinatal arterial ischemic strokes (left hemisphere perinatal stroke (LHPS) participants) and 11 healthy sibling controls using a "top voxel" approach that allowed us to compare the same number of active voxels across each participant and in each hemisphere for controls. We found (1) LHPS participants consistently recruited the same RH areas that were a mirror-image of typical LH areas, and (2) the RH areas recruited in LHPS participants aligned better with the strongly activated LH areas of the typically developed brains of control participants (when flipped images were compared) than the weakly activated RH areas. Our findings suggest that the successful development of language processing in the RH after a LH perinatal stroke may in part depend on recruiting an arrangement of frontotemporal areas reflective of the typical dominant LH.

Positive and negative effects of the COVID-19 pandemic on families of young children in rural Colombia and implications for child outcome research.

BACKGROUND: The COVID-19 pandemic has impacted the lives of children and families worldwide. The objective of this study is to examine exposures and impact of the COVID-19 pandemic on preschool-aged children and caregivers in the Atlántico region of Colombia. METHODS: The COVID-19 Exposure and Family Impact Scales (CEFIS) questionnaire was administered in Fall 2021 to 63 caregivers of children in Sabanalarga, Colombia enrolled in a neurodevelopment study as healthy controls. The CEFIS assesses pandemic-related exposures/events and impact; higher scores indicate greater exposure and negative impact. Descriptive and correlation analyses among exposure and impact scores were conducted. RESULTS: Caregivers reported a mean (standard deviation[SD]) of 11.1 (3.2) among 25 COVID-19-related exposures/events; most common types included stay-at-home orders, school closures, disruptions to living conditions and income loss. Total number of events was correlated with higher caregiver (P < .001) and child distress (P = .002). However, the mean (SD) impact score of 2.0 (0.6) suggests a trend toward more positive impact than negative. Caregivers reported improvements to sleep, exercise and family interactions. Some caregivers (n = 21) qualitatively reported negative effects including unemployment, fear/anxiety and inability to visit family, and positive effects such as unification, family closeness and spending more time with children. CONCLUSIONS: This study highlights the importance of comprehensively exploring positive and negative impacts of COVID-19 and families' subsequent resilience and transformation. Using tools like the CEFIS, those seeking to mitigate negative impacts can contextualize data to better understand study outcomes and tailor services, resources and policy to families' unique needs. CEFIS data likely depend on timing, economic/public health resources and cultural values; future work should prioritize understanding the generalizability of CEFIS findings across samples.

Characterization and Prediction of Short-term Outcomes in Memory After Temporal Lobe Resection in Children With Epilepsy.

BACKGROUND AND OBJECTIVES: The aim of this study was to characterize short-term outcomes in episodic memory, as assessed by the Children's Memory Scale (CMS), after temporal lobe resection in children with epilepsy using empirical methods for assessing cognitive change (i.e., reliable change indices [RCI] and standardized regression-based change scores [SRB]) and develop and internally validate clinically applicable models to predict postoperative memory decline. METHODS: This retrospective cohort study included children aged 6-16 years who underwent resective epilepsy surgery that included the temporal lobe (temporal only: "temporal" and multilobar: "temporal plus") and who completed preoperative and postoperative neuropsychological assessments including the CMS. Change scores on the CMS delayed memory subtests (Faces, Stories, and Word Pairs) were classified as decline, no change, or improvement using epilepsy-specific RCI and SRB. Logistic regression models for predicting postoperative memory decline were developed and internally validated with bootstrapping. RESULTS: Of the 126 children included, most of them demonstrated either no significant change (54%-69%) or improvement (8%-14%) in memory performance using RCI on individual measures at a median of 7 months after surgery. A subset of children (23%-33%) showed postoperative declines. Change distributions obtained using RCI and SRB were not statistically significantly different from each other. Preoperative memory test score, surgery side, surgery extent, and preoperative full-scale IQ were predictors of memory decline. Prediction models for memory decline included subsets of these variables with bias-corrected concordance statistics ranging from 0.70 to 0.75. The models were well calibrated although slightly overestimated the probability of verbal memory decline in high-risk patients. DISCUSSION: This study used empiric methodology to characterize memory outcome in children after temporal lobe resection. Provided online calculator and nomograms may be used by clinicians to estimate the risk of postoperative memory decline for individual patients before surgery.

