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The current recommendation for umbilical cord management of non-vigorous infants (limp, pale, and not breathing) who need resuscitation at birth is to immediately clamp the umbilical cord. This recommendation is due in part to insufficient evidence for delayed cord clamping (DCC) or umbilical cord milking (UCM). These methods may provide a neuroprotective mechanism that also facilitates cardiovascular transition for non-vigorous infants at birth.

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The aims of this study were to investigate the consequences of prolonged patterns of alcohol and marijuana use on white matter integrity and neurocognitive functioning in late adolescence, and examine neurodevelopmental trajectories over three years of regular follow-up visits. Three groups of demographically similar teens received assessments every 1.5 years (controls with consistently minimal substance use, n=16; teens who gradually increase their heavy episodic drinking n=17, and continuous binge drinkers with heavy marijuana use, n=21), including comprehensive neuropsychological evaluations, diffusion tensor imaging, and detailed substance use interviews. One-way ANOVA identified fifteen white matter clusters that significantly differed between groups at 3-year follow-up, ages 19-22; controls consistently demonstrated higher values of tissue integrity across fiber tracts. Repeated measures ANOVA revealed significant declines in white matter integrity from baseline to 3-year follow-up in the subsample of substance users, along with poorer global neurocognitive performance in alcohol users with heavy marijuana use by the 18-month follow-up. Findings suggest healthier brain white matter microstructure and better neurocognitive performance for teens free from heavy alcohol and marijuana use. Long-term engagement in these substances may adversely influence white matter and increase vulnerability for development of neuropathology purported to underlie future risk-taking and addictive behaviors.

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Characterizing the effects of alcohol and marijuana use on adolescent brain development is important for understanding potential alterations in neurodevelopment. Several cross sectional studies have identified group differences in white matter integrity after initiation of heavy alcohol and marijuana use, however none have explored white matter trajectories in adolescents pre- and post initiation of use, particularly for marijuana users. This study followed 16 adolescents with minimal alcohol and marijuana use at ages 16-18 over three years. At follow-up, teens were 19-22 years old; half of the participants initiated heavy alcohol use and half initiated heavy alcohol and marijuana use. Repeated-measures ANOVA revealed 20 clusters in association and projection fibers tracts (p < 0.01) in which a group by time interaction was found. Most consistently, white matter integrity (i.e., fractional anisotropy) decreased for those who initiated both heavy alcohol and marijuana use over the follow-up interval. No effect of time or change in white matter integrity was seen for those who initiated alcohol use only in the majority of clusters. In most regions, at the baseline time point, teens who would later initiate both alcohol and marijuana use demonstrated white matter integrity greater than or equal to teens that initiated alcohol use only. Findings suggest poorer tissue integrity associated with combined initiation of heavy alcohol and marijuana use in late adolescence. While OPEN ACCESS pre-existing differences may also be related to likelihood of substance use, the present data suggest an effect on tissue integrity for these teens transitioning to combined alcohol and marijuana use in later adolescence.

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White matter development is important for efficient communication between brain regions, higher order cognitive functioning, and complex behaviors. Adolescents have a higher propensity for engaging in risky behaviors, yet few studies have explored associations between white matter integrity and risk taking directly. Altered white matter integrity in mid-adolescence was hypothesized to predict subsequent risk taking behaviors 1.5 years later. Adolescent substance users (predominantly alcohol and marijuana, n = 47) and demographically similar nonusers (n = 49) received diffusion tensor imaging at baseline (ages 16-19), and risk taking measures at both baseline and an 18-month follow-up (i.e., at ages 17-20). Brain regions of interest were the fornix, superior corona radiata, superior longitudinal fasciculus, and superior fronto-occipital fasciculus. In substance-using youth (n = 47), lower white matter integrity at baseline in the fornix and superior corona radiata predicted follow-up substance use (ΔR2 = 10-12%, ps < .01), and baseline fornix integrity predicted follow-up delinquent behaviors (ΔR2 = 10%, p < .01) 1.5 years later. Poorer fronto-limbic white matter integrity was linked to a greater propensity for future risk taking behaviors among youth who initiated heavy substance use by mid-adolescence. Most notable were relationships between projection and limbic-system fibers and future substance-use frequency. Subcortical white matter coherence, along with an imbalance between the maturation levels in cognitive control and reward systems, may disadvantage the resistance to engage in risk taking behaviors during adolescence.

