Atypical brain structure mediates reduced IQ in young adults born preterm with very low birth weight.

Preterm birth with very low birth weight (VLBW) confers heightened risk for perinatal brain injury and long-term cognitive deficits, including a reduction in IQ of up to one standard deviation. Persisting gray and white matter aberrations have been documented well into adolescence and adulthood in preterm born individuals. What has not been documented so far is a plausible causal link between reductions in cortical surface area or subcortical brain structure volumes, and the observed reduction in IQ. The NTNU Low Birth Weight in a Lifetime Perspective study is a prospective longitudinal cohort study, including a preterm born VLBW group (birthweight ≤1500 g) and a term born control group. Structural magnetic resonance imaging data were obtained from 38 participants aged 19, born preterm with VLBW, and 59 term-born peers. The FreeSurfer software suite was used to obtain measures of cortical thickness, cortical surface area, and subcortical brain structure volumes. Cognitive ability was estimated using the Wechsler Adult Intelligence Scale, 3rd Edition, including four IQ-indices: Verbal comprehension, Working memory, Perceptual organization, and Processing speed. Statistical mediation analyses were employed to test for indirect effects of preterm birth with VLBW on IQ, mediated by atypical brain structure. The mediation analyses revealed negative effects of preterm birth with VLBW on IQ that were partially mediated by reduced surface area in multiple regions of frontal, temporal, parietal and insular cortex, and by reductions in several subcortical brain structure volumes. The analyses did not yield sufficient evidence of mediation effects of cortical thickness on IQ. This is, to our knowledge, the first time a plausible causal relationship has been established between regional cortical area reductions, as well as reductions in specific subcortical and cerebellar structures, and general cognitive ability in preterm born survivors with VLBW.

Multidisciplinary and neuroimaging findings in preterm born very low birthweight individuals from birth to 28 years of age: A systematic review of a Norwegian prospective cohort study.

BACKGROUND: Children born preterm with very low birthweight (VLBW) face long-lasting neurodevelopmental challenges, where multidisciplinary assessments are warranted. The International Classification of Functioning, Disability and Health (ICF) provides a framework for understanding and conceptualising these outcomes. OBJECTIVES: We aimed to review clinical and neuroimaging findings from birth to adulthood in a Norwegian cohort of individuals born preterm with VLBW (gestational age <37 weeks, birthweight ≤1500 g) within the framework of ICF. DATA SOURCES: We searched PubMed and Embase for articles reporting results of the Norwegian University of Science and Technology (NTNU) Low Birth Weight in a Lifetime Perspective study. STUDY SELECTION AND DATA EXTRACTION: We included original articles reporting proportions of adverse outcomes, mean group differences, risk factors or associations between outcomes. Data were extracted according to ICF's two-level classification. Body functions and structures comprised outcomes of brain structures, cognition, mental health, vision, pain and physical health. Activities and participation comprised motor skills, general and social functioning, education, employment, and health-related quality of life. SYNTHESIS: We performed a qualitative synthesis of included articles. Where mean (SD) was reported, we calculated group differences in SD units. RESULTS: Fifty-eight publications were included. Within body functions and structures, increased prevalence of brain structure pathology, lower cognitive performance, mental health problems, visual and physical health impairments through childhood, adolescence and young adulthood were reported among preterm VLBW participants compared with controls. Within activities and participation, motor problems, lower general and social functioning, and lower academic attainment were found. Perinatal factors were associated with several outcomes, and longitudinal findings suggested persistent consequences of being born preterm with VLBW. CONCLUSIONS: Being born preterm with VLBW has long-term influences on body functions and structures, activities and participation. The ICF is appropriate for assessing general domains of functioning and guiding the management of individuals born preterm with VLBW.

Reduced white matter fractional anisotropy mediates cortical thickening in adults born preterm with very low birthweight.