Leveraging expertise and optimizing clinical research: Initial success of a pediatric epilepsy surgery collaborative.

OBJECTIVE: Improve data-driven research to inform clinical decision-making with pediatric epilepsy surgery patients by expanding the Pediatric Epilepsy Research Consortium Epilepsy Surgery (PERC-Surgery) Workgroup to include neuropsychological data. This article reports on the process and initial success of this effort and characterizes the cognitive functioning of the largest multi-site pediatric epilepsy surgery cohort in the United States. METHODS: Pediatric neuropsychologists from 18 institutions completed surveys regarding neuropsychological practice and the impact of involvement in the collaborative. Neuropsychological data were entered through an online database. Descriptive analyses examined the survey responses and cognitive functioning of the cohort. Statistical analyses examined which patients were evaluated and if composite scores differed by domain, demographics, measures used, or epilepsy characteristics. RESULTS: Positive impact of participation was evident by attendance, survey responses, and the neuropsychological data entry of 534 presurgical epilepsy patients. This cohort, ages 6 months to 21 years, were majority White and non-Hispanic, and more likely to have private insurance. Mean intelligence quotient (IQ) scores were below to low average, with weaknesses in working memory and processing speed. Full-scale IQ (FSIQ) was lowest for patients with younger age at seizure onset, daily seizures, and magnetic resonance imaging (MRI) abnormalities. SIGNIFICANCE: We established a collaborative network and fundamental infrastructure to address questions outlined by the Epilepsy Research Benchmarks. There is a wide range in the age and IQ of patients considered for pediatric epilepsy surgery, yet it appears that social determinants of health impact access to care. Consistent with other national cohorts, this US cohort has a downward shift in IQ associated with seizure severity.

Cingulate-Prefrontal Connectivity During Dynamic Cognitive Control Mediates Association Between p Factor and Adaptive Functioning in a Transdiagnostic Pediatric Sample.

BACKGROUND: Covariation among psychiatric symptoms is being actively pursued for transdiagnostic dimensions of psychopathology with predictive utility. A superordinate dimension, the p factor, reflects overall psychopathology burden and has support from genetic and neuroimaging correlates. However, the neurocognitive correlates that link an elevated p factor to maladaptive outcomes are unknown. We tested the mediating potential of dynamic adjustments in cognitive control rooted in functional connections anchored by the dorsal anterior cingulate cortex (dACC) in a transdiagnostic pediatric sample. METHODS: A multiple mediation model tested the association between the p factor (derived by principal component analysis of Child Behavior Checklist syndrome scales) and outcome measured with the Vineland Adaptive Behavior Scale-II in 89 children ages 8 to 13 years (23 female) with a variety of primary neurodevelopmental diagnoses who underwent functional magnetic resonance imaging during a socioaffective Stroop-like task with eye gaze as distractor. Mediators included functional connectivity of frontoparietal- and salience network-affiliated dACC seeds during conflict adaptation. RESULTS: Higher p factor scores were related to worse adaptive functioning. This effect was partially mediated by conflict adaptation-dependent functional connectivity between the frontoparietal network-affiliated dACC seed and the right dorsolateral prefrontal cortex. Post hoc follow-up indicated that the p factor was related to all Vineland Adaptive Behaviors Scale-II domains; the association was strongest for socialization followed by daily living skills and then communication. Mediation results remained significant for socialization only. CONCLUSIONS: Higher psychopathology burden was associated with worse adaptive functioning in early adolescence. This association was mediated by weaker dACC-dorsolateral prefrontal cortex functional connectivity underlying modulation of cognitive control in response to contextual contingencies. Our results contribute to the identification of transdiagnostic and developmentally relevant neurocognitive endophenotypes of psychopathology.

Impact of development and recent-onset epilepsy on language dominance.

