Attentional shifting and disengagement in Rett syndrome.

OBJECTIVE: The purpose of the present study was to deepen our understanding of attention (a core cognitive ability) in Rett syndrome (RTT), an x-linked neurodevelopmental disorder caused by mutations in the MECP2 gene. We focused on 2 key aspects of visual orienting-shifting and disengaging attention-both of which are critical for exploring the visual world. We used gaze-based measures and eye-tracking technology to minimize demands on the limited verbal and motor abilities associated with RTT. METHOD: Shifting and disengaging attention were examined in 31 children (2-12 years) with Rett Syndrome (RTT) and 31 age-matched typically developing (TD) controls. Using the gap-overlap paradigm, the frequency and speed of shifting attention from a central to peripheral target were compared on Baseline trials, where the central stimulus disappears as the peripheral target appears, and Overlap trials, where the central stimulus remains, thus requiring disengagement. RESULTS: Our findings revealed that children with RTT had more "sticky fixations" (p < .001). That is, they had fewer saccades to the peripheral target than TD children, and this was true on both baseline (77% vs. 95%), and overlap trials (63% vs. 90%). The younger children in the RTT group also had slower saccadic RTs (SRTs) than their TD counterparts (p = .04). Within the RTT group, SRTs correlated with symptom severity. Surprisingly, disengagement cost (the relative difference between gap and overlap SRTs) did not differ across groups. CONCLUSION: Our results suggest that children with Rett have difficulty shifting attention and, to a lesser extent, disengaging attention, whereas with other disorders, problems with disengagement are paramount. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Development of a Brief Parent-Report Screen for Common Gastrointestinal Disorders in Autism Spectrum Disorder.

Gastrointestinal dysfunction in children with autism spectrum disorder (ASD) is common and associated with problem behaviors. This study describes the development of a brief, parent-report screen that relies minimally upon the child's ability to report or localize pain for identifying children with ASD at risk for one of three common gastrointestinal disorders (functional constipation, functional diarrhea, and gastroesophageal reflux disease). In a clinical sample of children with ASD, this 17-item screen identified children having one or more of these disorders with a sensitivity of 84%, specificity of 43%, and a positive predictive value of 67%. If found to be valid in an independent sample of children with ASD, the screen will be useful in both clinical practice and research.

Impaired Visual Search in Children with Rett Syndrome.

AIM: This study aims to investigate selective attention in Rett syndrome, a severely disabling neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene. METHOD: The sample included 28 females with Rett syndrome (RTT) and 32 age-matched typically developing controls. We used a classic search task, in conjunction with eye-tracking technology. Each trial included the target and several distractors. The distractors varied in number and differed from targets in either a "single feature" (color or shape), creating a pop-out effect, or in a "conjunction of features" (color and shape), requiring serial search. Children searched for the target in arrays containing five or nine objects; trials ended when the target was fixated (or 4000 ms elapsed). RESULTS: Children with Rett syndrome had more difficulty finding the target than typically developing children in both conditions (success rates less than 50% versus 80%) and their success rates were little influenced by display size or age. Even when successful, children with RTT took significantly longer to respond (392 to 574 ms longer), although saccadic latency differences were observed only in the single-feature condition. Both groups showed the expected slowing of saccadic reaction times for larger arrays in the conjunction-feature condition. Search failures in RTT were not related to symptom severity. CONCLUSIONS: Our findings provide the first evidence that selective attention, the ability to focus on or select a particular element or object in the environment, is compromised by Rett syndrome. They reinforce the notion that gaze-based tasks hold promise for quantifying the cognitive phenotype of RTT.

ADHD Symptoms in a Non-Referred Low Birthweight/Preterm Cohort: Longitudinal Profiles, Outcomes, and Associated Features.

