Nocturnal hypoglycemia is associated with next day cognitive performance in adults with type 1 diabetes: Pilot data from the GluCog study.

OBJECTIVE:  Individuals with type 1 diabetes (T1D) have increased risk for cognitive dysfunction and high rates of sleep disturbance. Despite associations between glycemia and cognitive performance using cross-sectional and experimental methods few studies have evaluated this relationship in a naturalistic setting, or the impact of nocturnal versus daytime hypoglycemia. Ecological Momentary Assessment (EMA) may provide insight into the dynamic associations between cognition, affective, and physiological states. The current study couples EMA data with continuous glucose monitoring (CGM) to examine the within-person impact of nocturnal glycemia on next day cognitive performance in adults with T1D. Due to high rates of sleep disturbance and emotional distress in people with T1D, the potential impacts of sleep characteristics and negative affect were also evaluated. METHODS:  This pilot study utilized EMA in 18 adults with T1D to examine the impact of glycemic excursions, measured using CGM, on cognitive performance, measured via mobile cognitive assessment using the TestMyBrain platform. Multilevel modeling was used to test the within-person effects of nocturnal hypoglycemia and hyperglycemia on next day cognition. RESULTS:  Results indicated that increases in nocturnal hypoglycemia were associated with slower next day processing speed. This association was not significantly attenuated by negative affect, sleepiness, or sleep quality. CONCLUSIONS:  These results, while preliminary due to small sample size, showcase the power of intensive longitudinal designs using ambulatory cognitive assessment to uncover novel determinants of cognitive fluctuation in real world settings, an approach that may be utilized in other populations. Findings suggest reducing nocturnal hypoglycemia may improve cognition in adults with T1D.

Ecological Momentary Assessment of Cognition in Clinical and Community Samples: Reliability and Validity Study.

BACKGROUND: The current methods of evaluating cognitive functioning typically rely on a single time point to assess and characterize an individual's performance. However, cognitive functioning fluctuates within individuals over time in relation to environmental, psychological, and physiological contexts. This limits the generalizability and diagnostic utility of single time point assessments, particularly among individuals who may exhibit large variations in cognition depending on physiological or psychological context (eg, those with type 1 diabetes [T1D], who may have fluctuating glucose concentrations throughout the day). OBJECTIVE: We aimed to report the reliability and validity of cognitive ecological momentary assessment (EMA) as a method for understanding between-person differences and capturing within-person variation in cognition over time in a community sample and sample of adults with T1D. METHODS: Cognitive performance was measured 3 times a day for 15 days in the sample of adults with T1D (n=198, recruited through endocrinology clinics) and for 10 days in the community sample (n=128, recruited from TestMyBrain, a web-based citizen science platform) using ultrabrief cognitive tests developed for cognitive EMA. Our cognitive EMA platform allowed for remote, automated assessment in participants' natural environments, enabling the measurement of within-person cognitive variation without the burden of repeated laboratory or clinic visits. This allowed us to evaluate reliability and validity in samples that differed in their expected degree of cognitive variability as well as the method of recruitment. RESULTS: The results demonstrate excellent between-person reliability (ranging from 0.95 to 0.99) and construct validity of cognitive EMA in both the sample of adults with T1D and community sample. Within-person reliability in both samples (ranging from 0.20 to 0.80) was comparable with that observed in previous studies in healthy older adults. As expected, the full-length baseline and EMA versions of TestMyBrain tests correlated highly with one another and loaded together on the expected cognitive domains when using exploratory factor analysis. Interruptions had higher negative impacts on accuracy-based outcomes (ß=-.34 to -.26; all P values <.001) than on reaction time-based outcomes (ß=-.07 to -.02; P<.001 to P=.40). CONCLUSIONS: We demonstrated that ultrabrief mobile assessments are both reliable and valid across 2 very different clinic versus community samples, despite the conditions in which cognitive EMAs are administered, which are often associated with more noise and variability. The psychometric characteristics described here should be leveraged appropriately depending on the goals of the cognitive assessment (eg, diagnostic vs everyday functioning) and the population being studied.