OBJECTIVE: Reorganization of the language network from typically left-lateralized frontotemporal regions to bilaterally distributed or right-lateralized networks occurs in anywhere from 25%-30% of patients with focal epilepsy. In patients who have been recently diagnosed with epilepsy, an important question remains as to whether it is the presence of seizures or the underlying epilepsy etiology that leads to atypical language representations. This question becomes even more interesting in pediatric samples, where the typical developmental processes of the language network may confer more variability and plasticity in the language network. We assessed a carefully selected cohort of children with recent-onset epilepsy to examine whether it is the effects of seizures or their underlying cause that leads to atypical language lateralization. METHODS: We used functional magnetic resonance imaging (fMRI) to compare language laterality in children with recently diagnosed focal unaware epilepsy and age-matched controls. Age at epilepsy onset (age 4 to 6 years vs age 7 to 12 years) was also examined to determine if age at onset influenced laterality. RESULTS: The majority of recent-onset patients and controls exhibited left-lateralized language. There was a significant interaction such that the relationship between epilepsy duration and laterality differed by age at onset. In children with onset after age 6, a longer duration of epilepsy was associated with less left-lateralized language dominance. In contrast, in children with onset between 4 and 6 years of age, a longer duration of epilepsy was not associated with less left language dominance. SIGNIFICANCE: Our results demonstrate that although language remained largely left-lateralized in children recently diagnosed with epilepsy, the impact of seizure duration depended on age at onset, indicating that the timing of developmental and disease factors are important in determining language dominance.

Language and developmental plasticity after perinatal stroke.

The mature human brain is lateralized for language, with the left hemisphere (LH) primarily responsible for sentence processing and the right hemisphere (RH) primarily responsible for processing suprasegmental aspects of language such as vocal emotion. However, it has long been hypothesized that in early life there is plasticity for language, allowing young children to acquire language in other cortical regions when LH areas are damaged. If true, what are the constraints on functional reorganization? Which areas of the brain can acquire language, and what happens to the functions these regions ordinarily perform? We address these questions by examining long-term outcomes in adolescents and young adults who, as infants, had a perinatal arterial ischemic stroke to the LH areas ordinarily subserving sentence processing. We compared them with their healthy age-matched siblings. All participants were tested on a battery of behavioral and functional imaging tasks. While stroke participants were impaired in some nonlinguistic cognitive abilities, their processing of sentences and of vocal emotion was normal and equal to that of their healthy siblings. In almost all, these abilities have both developed in the healthy RH. Our results provide insights into the remarkable ability of the young brain to reorganize language. Reorganization is highly constrained, with sentence processing almost always in the RH frontotemporal regions homotopic to their location in the healthy brain. This activation is somewhat segregated from RH emotion processing, suggesting that the two functions perform best when each has its own neural territory.

Resting-state functional MRI for motor cortex mapping in childhood-onset focal epilepsy.

BACKGROUND AND PURPOSE: Task-based functional MRI (fMRI) mapping of the motor function prior to epilepsy surgery has limitations in children with epilepsy. We present a data-driven method to automatically delineate the motor cortex using task-free, resting-state fMRI (rsfMRI) data. METHODS: We used whole-brain rsfMRI for independent component analysis (ICA). A template matching process with Discriminability Index-based Component Identification score was used for each participant to select and combine motor ICA components in their native brain space, resulting in a whole-brain ICA Motor Map (wIMM). We validated wIMM by comparing individual results with bilateral finger-tapping motor task fMRI activation, and evaluated its reproducibility in controls. RESULTS: Data from 64 patients and 12 controls were used to generate group wIMM maps. The hit rate between wIMM and motor task activation ranged from 60% to 79% across all participants. Sensitivity of wIMM for capturing the task activation peak was 87.5% among 32 patients and 100% in 12 controls with available motor task results. We also showed high similarity in repeated runs in controls. CONCLUSIONS: Our results show the sensitivity and reproducibility of an automated motor mapping method based on ICA analysis of rsfMRI in children with epilepsy. The ICA maps may provide different, but useful, information than task fMRI. Future studies will expand our method to mapping other brain functions, and may lead to a surgical planning tool for patients who cannot perform task fMRI and help predict their postsurgical function.

A Weak Shadow of Early Life Language Processing Persists in the Right Hemisphere of the Mature Brain.

