Extended trajectory of spatial memory errors in typical and atypical development: The role of binding and precision.

Spatial reconstruction, a method for evaluating how individuals remember the placement of objects, has traditionally been evaluated through the aggregate estimation of placement errors. However, this approach may obscure the nature of task errors. Specifically, recent data has suggested the importance of examining the precision of responses, as well as absolute performance on item-context bindings. In contrast to traditional analysis approaches based on the distance between the target and the reconstructed item, in this study we further explored three types of errors (swap error, global error, and local distance) that may all contribute to the distance, with particular emphasis on swap errors and local distance due to their associations with item-context bindings and memory precision, respectively. We examined these errors in children aged 3-18 years, making comparisons between children with typical development (TD) and children with Down syndrome (DS), a population with known memory challenges. As expected, older children outperformed younger children in terms of overall memory accuracy. Of importance is that we measured uneven maturational trajectories of memory abilities across the various error types. Specifically, both remembered locations (irrespective of object identity) and swap errors (object-location binding errors) align with the overall memory accuracy. Memory precision, as measured by local distance in simpler set size 2 trials, mirrored overall memory accuracy. However, for more complex set size 3 trials, local distance remained stable before age 8 and showed age-related change thereafter. The group with DS showed reduced precision compared to a TD matched group, and measures of precision, and to a lesser extent binding errors, correlated with standard neuropsychological outcomes. Overall, our study contributed to a fine-grained understanding of developing spatial memory ability in a large sample of typical developing children and a memory impaired population. These findings contribute to a growing body of research examining precision as a key factor in memory performance.

Preliminary psychometric properties of an inhibition task in young children with Down syndrome.

Background: Executive function (EF) skills are important treatment targets for people with Down syndrome (DS); however, few EF measures have been evaluated for use with young children in this population. Methods: The present study evaluated preliminary psychometric properties of a measure of the EF component of inhibition. Participants were 73 children with DS between 2.5 and 8.67 years old who completed an adapted ability to delay task using a desirable toy. Results: Across two separate trials, latencies to touch the toys were significantly correlated. Latencies increased overall with chronological and mental age, with caveats for the youngest and oldest participants. Conclusion: Findings suggest that an adapted prohibition task is an appropriate method of measuring inhibition for children with DS between 4 and 7 years old, though many children in this chronological age range are at early stages of acquiring this skill set.

Short-term and Long-term Stability of the Autism Diagnostic Observation Schedule (ADOS-2) Calibrated Comparison Scores (CCS) and Classification Scores in Youth with Down Syndrome or Fragile X Syndrome with Intellectual Disability.

Autism diagnosis in individuals with fragile X syndrome (FXS) or Down syndrome (DS) with co-occurring intellectual disability is complex since clinicians often must consider other co-occurring behavioral features. Understanding how best to assess the features of autism in individuals with these conditions is crucial. In this study, we consider the short-term and long-term psychometric consistency of the Autism Diagnostic Observation Schedule-2 (ADOS-2) calibrated comparison scores (CCSs) and ASD classifications in individuals with FXS or DS. 76 individuals with DS (39 males; Mage = 15.27) and 90 individuals with FXS (71 males; Mage = 14.52 years) completed an assessment battery (ADOS-2, abbreviated IQ assessment and semi-structured language sample) at three timepoints (initial visit, short-term stability visit, long-term stability visit). All CCSs were found to have short-and long-term consistency for both groups, with lowest reliability scores for the repetitive behaviors (RRB) CCSs. Decreased reliability of RRB CCSs was found in the DS group than the FXS group. Variable short- and long-term ASD classifications were observed in both groups, with significantly higher variability in the DS group. Across groups, participants with variable classifications had lower ADOS-2 CCSs and higher language scores than those with stable ASD classifications. In the FXS group, those with variable classifications earned higher cognitive scores than did participants with stable ASD classifications. These findings highlight the high incidence of autism symptomatology in individuals with DS or FXS and co-occurring intellectual disability, while elucidating the short- and long-term variability of symptom expression in the context of structured observational tasks such as the ADOS-2.

Longitudinal follow-up of metformin treatment in Fragile X Syndrome.

