Polygenic association between attention-deficit/hyperactivity disorder liability and cognitive impairments.

BACKGROUND: A recent genome-wide association study (GWAS) identified 12 independent loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). Polygenic risk scores (PRS), derived from the GWAS, can be used to assess genetic overlap between ADHD and other traits. Using ADHD samples from several international sites, we derived PRS for ADHD from the recent GWAS to test whether genetic variants that contribute to ADHD also influence two cognitive functions that show strong association with ADHD: attention regulation and response inhibition, captured by reaction time variability (RTV) and commission errors (CE). METHODS: The discovery GWAS included 19 099 ADHD cases and 34 194 control participants. The combined target sample included 845 people with ADHD (age: 8-40 years). RTV and CE were available from reaction time and response inhibition tasks. ADHD PRS were calculated from the GWAS using a leave-one-study-out approach. Regression analyses were run to investigate whether ADHD PRS were associated with CE and RTV. Results across sites were combined via random effect meta-analyses. RESULTS: When combining the studies in meta-analyses, results were significant for RTV (R2 = 0.011, ß = 0.088, p = 0.02) but not for CE (R2 = 0.011, ß = 0.013, p = 0.732). No significant association was found between ADHD PRS and RTV or CE in any sample individually (p > 0.10). CONCLUSIONS: We detected a significant association between PRS for ADHD and RTV (but not CE) in individuals with ADHD, suggesting that common genetic risk variants for ADHD influence attention regulation.

Characteristics of child psychiatric outpatients with slow processing speed and potential mechanisms of academic impact.

While slow processing speed (PS) is well documented in youth with ADHD, growing evidence suggests that this difficulty affects children with other neuropsychiatric conditions. Clarifying the relationship between slow PS and different forms of psychopathology is important clinically, given the potential impact of PS on academic functioning, and conceptually. In 751 youth, ages 6-21, consecutively referred for neuropsychiatric evaluation, we examined the association between slow PS (i.e., Wechsler PS Index < 85) and seven neuropsychiatric diagnostic groups. In 492 of these youth, we also related slow PS to eight psychopathology symptom dimensions. Finally, we modeled the relationship between PS, other cognitive functions and academic achievement. Data are from the Longitudinal Study of Genetic Influences on Cognition. Analyses included one-sample t tests, ANOVA, logistic regression, mixed modeling, and structural equation modeling (SEM), controlling for age, sex, and medication. Compared to normative data, all clinical groups showed PS decrements. Compared to referred youth without full diagnoses and accounting for other psychopathology, risk for slow PS was elevated in youth with autism spectrum disorder (OR = 1.8), psychotic disorders (OR = 3.4) and ADHD-inattentive type (OR = 1.6). Having multiple comorbidities also increased risk for slow PS. Among dimensions, inattention (OR = 1.5) associated with slow PS but did not fully explain the association with autism or psychosis. In SEM, PS had direct effects on academic achievement and indirect effects through working memory. Findings extend evidence that PS relates to multiple aspects of child psychopathology and associates with academic achievement in child psychiatric outpatients.

Slow Processing Speed and Sluggish Cognitive Tempo in Pediatric Attention-Deficit/Hyperactivity Disorder: Evidence for Differentiation of Functional Correlates.

The association between slow processing speed and sluggish cognitive tempo (SCT), a phenotype described within attention-deficit/hyperactivity disorder (ADHD) samples over the past decade, remains unclear. We examined whether SCT and processing speed predict different functional correlates within children and adolescents with ADHD. Participants were 193 clinically-referred youth meeting DSM ADHD criteria without comorbid conditions (mean age = 9.9 years, SD = 2.5; age range 6-16). The incremental utility of SCT and processing speed to predict (1) adaptive functioning and (2) academic achievement, after controlling for age, sex, medication status, and ADHD symptom burden, was assessed using hierarchical multiple regressions. SCT symptoms significantly predicted adaptive functioning, accounting for 6% of the variance, but did not predict academic achievement. Processing speed did not add incrementally to the prediction of adaptive functioning, but did predict academic achievement, accounting for 4% of the variance. Results suggest that SCT and processing speed differentially predict functional abilities not accounted for by ADHD symptom burden.

Characteristics of Child Psychiatric Outpatients at Highest Risk for Suicidal Thoughts and Behaviors.