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BACKGROUND: The influence of repeated substance use during adolescent neurodevelopment remains unclear as there have been few prospective investigations. The aims of this study were to identify longitudinal changes in fiber tract integrity associated with alcohol- and marijuana-use severity over the course of 1.5 years. METHODS: Adolescents with extensive marijuana- and alcohol-use histories by mid-adolescence (n = 41) and youth with consistently minimal if any substance use (n = 51) were followed over 18 months. Teens received diffusion tensor imaging and detailed substance-use assessments with toxicology screening at baseline and 18-month follow-ups (i.e., 182 scans in all), as well as interim substance-use interviews each 6 months. RESULTS: At an 18-month follow-up, substance users showed poorer white matter integrity in 7 tracts: (i) right superior longitudinal fasciculus, (ii) left superior longitudinal fasciculus, (iii) right posterior thalamic radiations, (iv) right prefrontal thalamic fibers, (v) right superior temporal gyrus white matter, (vi) right inferior longitudinal fasciculus, and (vii) left posterior corona radiata (ps < 0.01). More alcohol use during the interscan interval predicted higher mean diffusivity (i.e., worsened integrity) in right (p < 0.05) and left (p = 0.06) superior longitudinal fasciculi, above and beyond baseline values in these bundles. Marijuana use during the interscan interval did not predict change over time. More externalizing behaviors at Time 1 predicted lower fractional anisotropy and higher radial diffusivity (i.e., poorer integrity) of the right prefrontal thalamic fibers (p < 0.025). CONCLUSIONS: Findings add to previous cross-sectional studies reporting white matter disadvantages in youth with substance-use histories. In particular, alcohol use during adolescent neurodevelopment may be linked to reductions in white matter quality in association fiber tracts with frontal connections. In contrast, youth who engage in a variety of risk-taking behaviors may have unique neurodevelopmental trajectories characterized by truncated development in fronto-thalamic tracts, which could have functional and clinical consequences in young adulthood.

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Frontoparietal connections underlie key executive cognitive functions. Abnormalities in the frontoparietal network have been observed in chronic alcoholics and associated with alcohol-related cognitive deficits. It remains unclear whether neurobiological differences in frontoparietal circuitry exist in substance-naïve youth who are at-risk for alcohol use disorders. This study used functional connectivity magnetic resonance imaging and diffusion tensor imaging to examine frontoparietal connectivity and underlying white matter microstructure in 20 substance-naïve youth with a family history of alcohol dependence and 20 well-matched controls without familial substance use disorders. Youth with a family history of alcohol dependence showed significantly less functional connectivity between posterior parietal and dorsolateral prefrontal seed regions (ps<.05), as compared to family history negative controls; however, they did not show differences in white matter architecture within tracts subserving frontoparietal circuitry (ps>.34). Substance-naïve youth with a family history of alcohol dependence show less frontoparietal functional connectivity in the absence of white matter microstructural abnormalities as compared to youth with no familial risk. This may suggest a potential neurobiological marker for the development of substance use disorders.

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BACKGROUND: Sex-specific trajectories in white matter development during adolescence may help explain cognitive and behavioral divergences between males and females. Knowledge of sex differences in typically developing adolescents can provide a basis for interpreting sexual dimorphisms in abilities and actions. METHOD: We examined 58 healthy adolescents (12-14years of age) with diffusion tensor imaging (DTI). Diffusion parameters fractional anisotropy (FA), and mean (MD), radial (RD), and axial diffusivities (AD) were subjected to whole-brain voxel-wise group comparisons using tract-based spatial statistics. Sex differences in white matter microstructure were examined in relation to pubertal development. RESULTS: Early adolescent females (n=29) evidenced higher FA in the right superior corona radiata, higher FA and AD in bilateral corticospinal tracts (≥164µl, p<.01), and lower MD in the right inferior longitudinal fasciculus (ILF) and left forceps major (≥164µl, p<.01) than age-matched males (n=29). Males did not show any areas of higher FA or lower MD than females, but had higher AD in the right superior longitudinal fasciculus, ILF, and forceps minor (≥ 164µl, p<.01). Pubertal stage did not account for sex disparities. CONCLUSION: In early adolescence, females' motor tracts may reflect widespread changes, while males may undergo relatively more microstructural change in projection and association fibers.

