April R. Levin

Early treatment suppresses the development of spike-wave epilepsy in a rat model

Purpose: Current treatments for epilepsy may control seizures, but have no known effects on the underlying disease. We sought to determine whether early treatment in a model of genetic epilepsy would reduce the severity of the epilepsy phenotype in adulthood.

Clinical use of ictal SPECT in secondarily generalized tonic–clonic seizures

Partial seizures produce increased cerebral blood flow in the region of seizure onset. These regional cerebral blood flow increases can be detected by single photon emission computed tomography (ictal SPECT), providing a useful clinical tool for seizure localization. However, when partial seizures secondarily generalize, there are often questions of interpretation since propagation of seizures could produce ambiguous results. Ictal SPECT from secondarily generalized seizures has not been thoroughly investigated. We analysed ictal SPECT from 59 secondarily generalized tonic-clonic seizures obtained during epilepsy surgery evaluation in 53 patients. Ictal versus baseline interictal SPECT difference analysis was performed using ISAS (http://spect.yale.edu). SPECT injection times were classified based on video/EEG review as either pre-generalization, during generalization or in the immediate post-ictal period. We found that in the pre-generalization and generalization phases, ictal SPECT showed significantly more regions of cerebral blood flow increases than in partial seizures without secondary generalization. This made identification of a single unambiguous region of seizure onset impossible 50% of the time with ictal SPECT in secondarily generalized seizures. However, cerebral blood flow increases on ictal SPECT correctly identified the hemisphere (left versus right) of seizure onset in 84% of cases. In addition, when a single unambiguous region of cerebral blood flow increase was seen on ictal SPECT, this was the correct localization 80% of the time. In agreement with findings from partial seizures without secondary generalization, cerebral blood flow increases in the post-ictal period and cerebral blood flow decreases during or following seizures were not useful for localizing seizure onset. Interestingly, however, cerebral blood flow hypoperfusion during the generalization phase (but not pre-generalization) was greater on the side opposite to seizure onset in 90% of patients. These findings suggest that, with appropriate cautious interpretation, ictal SPECT in secondarily generalized seizures can help localize the region of seizure onset.

Social Communication Difficulties and Autism in Previously Institutionalized Children

OBJECTIVE To determine the risk of difficulties with social communication and restricted/repetitive behaviors as well as the rate of autism in children institutionalized in early infancy and to assess the impact of a foster care intervention on ameliorating this risk. METHOD Children abandoned at birth and raised in institutions in Bucharest, Romania were randomly assigned to a care-as-usual group (institutional care, CAUG), or placed in family-centered foster care (FCG) as part of the Bucharest Early Intervention Project (BEIP). At approximately 10 years of age, the Social Communication Questionnaire (SCQ) was administered to caregivers of children in both groups as well as to parents of a typically developing community sample (Never-Institutionalized group [NIG]) residing in Bucharest, Romania. Children scoring ≥12 on the SCQ underwent clinical evaluation for autism spectrum disorder (ASD). RESULTS Caregivers of children with a history of institutionalization reported that these children had significantly more deviant behavior than never-institutionalized children on all subdomains of the SCQ (all p < 0.001). Children in the FCG had significantly lower scores on the SCQ than children in the CAUG (p < .001), particularly in the reciprocal social interaction domain, indicating that the intervention reduced problems in social communication. Three of 60 CAUG children, 2 of 57 FCG children, and none of the NIG children received a formal ASD diagnosis. CONCLUSION Early institutional rearing was associated with an increased risk of social communication difficulties and ASD. A family-centered foster care intervention improved social communication skills.

Motor Outcomes in Children Exposed to Early Psychosocial Deprivation

OBJECTIVES To determine the effect of psychosocial deprivation early in life on motor development, assess the impact of a foster care intervention on improving motor development, and assess the association between motor and cognitive outcomes in children with a history of institutional care. STUDY DESIGN In a randomized controlled trial, children living in Romanian institutions were randomly assigned to care as usual in the institution or placed in family-centered foster care as part of the Bucharest Early Intervention Project. The average age at placement into foster care was 23 months. At age 8 years, the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Short Form (BOT2-SF) was applied to assess the motor proficiency of children in both groups, as well as a never-institutionalized group from the Romanian community. RESULTS Children in the never-institutionalized group did significantly better on the BOT2-SF than children who had ever been institutionalized (P < .001). There was no significant difference in performance between children in the care as usual group and the foster care group. This finding also held true for all individual items on the BOT2-SF except sit-ups. Regression analyses revealed that the between-group and within-group differences in BOT2-SF scores were largely mediated by IQ. CONCLUSION Early deprivation had a negative effect on motor development that was not resolved by placement in foster care. This effect was predominantly mediated by IQ. This study highlights the importance of monitoring for and addressing motor delays in children with a history of institutionalization, particularly those children with low IQ.

Inhibition-Based Biomarkers for Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a behaviorally defined and heterogeneous disorder. Biomarkers for ASD offer the opportunity to improve prediction, diagnosis, stratification by severity and subtype, monitoring over time and in response to interventions, and overall understanding of the underlying biology of this disorder. A variety of potential biomarkers, from the level of genes and proteins to network-level interactions, is currently being examined. Many of these biomarkers relate to inhibition, which is of particular interest because in many cases ASD is thought to be a disorder of imbalance between excitation and inhibition. Abnormalities in inhibition at the cellular level lead to emergent properties in networks of neurons. These properties take into account a more complete genetic and cellular background than findings at the level of individual genes or cells, and are able to be measured in live humans, offering additional potential as diagnostic biomarkers and predictors of behaviors. In this review we provide examples of how altered inhibition may inform the search for ASD biomarkers at multiple levels, from genes to cells to networks.