On average, compared to non-referred youth, child psychiatric outpatients show elevated rates of suicidal thoughts and behaviors (STBs), which are predictors of completed suicide. Determining the psychopathology features that associate with highest risk for STBs among youth outpatients may yield opportunities for targeted prevention/intervention. Yet, outpatient studies are limited and have not systematically examined comorbidity and dimensional psychopathology. In 758 youth, aged 6-18, consecutively referred for neuropsychiatric evaluation, we examined the extent to which diagnostic groups, comorbid subgroups and dimensional symptoms associated with STBs. After controlling for comorbidity, mood, anxiety and conduct disorders associated with elevated STB risk. Regarding dimensions, symptoms of depression, aggression and psychosis all contributed to higher STB risk. Although ADHD (as a diagnosis or dimension) did not associate with elevated STB risk independently, ADHD that was comorbid with other conditions did. Suicide prevention/intervention efforts should be investigated in youth outpatients with the highest risk for STBs.

Cross-Disorder Cognitive Impairments in Youth Referred for Neuropsychiatric Evaluation.

OBJECTIVES: Studies suggest that impairments in some of the same domains of cognition occur in different neuropsychiatric conditions, including those known to share genetic liability. Yet, direct, multi-disorder cognitive comparisons are limited, and it remains unclear whether overlapping deficits are due to comorbidity. We aimed to extend the literature by examining cognition across different neuropsychiatric conditions and addressing comorbidity. METHODS: Subjects were 486 youth consecutively referred for neuropsychiatric evaluation and enrolled in the Longitudinal Study of Genetic Influences on Cognition. First, we assessed general ability, reaction time variability (RTV), and aspects of executive functions (EFs) in youth with non-comorbid forms of attention-deficit/hyperactivity disorder (ADHD), mood disorders and autism spectrum disorder (ASD), as well as in youth with psychosis. Second, we determined the impact of comorbid ADHD on cognition in youth with ASD and mood disorders. RESULTS: For EFs (working memory, inhibition, and shifting/ flexibility), we observed weaknesses in all diagnostic groups when participants' own ability was the referent. Decrements were subtle in relation to published normative data. For RTV, weaknesses emerged in youth with ADHD and mood disorders, but trend-level results could not rule out decrements in other conditions. Comorbidity with ADHD did not impact the pattern of weaknesses for youth with ASD or mood disorders but increased the magnitude of the decrement in those with mood disorders. CONCLUSIONS: Youth with ADHD, mood disorders, ASD, and psychosis show EF weaknesses that are not due to comorbidity. Whether such cognitive difficulties reflect genetic liability shared among these conditions requires further study. (JINS, 2018, 24, 91-103).

Psychological Distress and Widespread Pain Contribute to the Variance of the Central Sensitization Inventory: A Cross-Sectional Study in Patients with Chronic Pain.

OBJECTIVES: Central sensitization (CS) implies increased sensitivity of the nervous system, resulting in increased pain sensitivity as well as widespread pain. Recently, the Central Sensitization Inventory (CSI) was developed to assess symptoms of CS and central sensitivity syndromes. The aim of this study was to examine the convergent validity of the CSI by comparing the outcome to psychosocial factors and clinical features of CS. METHODS: In a cross-sectional explorative study, patients with chronic pain completed multiple questionnaires, including the CSI, Pain Catastrophizing Scale, and Symptom Checklist 90, for psychological distress, duration of pain, intensity of pain, widespread pain, and lateralization of pain. Based on bivariate correlations, relevant predictors of CS were selected and used to fit an exploratory structural equation model (SEM) of CS. RESULTS: In total, 114 patients with chronic pain were included, 56.1% being women. The average pain duration was 88 months. The mean total score on the CSI was 36.09 (15.26). The CSI was strongly related to known contributing and related factors of CS. SEM analysis showed that both psychological distress and widespread pain contributed significantly to the variance in symptoms of CS in patients with chronic pain. CONCLUSION: In this study, the convergent validity of the CSI was measured with demonstration of a strong relationship between contributing factors and clinical features of CS. These findings of convergent validity, considering former studies of the CSI, underline the use of the questionnaire in the clinical practice.

Cardiac function and cognition in older community-dwelling cardiac patients.