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Dynamic changes in neurochemistry, fiber architecture, and tissue composition occur in the adolescent brain. The course of these maturational processes is being charted with greater specificity, owing to advances in neuroimaging and indicate grey matter volume reductions and protracted development of white matter in regions known to support complex cognition and behavior. Though fronto-subcortical circuitry development is notable during adolescence, asynchronous maturation of prefrontal and limbic systems may render youth more vulnerable to risky behaviors such as substance use. Indeed, binge-pattern alcohol consumption and comorbid marijuana use are common among adolescents, and are associated with neural consequences. This review summarizes the unique characteristics of adolescent brain development, particularly aspects that predispose individuals to reward seeking and risky choices during this phase of life, and discusses the influence of substance use on neuromaturation. Together, findings in this arena underscore the importance of refined research and programming efforts in adolescent health and interventional needs.

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OBJECTIVE: Lifetime alcohol hangover and withdrawal symptoms in youth have been shown to predict poorer recall of verbal and nonverbal information, as well as reduced visuospatial skills. Some evidence has suggested that negative effects of alcohol on the brain may be buffered in part by potential neuroprotective properties of cannabinoids. We hypothesized that a history of more alcohol hangover symptoms would predict worse performances on measures of verbal and visual memory, and that this relationship would be moderated by marijuana involvement. METHOD: Participants were 130 adolescents (65 with histories of heavy marijuana use, and 65 non-marijuana-using controls), ranging in age from 15.7 to 19.1 years. Neuropsychological tests for visual and verbal memory and interviews assessing lifetime and recent substance use, hangover/withdrawal symptoms, and abuse and dependence criteria were administered. RESULTS: Regression models revealed that greater alcohol hangover symptoms predicted worse verbal learning (p < .05) and memory (p < .05) (California Verbal Learning Test, Second Edition) scores for non-marijuana users, but alcohol hangover symptoms were not linked to performance among marijuana users. Alcohol hangover symptoms did not predict visual memory in either group. CONCLUSIONS: Results confirm previous studies linking adolescent heavy drinking to reduced verbal learning and memory performance. However, this relationship is not seen in adolescents with similar levels of alcohol involvement who also are heavy users of marijuana.

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BACKGROUND: Late adolescence is comprised of considerable developmental transitions, though brain maturational changes during this period are subtle and difficult to quantitatively evaluate from standard brain imaging acquisitions. To date, primarily cross-sectional studies have characterized typical developmental changes during adolescence, but these processes need further description within a longitudinal framework. METHOD: To assess the developmental trajectory of typical white matter development, we examined 22 healthy adolescents with serial diffusion tensor images (DTI) collected at a mean age of 17.8 years and 16-months later. Diffusion parameters fractional anisotropy, and mean, radial, and axial diffusivity were subjected to whole-brain voxelwise time point comparisons using tract-based spatial statistics. RESULTS: At follow-up, adolescents showed a significant change (>or=153 contiguous voxels each at p<0.01) in diffusion properties, including in bilateral superior longitudinal fasciculi, superior corona radiata, anterior thalamic radiations, and posterior limb of the internal capsule. Overall, correlations with cognitive performances suggested behavioral improvement corresponding with white matter changes. CONCLUSION: These longitudinal DTI findings support continued microstructural change in white matter during late adolescence, and suggest ongoing refinement of projection and association fibers into early adulthood.

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The goal of this work was to study white matter (WM) integrity in children with cystinosis, a rare lysosomal storage disorder resulting in cystine accumulation in peripheral and central nervous system tissue. Based on previous reports of cystine crystal formation in myelin precursors as well as evidence for specific cognitive deficits in visuospatial functioning, diffusion tensor imaging (DTI) was applied to 24 children with cystinosis (age 3-7 years) and to 24 typically developing age-matched controls. Scalar diffusion indices, fractional anisotropy (FA) and mean diffusivity (MD), were examined in manually defined regions of interest within the parietal and inferior temporal lobes. Diffusion indices were correlated with performance on measures of visuospatial cognition and with white blood cell cystine levels. Bilaterally decreased FA and increased MD were evident in the inferior and superior parietal lobules in children with cystinosis, with comparable FA and MD to controls in inferior temporal WM, and implicate a dissociation of the dorsal and ventral visual pathways. In older cystinosis children (age>5), diminutions in visuospatial performance were associated with reduced FA in the right inferior parietal lobule. In addition, increased MD was found in the presence of high cystine levels in all children with cystinosis. This study provides new information that the average diffusion properties in children with cystinosis deviate from typically developing children. Findings suggest the presence of early microstructural WM changes in addition to a secondary effect of cystine accumulation. These alterations may impact the development of efficient fiber networks important for visuospatial cognition.

