Measurement of Developmental and Behavioral Concerns in Toddlers With Tuberous Sclerosis Complex.

BACKGROUND: The TAND (Tuberous Sclerosis Complex [TSC]-Associated Neuropsychiatric Disorders) Checklist was developed as a clinical screener for neurodevelopmental disorders in TSC. Most studies have described patterns in older children and adults. This study sought to better understand behavioral concerns as measured by the TAND Checklist in young children with TSC. METHODS: We examined patterns of caregiver responses to the TAND Checklist in 90 toddlers with TSC (12 to 23 months n = 60; 24 to 36 months n = 30) through data collected during baseline visits across two TSC early intervention studies. RESULTS: Over 90% of caregivers reported at least one behavioral concern related to TAND. The number of concerns increased with age. Delayed language was the most frequently reported concern across ages (12 to 23 months: 58.3%, 24 to 36 months: 86.7%). Questions related to behavioral concerns were largely relevant in this age range, but questions in other areas, such as neuropsychological or academic function, were not. CONCLUSIONS: TAND symptoms are very common in toddlers with TSC, and these symptoms may increase with age. The TAND Checklist is a useful tool for identifying behavioral concerns efficiently, but several items and sections are not suited to younger children. Results support the development of an abbreviated form of the TAND Checklist for toddlers.

Concomitant medication use in children with autism spectrum disorder: Data from the Autism Biomarkers Consortium for Clinical Trials.

LAY ABSTRACT: Children with autism spectrum disorder are prescribed a variety of medications that affect the central nervous system (psychotropic medications) to address behavior and mood. In clinical trials, individuals taking concomitant psychotropic medications often are excluded to maintain homogeneity of the sample and prevent contamination of biomarkers or clinical endpoints. However, this choice may significantly diminish the clinical representativeness of the sample. In a recent multisite study designed to identify biomarkers and behavioral endpoints for clinical trials (the Autism Biomarkers Consortium for Clinical Trials), school-age children with autism spectrum disorder were enrolled without excluding for medications, thus providing a unique opportunity to examine characteristics of psychotropic medication use in a research cohort and to guide future decisions on medication-related inclusion criteria. The aims of the current analysis were (1) to quantify the frequency and type of psychotropic medications reported in school-age children enrolled in the ABC-CT and (2) to examine behavioral features of children with autism spectrum disorder based on medication classes. Of the 280 children with autism spectrum disorder in the cohort, 42.5% were taking psychotropic medications, with polypharmacy in half of these children. The most commonly reported psychotropic medications included melatonin, stimulants, selective serotonin reuptake inhibitors, alpha agonists, and antipsychotics. Descriptive analysis showed that children taking antipsychotics displayed a trend toward greater overall impairment. Our findings suggest that exclusion of children taking concomitant psychotropic medications in trials could limit the clinical representativeness of the study population, perhaps even excluding children who may most benefit from new treatment options.

A telehealth approach to improving clinical trial access for infants with tuberous sclerosis complex.

BACKGROUND: Research in rare genetic syndromes associated with ASD is often hampered by the wide geographic distribution of families and the presence of medical comorbidities, such as epilepsy, that may preclude travel to clinical sites. These challenges can limit the sample size and generalizability of the cohorts included in both natural history studies and clinical trials. Tuberous sclerosis complex (TSC) is a rare genetic syndrome that confers an elevated risk for autism spectrum disorder (ASD), with social communication delays identified in this population as early as 12 months of age. Early identification of risk necessitates parallel testing of early intervention, prompting the first randomized controlled clinical trial of behavioral intervention for infants with TSC (NCT03422367). However, considerable early recruitment challenges have mandated the systematic identification of enrollment barriers followed by modification of the study design to address these barriers. METHODS: Caregivers were interviewed regarding barriers to enrollment (phase 1). Adaptations to the intervention were made to address these barriers (phase 2). Outcomes based on this modification to the study design were defined by enrollment rate and participant demographics. RESULTS: Qualitative reports from caregivers indicated that distance and time were the primary barriers to clinical trial enrollment. The intervention was then modified to a remote model, with at-home, parent-delivered intervention, and weekly video conferencing with interventionists at the study sites. Enrollment increased 10-fold (from 3 to 30 participants) within 1 year and included a more diverse and clinically representative cohort of infants. CONCLUSION: The design and implementation of more scalable methods to disseminate research remotely can substantially improve access to clinical trials in rare neurodevelopmental disorders. The lessons learned from this trial can serve as a model for future studies not only in rare conditions, but in other populations that lack adequate access, such as families with limited financial or clinical resources. Continued efforts will further refine delivery methods to enhance efficiency and ease of these delivery systems for families.