Accurate Prediction of Momentary Cognition From Intensive Longitudinal Data.

BACKGROUND: Deficits in cognitive performance are implicated in the development and maintenance of psychopathology. Emerging evidence further suggests that within-person fluctuations in cognitive performance may represent sensitive early markers of neuropsychiatric decline. Incorporating routine cognitive assessments into standard clinical care-to identify between-person differences and monitor within-person fluctuations-has the potential to improve diagnostic screening and treatment planning. In support of these goals, it is critical to understand to what extent cognitive performance varies under routine, remote assessment conditions (i.e., momentary cognition) in relation to a wide range of possible predictors. METHODS: Using data-driven, high-dimensional methods, we ranked strong predictors of momentary cognition and evaluated out-of-sample predictive accuracy. Our approach leveraged innovations in digital technology, including ambulatory assessment of cognition and behavior 1) at scale (n = 122 participants, n = 94 females), 2) in naturalistic environments, and 3) within an intensive longitudinal study design (mean = 25.5 assessments/participant). RESULTS: Reaction time (R2 > 0.70) and accuracy (0.56 >R2 > 0.35) were strongly predicted by age, between-person differences in mean performance, and time of day. Effects of self-reported, intraindividual fluctuations in environmental (e.g., noise) and internal (e.g., stress) states were also observed. CONCLUSIONS: Our results provide robust estimates of effect size to characterize sources of cognitive variability, to support the identification of optimal windows for psychosocial interventions, and to possibly inform clinical evaluation under remote neuropsychological assessment conditions.

A Prospective Evaluation of Infant Cerebellar-Cerebral Functional Connectivity in Relation to Behavioral Development in Autism Spectrum Disorder.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder diagnosed based on social impairment, restricted interests, and repetitive behaviors. Contemporary theories posit that cerebellar pathology contributes causally to ASD by disrupting error-based learning (EBL) during infancy. The present study represents the first test of this theory in a prospective infant sample, with potential implications for ASD detection. Methods: Data from the Infant Brain Imaging Study (n = 94, 68 male) were used to examine 6-month cerebellar functional connectivity magnetic resonance imaging in relation to later (12/24-month) ASD-associated behaviors and outcomes. Hypothesis-driven univariate analyses and machine learning-based predictive tests examined cerebellar-frontoparietal network (FPN; subserves error signaling in support of EBL) and cerebellar-default mode network (DMN; broadly implicated in ASD) connections. Cerebellar-FPN functional connectivity was used as a proxy for EBL, and cerebellar-DMN functional connectivity provided a comparative foil. Data-driven functional connectivity magnetic resonance imaging enrichment examined brain-wide behavioral associations, with post hoc tests of cerebellar connections. Results: Cerebellar-FPN and cerebellar-DMN connections did not demonstrate associations with ASD. Functional connectivity magnetic resonance imaging enrichment identified 6-month correlates of later ASD-associated behaviors in networks of a priori interest (FPN, DMN), as well as in cingulo-opercular (also implicated in error signaling) and medial visual networks. Post hoc tests did not suggest a role for cerebellar connections. Conclusions: We failed to identify cerebellar functional connectivity-based contributions to ASD. However, we observed prospective correlates of ASD-associated behaviors in networks that support EBL. Future studies may replicate and extend network-level positive results, and tests of the cerebellum may investigate brain-behavior associations at different developmental stages and/or using different neuroimaging modalities.

Social motivation in infancy is associated with familial recurrence of ASD.

