Individual differences in internalizing symptoms in late childhood: A variance decomposition into cortical thickness, genetic and environmental differences.

The brain undergoes extensive development during late childhood and early adolescence. Cortical thinning is a prominent feature of this development, and some researchers have suggested that differences in cortical thickness may be related to internalizing symptoms, which typically increase during the same period. However, research has yielded inconclusive results. We utilized a new method that estimates the combined effect of individual differences in vertex-wise cortical thickness on internalizing symptoms. This approach allows for many small effects to be distributed across the cortex and avoids the necessity of correcting for multiple tests. Using a sample of 8763 children aged 8.9 to 11.1 from the ABCD study, we decomposed the total variation in caregiver-reported internalizing symptoms into differences in cortical thickness, additive genetics, and shared family environmental factors and unique environmental factors. Our results indicated that individual differences in cortical thickness accounted for less than 0.5% of the variation in internalizing symptoms. In contrast, the analysis revealed a substantial effect of additive genetics and family environmental factors on the different components of internalizing symptoms, ranging from 06% to 48% and from 0% to 34%, respectively. Overall, while this study found a minimal association between cortical thickness and internalizing symptoms, additive genetics, and familial environmental factors appear to be of importance for describing differences in internalizing symptoms in late childhood. RESEARCH HIGHLIGHTS: We utilized a new method for modelling the total contribution of vertex-wise individual differences in cortical thickness to internalizing symptoms in late childhood. The total contribution of individual differences in cortical thickness accounted for <0.5% of the variance in internalizing symptoms. Additive genetics and shared family environmental variation accounted for 17% and 34% of the variance in internalizing symptoms, respectively. Our results suggest that cortical thickness is not an important indicator for internalizing symptoms in childhood, whereas genetic and environmental differences have a substantial impact.

Assessing regional intracortical myelination in schizophrenia spectrum and bipolar disorders using the optimized T1w/T2w-ratio.

BACKGROUND: Dysmyelination could be part of the pathophysiology of schizophrenia spectrum (SCZ) and bipolar disorders (BPD), yet few studies have examined myelination of the cerebral cortex. The ratio of T1- and T2-weighted magnetic resonance images (MRI) correlates with intracortical myelin. We investigated the T1w/T2w-ratio and its age trajectories in patients and healthy controls (CTR) and explored associations with antipsychotic medication use and psychotic symptoms. METHODS: Patients with SCZ (n = 64; mean age = 30.4 years, s.d. = 9.8), BPD (n = 91; mean age 31.0 years, s.d. = 10.2), and CTR (n = 155; mean age = 31.9 years, s.d. = 9.1) who participated in the TOP study (NORMENT, University of Oslo, Norway) were clinically assessed and scanned using a General Electric 3 T MRI system. T1w/T2w-ratio images were computed using an optimized pipeline with intensity normalization and field inhomogeneity correction. Vertex-wise regression models were used to compare groups and examine group × age interactions. In regions showing significant differences, we explored associations with antipsychotic medication use and psychotic symptoms. RESULTS: No main effect of diagnosis was found. However, age slopes of the T1w/T2w-ratio differed significantly between SCZ and CTR, predominantly in frontal and temporal lobe regions: Lower T1w/T2w-ratio values with higher age were found in CTR, but not in SCZ. Follow-up analyses revealed a more positive age slope in patients who were using antipsychotics and patients using higher chlorpromazine-equivalent doses. CONCLUSIONS: While we found no evidence of reduced intracortical myelin in SCZ or BPD relative to CTR, different regional age trajectories in SCZ may suggest a promyelinating effect of antipsychotic medication.

Parental education and income are linked to offspring cortical brain structure and psychopathology at 9-11 years.

Background: A child's socioeconomic environment can shape central aspects of their life, including vulnerability to mental disorders. Negative environmental influences in youth may interfere with the extensive and dynamic brain development occurring at this time. Indeed, there are numerous yet diverging reports of associations between parental socioeconomic status (SES) and child cortical brain morphometry. Most of these studies have used single metric- or unimodal analyses of standard cortical morphometry that downplay the probable scenario where numerous biological pathways in sum account for SES-related cortical differences in youth. Methods: To comprehensively capture such variability, using data from 9758 children aged 8.9-11.1 years from the ABCD Study®, we employed linked independent component analysis (LICA) and fused vertex-wise cortical thickness, surface area, curvature and grey-/white-matter contrast (GWC). LICA revealed 70 uni- and multimodal components. We then assessed the linear relationships between parental education, parental income and each of the cortical components, controlling for age, sex, genetic ancestry, and family relatedness. We also assessed whether cortical structure moderated the negative relationships between parental SES and child general psychopathology. Results: Parental education and income were both associated with larger surface area and higher GWC globally, in addition to local increases in surface area and to a lesser extent bidirectional GWC and cortical thickness patterns. The negative relation between parental income and child psychopathology were attenuated in children with a multimodal pattern of larger frontal- and smaller occipital surface area, and lower medial occipital thickness and GWC. Conclusion: Structural brain MRI is sensitive to SES diversity in childhood, with GWC emerging as a particularly relevant marker together with surface area. In low-income families, having a more developed cortex across MRI metrics, appears beneficial for mental health.