Early patterns of functional brain development associated with autism spectrum disorder in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a rare genetic disorder that confers a high risk for autism spectrum disorders (ASD), with behavioral predictors of ASD emerging early in life. Deviations in structural and functional neural connectivity are highly implicated in both TSC and ASD. For the first time, we explore whether electroencephalographic (EEG) measures of neural network function precede or predict the emergence of ASD in TSC. We determine whether altered brain function (a) is present in infancy in TSC, (b) differentiates infants with TSC based on ASD diagnostic status, and (c) is associated with later cognitive function. We studied 35 infants with TSC (N = 35), and a group of typically developing infants (N = 20) at 12 and 24 months of age. Infants with TSC were later subdivided into ASD and non-ASD groups based on clinical evaluation. We measured features of spontaneous alpha oscillations (6-12 Hz) that are closely associated with neural network development: alpha power, alpha phase coherence (APC), and peak alpha frequency (PAF). Infants with TSC demonstrated reduced interhemispheric APC compared to controls at 12 months of age, and these differences were found to be most pronounced at 24 months in the infants who later developed ASD. Across all infants, PAF at 24 months was associated with verbal and nonverbal cognition at 36 months. Associations between early network function and later neurodevelopmental and cognitive outcomes highlight the potential utility of early scalable EEG markers to identify infants with TSC requiring additional targeted intervention initiated very early in life. Autism Res 2019, 12: 1758-1773. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Approximately half of infants with tuberous sclerosis complex (TSC) develop autism. Here, using EEG, we find that there is a reduction in communication between brain regions during infancy in TSC, and that the infants who show the largest reductions are those who later develop autism. Being able to identify infants who show early signs of disrupted brain development may improve the timing of early prediction and interventions in TSC, and also help us to understand how early brain changes lead to autism.

Early autism symptoms in infants with tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic syndrome that confers significantly increased risk for autism spectrum disorder (ASD), with 50-60% of infants with TSC meeting criteria for ASD by 3 years of age. In a previous study of the current longitudinal cohort, we found that infants with TSC who develop ASD (TSC/ASD) evidence decreased cognitive abilities that diverge from infants with TSC and no ASD (TSC/no ASD). We extended this work by asking whether TSC/ASD infants (n = 13) differed from TSC/no ASD infants (n = 10) and infants with low developmental risk and no ASD (LR; n = 21) in their social communication functioning during the first year of life. We measured early ASD symptoms with the Autism Observation Scale for Infants (AOSI) at 9 and 12 months of age. At both ages, infants in the TSC/ASD group had significantly higher AOSI total scores than infants in the TSC/no ASD and LR groups, which were not fully explained by differences in cognitive abilities. Several items on the AOSI at both ages were predictive of ASD outcome, particularly those representing core social communication deficits (e.g., social referencing). Our findings signal the need for further study of this population within the first year and provide strong justification for early identification and early intervention targeting social communication skills in infants with TSC. Autism Res 2017, 10: 1981-1990. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We examined early signs of autism spectrum disorder (ASD) in infants with tuberous sclerosis complex (TSC), approximately 50% of whom will meet criteria for ASD by age 3. Infants with TSC and ASD showed deficits in social communication behaviors by 9 months of age that were clearly distinguishable from behaviors in infants with TSC who do not develop ASD and low risk infants. Results support the importance of early ASD screening and intervention for infants with TSC.

Symptom profiles of autism spectrum disorder in tuberous sclerosis complex.

OBJECTIVE: To determine the extent to which deficits associated with autism spectrum disorder (ASD) in toddlers with tuberous sclerosis complex (TSC) overlap with those in toddlers with nonsyndromic ASD (nsASD) and to examine cognitive function and epilepsy severity in toddlers with TSC and comorbid ASD. This is the endpoint analysis from a longitudinal investigation of ASD risk factors in children with TSC. METHODS: Measures included the Autism Diagnostic Observation Schedule (ADOS), the Mullen Scales of Early Learning, and clinical epilepsy variables. A repeated-measures analysis of variance was performed with between-subjects factor of group (typically developing, TSC/no ASD, TSC/ASD, nsASD) and within-subjects factors of individual ADOS item scores in the social communication and repetitive behavior/restricted interest domains. Within the TSC group, comparisons of epilepsy characteristics and cognitive domains were performed using independent-samples t tests. RESULTS: Children with TSC/ASD demonstrated a profile of social communication impairment that had complete convergence with nsASD. Measured social communication impairments included gestures, pointing, eye contact, responsive social smile, and shared enjoyment. This convergence was observed despite the high comorbidity between ASD and cognitive impairment in TSC. CONCLUSIONS: This study supports the clinical diagnosis of ASD in young children with TSC and demonstrates remarkable convergence of autism symptoms between TSC/ASD and nsASD. Our results strongly suggest the need for early intervention in toddlers with TSC, with treatment strategies targeting social communication function as well as broader developmental domains, before the onset of autism symptoms.