Development of the cerebral cortex may be affected by aberrant white matter development. Preterm birth with very low birth weight (VLBW) has been associated with reduced fractional anisotropy of white matter and changes in cortical thickness and surface area. We use a new methodological approach to combine white and gray matter data and test the hypothesis that white matter injury is primary, and acts as a mediating factor for concomitant gray matter aberrations, in the developing VLBW brain. T1 and dMRI data were obtained from 47 young adults born preterm with VLBW and 73 term-born peers (mean age = 26). Cortical thickness was measured across the cortical mantle and compared between the groups, using the FreeSurfer software suite. White matter pathways were reconstructed with the TRACULA software and projected to their cortical end regions, where cortical thickness was averaged. In the VLBW group, cortical thickness was increased in anteromedial frontal, orbitofrontal, and occipital regions, and fractional anisotropy (FA) was reduced in frontal lobe pathways, indicating compromised white matter integrity. Statistical mediation analyses demonstrated that increased cortical thickness in the frontal regions was mediated by reduced FA in the corpus callosum forceps minor, consistent with the notion that white matter injury can disrupt frontal lobe cortical development. Combining statistical mediation analysis with pathway projection onto the cortical surface offers a powerful novel tool to investigate how cortical regions are differentially affected by white matter injury.

Psychiatric symptoms and risk factors in adults born preterm with very low birthweight or born small for gestational age at term.

BACKGROUND: We aimed to examine psychiatric symptoms in adults born preterm with very low birthweight or born at term small for gestational age compared with normal birthweight peers, and examine associations with perinatal factors and childhood motor and cognitive function. METHODS: In this longitudinal cohort study, one preterm born group with very low birthweight (VLBW: birthweight ≤1500 g), one term-born Small for Gestational Age (SGA: birthweight <10th percentile) group and one term-born non-SGA control group, were assessed at 26 years of age. Primary outcomes were scores on self-reported questionnaires: Achenbach System of Empirically Based Assessment - Adult Self-Report, The Autism-Spectrum Quotient and Peters et al. Delusions Inventory. Exposure variables were perinatal data, while childhood motor and cognitive function were examined as possible early markers. RESULTS: Both the preterm VLBW and the term SGA group reported higher levels of attention, internalizing and externalizing problems compared to the control group. In addition, the VLBW participants reported more critical items and a higher proportion had intermediate level autistic traits, while the SGA participants reported more intrusive behavior. Increasing length of respiratory support and hospital stay in the neonatal period, and motor problems in early adolescence, were associated with adult psychiatric symptoms in the VLBW group. CONCLUSIONS: Psychiatric symptoms were frequent in the preterm VLBW group and also in the term-born SGA group. Those who were sickest as babies were most at risk. Motor problems can possibly serve as an early marker of adult psychiatric symptoms in low birthweight individuals.

Preterm birth leads to hyper-reactive cognitive control processing and poor white matter organization in adulthood.

Individuals born preterm with very low birth weight (VLBW; birth weight ≤ 1500 g) are at high risk for perinatal brain injuries and deviant brain development, leading to increased chances of later cognitive, emotional, and behavioral problems. Here we investigated the neuronal underpinnings of both reactive and proactive cognitive control processes in adults with VLBW. We included 32 adults born preterm with VLBW (before 37th week of gestation) and 32 term-born controls (birth weight ≥10th percentile for gestational age) between 22 and 24 years of age that have been followed prospectively since birth. Participants performed a well-validated Not-X continuous performance test (CPT) adapted for use in a mixed block- and event-related fMRI protocol. BOLD fMRI and DTI data was acquired on a 3T scanner. Performance on the Not-X CPT was highly similar between groups. However, the VLBW group demonstrated hyper-reactive cognitive control processing and disrupted white matter organization. The hyper-reactive brain activation signature in VLBW adults was associated with lower gestational age, lower fluid intelligence score, and anxiety problems. Automated Multi-Atlas Tract Extraction (AutoMATE) analyses revealed that this disruption of normal brain function was accompanied by poorer white matter organization in the anterior thalamic radiation and the cingulum, as reflected in both reduced fractional anisotropy and increased mean diffusivity. These findings show that the preterm behavioral phenotype is associated with predominantly reactive-, rather than proactive cognitive control processing, as well as white matter abnormalities, that may underlie common difficulties that many preterm born individuals experience in everyday life.

A longitudinal study of associations between psychiatric symptoms and disorders and cerebral gray matter volumes in adolescents born very preterm.