Pre-diagnostic deficits in social motivation are hypothesized to contribute to autism spectrum disorder (ASD), a heritable neurodevelopmental condition. We evaluated psychometric properties of a social motivation index (SMI) using parent-report item-level data from 597 participants in a prospective cohort of infant siblings at high and low familial risk for ASD. We tested whether lower SMI scores at 6, 12, and 24 months were associated with a 24-month ASD diagnosis and whether social motivation's course differed relative to familial ASD liability. The SMI displayed good internal consistency and temporal stability. Children diagnosed with ASD displayed lower mean SMI T-scores at all ages and a decrease in mean T-scores across age. Lower group-level 6-month scores corresponded with higher familial ASD liability. Among high-risk infants, strong decline in SMI T-scores was associated with 10-fold odds of diagnosis. Infant social motivation is quantifiable by parental report, differentiates children with versus without later ASD by age 6 months, and tracks with familial ASD liability, consistent with a diagnostic and susceptibility marker of ASD. Early decrements and decline in social motivation indicate increased likelihood of ASD, highlighting social motivation's importance to risk assessment and clarification of the ontogeny of ASD.

Infant Visual Brain Development and Inherited Genetic Liability in Autism.

OBJECTIVE: Autism spectrum disorder (ASD) is heritable, and younger siblings of ASD probands are at higher likelihood of developing ASD themselves. Prospective MRI studies of siblings report that atypical brain development precedes ASD diagnosis, although the link between brain maturation and genetic factors is unclear. Given that familial recurrence of ASD is predicted by higher levels of ASD traits in the proband, the authors investigated associations between proband ASD traits and brain development among younger siblings. METHODS: In a sample of 384 proband-sibling pairs (89 pairs concordant for ASD), the authors examined associations between proband ASD traits and sibling brain development at 6, 12, and 24 months in key MRI phenotypes: total cerebral volume, cortical surface area, extra-axial cerebrospinal fluid, occipital cortical surface area, and splenium white matter microstructure. Results from primary analyses led the authors to implement a data-driven approach using functional connectivity MRI at 6 months. RESULTS: Greater levels of proband ASD traits were associated with larger total cerebral volume and surface area and larger surface area and reduced white matter integrity in components of the visual system in siblings who developed ASD. This aligned with weaker functional connectivity between several networks and the visual system among all siblings during infancy. CONCLUSIONS: The findings provide evidence that specific early brain MRI phenotypes of ASD reflect quantitative variation in familial ASD traits. Multimodal anatomical and functional convergence on cortical regions, fiber pathways, and functional networks involved in visual processing suggest that inherited liability has a role in shaping the prodromal development of visual circuitry in ASD.

Inter- and intra-tract analysis of white matter abnormalities in individuals with early-treated phenylketonuria (PKU).

Even with early and continuous treatment, individuals with phenylketonuria (PKU) may exhibit abnormalities of cortical white matter (WM). The present study utilizes a new analysis approach called Automated Fiber-Tract Quantification (AFQ) to advance our understanding of the tract-specific patterns of change in WM abnormalities in individuals with early-treated PKU (ETPKU). Diffusion Tensor Imaging (DTI) data from a sample of 22 individuals with ETPKU and a demographically-matched sample of 21 healthy individuals without PKU was analyzed using AFQ. In addition, a subsample of 8 individuals with ETPKU was reevaluated six months later after demonstrating a significant reduction in blood phe levels following initiation of sapropterin treatment. Within-tract AFQ analyses revealed significant location-by-group interactions for several WM tracts throughout the brain. In most cases, ETPKU-related disruptions in mean diffusivity (MD) were more apparent in posterior (as compared to anterior) aspects of a given tract. Reduction in blood phe levels with the aforementioned ETPKU subsample was associated with a similar pattern of improvement (posterior-to-anterior) within most tracts. Taken together, these findings suggest that there is a systematic pattern of change in WM abnormalities in individuals with ETPKU in a posterior-to-anterior manner along individual WM tracts.

Brain function distinguishes female carriers and non-carriers of familial risk for autism.