Resting and task-modulated high-frequency brain rhythms measured by scalp encephalography in infants with tuberous sclerosis complex.

The electrophysiological correlates of cognitive deficits in tuberous sclerosis complex (TSC) are not well understood, and modulations of neural dynamics by neuroanatomical abnormalities that characterize the disorder remain elusive. Neural oscillations (rhythms) are a fundamental aspect of brain function, and have dominant frequencies in a wide frequency range. The spatio-temporal dynamics of these frequencies in TSC are currently unknown. Using a novel signal decomposition approach this study investigated dominant cortical frequencies in 10 infants with TSC, in the age range 18-30 months, and 12 age-matched healthy controls. Distinct spectral characteristics were estimated in the two groups. High-frequency [in the high-gamma (>50 Hz) and ripple (>80 Hz) ranges], non-random EEG components were identified in both TSC and healthy infants at 18 months. Additional components in the lower gamma (30-50 Hz) ranges were also identified, with higher characteristic frequencies in TSC than in controls. Lower frequencies were statistically identical in both sub-groups. A significant shift in the high-frequency spectral content of the EEG was observed as a function of age, independently of task performance, possibly reflecting an overall maturation of developing neural circuits. This shift occurred earlier in healthy infants than in TSC, i.e., by age 20 months the highest dominant frequencies were in the high gamma range, whereas in TSC dominant frequencies above 100 Hz were still measurable. At age 28-30 months a statistically significant decrease in dominant high frequencies was observed in both TSC and healthy infants, possibly reflecting increased myelination and neuronal connection strengthening with age. Although based on small samples, and thus preliminary, the findings in this study suggest that dominant cortical rhythms, a fundamental aspect of neurodynamics, may be affected in TSC, possibly leading to impaired information processing in the brain.

Brain functional networks in syndromic and non-syndromic autism: a graph theoretical study of EEG connectivity.

BACKGROUND: Graph theory has been recently introduced to characterize complex brain networks, making it highly suitable to investigate altered connectivity in neurologic disorders. A current model proposes autism spectrum disorder (ASD) as a developmental disconnection syndrome, supported by converging evidence in both non-syndromic and syndromic ASD. However, the effects of abnormal connectivity on network properties have not been well studied, particularly in syndromic ASD. To close this gap, brain functional networks of electroencephalographic (EEG) connectivity were studied through graph measures in patients with Tuberous Sclerosis Complex (TSC), a disorder with a high prevalence of ASD, as well as in patients with non-syndromic ASD. METHODS: EEG data were collected from TSC patients with ASD (n = 14) and without ASD (n = 29), from patients with non-syndromic ASD (n = 16), and from controls (n = 46). First, EEG connectivity was characterized by the mean coherence, the ratio of inter- over intra-hemispheric coherence and the ratio of long- over short-range coherence. Next, graph measures of the functional networks were computed and a resilience analysis was conducted. To distinguish effects related to ASD from those related to TSC, a two-way analysis of covariance (ANCOVA) was applied, using age as a covariate. RESULTS: Analysis of network properties revealed differences specific to TSC and ASD, and these differences were very consistent across subgroups. In TSC, both with and without a concurrent diagnosis of ASD, mean coherence, global efficiency, and clustering coefficient were decreased and the average path length was increased. These findings indicate an altered network topology. In ASD, both with and without a concurrent diagnosis of TSC, decreased long- over short-range coherence and markedly increased network resilience were found. CONCLUSIONS: The altered network topology in TSC represents a functional correlate of structural abnormalities and may play a role in the pathogenesis of neurological deficits. The increased resilience in ASD may reflect an excessively degenerate network with local overconnection and decreased functional specialization. This joint study of TSC and ASD networks provides a unique window to common neurobiological mechanisms in autism.

Impaired language pathways in tuberous sclerosis complex patients with autism spectrum disorders.