Introduction: Metformin has been used as a targeted treatment to potentially improve cognition and slow the typical IQ decline that occurs during development among individuals with fragile X syndrome (FXS). In this follow-up study, we are following the trajectory of IQ and adaptive behavior changes over 1 to 3 years in individuals with FXS who are clinically treated with metformin in an open label trial. Method: Individuals with FXS ages 6 to 25 years (mean 13.15 ± 5.50) and nonverbal IQ mean 57.69 (±15.46) were treated for 1-3 years (1.88 ± 0.63). They all had a baseline IQ test using the Leiter-III non-verbal cognitive assessment and the Vineland-III adaptive behavior assessment before the start of metformin. Repeat Leiter-III and Vineland-III were completed after at least 1 year of metformin (500-1,000 mg/dose given twice a day). Result: There were no significant changes in non-verbal IQ or in the adaptive behavior measurements at FDR < 0.05. The findings thus far indicate that both IQ and adaptive behavior are stable over time, and we did not see a significant decline in either measure. Conclusion: Overall, the small sample size and short follow-up duration limit the interpretation of the effects of metformin on cognitive development and adaptive functioning. There is individual variability but overall for the group there was no significant decline in IQ or adaptive behavior.

Specific EEG resting state biomarkers in FXS and ASD.

BACKGROUND: Fragile X syndrome (FXS) and autism spectrum disorder (ASD) are neurodevelopmental conditions that often have a substantial impact on daily functioning and quality of life. FXS is the most common cause of inherited intellectual disability (ID) and the most common monogenetic cause of ASD. Previous literature has shown that electrophysiological activity measured by electroencephalogram (EEG) during resting state is perturbated in FXS and ASD. However, whether electrophysiological profiles of participants with FXS and ASD are similar remains unclear. The aim of this study was to compare EEG alterations found in these two clinical populations presenting varying degrees of cognitive and behavioral impairments. METHODS: Resting state EEG signal complexity, alpha peak frequency (APF) and power spectral density (PSD) were compared between 47 participants with FXS (aged between 5-20), 49 participants with ASD (aged between 6-17), and 52 neurotypical (NT) controls with a similar age distribution using MANCOVAs with age as covariate when appropriate. MANCOVAs controlling for age, when appropriate, and nonverbal intelligence quotient (NVIQ) score were subsequently performed to determine the impact of cognitive functioning on EEG alterations. RESULTS: Our results showed that FXS participants manifested decreased signal complexity and APF compared to ASD participants and NT controls, as well as altered power in the theta, alpha and low gamma frequency bands. ASD participants showed exaggerated beta power compared to FXS participants and NT controls, as well as enhanced low and high gamma power compared to NT controls. However, ASD participants did not manifest altered signal complexity or APF. Furthermore, when controlling for NVIQ, results of decreased complexity in higher scales and lower APF in FXS participants compared to NT controls and ASD participants were not replicated. CONCLUSIONS: These findings suggest that signal complexity and APF might reflect cognitive functioning, while altered power in the low gamma frequency band might be associated with neurodevelopmental conditions, particularly FXS and ASD.

Predictors, Parental Views, and Concordance Across Diagnostic Sources of Autism in Male Youth with Fragile X Syndrome: Clinical Best Estimate and Community Diagnoses.

Persons with fragile X syndrome (FXS) with cooccurring autism spectrum disorder (ASD) are at risk for poorer educational, medical, employment, and independent living outcomes. Thus, the identification of ASD in those with FXS is fundamental to ensuring access to appropriate supports to achieve good quality of life. Yet, optimal diagnostic methods and the exact rate of ASD comorbidity remains controversial, and description of ASD identification in the community in FXS has been limited. This study characterized ASD in a sample of 49 male youth with FXS across multiple diagnostic sources: parent-reported community diagnoses, classification derived from ADOS-2 and ADI-R thresholds, and clinical best-estimate classifications from an expert multidisciplinary team. High concordance was found between ADOS-2/ADI-R and clinical best estimate classifications, with both methods supporting ASD in ~ 75% of male youth with FXS. In contrast, 31% had a community diagnosis. Findings supported gross under-identification of ASD in male youth with FXS in community settings; 60% of those who met clinical best estimate criteria for ASD had not received a diagnosis in the community. Moreover, community diagnoses were poorly aligned with the presence of ASD symptoms as perceived by parents and professionals and, unlike clinical best estimate diagnoses, were not associated with cognitive, behavioral, or language features. Findings highlight under-identification of ASD in community settings as a significant barrier to service access for male youth with FXS. Clinical recommendations should emphasize the benefits of seeking a professional ASD evaluation for children with FXS who are noted to display key ASD symptoms.

Psychometric evaluation of a working memory assessment measure in young children with Down syndrome.