BACKGROUND: Autism spectrum disorder (ASD) is characterized by high population-level heritability and a three-to-one male-to-female ratio that occurs independent of sex linkage. Prior research in a mixed-sex pediatric sample identified neural signatures of familial risk elicited by passive viewing of point light motion displays, suggesting the possibility that both resilience and risk of autism might be associated with brain responses to biological motion. To confirm a relationship between these signatures and inherited risk of autism, we tested them in families enriched for genetic loading through undiagnosed ("carrier") females. METHODS: Using functional magnetic resonance imaging, we examined brain responses to passive viewing of point light displays-depicting biological versus non-biological motion-in a sample of undiagnosed adult females enriched for inherited susceptibility to ASD on the basis of affectation in their respective family pedigrees. Brain responses in carrier females were compared to responses in age-, SRS-, and IQ-matched non-carrier-females-i.e., females unrelated to individuals with ASD. We conducted a hypothesis-driven analysis focused on previously published regions of interest as well as exploratory, brain-wide analyses designed to characterize more fully the rich responses to this paradigm. RESULTS: We observed robust responses to biological motion. Notwithstanding, the 12 regions implicated by prior research did not exhibit the hypothesized interaction between group (carriers vs. controls) and point light displays (biological vs. non-biological motion). Exploratory, brain-wide analyses identified this interaction in three novel regions. Post hoc analyses additionally revealed significant variations in the time course of brain activation in 20 regions spanning occipital and temporal cortex, indicating group differences in response to point light displays (irrespective of the nature of motion) for exploration in future studies. LIMITATIONS: We were unable to successfully eye-track all participants, which prevented us from being able to control for potential differences in eye gaze position. CONCLUSIONS: These methods confirmed pronounced neural signatures that differentiate brain responses to biological and scrambled motion. Our sample of undiagnosed females enriched for family genetic loading enabled discovery of numerous contrasts between carriers and non-carriers of risk of ASD that may index variations in visual attention and motion processing related to genetic susceptibility and inform our understanding of mechanisms incurred by inherited liability for ASD.

Timing of the Diagnosis of Autism in African American Children.

OBJECTIVES: African American (AA) children affected by autism spectrum disorder (ASD) experience delays in diagnosis and obstacles to service access, as well as a disproportionate burden of intellectual disability (ID) as documented in surveillance data recently published by the US Centers for Disease Control and Prevention. Our objective in this study was to analyze data from the largest-available repository of diagnostic and phenotypic information on AA children with ASD, and to explore the wide variation in outcome within the cohort as a function of sociodemographic risk and specific obstacles to service access for the purpose of informing a national approach to resolution of these disparities. METHODS: Parents of 584 AA children with autism consecutively enrolled in the Autism Genetic Resource Exchange across 4 US data collection sites completed event history calendar interviews of the diagnostic odysseys for their children with ASD. These data were examined in relation to developmental outcomes of the children with autism and their unaffected siblings. RESULTS: The average age of ASD diagnosis was 64.9 months (±49.6), on average 42.3 months (±45.1) after parents' first concerns about their children's development. The relationship between timing of diagnosis and ASD severity was complex, and ID comorbidity was not predicted in a straightforward manner by familial factors associated with cognitive variation in the general population. CONCLUSIONS: These findings document significant opportunity to expedite diagnosis, the need to further understand causes of ID comorbidity, and the necessity to identify effective approaches to the resolution of disparities in severity-of-outcome for AA children with autism.

Accelerating Motor Skill Acquisition for Bicycle Riding in Children with ASD: A Pilot Study.

Motor impairment is common in autism spectrum disorder (ASD) and, as such, a potential target for interventions to improve adaptive functioning. This study investigated motor skill acquisition in children with ASD (n = 15, 12 males; ages 7-16 years) during iCan Bike Camp, a 1-week, community-based intervention (5 × 75-min sessions) to teach independent bicycle riding. After completing the camp's task-oriented, individualized training program, all participants demonstrated motor skill acquisition on the bicycle, and nine participants rode independently at least 70 feet. Exploratory analyses showed that motor coordination and social communication correlated with rates of skill acquisition. These findings indicate the feasibility and efficacy of brief, community-based motor interventions to teach bicycle riding-an important developmental skill supporting adaptive functioning-to children with ASD.

Neuropsychiatric "Comorbidity" as Causal Influence in Autism.