OBJECTIVE: This study's objective is to differentiate possible ADHD syndromes on the basis of symptom trajectories, prognosis, and associated clinical features in a high-risk cohort. METHOD: Latent class analysis of inattentive (IA) and hyperactive-impulsive (HI) symptoms in 387 non-disabled members of a regional low birthweight/preterm birth cohort who were evaluated for ADHD at 6, 9, and 16 years. Adolescent functional outcomes and other clinical features were examined across the classes. RESULTS: Three latent classes were identified: unaffected (modest IA and HI symptom prevalences at six, remitting by nine), school age limited (relatively high IA and HI symptom prevalences at six and nine, declining by 16), and persistent inattentive (high IA and HI prevalences at six and nine, with high IA levels persisting to 16). The persistent inattentive class was distinctively associated with poor functioning, motor problems, other psychiatric disorders, and social difficulties as indexed by a positive screen for autism spectrum disorder at 16. CONCLUSION: These findings differentiate a potential persistent inattentive syndrome relevant to ADHD evaluation and treatment.

Sustained attention in the face of distractors: A study of children with Rett syndrome.

OBJECTIVE: The object of the present study is to advance our understanding of the cognitive profile of Rett syndrome (RTT), an X-linked neurodevelopmental disorder caused by mutations in the MECP2 gene. We focus on sustained attention, which plays a critical role in driving cognitive growth, and use an innovative, gaze-based task that minimizes demands on the limited verbal and motor abilities associated with RTT. METHOD: The task required the ability to sustain attention on a visual target (a butterfly) while inhibiting a prepotent response to look to moving distractors (trees and clouds) presented in the peripheral visual field. The sample included children with RTT (N = 32) and their typically developing (TD) counterparts (N = 32), aged 2-12 years. RESULTS: Our findings revealed that children with RTT had more difficulty sustaining attention (with the TD group averaging 60% looking at the butterfly vs. only 25% for the RTT group). Furthermore, RTT was associated with difficulties in 3 fundamental factors influencing sustained attention: engagement, distractibility, and reengagement. The RTT group was slower to engage, more distractible, and slower to reengage. CONCLUSION: Our findings identify a fundamental disruption to sustained attention in RTT, determine factors related to this impairment, and pinpoint cognitive areas that could serve as markers for evaluating the effectiveness of pharmacological and behavioral interventions. (PsycINFO Database Record

Pharmacologic Treatment of Rett Syndrome With Glatiramer Acetate.

BACKGROUND: Rett syndrome (RTT) is a severe neurological disease that primarily affects females. The level of brain derived neurotropic factor (BDNF) expression directly correlates with the severity of RTT related symptoms. Because Glatiramer acetate (GA) stimulates secretion of BDNF in the brain, we conducted the study with the objective to assess its efficacy in improving gait velocity cognition, respiratory function, electroencephalographic findings, and quality of life in patients with RTT. METHODS: Phase two, open label, single center trial. INCLUSION CRITERIA: ambulatory girls with genetically confirmed RTT, 10 years or older. Pre- and post-treatment measures were compared using the non-parametric Wilcoxon signed rank sum test and paired t-tests. RESULTS: Ten patients were enrolled and completed the trial. Gait velocity improved significantly (improvement range 13%-95%, p=0.03 for both tests) and emerged as an especially valuable outcome measure with excellent test- retest reliability of the 2 trials within sessions (intraclass correlation coefficient=0.94). Memory, and the breath holding index also improved significantly (p≤0.03). Epileptiform discharges decreased in all four patients who had them at baseline. There was a trend towards improved quality of life, which did not reach statistical significance. CONCLUSIONS: This prospective open-label trial provides important preliminary information related to the efficacy of GA in improving gait velocity in female patients with RTT who are 10 years or older. The results of this trial justify the need for larger scale controlled trials of GA as well as provide a template for assessing the efficacy of other interventions in RTT.

Aspects of Attention in Rett Syndrome.

BACKGROUND: We sought to examine fundamental aspects of attention in children with Rett syndrome, a severely disabling neurodevelopmental disorder caused by spontaneous mutations in the X-linked MECP2 gene. To gauge their attention, we used eye tracking, which bypasses the profound impairments in expressive language and hand use in Rett syndrome. We report two aspects of attention-shifting and sustaining-basic abilities known to drive cognitive growth. METHODS: Two groups were compared: those with Rett syndrome (N = 20; 3-15 years) and a typically developing comparison group (N = 14; 3-16 years), using a task in which an attractive central stimulus was followed, after a short gap, by a dynamic target presented to one side. Time to shift to the target location (reactive and anticipatory saccades) and time fixating the target were assessed. RESULTS: Children with Rett syndrome were consistently slower to shift (largely because of fewer anticipations); their reactive saccades were also slower than those of typically developing children, but not significantly so. The Rett syndrome group spent considerable time looking at the target (over 75% of available time), although significantly less so than the typically developing group. CONCLUSIONS: These findings indicate that children with Rett syndrome could maintain attention on a stimulus and orient relatively quickly to the appearance of a target in the visual field. However, they had difficulty in anticipating predictable events, a difficulty in endogenous attention that is likely to have deleterious implications for executive functioning.