The Harvard Automated Processing Pipeline for Electroencephalography (HAPPE): Standardized Processing Software for Developmental and High-Artifact Data

Electroenchephalography (EEG) recordings collected with developmental populations present particular challenges from a data processing perspective. These EEGs have a high degree of artifact contamination and often short recording lengths. As both sample sizes and EEG channel densities increase, traditional processing approaches like manual data rejection are becoming unsustainable. Moreover, such subjective approaches preclude standardized metrics of data quality, despite the heightened importance of such measures for EEGs with high rates of initial artifact contamination. There is presently a paucity of automated resources for processing these EEG data and no consistent reporting of data quality measures. To address these challenges, we propose the Harvard Automated Processing Pipeline for EEG (HAPPE) as a standardized, automated pipeline compatible with EEG recordings of variable lengths and artifact contamination levels, including high-artifact and short EEG recordings from young children or those with neurodevelopmental disorders. HAPPE processes event-related and resting-state EEG data from raw files through a series of filtering, artifact rejection, and re-referencing steps to processed EEG suitable for time-frequency-domain analyses. HAPPE also includes a post-processing report of data quality metrics to facilitate the evaluation and reporting of data quality in a standardized manner. Here, we describe each processing step in HAPPE, perform an example analysis with EEG files we have made freely available, and show that HAPPE outperforms seven alternative, widely-used processing approaches. HAPPE removes more artifact than all alternative approaches while simultaneously preserving greater or equivalent amounts of EEG signal in almost all instances. We also provide distributions of HAPPEs data quality metrics in an 867 file dataset as a reference distribution and in support of HAPPEs performance across EEG data with variable artifact contamination and recording lengths. HAPPE software is freely available under the terms of the GNU General Public License at https://github.com/lcnhappe/happe.

Reduced frontal gamma power at 24 months is associated with better expressive language in toddlers at risk for autism

Gamma oscillations have been associated with early language development in typically developing toddlers, and gamma band abnormalities have been observed in individuals with ASD, as well high-risk infant siblings (those having an older sibling with autism), as early as 6-months of age. The current study investigated differences in baseline frontal gamma power and its association with language development in toddlers at high versus low familial risk for autism. EEG recordings as well as cognitive and behavioral assessments were acquired at 24-months as part of prospective, longitudinal study of infant siblings of children with and without autism. Diagnosis of autism was determined at 24–36 months, and data was analyzed across three outcome groups - low risk without ASD (n=43), high-risk without ASD (n=42), and high-risk with ASD (n=16). High-risk toddlers without ASD had reduced baseline frontal gamma power (30–50Hz) compared to low-risk toddlers. Among high-risk toddlers increased frontal gamma was only marginally associated with ASD diagnosis (p=0.06), but significantly associated with reduced expressive language ability (p=0.007). No association between gamma power and language was present in the low-risk group. These findings suggest that differences in gamma oscillations in high-risk toddlers may represent compensatory mechanisms associated with improved developmental outcomes.

BEAPP: The Batch Electroencephalography Automated Processing Platform

Electroencephalography (EEG) offers information about brain function relevant to a variety of neurologic and neuropsychiatric disorders. EEG contains complex, high-temporal-resolution information, and computational assessment maximizes our potential to glean insight from this information. Here we present the Batch EEG Automated Processing Platform (BEAPP), an automated, flexible EEG processing platform incorporating freely available software tools for batch processing of multiple EEG files across multiple processing steps. BEAPP does not prescribe a specified EEG processing pipeline; instead, it allows users to choose from a menu of options for EEG processing, including steps to manage EEG files collected across multiple acquisition setups (e.g., for multisite studies), minimize artifact, segment continuous and/or event-related EEG, and perform basic analyses. Overall, BEAPP aims to streamline batch EEG processing, improve accessibility to computational EEG assessment, and increase reproducibility of results.

Autism associated with early institutionalization, high intelligence, and naturalistic behavior therapy in a 7-year-old boy.

CASE Paul is a 7-year-old boy with a history of cerebral palsy and left-side weakness secondary to perinatal injury. He was adopted to the United States at 19 months from a baby home in Eastern Europe, where the caregiver to child ratio was 7:1. Paul spent most of his early developmental period in a crib. On adoption, he was nonverbal and nonambulatory, but these skills developed within 1 year. Paul was noted at 4 years of age to be struggling socially and also to exhibit restricted interests (e.g., memorizing maps and world leaders). He was referred for neuropsychological testing at age 5 and was found to have cognitive skills in the gifted range (verbal intelligence quotient, IQ =143; 99.8%) but exhibited markedly reduced social reciprocity with high levels of restricted interests and repetitive behaviors, leading to a diagnosis of autism spectrum disorder (ASD) in the context of early institutionalization. Given his cooperative and attentive presentation, high IQ, and ability to imitate, Floortime, a more naturalistic behavioral therapy for ASD, was recommended rather than traditional applied behavior analysis, which is more commonly available in the region. In addition, Paul was provided with group speech and language therapy with a social/pragmatic focus. After 1 year, Pauls socialization improved but he struggled to initiate interactions and maintain friendships. He focused instead on his restricted interests and played alone. After 2 years of intervention, Paul presents as highly sociable with well-sustained eye gaze, interactive play, and successful friendships. Still, without direction and structure, Paul will happily draw maps for hours at a time. He is hyperlexic and working far above grade level across subjects. His mother now questions--is this still truly institutional autism or is he simply too intelligent to relate to same-age peers?