BACKGROUND: Being born preterm with very low birthweight (VLBW ≤ 1500 g) poses a risk for cortical and subcortical gray matter (GM) abnormalities, as well as for having more psychiatric problems during childhood and adolescence than term-born individuals. The aim of this study was to investigate the relationship between cortical and subcortical GM volumes and the course of psychiatric disorders during adolescence in VLBW individuals. METHODS: We followed VLBW individuals and term-born controls (birth weight ≥10th percentile) from 15 (VLBW;controls n = 40;56) to 19 (n = 44;60) years of age. Of these, 30;37 individuals were examined longitudinally. Cortical and subcortical GM volumes were extracted from MRPRAGE images obtained with the same 1.5 T MRI scanner at both time points and analyzed at each time point with the longitudinal stream of the FreeSurfer software package 5.3.0. All participants underwent clinical interviews and were assessed for psychiatric symptoms and diagnosis (Schedule for Affective Disorders and Schizophrenia for School-age Children, Children's Global Assessment Scale, Attention-Deficit/Hyperactivity Disorder Rating Scale-IV). VLBW adolescents were divided into two groups according to diagnostic status from 15 to 19 years of age: persisting/developing psychiatric diagnosis or healthy/becoming healthy. RESULTS: Reduction in subcortical GM volume at 15 and 19 years, not including the thalamus, was limited to VLBW adolescents with persisting/developing diagnosis during adolescence, whereas VLBW adolescents in the healthy/becoming healthy group had similar subcortical GM volumes to controls. Moreover, across the entire VLBW group, poorer psychosocial functioning was predicted by smaller subcortical GM volumes at both time points and with reduced GM volume in the thalamus and the parietal and occipital cortex at 15 years. Inattention problems were predicted by smaller GM volumes in the parietal and occipital cortex. CONCLUSIONS: GM volume reductions in the parietal and occipital cortex as well as smaller thalamic and subcortical GM volumes were associated with the higher rates of psychiatric symptoms found across the entire VLBW group. Significantly smaller subcortical GM volumes in VLBW individuals compared with term-born peers might pose a risk for developing and maintaining psychiatric diagnoses during adolescence. Future research should explore the possible role of reduced cortical and subcortical GM volumes in the pathogenesis of psychiatric illness in VLBW adolescents.

No improvement of neuronal metabolism in the reperfusion phase with melatonin treatment after hypoxic-ischemic brain injury in the neonatal rat.

Mitochondrial impairment is a key feature underlying neonatal hypoxic-ischemic (HI) brain injury and melatonin is potentially neuroprotective through its effects on mitochondria. In this study, we have used (1) H and (13) C NMR spectroscopy after injection of [1-(13) C]glucose and [1,2-(13) C]acetate to examine neuronal and astrocytic metabolism in the early reperfusion phase after unilateral HI brain injury in 7-day-old rat pups, exploring the effects of HI on mitochondrial function and the potential protective effects of melatonin on brain metabolism. One hour after hypoxia-ischemia, astrocytic metabolism was recovered and glycolysis was normalized, whereas mitochondrial metabolism in neurons was clearly impaired. Pyruvate carboxylation was also lower in both hemispheres after HI. The transfer of glutamate from neurons to astrocytes was higher whereas the transfer of glutamine from astrocytes to neurons was lower 1 h after HI in the contralateral hemisphere. Neuronal metabolism was equally affected in pups treated with melatonin (10 mg/kg) immediately after HI as in vehicle treated pups indicating that the given dose of melatonin was not capable of protecting the neuronal mitochondria in this early phase after HI brain injury. However, any beneficial effects of melatonin might have been masked by modulatory effects of the solvent dimethyl sulfoxide on cerebral metabolism. Neuronal and astrocytic metabolism was examined by (13) C and (1) H NMR spectroscopy in the early reperfusion phase after unilateral hypoxic-ischemic brain injury and melatonin treatment in neonatal rats. One hour after hypoxia-ischemia astrocytic mitochondrial metabolism had recovered and glycolysis was normalized, whereas mitochondrial metabolism in neurons was impaired. Melatonin treatment did not show a protective effect on neuronal metabolism.