Persistence of Cerebral Palsy Diagnosis: Assessment of a Low-Birth-Weight Cohort at Ages 2, 6, and 9 Years.

We examined the stability of nondisabling and disabling cerebral palsy at age 2 in a longitudinally followed tri-county low-birth-weight (<2000 g) birth cohort. A total of 1105 newborns were enrolled, 901 (81.5%) survived to age 2, and 86% (n = 777) were followed up. Of the 113 cerebral palsy diagnoses at age 2, 61 (9% of the cohort, n = 61/777) had disabling cerebral palsy and 52 (7%, n = 52/777) had nondisabling cerebral palsy. Of 48 followed children diagnosed with disabling cerebral palsy at age 2, 98% were again classified as having cerebral palsy at school age, and 1 had an uncertain cerebral palsy status. By contrast, 41% (n = 17) of the 43 children diagnosed with nondisabling cerebral palsy at age 2 were classified as not having cerebral palsy. Of the 517 followed children who were not diagnosed with cerebral palsy at age 2, 7% (n = 35) were classified as having late emerging nondisabling cerebral palsy at school age.

Pathways From Toddler Information Processing to Adolescent Lexical Proficiency.

This study examined the relation of 3-year core information-processing abilities to lexical growth and development. The core abilities covered four domains-memory, representational competence (cross-modal transfer), processing speed, and attention. Lexical proficiency was assessed at 3 and 13 years with the Peabody Picture Vocabulary Test (PPVT) and verbal fluency. The sample (N = 128) consisted of 43 preterms (< 1750 g) and 85 full-terms. Structural equation modeling indicated concurrent relations of toddler information processing and language proficiency and, independent of stability in language, direct predictive links between (a) 3-year cross-modal ability and 13-year PPVT and (b) 3-year processing speed and both 13-year measures, PPVT and verbal fluency. Thus, toddler information processing was related to growth in lexical proficiency from 3 to 13 years.

Rett syndrome: recognition of facial expression and its relation to scanning patterns.

BACKGROUND: Rett syndrome is a severely disabling neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene. Very little is known about its cognitive phenotype and nothing about recognition of emotional expression, a key factor for social interaction and communication. Using eye tracking technology, a technique uniquely suited for studying cognition in this disorder, we examined this ability here. METHODS: Rett syndrome female patients (n = 37; 2-31 years) and a typically developing age- and gender-matched comparison group (n =34; 2-30 years) were assessed on recognition of three basic emotions (happy, sad, and fear) using six visual paired-comparison problems. Each problem consisted of a 10-second familiarization, in which two identical faces posing one emotion were presented, followed by a 10-second test, in which the familiar emotion was paired with a novel one posed by the same model. Recognition was inferred from preferential looking to the novel target on test. During familiarization, attention was measured by total looking time, number and/or length of fixations, and gaze dispersion across three key facial features (eyes, nose, and mouth). RESULTS: Individuals with Rett syndrome had difficulty recognizing most emotional expressions, unlike the typically developing comparison group. Also, their scanpaths were atypical-less looking, fewer and/or longer fixations, and less time devoted to all facial features (48% versus 72%), particularly the mouth. Significant correlations between looking to critical features and recognition underscored the importance of scanning. CONCLUSIONS: Our results suggest that individuals with Rett syndrome have difficulty reading emotional expressions and that these problems are linked to atypicalities in scanning.

Rett syndrome: an eye-tracking study of attention and recognition memory.