Studies of language organization show a striking change in cerebral dominance for language over development: We begin life with a left hemisphere (LH) bias for language processing, which is weaker than that in adults and which can be overcome if there is a LH injury. Over development this LH bias becomes stronger and can no longer be reversed. Prior work has shown that this change results from a significant reduction in the magnitude of language activation in right hemisphere (RH) regions in adults compared to children. Here we investigate whether the spatial distribution of language activation, albeit weaker in magnitude, still persists in homotopic RH regions of the mature brain. Children aged 4-13 (n = 39) and young adults (n = 14) completed an auditory sentence comprehension fMRI (functional magnetic resonance imaging) task. To equate neural activity across the hemispheres, we applied fixed cutoffs for the number of active voxels that would be included in each hemisphere for each participant. To evaluate homotopicity, we generated left-right flipped versions of each activation map, calculated spatial overlap between the LH and RH activity in frontal and temporal regions, and tested for mean differences in the spatial overlap values between the age groups. We found that, in children as well as in adults, there was indeed a spatially intact shadow of language activity in the right frontal and temporal regions homotopic to the LH language regions. After a LH stroke in adulthood, recovering early-life activation in these regions might assist in enhancing recovery of language abilities.

Leveraging electronic patient diaries in SUDEP risk evaluation.

OBJECTIVE: Our aim was to describe the risk factors known to be related to sudden unexpected death in epilepsy (SUDEP) that can be extracted from patients that utilizes an online seizure diary tool (SeizureTracker™). METHOD: We conducted a descriptive analysis of SeizureTracker™ users across factors relevant to SUDEP risk. We also compared our app-using cohort to published SUDEP case-control studies. RESULTS: We report across seven risk factors from 30,813 users of SeizureTracker™ who had a median length of time using the app of 5.69 years (range from 1 month to 15 years). We found that they are at greater risk for SUDEP than groups from published studies (p < .00001) based on the risk factor of generalized tonic-clonic seizures. SIGNIFICANCE: We demonstrated that the population using the SeizureTracker™ tool can be a valuable population for expanding investigation of SUDEP risk factors and is a first step towards establishing a large sample with a method to ascertain data prospectively that might be critical to developing a SUDEP risk algorithm.

Functional Connectivity as a Potential Mechanism for Language Plasticity.

BACKGROUND AND OBJECTIVES: Task fMRI is a clinical tool for language lateralization, but has limitations, and cannot provide information about network-level plasticity. Additional methods are needed to improve the precision of presurgical language mapping. We investigate language resting-state functional connectivity (RS fMRI; FC) in typically developing children (TD) and children with epilepsy. Our objectives were to (1) understand how FC components differ between TD children and those with epilepsy; (2) elucidate how the location of disease (frontal/temporal epilepsy foci) affects FC; and (3) investigate the relationship between age and FC. METHODS: Our sample included 55 TD children (mean age 12 years, range 7-18) and 31 patients with focal epilepsy (mean age 13 years, range 7-18). All participants underwent RS fMRI. Using a bilateral canonical language map as target, vertex-wise intrahemispheric FC map and interhemispheric FC map for each participant were computed and thresholded at top 10% to compute an FC laterality index (FCLI; [(L - R)/(L + R)]) of the frontal and temporal regions for both integration (intrahemispheric FC; FCLIi) and segregation (interhemispheric FC; FCLIs) maps. RESULTS: We found FC differences in the developing language network based on disease, seizure foci location, and age. Frontal and temporal FCLIi was different between groups (t[84] = 2.82, p < 0.01; t[84] = 4.68, p < 0.01, respectively). Frontal epilepsy foci had the largest differences from TD (Cohen d frontal FCLIi = 0.84, FCLIs = 0.51; temporal FCLIi = 1.29). Development and disease have opposing influences on the laterality of FC based on groups. In the frontal foci group, FCLIi decreased with age (r = -0.42), whereas in the temporal foci group, FCLIi increased with age (r = 0.40). Within the epilepsy group, increases in right frontal integration FCLI relates to increased right frontal task activation in our mostly left language dominant group (r = 0.52, p < 0.01). Language network connectivity is associated with higher verbal intelligence in children with epilepsy (r = 0.45, p < 0.05). DISCUSSION: These findings lend preliminary evidence that FC reflects network plasticity in the form of adaptation and compensation, or the ability to recruit support and reallocate resources within and outside of the traditional network to compensate for disease. FC expands on task-based fMRI and provides complementary and potentially useful information about the language network that is not captured using task-based fMRI alone.