BACKGROUND: Cognitive deficits have been reported in older cardiac patients. An underlying mechanism for these findings may be reduced cardiac function. The relationship between cardiac function as represented by different echocardiographic measures and different cognitive function domains in older cardiac patients remains unknown. METHODS: An older (≥70 years) heterogeneous group of 117 community-dwelling cardiac patients under medical supervision by a cardiologist underwent thorough echocardiographic assessment including left ventricular ejection fraction, cardiac index, left atrial volume index, left ventricular mass index, left ventricular diastolic function, and valvular calcification. During a home visit, a neuropsychological assessment was performed within 7.1 ± 3.8 months after echocardiographic assessment; the neuropsychological assessment included three subtests of a word-learning test (encoding, recall, recognition) to examine one memory function domain and three executive function tests, including digit span backwards, Trail Making Test B minus A, and the Stroop colour-word test. RESULTS: Regression analyses showed no significant linear or quadratic associations between any of the echocardiographic functions and the cognitive function measures. CONCLUSIONS: None of the echocardiographic measures as representative of cardiac function was correlated with memory or executive function in this group of community-dwelling older cardiac patients. These findings contrast with those of previous studies.

Development of repeated sprint ability in talented youth basketball players.

Factors affecting repeated sprint ability (RSA) were evaluated in a mixed-longitudinal sample of 48 elite basketball players 14-19 years of age (16.1 ± 1.7 years). Players were observed on 6 occasions during the 2008-09 and 2009-10 seasons. Three following basketball-specific field tests were administered on each occasion: the shuttle sprint test for RSA, the vertical jump for lower body explosive strength (power), and the interval shuttle run test for interval endurance capacity. Height and weight were measured; body composition was estimated (percent fat, lean body mass). Multilevel modeling of RSA development curve was used with 32 players (16.0 ± 1.7 years) who had 2 or more observations. The 16 players (16.1 ± 1.8 years) measured on only 1 occasion were used as a control group to evaluate the appropriateness of the model. Age, lower body explosive strength, and interval endurance capacity significantly contributed to RSA (p ≤ 0.05). Repeated sprint ability improved with age from 14 to 17 years (p ≤ 0.05) and reached a plateau at 17-19 years. Predicted RSA did not significantly differ from measured RSA in the control group (p ≥ 0.05). The results suggest a potentially important role for the training of lower body explosive strength and interval endurance capacity in the development of RSA among youth basketball players. Age-specific reference values for RSA of youth players may assist basketball coaches in setting appropriate goals for individual players.

Polygenic Variation Underlying Educational Attainment and Attention-Deficit/Hyperactivity Disorder Indexes Behavior Ratings of Executive Functions in Child Psychiatry Outpatients.

OBJECTIVE: We leveraged common genetic variation underlying ADHD, educational attainment (EA) and cognition (COG) to understand the nature of the Behavior Rating Inventory for Executive Functions (BRIEF) and its relationship to academic functioning. METHOD: Participants were 991 youth, ages 7 to 17, consecutively referred for neuropsychiatric evaluation. Polygenic scores (PGS) for ADHD, EA, and COG were related to the BRIEF using regression analyses. Structural equation models were used to examine the associations between the PGS, BRIEF and academic outcomes (math, reading, and special education services [EDPLAN]). RESULTS: After modeling the PGS together, only the EA and ADHD PGS significantly associated with the BRIEF. The BRIEF partially mediated the relationships between EA PGS with math and EDPLAN and fully mediated the relationship between ADHD PGS and EDPLAN. CONCLUSION: Genetic data extend evidence that the BRIEF measures a construct relevant to educational success that differs from what is indexed by cognitive testing.

Behavior ratings of executive functions index multiple domains of psychopathology and school functioning in child psychiatric outpatients.

Behavior rating scales of executive functions (EFs) are convenient and associate with academic and other outcomes; however, prior studies indicate limited correlations with psychometric tests of EFs. To better understand their potential for clinical utility, we examined the extent to which parent ratings on the Behavior Rating Inventory of Executive Function (BRIEF) related to psychopathology constructs and psychometric test scores in a sample of N = 692 psychiatric outpatients aged 8-17. Then, in a subsample of the youth (N = 261), we related the BRIEF, psychopathology constructs, and psychometric test scores to teacher ratings of school functioning. BRIEF scales were significantly associated with multiple types of psychopathology including ADHD, autism spectrum, mood, anxiety, conduct, oppositional defiant, and psychotic disorders. While the BRIEF showed limited associations with psychometric EF tests, its Global Executive Composite score explained additional variance in teacher-reported functioning beyond what was predicted by clinical diagnoses (additional explained variance of 9.9% in study skills) and psychometric tests (additional explained variance of 2.1% in learning problems and 4.5% in study skills). The Global Executive Composite was not significantly related to teacher-rated school functioning after psychiatric symptoms were accounted for. These findings support further investigation of the unique contribution of the BRIEF in clinical practice.