AIM: The aim of this study was to examine attention and recognition memory for faces and patterns in Rett syndrome, a severely disabling neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene. METHOD: Because Rett syndrome impairs speech and hand use, precluding most neuropsychological testing, the visual paired-comparison paradigm (VPC) was used, together with eye tracking. In the VPC, two identical stimuli are presented for familiarization. On test, the familiar stimulus and a new one are paired, and recognition inferred from preferential looking to the novel target. Attention is measured by looking time, gaze dispersion, and number/length of fixations. Twenty-seven female patients with Rett syndrome (mean age 10y 6mo; SD 6y 8mo, age range 2-22y) from the Rett clinic at a children's hospital were assessed in this study, along with 30 age- and sex-matched typically developing participants (outpatients from the same hospital). RESULTS: Although patients with Rett syndrome showed recognition of both faces and patterns, with novelty scores greater than chance (50%), their performance was significantly poorer than that of the typically developing comparison group. Their attention to both was less mature and marked by a more narrowly focused gaze, with fewer and longer fixations. When inspecting faces, attention to the eyes was similar in both groups; however, patients with Rett syndrome tended to ignore the nose and mouth. INTERPRETATION: This is one of the first studies to characterize attention and memory in individuals with Rett syndrome. Visually based techniques, such as the VPC, open a new avenue for quantifying the cognitive phenotype associated with this syndrome.

Association between transient hypothyroxinaemia of prematurity and adult autism spectrum disorder in a low-birthweight cohort: an exploratory study.

BACKGROUND: Transient hypothyroxinaemia of prematurity (THOP) is associated with increased risk of cerebral palsy and lower IQ in low-birthweight infants. This study explores whether THOP is also associated with increased risk of autism spectrum disorders (ASD). METHODS: This secondary analysis uses data from a birth cohort of newborns weighing 500 -2000 g (n = 1105) who were followed to age 21 years, when they were assessed for ASD in the second of a two-stage process. Of the 187 assessed at age 21, 14 had ASD. Neonatal thyroxine results were available for 12/14 and 165/173 participants diagnosed with and without ASD, respectively. THOP was defined as thyroxine z-score <-2.6. Unadjusted relative risks (RR) and confidence intervals (CI) were calculated. RESULTS: The mean neonatal thyroxine z-score in young adults diagnosed with ASD was 0.5 SD lower [95% CI -0.16, 1.06] than in those without ASD. Participants with THOP were at 2.5-fold greater risk of ASD (RR 2.5 [95% CI 0.7, 8.4]). While neither of these differences was statistically significant, in a secondary subgroup analysis of those whose mothers did not have hypertension during pregnancy, THOP significantly increased the RR for ASD (5.0 [95% CI 1.2, 20.5]). CONCLUSION: While the primary relation between THOP and ASD found here is not statistically significant, the magnitude of association and significant relationship observed in the subgroup whose mothers did not have hypertension during pregnancy suggest that it is worthy of further investigation.

Autism spectrum disorder is associated with ventricular enlargement in a low birth weight population.

OBJECTIVE: To determine the relation of neonatal cranial ultrasound abnormalities to autism spectrum disorders (ASD) in low birth weight (LBW) adult survivors, a population at increased ASD risk. STUDY DESIGN: This is a secondary analysis of a prospectively-followed regional birth cohort of 1105 LBW infants systematically screened for perinatal brain injury with cranial ultrasound in the first week of life and later assessed for ASD using a two-stage process [screening at age 16 years (n = 623) followed by diagnostic assessment at age 21 years of a systematically selected subgroup of those screened (n = 189)]; 14 cases of ASD were identified. For this analysis, cranial ultrasound abnormalities were defined as ventricular enlargement (indicative of diffuse white matter injury), parenchymal lesions (indicative of focal white matter injury), and isolated germinal matrix/intraventricular hemorrhage. RESULTS: Compared with no cranial ultrasound abnormalities, any type of white matter injury (ventricular enlargement and/or parenchymal lesion) tripled the risk for screening positively for ASD [3.0 (2.2, 4.1)]. However, the risk of being diagnosed with ASD depended on type of white matter injury. With ventricular enlargement, the risk of ASD diagnosis was almost seven-fold that of no cranial ultrasound abnormality [6.7 (2.3, 19.7)], and no elevated risk was found for parenchymal lesion without ventricular enlargement [1.8 (0.2, 13.6)]. Isolated germinal matrix/intraventricular hemorrhage did not increase risk for a positive ASD screen or diagnosis. CONCLUSION: In LBW neonates, cranial ultrasound evidence of ventricular enlargement is a strong and significant risk factor for subsequent development of rigorously-diagnosed ASD.