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BACKGROUND: Progressive myelination during adolescence implicates an increased vulnerability to neurotoxic substances and enduring neurocognitive consequences. This study examined the cognitive manifestations of altered white matter microstructure in chronic marijuana and alcohol-using (MJ+ALC) adolescents. METHODS: Thirty-six MJ+ALC adolescents (ages 16-19) and 36 demographically similar controls were evaluated with diffusion tensor imaging (Bava et al., 2009) and neurocognitive tests. Regions of group difference in fractional anisotropy (FA) and mean diffusivity (MD) were analyzed in relation to cognitive performance. RESULTS: In users, lower FA in temporal areas related to poorer performance on attention, working memory, and speeded processing tasks. Among regions where users had higher FA than controls, occipital FA was positively associated with working memory and complex visuomotor sequencing, whereas FA in anterior regions was negatively associated with verbal memory performance. CONCLUSIONS: Findings suggest differential influences of white matter development on cognition in MJ+ALC using adolescents than in non-using peers. Neuroadaptation may reflect additive and subtractive responses to substance use that are complicated by competing maturational processes.

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Chronic marijuana use during adolescence is frequently comorbid with heavy alcohol consumption and associated with CNS alterations, yet the influence of early cannabis and alcohol use on microstructural white matter integrity is unclear. Building on evidence that cannabinoid receptors are present in myelin precursors and affect glial cell processing, and that excessive ethanol exposure is associated with persistently impaired myelination, we used diffusion tensor imaging (DTI) to characterize white matter integrity in heavy substance using and non-using adolescents. We evaluated 36 marijuana and alcohol-using (MJ+ALC) adolescents (ages 16-19) and 36 demographically similar non-using controls with DTI. The diffusion parameters fractional anisotropy (FA) and mean diffusivity (MD) were subjected to whole-brain voxelwise group comparisons using tract-based spatial statistics (Smith, S.M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T.E., Mackay, C.E., Watkins, K.E., Ciccarelli, O., Cader, M.Z., Matthews, P.M., Behrens, T.E., 2006. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31, 1487-1505). MJ+ALC teens had significantly lower FA than controls in 10 regions, including left superior longitudinal fasciculus (SLF), left postcentral gyrus, bilateral crus cerebri, and inferior frontal and temporal white matter tracts. These diminutions occurred in the context of increased FA in right occipital, internal capsule, and SLF regions. Changes in MD were less distributed, but increased MD was evident in the right occipital lobe, whereas the left inferior longitudinal fasciculus showed lower MD in MJ+ALC users. Findings suggest that fronto-parietal circuitry may be particularly impacted in adolescent users of the most prevalent intoxicants: marijuana and alcohol. Disruptions to white matter in this young group could indicate aberrant axonal and myelin maturation with resultant compromise of fiber integrity. Findings of increased anisotropic diffusion in alternate brain regions suggest possible neuroadaptive processes and can be examined in future studies of connectivity to determine how aberrancies in specific tracts might influence efficient cognitive processing.

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BACKGROUND: White matter integrity has been found to be compromised in adult alcoholics, but it is unclear when in the course of alcohol exposure white matter abnormalities become apparent. This study assessed microstructural white matter integrity among adolescent binge drinkers with no history of an alcohol use disorder. METHODS: We used diffusion tensor imaging to examine fractional anisotropy (FA), a measure of directional coherence of white matter tracts, among teens with (n = 14) and without (n = 14) histories of binge drinking but no history of alcohol use disorder, matched on age, gender, and education. RESULTS: Binge drinkers had lower FA than controls in 18 white matter areas (clusters > or =27 contiguous voxels, each with p < 0.01) throughout the brain, including the corpus callosum, superior longitudinal fasciculus, corona radiata, internal and external capsules, and commissural, limbic, brainstem, and cortical projection fibers, while exhibiting no areas of higher FA. Among binge drinkers, lower FA in 6 of these regions was linked to significantly greater lifetime hangover symptoms and/or higher estimated peak blood alcohol concentrations. CONCLUSIONS: Binge drinking adolescents demonstrated widespread reductions of FA in major white matter pathways. Although preliminary, these results could indicate that infrequent exposure to large doses of alcohol during youth may compromise white matter fiber coherence.