The purpose of this study was to examine the relationship between language pathways and autism spectrum disorders (ASDs) in patients with tuberous sclerosis complex (TSC). An advanced diffusion-weighted magnetic resonance imaging (MRI) was performed on 42 patients with TSC and 42 age-matched controls. Using a validated automatic method, white matter language pathways were identified and microstructural characteristics were extracted, including fractional anisotropy (FA) and mean diffusivity (MD). Among 42 patients with TSC, 12 had ASD (29%). After controlling for age, TSC patients without ASD had a lower FA than controls in the arcuate fasciculus (AF); TSC patients with ASD had even a smaller FA, lower than the FA for those without ASD. Similarly, TSC patients without ASD had a greater MD than controls in the AF; TSC patients with ASD had even a higher MD, greater than the MD in those without ASD. It remains unclear why some patients with TSC develop ASD, while others have better language and socio-behavioral outcomes. Our results suggest that language pathway microstructure may serve as a marker of the risk of ASD in TSC patients. Impaired microstructure in language pathways of TSC patients may indicate the development of ASD, although prospective studies of language pathway development and ASD diagnosis in TSC remain essential.

Loss of white matter microstructural integrity is associated with adverse neurological outcome in tuberous sclerosis complex.

RATIONALE AND OBJECTIVES: Tuberous sclerosis complex (TSC) is a genetic neurocutaneous syndrome in which cognitive and social-behavioral outcomes for patients vary widely in an unpredictable manner. The cause of adverse neurologic outcome remains unclear. The aim of this study was to investigate the hypothesis that disordered white matter and abnormal neural connectivity are associated with adverse neurologic outcomes. MATERIALS AND METHODS: Structural and diffusion magnetic resonance imaging was carried out in 40 subjects with TSC (age range, 0.5-25 years; mean age, 7.2 years; median age, 5 years), 12 of whom had autism spectrum disorders (ASD), and in 29 age-matched controls. Tractography of the corpus callosum was used to define a three-dimensional volume of interest. Regional averages of four diffusion scalar parameters of the callosal projections were calculated for each subject. These were the average fractional anisotropy (AFA) and the average mean, radial, and axial diffusivity. RESULTS: Subjects with TSC had significantly lower AFA and higher average mean, radial, and axial diffusivity values compared to controls. Subjects with TSC and ASD had significantly lower AFA values compared to those without ASD and compared to controls. Subjects with TSC without ASD had similar AFA values compared to controls. CONCLUSION: Diffusion tensor scalar parameters provided measures of properties of the three-dimensional callosal projections. In TSC, changes in these parameters may reflect microstructural changes in myelination, axonal integrity, or extracellular environment. Alterations in white matter microstructural properties were associated with TSC, and larger changes were associated with TSC and ASD, thus establishing a relationship between altered white matter microstructural integrity and brain function.

Diffusion features of white matter in tuberous sclerosis with tractography.

Normal-appearing white matter has been shown via diffusion tensor imaging to be affected in tuberous sclerosis complex. Under the hypothesis that some systems might be differentially affected, including the visual pathways and systems of social cognition, diffusion properties of various regions of white matter were compared. For 10 patients and 6 age-matched control subjects, 3 T magnetic resonance imaging was assessed using diffusion tensor imaging obtained in 35 directions. Three-dimensional volumes corresponding to the geniculocalcarine tracts were extracted via tractography, and two-dimensional regions of interest were used to sample other regions. Regression analysis indicated lower fractional anisotropy in the splenium of corpus callosum and geniculocalcarine tracts in tuberous sclerosis complex group, as well as lower axial diffusivity in the internal capsule, superior temporal gyrus, and geniculocalcarine tracts. Mean and radial diffusivity of the splenium of corpus callosum were higher in the tuberous sclerosis complex group. The differences in diffusion properties of white matter between tuberous sclerosis complex patients and control subjects suggest disorganized and structurally compromised axons with poor myelination. The visual and social cognition systems appear to be differentially involved, which might in part explain the behavioral and cognitive characteristics of the tuberous sclerosis complex population.

Characterization of autism in young children with tuberous sclerosis complex.

Both cognitive impairment and autism are common in the tuberous sclerosis complex, but the relationship between the 2 diagnoses has not been formally explored. The authors evaluated 20 clinic-referred children with tuberous sclerosis complex at ages 18, 24, 36, and 60 months and classified them as autism, autism spectrum disorder, or normal on the basis of the Autism Diagnostic Observation Schedule. Using the Mullen Scale of Early Learning, cognitive function in each subgroup was assessed. The authors then analyzed the subscores of the Autism Diagnostic Observation Schedule in children with autism. Children with autism showed significantly more global cognitive impairment than those without autism. In addition, all children had some baseline cognitive impairment and the majority had deficits in play scores. The authors conclude that clinic-referred children with tuberous sclerosis complex and autism are at considerable risk for cognitive impairment. These characteristics may help to guide more tailored services for these high-risk children.