Information Processing from Infancy to 11 Years: Continuities and Prediction of IQ.

This study provides the first direct evidence of cognitive continuity for multiple specific information processing abilities from infancy and toddlerhood to pre-adolescence, and provides support for the view that infant abilities and form the basis of later childhood abilities. Data from a large sample of children (N = 131) were obtained at five different time points (7, 12, 24, 36 months, and 11 years) for a large battery of tasks representing four cognitive domains (attention, processing speed, memory, and representational competence). Structural equation models of continuity were assessed for each domain, in which it was assumed that infant abilities → toddler abilities → 11-year abilities. Abilities at each age were represented by latent variables, which minimize task-specific variance and measurement error. The model for each domain fit the data. Moreover, abilities from the three age periods predicted global outcome, with infant, toddler, and contemporaneous 11-year measures, respectively, accounting for 12.3%, 18.5%, and 45.2% of the variance in 11-year IQ. These findings strengthen contentions that specific cognitive abilities that can be identified in infancy show long-term continuity and contribute importantly to later cognitive competence.

Implications of infant cognition for executive functions at age 11.

Recent work suggests that executive functions, the cornerstone of higher-level cognitive operations, are driven by basic information processing abilities. Using structural equation modeling, with latent variables, the present study provides the first evidence that this driving force begins in infancy, such that abilities in infancy predict executive functions at age 11. Information processing abilities in three domains (attention, processing speed, and memory) were assessed when participants were infants (7 and 12 months) and toddlers (24 and 36 months) and were used to predict three executive functions (working memory, inhibition, and shifting) when participants were 11 years old. A model relating infant abilities to age-11 executive functions fit well, and accounted for 9% to 19% of the variance in the executive functions. Paths from both speed and memory in infancy to age-11 working memory were significant, as was the path from Speed in infancy to age-11 Shifting. A model using abilities in toddlerhood as predictors fit similarly. These findings implicate early basic cognitive abilities in the development of executive functions.

Prevalence of autism spectrum disorder in adolescents born weighing <2000 grams.

OBJECTIVE: To estimate the diagnostic prevalence of autism spectrum disorders (ASDs) in a low birth weight (LBW) cohort. METHODS: Participants belonged to a regional birth cohort of infants (N = 1105) born weighing <2000 g between October 1, 1984, and July 3, 1989, and followed up by periodic assessments to 21 years of age. At 16 years (n = 623), adolescents were screened for ASD using a wide net (previous professional diagnosis of an ASD or a score above a liberal cutoff on the Social Communication Questionnaire or the Autism Spectrum Symptoms Questionnaire). At 21 years (n = 189), 60% of screen positives and 24% of screen negatives were assessed for diagnoses of ASD by the Autism Diagnostic Observation Schedule or the Autism Diagnostic Interview-Revised. RESULTS: Samples retained at ages 16 and 21 years were representative of samples assessed at earlier ages except for lower levels of social risk. Of positive screens, 11 of 70 had ASD; of negative screens, 3 of 119 had ASD. The fractions of the 2 screening groups with ASD (14.3% in screen-positives and 2.5% in screen negatives) were weighted by fractions of screen-positives and screen-negatives among the adolescents (18.8% and 81.2%, respectively). This calculation produced an estimated prevalence rate of ASD in the entire cohort of 5% (31 of 623). CONCLUSIONS: The diagnostic prevalence of ASD in this LBW preterm cohort was higher than that reported by the Centers for Disease Control and Prevention for 8-year-olds in the general US population in 2006.

Modeling a cascade of effects: the role of speed and executive functioning in preterm/full-term differences in academic achievement.

This study identified deficits in executive functioning in pre-adolescent preterms and modeled their role, along with processing speed, in explaining preterm/full-term differences in reading and mathematics. Preterms (< 1750 g) showed deficits at 11 years on a battery of tasks tapping the three basic executive functions identified by Miyake - updating/working memory, inhibition, and shifting. Confirmatory factor analysis showed that these executive functions, though correlated, were distinct from one another and from processing speed, which later proved to account for much of the intercorrelation among executive functions. In the best-fitting structural equation model, the negative effects of prematurity on achievement were completely mediated by the three executive functions and speed in a cascade of effects: prematurity → slower processing speed → poorer executive functioning (working memory) → lower achievement in math and reading.