Behavioral comorbidity is the rule rather than the exception in autism spectrum disorder (ASD), and the co-occurrence of autistic traits with subclinical manifestations of other psychiatric syndromes (eg, anxiety, developmental coordination disorder) extends to the general population, where there is strong evidence for overlap in the respective genetic causes. An ASD "comorbidity" can have several fundamentally distinct causal origins: it can arise due to shared genetic risk between ASD and non-ASD phenotypes (eg, ASD and microcephaly in the context of the MECP2 mutation), as a "secondary symptom" of ASD when engendered by the same causal influence (eg, epilepsy in channelopathies associated with ASD), due to chance co-occurrence of ASD with a causally independent liability (eg, ASD and diabetes), or as the late manifestation of an independent causal influence on ASD (eg, attention-deficit/hyperactivity disorder). Here, we review evidence for the latter, that is, the role of nonspecific causal influences on the development of ASD itself. The notion that nonspecific insults to neural development, either inherited or acquired, might augment the impact of ASD-specific genetic susceptibilities in contributing to its cause has not been appreciated in the literature on comorbidity, and has significant implications for both personalized intervention and future research. Prior biomarker studies of ASD have typically not accounted for variation in such traits. The statistical power of future studies, particularly in autism genetics and neuroimaging, can be enhanced by more comprehensive attention to the measurement of comorbid behavioral traits that index causal influences on the disorder, among not only cases but (importantly) controls.

White and gray matter brain development in children and young adults with phenylketonuria.

Phenylketonuria (PKU) is a recessive disorder characterized by disruption in the metabolism of the amino acid phenylalanine (Phe). Prior research indicates that individuals with PKU have substantial white matter (WM) compromise. Much less is known about gray matter (GM) in PKU, but a small body of research suggests volumetric differences compared to controls. To date, developmental trajectories of GM structure in individuals with PKU have not been examined, nor have trajectories of WM and GM been examined within a single study. To address this gap in the literature, we compared longitudinal brain development over a three-year period in individuals with PKU (n = 35; 18 male) and typically-developing controls (n = 71; 35 male) aged 7-21 years. Using diffusion tensor imaging (DTI) and structural magnetic resonance imaging (MRI), we observed whole-brain and regional WM differences between individuals with PKU and controls, which were often exacerbated with increasing age. In marked contrast with trajectories of WM development, trajectories of GM development did not differ between individuals with PKU and controls, indicating that neuropathology in PKU is more prominent in WM than GM. Within individuals with PKU, mediation analyses revealed that whole-brain mean diffusivity (MD) and regional MD in the corpus callosum and centrum semiovale mediated the relationship between dietary treatment compliance (i.e., Phe control) and executive abilities, suggesting a plausible neurobiological mechanism by which Phe control may influence cognitive outcomes. Our findings clarify the specificity, timing, and cognitive consequences of whole-brain and regional WM pathology, with implications for treatment and research in PKU.

Early Origins of Autism Comorbidity: Neuropsychiatric Traits Correlated in Childhood Are Independent in Infancy.

Previous research has suggested that behavioral comorbidity is the rule rather than the exception in autism. The present study aimed to trace the respective origins of autistic and general psychopathologic traits-and their association-to infancy. Measurements of autistic traits and early liability for general psychopathology were assessed in 314 twins at 18 months, ascertained from the general population using birth records. 222 twins were re-evaluated at 36 months. Standardized ratings of variation in social communication at 18 months were highly heritable and strongly predicted autistic trait scores at 36 months. These early indices of autistic liability were independent from contemporaneous ratings of behavior problems on the Brief Infant-Toddler Social and Emotional Assessment (which were substantially environmentally-influenced), and did not meaningfully predict internalizing or externalizing scores on the Achenbach Scales of Empirically Based Assessment at 36 months. In this general population infant twin study, variation in social communication was independent from variation in other domains of general psychopathology, and exhibited a distinct genetic structure. The commonly-observed comorbidity of specific psychiatric syndromes with autism may arise from subsequent interactions between autistic liability and independent susceptibilities to other psychopathologic traits, suggesting opportunities for preventive amelioration of outcomes of these interactions over the course of development.