Long-term follow-up of mental health, health-related quality of life and associations with motor skills in young adults born preterm with very low birth weight.

BACKGROUND: Being born with very low birth weight (VLBW: ≤ 1,500 g) is related to long-term disability and neurodevelopmental problems, possibly affecting mental health and health-related quality of life (HRQoL). However, studies in young adulthood yield mixed findings. The aim of this study was to examine mental health and HRQoL at 23 years, including changes from 20 to 23 years and associations with motor skills in VLBW young adults compared with controls. METHODS: In a geographically based follow-up study, 35 VLBW and 37 term-born young adults were assessed at 23 years by using Achenbach Adult Self-Report (ASR), Short Form 36 Health Survey (SF-36), Beck Depression Inventory (BDI) and various motor tests. The ASR and SF-36 were also used at 20 years. Longitudinal changes in ASR and SF-36 from 20 to 23 years were analysed by linear mixed models and associations with motor skills at 23 years by linear regression. RESULTS: At 23 years, total ASR score was 38.6 (SD: 21.7) in the VLBW group compared with 29.0 (SD: 18.6) in the control group (p = 0.048). VLBW participants had higher scores for attention problems, internalizing problems and critical items, and they reported to drink less alcohol than controls. BDI total score did not differ between groups. On SF-36, VLBW participants reported significantly poorer physical and social functioning, more role-limitations due to physical and emotional problems, more bodily pain and lower physical and mental component summaries than controls. In the VLBW group, total ASR score increased by 9.0 (95 % CI: 3.3 to 14.7) points from 20 to 23 years (p = 0.009 vs controls), physical and mental component summaries of SF-36 decreased by 2.9 (95 % CI: -4.8 to -1.1) and 4.4 (95 % CI: -7.1 to -1.7) points, respectively (p = 0.012 and p = 0.022 vs controls). Among VLBW participants, more mental health problems and lower physical and mental HRQoL were associated with poorer motor skills at 23 years. CONCLUSIONS: VLBW young adults reported poorer and declining mental health and HRQoL in the transitional phase into adulthood. They seemed to have a cautious lifestyle with more internalizing problems and less alcohol use. The associations of mental health problems and HRQoL with motor skills are likely to reflect a shared aetiology.

Computerized working memory training has positive long-term effect in very low birthweight preschool children.

AIM: Working memory deficits are frequently found in children born preterm and have been linked to learning disabilities, and cognitive and behavioural problems. Our aim was to evaluate if a computerized working memory training program has long-term positive effects on memory, learning, and behaviour in very-low-birthweight (VLBW) children at age 5 to 6 years. METHOD: This prospective, intervention study included 20 VLBW preschool children in the intervention group and 17 age-matched, non-training VLBW children in the comparison group. The intervention group trained with the Cogmed JM working memory training program daily for 5 weeks (25 training sessions). Extensive neuropsychological assessment and parental questionnaires were performed 4 weeks after intervention and at follow-up 7 months later. For most of the statistical analyses, general linear models were applied. RESULTS: At follow-up, higher scores and increased or equal performance gain were found in the intervention group than the comparison group on memory for faces (p=0.012), narrative memory (p=0.002), and spatial span (p=0.003). No group differences in performance gain were found for attention and behaviour. INTERPRETATION: Computerized working memory training seems to have positive and persisting effects on working memory, and visual and verbal learning, at 7-month follow-up in VLBW preschool children. We speculate that such training is beneficial by improving the ability to learn from the teaching at school and for further cognitive development.

Prevalence and comorbidity of mental disorders among adolescents living in residential youth care.