Differences in cognitive and academic performance during the COVID-19 pandemic in child psychiatric outpatients.

This study examined the impact of the COVID-19 pandemic on cognitive and academic functioning in 574 youth presenting for outpatient clinical neuropsychiatric evaluations. We extended the prior literature by (a) determining the extent to which academic difficulties documented in population and community samples also occurred in child psychiatric outpatients; (b) evaluating the impact of the pandemic on neuropsychological functions relevant to academic performance (overall cognition, executive functions, and graphomotor skill); and (c) investigating the moderating impact of attention deficit hyperactivity disorder (ADHD) diagnosis. We compared cross-sectional scores on standardized measures for groups of youth evaluated at three time periods related to the COVID-19 pandemic: (a) prior to onset (PRIOR; N = 198), (b) during Year 1 (Y1; N = 149), and (c) during Year 2 (Y2; N = 227). Relative to overall cognitive ability, math scores were lower in Y1 and Y2 and reading scores were lower in Y2. Additionally, relative to overall cognitive ability, youth showed lower working memory in Y1 and lower processing speed in Y1 and Y2. Graphomotor skill and parent-rated executive functions (EF) did not vary significantly across the three time periods. ADHD status did not moderate psychometric test scores but did moderate parent-rated EF. These data suggest that the COVID-19 pandemic has negatively impacted academic and executive functions in child psychiatry outpatients. More research is needed to understand the long-term implications for development. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Distinct patterns of emotional and behavioral change in child psychiatry outpatients during the COVID-19 pandemic.

BACKGROUND: Studies are documenting the impact of the COVID-19 pandemic on youth mental health. We extended this literature by characterizing a child psychiatric outpatient sample in the United States during the middle of the 2020-2021 school year. We also used a computational strategy to identify distinct patterns of psychopathology symptom change and examined correlates and predictors of such change. Among potential predictors were cognition and clinical diagnoses, which have not been studied in this context previously. METHODS: Participants were 171 youth (aged 10.6 ± 3.1) referred for neuropsychiatric evaluation who enrolled in research and whose parents filled out a survey on COVID-19. The questionnaire included eight psychiatric and six psychosocial domains rated retrospectively prior to the pandemic and currently at the time of evaluation. We examined change in severity of individual domains with Wilcoxon signed-rank tests. We used a latent profile analysis (LPA) to identify groups with distinct symptom change profiles. Using multinomial logistic regression, we examined potential predictors and correlates of LPA-derived groups. Models controlled for age, sex, and assessment date and corrected for multiple testing. RESULTS: Although the majority of individual psychopathology domains were worse on average during the 2020-2021 school year, youth showed distincive patterns of symptom change. In addition to a large group (72.2%) with relatively stable symptoms and a small group (6.4%) that improved on most symptoms, there were two groups with different constellations of worsening symptoms. These latter groups both showed increased sadness, anxiety and oppositionality; however, one had increased hyperactivity/impulsivity and no change in hopelessness while the other showed greater hopelessness and no change in hyperactivity. Symptoms related to the distinguishable domains of these groups predicted group membership, and changes in screen time, conflict with parents and social isolation were correlates of worsening. Cognition and lifetime clinical diagnoses failed to predict group membership. CONCLUSIONS: In youth outpatients, psychiatric and psychosocial difficulties were worse on average during the school year following the spring 2020 COVID-19 lockdown; yet, some youth experienced greater and distinctive symptom change. A personalized approach to support may be needed as youth emerge from this period.

Integrating questionnaire measures for transdiagnostic psychiatric phenotyping using word2vec.