Genetic and brain similarity independently predict childhood anthropometrics and neighborhood socioeconomic conditions.

Linking the developing brain with individual differences in clinical and demographic traits is challenging due to the substantial interindividual heterogeneity of brain anatomy and organization. Here we employ an integrative approach that parses individual differences in both cortical thickness and common genetic variants, and assess their effects on a wide set of childhood traits. The approach uses a linear mixed model framework to obtain the unique effects of each type of similarity, as well as their covariance. We employ this approach in a sample of 7760 unrelated children in the ABCD cohort baseline sample (mean age 9.9, 46.8% female). In general, associations between cortical thickness similarity and traits were limited to anthropometrics such as height, weight, and birth weight, as well as a marker of neighborhood socioeconomic conditions. Common genetic variants explained significant proportions of variance across nearly all included outcomes, although estimates were somewhat lower than previous reports. No significant covariance of the effects of genetic and cortical thickness similarity was found. The present findings highlight the connection between anthropometrics as well as neighborhood socioeconomic conditions and the developing brain, which appear to be independent from individual differences in common genetic variants in this population-based sample.

Assessing the Longitudinal Associations Between Decision-Making Processes and Attention Problems in Early Adolescence.

Cognitive functions and psychopathology develop in parallel in childhood and adolescence, but the temporal dynamics of their associations are poorly understood. The present study sought to elucidate the intertwined development of decision-making processes and attention problems using longitudinal data from late childhood (9-10 years) to mid-adolescence (11-13 years) from the Adolescent Brain Cognitive Development (ABCD) Study (n = 8918). We utilised hierarchical drift-diffusion modelling of behavioural data from the stop-signal task, parent-reported attention problems from the Child Behavior Checklist (CBCL), and multigroup univariate and bivariate latent change score models. The results showed faster drift rate was associated with lower levels of inattention at baseline, as well as a greater reduction of inattention over time. Moreover, baseline drift rate negatively predicted change in attention problems in females, and baseline attention problems negatively predicted change in drift rate. Neither response caution (decision threshold) nor encoding- and responding processes (non-decision time) were significantly associated with attention problems. There were no significant sex differences in the associations between decision-making processes and attention problems. The study supports previous findings of reduced evidence accumulation in attention problems and additionally shows that development of this aspect of decision-making plays a role in developmental changes in attention problems in youth.

Puberty differentially predicts brain maturation in male and female youth: A longitudinal ABCD Study.

Research has demonstrated associations between pubertal development and brain maturation. However, existing studies have been limited by small samples, cross-sectional designs, and inconclusive findings regarding directionality of effects and sex differences. We examined the longitudinal temporal coupling of puberty status assessed using the Pubertal Development Scale (PDS) and magnetic resonance imaging (MRI)-based grey and white matter brain structure. Our sample consisted of 8896 children and adolescents at baseline (mean age = 9.9) and 6099 at follow-up (mean age = 11.9) from the Adolescent Brain and Cognitive Development (ABCD) Study cohort. Applying multigroup Bivariate Latent Change Score (BLCS) models, we found that baseline PDS predicted the rate of change in cortical thickness among females and rate of change in cortical surface area for both males and females. We also found a correlation between baseline PDS and surface area and co-occurring changes over time in males. Diffusion tensor imaging (DTI) analyses revealed correlated change between PDS and fractional anisotropy (FA) for both males and females, but no significant associations for mean diffusivity (MD). Our results suggest that pubertal status predicts cortical maturation, and that the strength of the associations differ between sex. Further research spanning the entire duration of puberty is needed to understand the extent and contribution of pubertal development on the youth brain.

Reaction Time Variability in Children Is Specifically Associated With Attention Problems and Regional White Matter Microstructure.

BACKGROUND: Increased intraindividual variability (IIV) in reaction times (RTs) has been suggested as a key cognitive and behavioral marker of attention problems, but findings for other dimensions of psychopathology are less consistent. Moreover, while studies have linked IIV to brain white matter microstructure, large studies testing the robustness of these associations are needed. METHODS: We used data from the Adolescent Brain Cognitive Development (ABCD) Study baseline assessment to test the associations between IIV and psychopathology (n = 8622, age = 8.9-11.1 years) and IIV and white matter microstructure (n = 7958, age = 8.9-11.1 years). IIV was investigated using an ex-Gaussian distribution analysis of RTs in correct response go trials in the stop signal task. Psychopathology was measured by the Child Behavior Checklist and a bifactor structural equation model was performed to extract a general p factor and specific factors reflecting internalizing, externalizing, and attention problems. To investigate white matter microstructure, fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were examined in 23 atlas-based tracts. RESULTS: Increased IIV in both short and long RTs was positively associated with the specific attention problems factor (Cohen's d = 0.13 and d = 0.15, respectively). Increased IIV in long RTs was also positively associated with radial diffusivity in the left and right corticospinal tract (both tracts, d = 0.12). CONCLUSIONS: Using a large sample and a data-driven dimensional approach to psychopathology, the results provide novel evidence for a small but specific association between IIV and attention problems in children and support previous findings on the relevance of white matter microstructure for IIV.