Most adolescents are placed in residential youth care (RYC) because of severe psychosocial strains and child maltreatment, which represent risk factors for developing mental disorders. To plan RYC units and ensure that residents receive evidence-based psychiatric interventions, it is necessary to obtain reliable and valid prevalence estimates of mental disorders in this population. However, there is a lacuna of research on diagnoses derived from standardized clinical interviews. The aim of this study was to assess the prevalence and comorbidity of mental disorders applying diagnostic interviews in an entire population of adolescents living in RYC in Norway. All young people in RYC were invited to participate in the study. Eighty-six RYC institutions with 601 eligible adolescents were included and 400 adolescents, 12-20 years old, participated in the study, yielding a response rate of 67 %. Anonymous Child Behaviour Checklist scores for 141 (70 %) of the declining residents were also available, allowing diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) for 541 youths to be estimated. Diagnoses were assessed by trained interviewers with the Child and Adolescent Psychiatric Assessment interview (CAPA). Seventy-six point two per cent (71.5-80.8 CI 95 %) of adolescents received at least one 3-month DSM-IV diagnosis. Prevalence rates for internalizing psychiatric disorders were higher than for behavioural disorders. Comorbidity was high between these two groups. Mental disorders were prevalent among children and youth in RYC. Our results create major concerns and challenge the existing organization of the RYC system.

Altered astrocyte-neuronal interactions after hypoxia-ischemia in the neonatal brain in female and male rats.

BACKGROUND AND PURPOSE: Increased susceptibility to excitotoxicity of the neonatal brain after hypoxia-ischemia (HI) may be caused by limited capacity of astrocytes for glutamate uptake, and mitochondrial failure probably plays a key role in the delayed injury cascade. Male infants have poorer outcome than females after HI, possibly linked to differential intermediary metabolism. METHODS: [1-(13)C]glucose and [1,2-(13)C]acetate were injected at zero, 6, and 48 hours after unilateral HI in 7-day-old rats. Intermediary metabolism was analyzed with magnetic resonance spectroscopy. RESULTS: Mitochondrial metabolism was generally reduced in the ipsilateral hemisphere for ≤6 hours after HI, whereas contralaterally, it was reduced in neurons but not in astrocytes. Transfer of glutamate from neurons to astrocytes was increased in the contralateral, but not in the ipsilateral hemisphere at 0 hour, and reduced bilaterally at 6 hours after HI. The transfer of glutamine from astrocytes to glutamatergic neurons was unaltered in both hemispheres, whereas the transfer of glutamine to GABAergic neurons was increased ipsilaterally at 0 hour. Anaplerosis (astrocytes) was decreased, whereas partial pyruvate recycling (astrocytes) was increased directly after HI. Male pups had lower astrocytic mitochondrial metabolism than females immediately after HI, whereas that of females was reduced longer and encompassed both neurons and astrocytes. CONCLUSIONS: The prolonged depression in mitochondrial metabolism indicates that mitochondria are vulnerable targets in the delayed injury after neonatal HI. The degree of astrocytic malfunction may be a valid indicator of outcome after hypoxic/HI brain injury and may be linked to the differential outcome in males and females.

Brain morphometry and cognition in young adults born small for gestational age at term.

OBJECTIVES: To examine brain volumes and cortical surface area and thickness and to relate these brain measures to cognitive function in young adults born small for gestational age (SGA) at term compared with non-SGA control patients. STUDY DESIGN: This population-based follow-up study at age 20 years included 58 term-born SGA (birth weight <10th percentile, mean: 2915 g) and 81 non-SGA controls (birth weight ≥ 10th percentile, mean: 3707 g). Brain volumes and cortical surface area and thickness were investigated with magnetic resonance imaging, which was successfully obtained in 47 SGA patients and 61 control patients. Cognitive function was assessed using the Wechsler Adult Intelligence Scale, 3rd edition. A subgroup analysis was performed in the SGA group among subjects diagnosed with fetal growth restriction (FGR) based on repeated fetal ultrasound measurements. RESULTS: The SGA group showed regional reductions in cortical surface area, particularly in the frontal, parietal, and temporal lobes. Total brain volume, cortical gray matter, cerebral white matter, and putamen volumes were reduced in the SGA group compared with control patients, but there were no differences in specific subcortical brain structure volumes when correcting for intracranial volume. Reductions were most pronounced among SGA subjects with FGR. No associations were found between brain measures and IQ measures in either group. CONCLUSION: Young adults born SGA at term show a global reduction in brain volume as well as regional reductions in cortical surface area. We speculate whether these reductions may be confined to those exposed to FGR. None of the brain measures correlated with cognition.