BACKGROUND: Recent initiatives in psychiatry emphasize the utility of characterizing psychiatric symptoms in a multidimensional manner. However, strategies for applying standard self-report scales for multiaxial assessment have not been well-studied, particularly where the aim is to support both categorical and dimensional phenotypes. METHODS: We propose a method for applying natural language processing to derive dimensional measures of psychiatric symptoms from questionnaire data. We utilized nine self-report symptom measures drawn from a large cellular biobanking study that enrolled individuals with mood and psychotic disorders, as well as healthy controls. To summarize questionnaire results we used word embeddings, a technique to represent words as numeric vectors preserving semantic and syntactic meaning. A low-dimensional approximation to the embedding space was used to derive the proposed succinct summary of symptom profiles. To validate our embedding-based disease profiles, these were compared to presence or absence of axis I diagnoses derived from structured clinical interview, and to objective neurocognitive testing. RESULTS: Unsupervised and supervised classification to distinguish presence/absence of axis I disorders using survey-level embeddings remained discriminative, with area under the receiver operating characteristic curve up to 0.85, 95% confidence interval (CI) (0.74,0.91) using Gaussian mixture modeling, and cross-validated area under the receiver operating characteristic curve 0.91, 95% CI (0.88,0.94) using logistic regression. Derived symptom measures and estimated Research Domain Criteria scores also associated significantly with performance on neurocognitive tests. CONCLUSIONS: Our results support the potential utility of deriving dimensional phenotypic measures in psychiatric illness through the use of word embeddings, while illustrating the challenges in identifying truly orthogonal dimensions.

Translating Discoveries in Attention-Deficit/Hyperactivity Disorder Genomics to an Outpatient Child and Adolescent Psychiatric Cohort.

OBJECTIVE: Genomic discoveries should be investigated in generalizable child psychiatric samples in order to justify and inform studies that will evaluate their use for specific clinical purposes. In youth consecutively referred for neuropsychiatric evaluation, we examined 1) the convergent and discriminant validity of attention-deficit/hyperactivity disorder (ADHD) polygenic risk scores (PRSs) in relation to DSM-based ADHD phenotypes; 2) the association of ADHD PRSs with phenotypes beyond ADHD that share its liability and have implications for outcome; and 3) the extent to which youth with high ADHD PRSs manifest a distinctive clinical profile. METHOD: Participants were 433 youth, ages 7-18 years, from the Longitudinal Study of Genetic Influences on Cognition. We used logistic/linear regression and mixed effects models to examine associations with ADHD-related polygenic variation from the largest ADHD genome-wide association study to date. We replicated key findings in 5,140 adult patients from a local health system biobank. RESULTS: Among referred youth, ADHD PRSs were associated with ADHD diagnoses, cross-diagnostic ADHD symptoms and academic impairment (odds ratios ∼1.4; R2 values ∼2%-3%), as well as cross-diagnostic variation in aggression and working memory. In adults, ADHD PRSs were associated with ADHD and phenotypes beyond the condition that have public health implications. Finally, youth with a high ADHD polygenic burden showed a more severe clinical profile than youth with a low burden (ß coefficients ∼.2). CONCLUSION: Among child and adolescent outpatients, ADHD polygenic risk was associated with ADHD and related phenotypes as well as clinical severity. These results extend the scientific foundation for studies of ADHD polygenic risk in the clinical setting and highlight directions for further research.

Reliability and validity of the Thinking Skills Inventory, a screening tool for cross-diagnostic skill deficits underlying youth behavioral challenges.

Deficits in a range of skill domains (including executive functioning, emotion regulation, social cognition and language/communication) are associated with disrupted youth behavior and functioning across mental health diagnoses. The identification of skill deficits are important for effective treatment planning, particularly for personalized interventions. While there are multiple ways to assess these skills, parent/caregiver reports represent an important information source. To date, no single, brief measure has been developed that gathers parent/caregiver ratings across this range of constructs. We have developed a short caregiver-report questionnaire (the Thinking Skills Inventory; TSI), to screen for skill deficits. Here, we examine the reliability and validity of this rating scale in 384 youth who were consecutively referred for neuropsychiatric evaluation. A primary caregiver completed the TSI as well as other established measures. Exploratory and confirmatory factor analyses support five subscales on the TSI: Attention and Working Memory, Language and Communication, Emotion Regulation, Cognitive Flexibility, and Social Thinking Skills. The subscales showed moderate to high internal consistency (Cronbach's alphas range from 0.84 to 0.91). Correlations with established caregiver-report measures confirm their convergent and discriminant validity, and associations with multiple clinical diagnoses and cross-diagnostic aggressive behavior further support the utility of the scale for our intended purpose. In sum, this free, brief measure is a valid and reliable way to identify variation in skill domains relevant to a range of psychopathology. The TSI may be useful in youth mental health settings to assist with treatment planning and to inform referral for further evaluation.

High Throughput Phenotyping for Dimensional Psychopathology in Electronic Health Records.