Functional connectivity hemispheric contrast (FC-HC): A new metric for language mapping.

Development of a task-free method for presurgical mapping of language function is important for use in young or cognitively impaired patients. Resting state connectivity fMRI (RS-fMRI) is a task-free method that may be used to identify cognitive networks. We developed a voxelwise RS-fMRI metric, Functional Connectivity Hemispheric Contrast (FC-HC), to map the language network and determine language laterality through comparison of within-hemispheric language network connections (Integration) to cross-hemispheric connections (Segregation). For the first time, we demonstrated robustness and efficacy of a RS-fMRI metric to map language networks across five groups (total N = 243) that differed in MRI scanning parameters, fMRI scanning protocols, age, and development (typical vs pediatric epilepsy). The resting state FC-HC maps for the healthy pediatric and adult groups showed higher values in the left hemisphere, and had high agreement with standard task language fMRI; in contrast, the epilepsy patient group map was bilateral. FC-HC has strong but not perfect agreement with task fMRI and thus, may reflect related and complementary information about language plasticity and compensation.

The neural basis of language development: Changes in lateralization over age.

We have long known that language is lateralized to the left hemisphere (LH) in most neurologically healthy adults. In contrast, findings on lateralization of function during development are more complex. As in adults, anatomical, electrophysiological, and neuroimaging studies in infants and children indicate LH lateralization for language. However, in very young children, lesions to either hemisphere are equally likely to result in language deficits, suggesting that language is distributed symmetrically early in life. We address this apparent contradiction by examining patterns of functional MRI (fMRI) language activation in children (ages 4 through 13) and adults (ages 18 through 29). In contrast to previous studies, we focus not on lateralization per se but rather on patterns of left-hemisphere (LH) and right-hemisphere (RH) activation across individual participants over age. Our analyses show significant activation not only in the LH language network but also in their RH homologs in all of the youngest children (ages 4 through 6). The proportion of participants showing significant RH activation decreases over age, with over 60% of adults lacking any significant RH activation. A whole-brain correlation analysis revealed an age-related decrease in language activation only in the RH homolog of Broca's area. This correlation was independent of task difficulty. We conclude that, while language is left-lateralized throughout life, the RH contribution to language processing is also strong early in life and decreases through childhood. Importantly, this early RH language activation may represent a developmental mechanism for recovery following early LH injury.

Data-driven identification of subtypes of executive function across typical development, attention deficit hyperactivity disorder, and autism spectrum disorders.

BACKGROUND: Impairment of executive function (EF), the goal-directed regulation of thoughts, actions, and emotions, drives negative outcomes and is common across neurodevelopmental disorders including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). A primary challenge to its amelioration is heterogeneity in symptom expression within and across disorders. Parsing this heterogeneity is necessary to attain diagnostic precision, a goal of the NIMH Research Domain Criteria Initiative. We aimed to identify transdiagnostic subtypes of EF that span the normal to impaired spectrum and establish their predictive and neurobiological validity. METHODS: Community detection was applied to clinical parent-report measures in 8-14-year-old children with and without ADHD and ASD from two independent cohorts (discovery N = 320; replication N = 692) to identify subgroups with distinct behavioral profiles. Support vector machine (SVM) classification was used to predict subgroup membership of unseen cases. Preliminary neurobiological validation was obtained with existing functional magnetic resonance imaging (fMRI) data on a subsample (N = 84) by testing hypotheses about sensitivity of EF subgroups versus DSM categories. RESULTS: We observed three transdiagnostic EF subtypes characterized by behavioral profiles that were defined by relative weakness in: (a) flexibility and emotion regulation; (b) inhibition; and (c) working memory, organization, and planning. The same tripartite structure was also present in the typically developing children. SVM trained on the discovery sample and tested on the replication sample classified subgroup membership with 77.0% accuracy. Split-half SVM classification on the combined sample (N = 1,012) yielded 88.9% accuracy (this SVM is available for public use). As hypothesized, frontal-parietal engagement was better distinguished by EF subtype than DSM diagnosis and the subgroup characterized with inflexibility failed to modulate right IPL activation in response to increased executive demands. CONCLUSIONS: The observed transdiagnostic subtypes refine current diagnostic nosology and augment clinical decision-making for personalizing treatment of executive dysfunction in children.