Neuron-astrocyte interactions, pyruvate carboxylation and the pentose phosphate pathway in the neonatal rat brain.

Glucose and acetate metabolism and the synthesis of amino acid neurotransmitters, anaplerosis, glutamate-glutamine cycling and the pentose phosphate pathway (PPP) have been extensively investigated in the adult, but not the neonatal rat brain. To do this, 7 day postnatal (P7) rats were injected with [1-(13)C]glucose and [1,2-(13)C]acetate and sacrificed 5, 10, 15, 30 and 45 min later. Adult rats were injected and sacrificed after 15 min. To analyse pyruvate carboxylation and PPP activity during development, P7 rats received [1,2-(13)C]glucose and were sacrificed 30 min later. Brain extracts were analysed using (1)H- and (13)C-NMR spectroscopy. Numerous differences in metabolism were found between the neonatal and adult brain. The neonatal brain contained lower levels of glutamate, aspartate and N-acetylaspartate but similar levels of GABA and glutamine per mg tissue. Metabolism of [1-(13)C]glucose at the acetyl CoA stage was reduced much more than that of [1,2-(13)C]acetate. The transfer of glutamate from neurons to astrocytes was much lower while transfer of glutamine from astrocytes to glutamatergic neurons was relatively higher. However, transport of glutamine from astrocytes to GABAergic neurons was lower. Using [1,2-(13)C]glucose it could be shown that despite much lower pyruvate carboxylation, relatively more pyruvate from glycolysis was directed towards anaplerosis than pyruvate dehydrogenation in astrocytes. Moreover, the ratio of PPP/glucose-metabolism was higher. These findings indicate that only the part of the glutamate-glutamine cycle that transfers glutamine from astrocytes to neurons is operating in the neonatal brain and that compared to adults, relatively more glucose is prioritised to PPP and pyruvate carboxylation. Our results may have implications for the capacity to protect the neonatal brain against excitotoxicity and oxidative stress.

Executive functions in very-low-birth-weight young adults: a comparison between self-report and neuropsychological test results.

Executive functions are goal-directed control mechanisms that modulate the operation of other cognitive processes. Preterm born very-low-birth-weight (VLBW: birth weight<1500 grams) children have more problems with attention/executive function than their term born peers. The objective of this study is to examine if VLBW young adults had more self-reported attention/ executive problems and lower neuropsychological test results than controls. Furthermore, to investigate the relationship between self-reported attention/executive problems, general cognitive ability (IQ) and test results. Forty-two VLBW [mean birth weight 1237 (219) grams, and gestational age 29.3 (2.4) weeks] and 63 term born controls at age 19 years completed The BRIEF-A self-report of attention/executive functions in everyday life. The Wechsler Adult Intelligence Scale III was used to obtain IQ scores; subtests from Delis-Kaplan were used to assess attention/executive function. There were no differences between the VLBW young adults and controls on any of the BRIEF-A measures, but the VLBW subjects had lower scores on 8 of the 18 neuropsychological subtests (p<.01). Some correlations between BRIEF-A and the Stroop and TMT tests were found in the VLBW group. VLBW young adults do not report more problems regarding attention/executive function in daily life than controls despite lower results on several neuropsychological tests.

Neuropsychological deficits in young adults born small-for-gestational age (SGA) at term.

Reduced IQ, learning difficulties and poor school performance have been reported in small-for-gestational-age (SGA) subjects. However, few studies include a comprehensive neuropsychological assessment. Our aim was to study neuropsychological functioning in young adults born SGA at term. A comprehensive neuropsychological test battery was administered to 58 SGA subjects (birth weight <10th centile) born at term, and 81 term non-SGA controls (birth weight ≥10th centile). The SGA group obtained significantly (p < .01) lower scores on the attention, executive and memory domains compared to non-SGA controls and showed higher risk of obtaining scores below -1.5 SD on the memory domain (odds ratio = 13.3, 95% confidence interval: 1.57, 112.47). At a subtest level, the SGA group obtained lower scores on most neuropsychological tests, with significant differences on 6 of 46 measures: the Trail Making Test 3 (letter sequencing), the Wechsler Memory Scale mental control and the auditory immediate memory scale, the Design Fluency, the Stroop 3 (inhibition) and the Visual Motor Integration (VMI) motor coordination subtest. Young adults born SGA score more poorly on neuropsychological tests compared with non-SGA controls. Differences were modest, with more significant differences in the memory domain.