BACKGROUND: Working memory involves the temporary storage and manipulation of information and is frequently an area of challenge for individuals with Down syndrome (DS). Despite the potential benefits of intervention, laboratory assessments of working memory that could capture intervention effects have not undergone rigorous evaluation for use with young children with DS. It is critical to evaluate assessments of working memory in young children with DS to ensure the reliable and accurate measurement of performance. AIM: This study evaluated an adapted laboratory measure of working memory for young children with DS 2-8 years old. METHOD: A self-ordered pointing task, the Garage Game, was administered to 78 children with DS (mean = 5.17 years; SD = 1.49). Adaptations were made to the task to minimize potential DS phenotype-related language and motor confounds. RESULTS: Results indicate that the measure is feasible, scalable, and developmentally sensitive, with minimal floor and practice effects for this population within this chronological and developmental age range. CONCLUSION: These findings demonstrate that the Garage Game is promising for use in studies of early working memory and treatment trials that aim to support the development of this critical dimension of executive functioning for children with DS.

Consistency and reliability of automated language measures across expressive language samples in autism.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with substantial clinical heterogeneity, especially in language and communication ability. There is a need for validated language outcome measures that show sensitivity to true change for this population. We used Natural Language Processing to analyze expressive language transcripts of 64 highly-verbal children and young adults (age: 6-23 years, mean 12.8 years; 78.1% male) with ASD to examine the validity across language sampling context and test-retest reliability of six previously validated Automated Language Measures (ALMs), including Mean Length of Utterance in Morphemes, Number of Distinct Word Roots, C-units per minute, unintelligible proportion, um rate, and repetition proportion. Three expressive language samples were collected at baseline and again 4 weeks later. These samples comprised interview tasks from the Autism Diagnostic Observation Schedule (ADOS-2) Modules 3 and 4, a conversation task, and a narration task. The influence of language sampling context on each ALM was estimated using either generalized linear mixed-effects models or generalized linear models, adjusted for age, sex, and IQ. The 4 weeks test-retest reliability was evaluated using Lin's Concordance Correlation Coefficient (CCC). The three different sampling contexts were associated with significantly (P < 0.001) different distributions for each ALM. With one exception (repetition proportion), ALMs also showed good test-retest reliability (median CCC: 0.73-0.88) when measured within the same context. Taken in conjunction with our previous work establishing their construct validity, this study demonstrates further critical psychometric properties of ALMs and their promising potential as language outcome measures for ASD research.

Expressive language sampling and outcome measures for treatment trials in fragile X and down syndromes: composite scores and psychometric properties.

The lack of psychometrically sound outcome measures has been a barrier to evaluating the efficacy of treatments proposed for core symptoms of intellectual disability (ID). Research on Expressive Language Sampling (ELS) procedures suggest it is a promising approach to measuring treatment efficacy. ELS entails collecting samples of a participant's talk in interactions with an examiner that are naturalistic but sufficiently structured to ensure consistency and limit examiner effects on the language produced. In this study, we extended previous research on ELS by analyzing an existing dataset to determine whether psychometrically adequate composite scores reflecting multiple dimensions of language can be derived from ELS procedures administered to 6- to 23-year-olds with fragile X syndrome (n = 80) or Down syndrome (n = 78). Data came from ELS conversation and narration procedures administered twice in a 4-week test-retest interval. We found that several composites emerged from variables indexing syntax, vocabulary, planning processes, speech articulation, and talkativeness, although there were some differences in the composites for the two syndromes. Evidence of strong test-retest reliability and construct validity of two of three composites were obtained for each syndrome. Situations in which the composite scores would be useful in evaluating treatment efficacy are outlined.

Adaptive, behavioral, and cognitive outcomes in individuals with fragile X syndrome with varying autism severity.

This study aimed to determine the association between severity of autism spectrum disorder (ASD) and cognitive, behavioral, and molecular measures in individuals with fragile X syndrome (FXS). Study inclusion criteria included individuals with FXS and (1) age 6-40 years, (2) full-scale IQ < 84, and (3) language ≥3-word phrases. ASD symptom severity was determined by Autism Diagnostic Observation Schedule-2 (ADOS-2). Other measures identified non-verbal IQ, adaptive skills, and aberrant behaviors. Molecular measures included blood FMR1 and CYFIP1 mRNA levels, FMRP and MMP9 levels. Analysis of variance (ANOVA) and Spearman's correlations were used to compare ASD severity groups. Data from 54 individuals was included with no/mild (N = 7), moderate (N = 18), and severe (N = 29) ASD. Individuals with high ASD severity had lower adaptive behavior scores (47.48 ± 17.49) than the no/mild group (69.00 ± 20.45, p = 0.0366); they also had more challenging behaviors, lethargy, and stereotypic behaviors. CYFIP1 mRNA expression levels positively correlated with the ADOS-2 comparison score(r2  = 0.33, p = 0.0349), with no significant correlations with other molecular markers. In conclusion, autism symptom severity is associated with more adverse cognitive and adaptive skills and specific behaviors in FXS, whereas CYFIP1 mRNA expression levels may be a potential biomarker for severity of ASD in FXS.