Neonatal head ultrasound abnormalities in preterm infants and adolescent psychiatric disorders.

CONTEXT: Infants born prematurely are at risk for a perinatal encephalopathy characterized by white and gray matter injuries that affect subsequent cortical development and neural connectivity and potentially increase risk for later psychiatric disorder. OBJECTIVE: To determine the relation of perinatal brain injury, as detected by neonatal head ultrasound, to psychiatric disorders in adolescents who were born prematurely. DESIGN: Prospective cohort. SETTING: Community. PARTICIPANTS: Adolescent survivors of a population-based low-birth-weight (<2000 g; 96% preterm; born 1984-1987) cohort (n = 1105) screened as neonates with serial head ultrasounds. Neonatal head ultrasound abnormalities were categorized as either (1) germinal matrix and/or intraventricular hemorrhage or (2) parenchymal lesions and/or ventricular enlargement. Of 862 eligible survivors, 628 (72.9%) were assessed at age 16 years. The sample consisted of 458 nondisabled survivors assessed in person. Main Outcome Measure  Adolescent current and lifetime psychiatric disorders assessed with parent report on the Diagnostic Interview Schedule for Children-IV. RESULTS: Compared with no abnormality, germinal matrix/intraventricular hemorrhage increased risk for current major depressive disorder (odds ratio, 2.7; 95% confidence interval, 1.0-6.8) and obsessive-compulsive disorder (9.5; 3.0-30.1). Parenchymal lesions/ventricular enlargement increased risk for current attention-deficit/hyperactivity disorder-inattentive type (odds ratio, 7.6; 95% confidence interval, 2.0-26.5), tic disorders (8.4; 2.4-29.6), and obsessive-compulsive disorder (7.6; 1.39-42.0). Parenchymal lesions/ventricular enlargement were not related to lifetime attention-deficit/hyperactivity disorder-inattentive type, but all other relations were similar for lifetime disorders. Control for other early risk factors did not alter these relations. Most of these relations persisted with control for concurrent cognitive or motor problems. CONCLUSION: In preterm infants, 2 distinct types of perinatal brain injury detectable with neonatal head ultrasound selectively increase risk in adolescence for psychiatric disorders in which dysfunction of subcortical-cortical circuits has been implicated.

Basic Information Processing Abilities at 11 years Account for Deficits in IQ Associated with Preterm Birth.

Although it is well established that preterms as a group do poorly relative to their full-term peers on tests of global cognitive functioning, the basis for this relative deficiency is less understood. The present paper examines preterm deficits in core cognitive abilities and determines their role in mediating preterm/full-term differences in IQ. The performance of 11-year-old children born preterm (birth weight <1750g) and their full-term controls were compared on a large battery of 15 tasks, covering four basic cognitive domains -- memory, attention, speed of processing and representational competence. The validity of these four domains was established using latent variables and confirmatory factor analysis (CFA). Preterms showed pervasive deficits within and across domains. Additionally, preterm deficits in IQ were completely mediated by these four cognitive domains in a structural equation model involving a cascade from elementary abilities (attention and speed), to more complex abilities (memory and representational competence), to IQ. The similarity of findings to those obtained with this cohort in infancy and toddlerhood suggest that preterm deficits persist - across time, across task, and from the non-verbal to the verbal period.

The structure of memory in infants and toddlers: an SEM study with full-terms and preterms.

There is considerable dispute about the nature of infant memory. Using SEM models, we examined whether popular characterizations of the structure of adult memory, including the two-process theory of recognition, are applicable in the infant and toddler years. The participants were a cohort of preterms and full-terms assessed longitudinally--at 1, 2, and 3 years--on a battery containing tasks of immediate and delayed recognition, recall, and memory span (a measure of short-term capacity). Results were in accord with adult models which assume that short- and long-term memory are distinct, and that two processes--familiarity and recollection--underlie recognition memory, while one alone--recollection--supports recall. The finding that prematurity, which entails risk of hippocampal compromise, affected recollection, but not familiarity, accords well with adult findings that hippocampal damage selectively affects recollection. These findings reveal striking similarity between the structure and theoretical underpinnings of infant and adult memory.