BACKGROUND: Relying on diagnostic categories of neuropsychiatric illness obscures the complexity of these disorders. Capturing multiple dimensional measures of neuropathology could facilitate the clinical and neurobiological investigation of cognitive and behavioral phenotypes. METHODS: We developed a natural language processing-based approach to extract five symptom dimensions, based on the National Institute of Mental Health Research Domain Criteria definitions, from narrative clinical notes. Estimates of Research Domain Criteria loading were derived from a cohort of 3619 individuals with 4623 hospital admissions. We applied this tool to a large corpus of psychiatric inpatient admission and discharge notes (2010-2015), and using the same cohort we examined face validity, predictive validity, and convergent validity with gold standard annotations. RESULTS: In mixed-effect models adjusted for sociodemographic and clinical features, greater negative and positive symptom domains were associated with a shorter length of stay (ß = -.88, p = .001 and ß = -1.22, p < .001, respectively), while greater social and arousal domain scores were associated with a longer length of stay (ß = .93, p < .001 and ß = .81, p = .007, respectively). In fully adjusted Cox regression models, a greater positive domain score at discharge was also associated with a significant increase in readmission risk (hazard ratio = 1.22, p < .001). Positive and negative valence domains were correlated with expert annotation (by analysis of variance [df = 3], R2 = .13 and .19, respectively). Likewise, in a subset of patients, neurocognitive testing was correlated with cognitive performance scores (p < .008 for three of six measures). CONCLUSIONS: This shows that natural language processing can be used to efficiently and transparently score clinical notes in terms of cognitive and psychopathologic domains.

The Dutch Central Sensitization Inventory (CSI): Factor Analysis, Discriminative Power, and Test-Retest Reliability.

OBJECTIVES: A standardized assessment of central sensitization can be performed with the Central Sensitization Inventory (CSI), an English questionnaire consisting of 25 items relating to current health symptoms. The aim of this study was to translate the CSI into Dutch, to perform a factor analysis to reveal the underlying structure, examine its discriminative power, and test-retest reliability. METHODS: The CSI was first translated into Dutch. A factor analysis was conducted on CSI data of a large group of chronic pain patients (n=368). The ability to discriminate between chronic pain patients (n=188) and pain-free controls (n=49) was determined and the test-retest reliability for chronic pain patients (n=36) and controls (n=45) with a time interval of 3 weeks was evaluated. RESULTS: The exploratory factor analysis resulted in a 4-factor model based on 20 items, representing the domains "General disability and physical symptoms" (Cronbach α=0.80), "Higher central sensitivity"(Cronbach α=0.78), "Urological and dermatological symptoms"(Cronbach α=0.60), and "Emotional distress"(Cronbach α=0.80). Furthermore, a parsimonious second-order factor model was found, where the factor "General central sensitization" was underlying the 4 first-order factors. Chronic pain patients scored significantly worse on all 4 factors. The test-retest reliability was excellent values in both chronic pain patients (ICC=0.88) and controls (ICC=0.91). DISCUSSION: The original CSI was translated into Dutch and did not reveal any problems during data acquisition. The domains represented by the 4 factors may be useful in setting up specific patient profiles and treatment targets. To conclude, the Dutch CSI revealed 4 distinguishable domains, showed good internal consistency for the total score and 3 out of 4 domains, good discriminative power, and excellent test-retest reliability.

Glutamine effects on brain growth in very preterm children in the first year of life.

BACKGROUND & AIMS: Glutamine supplementation in the neonatal period has been associated with increased brain structure volumes at school-age in very preterm children. The aim of this study was to clarify the emergence and specificity of differences in brain structure volumes, using growth trajectories of head circumference, weight, and length. METHODS: Sixty-five very preterm (<32 weeks gestation) children, who originally took part in a randomized controlled trial on glutamine supplementation, participated. Head circumference, weight, and length, were measured at the neonatal intensive care unit, and at routine follow-up assessments at the outpatient clinic and well baby clinics. Magnetic Resonance Imaging was used to determine brain structure volumes at school-age. Growth trajectories were investigated using multilevel modeling analyses. RESULTS: Head circumference in the first year of life was positively associated with white matter volume and grey matter volume (range r = 0.55-0.81, all p < 0.002) at school-age. Furthermore, neonatal glutamine supplementation was associated with increased head circumference growth (p = 0.008) in the first year of life, but not with increased growth in weight (p = 0.44) and length (p = 0.73). CONCLUSIONS: This study indicates a specific increase in head circumference growth in very preterm children that received neonatal glutamine supplementation, and suggests that group differences in brain structure volumes at school-age may have emerged during the first year of life.