Differential antiseizure medication sensitivity of the Affective Reactivity Index: A randomized controlled trial in new-onset pediatric focal epilepsy.

BACKGROUND: Irritability is a adverse effect of many antiseizure medications (ASMs), but there are no validated measures currently available to characterize this behavioral risk. We examined both child and parent/guardian versions of the Affective Reactivity Index (ARI), a validated measure developed for application in adolescent psychiatry, to determine its sensitivity to ASM-related irritability. We hypothesized irritability increases associated with levetiracetam (LEV) but not lamotrigine (LTG) or oxcarbazepine (OXC). METHOD: The ARI was administered to 71 child and parent/guardian pairs randomized to one of three common ASMs (LEV, LTG, OXC) used to treat new-onset focal (localization-related) epilepsy. Subjects were recruited as part of a prospective multicenter, randomized, open-label, parallel group design. The ARI was administered at baseline prior to treatment initiation and again at 3 months after ASM initiation. RESULTS: There was a significant increase in ARI ratings for both child and parent/guardian ratings for LEV but not LTG or OXC when assessed 3 months after treatment initiation. When examined on the individual subject level using a criterion of at least a 3-point ARI increase, there was an increase associated with LEV for child ratings but not parent/guardian scores. CONCLUSION: Both child and parent/guardian versions of the ARI appear sensitive to medication-induced irritability associated with LEV on both the group and individual levels. The findings extend the applicability of ARI from characterizing the presence of clinical irritability as a psychiatric diagnostic feature to a more modifiable aspect of behavior change related to medication management and support its use in clinical trial applications.

Cortical thickness in childhood left focal epilepsy: Thinning beyond the seizure focus.

OBJECTIVE: Structural brain differences are found in adults and children with epilepsy, yet pediatric samples have been heterogeneous regarding seizure type, magnetic resonance imaging (MRI) findings, and hemisphere of seizure focus. This study examines whether cortical thickness and surface area differ between children with left-hemisphere focal epilepsy (LHE) and age-matched typically developing (TD) peers. We examined whether age differentially moderated cortical thickness between groups and if cortical thickness was associated with duration of epilepsy, seizure frequency, or neuropsychological functioning. METHODS: Thirty-five children with LHE and 35 TD children completed neuropsychological testing and 3T MR imaging. Neuropsychological measures included general intelligence and executive functioning. All MRIs were normal. Surface-based morphometric processing and analyses were conducted using FreeSurfer 6.0. Regression analyses compared age by cortical thickness differences between groups. Correlational analyses examined associations between cortical thickness in these areas with neuropsychological functioning or epilepsy characteristics. RESULTS: Left-hemisphere focal epilepsy displayed decreased cortical thickness bilaterally compared to TD controls across 6 brain regions but no differences in surface area. Moderation analyses revealed quadratic relationships between age and cortical thickness for left frontoparietal-cingulate and right superior frontal regions. Higher performance intelligence quotient (IQ) (PIQ) and verbal IQ (VIQ) and fewer parent reported executive function problems were associated with greater cortical thickness in TD children. SIGNIFICANCE: Children with LHE displayed thinner cortex extending beyond the hemisphere of seizure focus. The nonlinear pattern of cortical thickness across age occurring in TD children is not evident in the same manner in children with LHE. These differences in cortical thickness patterns were greatest in children 8-12 years old. Greater cortical thickness was associated with higher IQ and fewer executive control problems in daily activities in TD children. Thus, differences in cortical thickness in the absence of differences in surface area, suggest cortical thickness may be a sensitive proxy of subtle neuroanatomical changes that are related to neuropsychological functioning.