High-level mobility in chronic traumatic brain injury and its relationship with clinical variables and magnetic resonance imaging findings in the acute phase.

OBJECTIVES: To compare high-level mobility in individuals with chronic moderate-to-severe traumatic brain injury (TBI) with matched healthy controls, and to investigate whether clinical variables and magnetic resonance imaging (MRI) findings in the acute phase can predict high-level motor performance in the chronic phase. DESIGN: A longitudinal follow-up study. SETTING: A level 1 trauma center. PARTICIPANTS: Individuals (N=136) with chronic TBI (n=65) and healthy matched peers (n=71). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: High-Level Mobility Assessment Tool (HiMAT) and the revised version of the HiMAT performed at a mean of 2.8 years (range, 1.5-5.4y) after injury. RESULTS: Participants with chronic TBI had a mean HiMAT score of 42.7 (95% confidence interval [CI], 40.2-45.2) compared with 47.7 (95% CI, 46.1-49.2) in the control group (P<.01). Group differences were also evident using the revised HiMAT (P<.01). Acute-phase clinical variables and MRI findings explained 58.8% of the variance in the HiMAT score (P<.001) and 59.9% in the revised HiMAT score (P<.001). Lower HiMAT scores were associated with female sex (P=.031), higher age at injury (P<.001), motor vehicle collisions (P=.030), and posttraumatic amnesia >7 days (P=.048). There was a tendency toward an association between lower scores and diffuse axonal injury in the brainstem (P=.075). CONCLUSIONS: High-level mobility was reduced in participants with chronic, either moderate or severe TBI compared with matched peers. Clinical variables in the acute phase were significantly associated with high-level mobility performance in participants with TBI, but the role of early MRI findings needs to be further investigated. The findings of this study suggest that the clinical variables in the acute phase may be useful in predicting high-level mobility outcome in the chronic phase.

Small for gestational age and intrauterine growth restriction decreases cognitive function in young adults.

OBJECTIVE: To examine the effect on adult cognitive function of being born small for gestational age (SGA), and to evaluate whether cognitive function is related to intrauterine growth restriction (IUGR). STUDY DESIGN: Fifty-nine SGA subjects (birth weight <10th percentile) and 81 controls (birth weight ≥10th percentile) born at term underwent cognitive assessment with the Wechsler Adult Intelligence Scale-Third Edition at age 19-20 years. Repeated ultrasound measures of fetal growth were available for weeks 25, 33, and 37 in a subgroup of 29 SGA subjects and 75 control subjects, and these were data used to dichotomize the 29 SGA subjects into those with IUGR and those without IUGR. IUGR was defined as growth deviating more than -2 SD from the mean value of the control group. The effect of maternal smoking during pregnancy was considered as well. Group differences were analyzed using a general linear model, controlling for sex and socioeconomic status. RESULTS: The SGA group had lower full IQ scores than the control group (mean difference, -6.3; 95% CI, -2.8 to -9.7; P = .001), including lower scores on 6 of the Wechsler Adult Intelligence Scale-Third Edition subtests. In the SGA subgroup with repeated ultrasound measures, 6 of 29 subjects (21%) had IUGR, and these subjects also had a lower IQ compared with controls (mean difference, -14.0; 95% CI: -4.8 to -23.3; P = .003). Maternal smoking during pregnancy was related to lower IQ in the control group but not in the SGA group, independent of IUGR or non-IUGR status. CONCLUSION: IQ scores were lower in young adults born SGA compared with controls. Our analysis suggest that this outcome is related to IUGR.

Longitudinal diffusion tensor and manganese-enhanced MRI detect delayed cerebral gray and white matter injury after hypoxia-ischemia and hyperoxia.