Developmental Trajectories of Executive and Verbal Processes in Children with Phenylketonuria.

Phenylketonuria (PKU) is a hereditary disorder characterized by disrupted phenylalanine metabolism and cognitive impairment. However, the precise nature and developmental trajectory of this cognitive impairment remains unclear. The present study used a verbal fluency task to dissociate executive and verbal processes in children with PKU (n = 23; 7-18 years) and controls (n = 44; 7-19 years). Data were collected at three longitudinal timepoints over a three-year period, and the contributions of age, group, and their interaction to fluency performance were evaluated. Results indicated impairments in executive processes in children with PKU, which were exacerbated by declining metabolic control.

Pretreatment cognitive and neural differences between sapropterin dihydrochloride responders and non-responders with phenylketonuria.

Sapropterin dihydrochloride (BH4) reduces phenylalanine (Phe) levels and improves white matter integrity in a subset of individuals with phenylketonuria (PKU) known as "responders." Although prior research has identified biochemical and genotypic differences between BH4 responders and non-responders, cognitive and neural differences remain largely unexplored. To this end, we compared intelligence and white matter integrity prior to treatment with BH4 in 13 subsequent BH4 responders with PKU, 16 subsequent BH4 non-responders with PKU, and 12 healthy controls. Results indicated poorer intelligence and white matter integrity in non-responders compared to responders prior to treatment. In addition, poorer white matter integrity was associated with greater variability in Phe across the lifetime in non-responders but not in responders. These results underscore the importance of considering PKU as a multi-faceted, multi-dimensional disorder and point to the need for additional research to delineate characteristics that predict response to treatment with BH4.

Different levels of learning interact to shape the congruency sequence effect.

The congruency effect in distracter interference tasks is often reduced after incongruent relative to congruent trials. Moreover, this congruency sequence effect (CSE) is influenced by learning related to concrete stimulus and response features as well as by learning related to abstract cognitive control processes. There is an ongoing debate, however, over whether interactions between these learning processes are best explained by an episodic retrieval account, an adaptation by binding account, or a cognitive efficiency account of the CSE. To make this distinction, we orthogonally manipulated the expression of these learning processes in a novel factorial design involving the prime-probe arrow task. In Experiment 1, these processes interacted in an over-additive fashion to influence CSE magnitude. In Experiment 2, we replicated this interaction while showing it was not driven by conditional differences in the size of the congruency effect. In Experiment 3, we ruled out an alternative account of this interaction as reflecting conditional differences in learning related to concrete stimulus and response features. These findings support an episodic retrieval account of the CSE, in which repeating a stimulus feature from the previous trial facilitates the retrieval and use of previous-trial control parameters, thereby boosting control in the current trial. In contrast, they do not fit with (a) an adaptation by binding account, in which CSE magnitude is directly related to the size of the congruency effect, or (b) a cognitive efficiency account, in which costly control processes are recruited only when behavioral adjustments cannot be mediated by low-level associative mechanisms.

The congruency sequence effect emerges when the distracter precedes the target.

The congruency effect in distracter interference tasks is typically smaller when the previous trial was incongruent as compared to congruent, suggesting the operation of a control process that minimizes the influence of irrelevant stimuli on behavior. However, both the conditions under which this congruency sequence effect (CSE) can be most easily observed without the typical learning and memory confounds, and the control process underlying it, remain controversial. We therefore tested a recent hypothesis that the CSE is most easily observed without the typical confounds when the distracter is processed before the target. In line with this "distracter head start" hypothesis, in Experiments 1 and 2 the CSE was larger when the distracter appeared before, relative to with, the target. Further, in Experiment 3, we observed a negative congruency effect after incongruent trials when a long interval separated the distracter from the target, consistent with a modulation of the response engendered by the distracter but not with a shift of attention toward the target. These findings reveal an important determinant of CSE magnitude when the typical learning and memory confounds are absent and new insights into the nature of control processes that contribute to this phenomenon.