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Neonatal stroke outcome studies demonstrate variable findings of either relatively spared intellectual function or persistent impairments. Volumetric measurement of the brain can provide more precise data on lesion-cognition outcomes. We studied 7 children with unilateral focal lesions from prenatal stroke. Whole-brain magnetic resonance imaging scans were analyzed to produce volumes of cortical gray matter, total white matter, cerebrospinal fluid, lesion, and lesion constricted fluid, and we ascertained the relationship of morphometric variables to intellectual and clinical outcome. Children with cystic encephalomalacia plus atrophy had poorer outcomes than children with atrophy or gliosis alone. These children also demonstrated the largest lesion size, smallest gray matter volume, and greatest proportion of hyperintense white matter in the affected hemisphere. Findings suggest that the type and size of the lesion, in addition to the integrity of white matter and residual cortex, may be better predictors of intellectual functioning than either of these indices alone.

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The present study used a chimeric stimuli task to assess the magnitude of the left-hemispace bias in children with congenital unilateral brain damage (n = 46) as compared to typically developing matched controls (n = 46). As would be expected, controls exhibited a significant left-hemispace bias. In the presence of left hemisphere (LH) damage, the left-hemispace preference was found to be present, but attenuated, whereas right hemisphere (RH) damage resulted in a less lateralized process. Examination of lesion severity revealed that large lesions in the RH were associated with a reversal of the typical left-hemispace bias, while small lesions resulted in a left bias approximating that of controls. In contrast, the left-hemispace preference in children with LH damage was similar across lesion size. We conclude that damage to either hemisphere early in brain development may alter hemispheric preference for processing of nonverbal stimuli, and that at least in the case of RH damage, alteration of the normal perceptual asymmetry may depend on the interaction between lesion side and severity.

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CONTEXT: It remains unclear whether altered regional brain physiological activity in patients with schizophrenia during working memory tasks relates to maintenance-related processes, manipulation-related (ie, executive) processes, or both. OBJECTIVE: To examine regional functional activations of the brain during maintenance- and manipulation-related working memory processing in patients with schizophrenia and in healthy comparison subjects. DESIGN: Functional images of the brain were acquired in 11 schizophrenic patients and 12 healthy control subjects (matched for age, sex, handedness, and parental education) during 2 spatial working memory paradigms, one contrasting maintenance-only processing with maintenance and manipulation processing and the other contrasting parametrically varying maintenance demands. RESULTS: Patients and controls showed activation of a large, spatially distributed network of cortical and subcortical regions during spatial working memory processing. When task demands required explicit manipulation of information held in memory, controls recruited right dorsolateral prefrontal cortex (Brodmann areas 45 and 46) to a significantly greater extent than patients. A similar effect was observed for the larger memory set sizes of the memory set size task. No other brain regions showed activation differences between groups for either task. These differences persisted when comparing activation maps for memory set sizes in which the 2 groups were equivalent in behavioral accuracy and when comparing subgroups of patients and controls matched for behavioral accuracy on either task. CONCLUSIONS: Physiological disturbances in the dorsolateral prefrontal cortex contribute differentially to patients' difficulties with maintaining spatial information across a brief delay, as well as with manipulating the maintained representation. These differences persisted when comparing conditions in which the 2 groups were equivalent in behavioral accuracy.

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OBJECTIVE: To examine the effects of early bilateral brain damage on Full Scale IQ (FSIQ), Verbal IQ (VIQ) and Performance IQ (PIQ). BACKGROUND: Early unilateral brain damage typically results in relatively spared intellectual function, with IQ in the normal range and no significant differences between VIQ and PIQ, regardless of the side of the lesion. However, little is known about intellectual function in children after bilateral damage. METHOD: FSIQ, VIQ, and PIQ scores of 10 children, ages 6-12 years, with early-onset bilateral focal lesions (BFL), were compared with those of age- and sex-matched controls. RESULTS: FSIQ was in the average range for BFL and control children. A bimodal distribution of VIQ was identified, resulting in 2 distinct groups, one performing above the average range and the other below. The unimpaired group displayed a significant discrepancy between VIQ and PIQ, with VIQ in the superior range and PIQ in the low average range. The impaired group did not demonstrate disparate VIQ and PIQ: both were in the borderline range. The 2 groups were differentiated by greater degree of cortical brain damage in the impaired than in the unimpaired group. CONCLUSIONS: The striking difference between the outcome of the unimpaired and impaired groups may reflect different processes of reorganization that are associated with the extent of cortical involvement.

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