BACKGROUND: Hypoxia-ischemia (HI) induces delayed inflammation and long-term gray and white matter brain injury that may be altered by hyperoxia. METHODS: HI and 2 h of hyperoxia (100% O2) or room air (21% O2) in 7-d-old (P7) rats were studied by magnetic resonance imaging at 7 Tesla during 42 d: apparent diffusion coefficient (ADC) maps on day 1; T(1)-weighted manganese-enhanced images on day 7; diffusion tensor images on days 21 and 42; and T2 maps at all time points. RESULTS: The long-term brain tissue destruction on T2 maps was more severe in HI+hyperoxia than HI+room air. ADC was lower in HI+hyperoxia vs. HI+room air and sham and was correlated with long-term outcome. Manganese enhancement indicating inflammation was seen in both the groups along with more microglial activation in HI+hyperoxia on day 7. Fractional anisotropy (FA) in corpus callosum was lower and radial diffusivity was higher in HI+hyperoxia than that in HI+room air and sham on day 21. From day 21 to day 42, FA and radial diffusivity in HI+hyperoxia were unchanged, whereas in HI+room air, FA increased and radial diffusivity decreased to values similar to sham. CONCLUSION: Hyperoxia caused a more severe tissue destruction, delayed irreversible white matter injury, and increased inflammatory response resulting in a worsening in the trajectory of injury after HI in developing gray and white matter.

Cognitive control deficits in adolescents born with very low birth weight (≤ 1500 g): evidence from dichotic listening.

The objective of the paper is to explore bottom-up auditory and top-down cognitive processing abilities as part of long-term outcome assessment of preterm birth. Fifty-five adolescents (age 13-15) born with very low birth weight (VLBW) were compared to 80 matched controls born to term, using three consonant-vowel dichotic listening (DL) instruction conditions (non-forced, forced-right and forced-left). DL scores were correlated with cortical gray matter thickness derived from T1-weighted structural MRI volumes using FreeSurfer to examine group differences also in the neural correlates of higher cognitive processes. While showing normal bottom-up processing, VLBW adolescents displayed impaired top-down controlled conflict processing related to significant cortical thickness differences in left superior temporal gryus and anterior cingulate cortex. Preterm birth with VLBW induces fundamental changes in brain function and structure posing a risk for long-term neurocognitive impairments. Deficits emerge in situations of increasing cognitive conflict and can be related to measures of executive functions as well as morphology.

Doxycycline treatment in a neonatal rat model of hypoxia-ischemia reduces cerebral tissue and white matter injury: a longitudinal magnetic resonance imaging study.

Doxycycline may potentially be a neuroprotective treatment for neonatal hypoxic-ischemic brain injury through its anti-inflammatory effects. The aim of this study was to examine any long-term neuroprotection by doxycycline treatment on cerebral gray and white matter. Hypoxic-ischemic brain injury was induced in 7-day-old rats. Pups were treated with either doxycycline (HI+doxy) or saline (HI+vehicle) by intraperitoneal injection at 1 h after hypoxia-ischemia (HI). At 6 h after HI, MnCl(2) was injected intraperitoneally for later manganese-enhanced magnetic resonance imaging (MRI). MRI was performed with diffusion-weighted imaging on day 1 and T(1) -weighted imaging and diffusion tensor imaging at 7, 21 and 42 days after HI. Animals were killed after MRI on day 42 and histological examinations of the brains were performed. There was a tendency towards lower lesion volumes on diffusion maps among HI+doxy than HI+vehicle rats at 1 day after HI. Volumetric MRI showed increasing differences between groups with time after HI, with less cyst formation and less cerebral tissue loss among HI+doxy than HI+vehicle pups. HI+doxy pups had less manganese enhancement on day 7 after HI, indicating reduced inflammation. HI+doxy pups had higher fractional anisotropy on diffusion tensor imaging in major white matter tracts in the injured hemisphere than HI+vehicle pups, indicating less injury to white matter and better myelination. Histological examinations supported the MRI results. Lesion size on early MRI was highly correlated with final injury measures. In conclusion, a single dose of doxycycline reduced long-term cerebral tissue loss and white matter injury after neonatal HI, with an increasing effect of treatment with time after injury.