Deviations from normative brain white and gray matter structure are associated with psychopathology in youth.

Combining imaging modalities and metrics that are sensitive to various aspects of brain structure and maturation may help identify individuals that show deviations in relation to same-aged peers, and thus benefit early-risk-assessment for mental disorders. We used one timepoint multimodal brain imaging, cognitive, and questionnaire data from 1280 eight- to twenty-one-year-olds from the Philadelphia Neurodevelopmental Cohort. We estimated age-related gray and white matter properties and estimated individual deviation scores using normative modeling. Next, we tested for associations between the estimated deviation scores, and with psychopathology domain scores and cognition. More negative deviations in DTI-based fractional anisotropy (FA) and the first principal eigenvalue of the diffusion tensor (L1) were associated with higher scores on psychosis positive and prodromal symptoms and general psychopathology. A more negative deviation in cortical thickness (CT) was associated with a higher general psychopathology score. Negative deviations in global FA, surface area, L1 and CT were also associated with poorer cognitive performance. No robust associations were found between the deviation scores based on CT and DTI. The low correlations between the different multimodal magnetic resonance imaging-based deviation scores suggest that psychopathological burden in adolescence can be mapped onto partly distinct neurobiological features.

Associations between brain imaging and polygenic scores of mental health and educational attainment in children aged 9-11.

Psychiatric disorders are highly heritable and polygenic, and many have their peak onset in late childhood and adolescence, a period of tremendous changes. Although the neurodevelopmental antecedents of mental illness are widely acknowledged, research in youth population cohorts is still scarce, preventing our progress towards the early characterization of these disorders. We included 7,124 children (9-11 years old) from the Adolescent Brain and Cognitive Development Study to map the associations of structural and diffusion brain imaging with common genetic variants and polygenic scores for psychiatric disorders and educational attainment. We used principal component analysis to derive imaging components, and calculated their heritability. We then assessed the relationship of imaging components with genetic and clinical psychiatric risk with univariate models and Canonical correlation analysis (CCA). Most imaging components had moderate heritability. Univariate models showed limited evidence and small associations of polygenic scores with brain structure at this age. CCA revealed two significant modes of covariation. The first mode linked higher polygenic scores for educational attainment with less externalizing problems and larger surface area. The second mode related higher polygenic scores for schizophrenia, bipolar disorder, and autism spectrum disorder to higher global cortical thickness, smaller white matter volumes of the fornix and cingulum, larger medial occipital surface area and smaller surface area of lateral and medial temporal regions. While cross-validation suggested limited generalizability, our results highlight the potential of multivariate models to better understand the transdiagnostic and distributed relationships between mental health and brain structure in late childhood.

Parental socioeconomic status is linked to cortical microstructure and language abilities in children and adolescents.

Gradients in parental socioeconomic status (SES) are closely linked to important life outcomes in children and adolescents, such as cognitive abilities, school achievement, and mental health. Parental SES may also influence brain development, with several magnetic resonance imaging (MRI) studies reporting associations with youth brain morphometry. However, MRI signal intensity metrics have not been assessed, but could offer a microstructural correlate, thereby increasing our understanding of SES influences on neurobiology. We computed a parental SES score from family income, parental education and parental occupation, and assessed relations with cortical microstructure as measured by T1w/T2w ratio (n = 504, age = 3-21 years). We found negative age-stabile relations between parental SES and T1w/T2w ratio, indicating that youths from lower SES families have higher ratio in widespread frontal, temporal, medial parietal and occipital regions, possibly indicating a more developed cortex. Effect sizes were small, but larger than for conventional morphometric properties i.e. cortical surface area and thickness, which were not significantly associated with parental SES. Youths from lower SES families had poorer language related abilities, but microstructural differences did not mediate these relations. T1w/T2w ratio appears to be a sensitive imaging marker for further exploring the association between parental SES and child brain development.

New insights into the dynamic development of the cerebral cortex in childhood and adolescence: Integrating macro- and microstructural MRI findings.

Through dynamic transactional processes between genetic and environmental factors, childhood and adolescence involve reorganization and optimization of the cerebral cortex. The cortex and its development plays a crucial role for prototypical human cognitive abilities. At the same time, many common mental disorders appear during these critical phases of neurodevelopment. Magnetic resonance imaging (MRI) can indirectly capture several multifaceted changes of cortical macro- and microstructure, of high relevance to further our understanding of the neural foundation of cognition and mental health. Great progress has been made recently in mapping the typical development of cortical morphology. Moreover, newer less explored MRI signal intensity and specialized quantitative T2 measures have been applied to assess microstructural cortical development. We review recent findings of typical postnatal macro- and microstructural development of the cerebral cortex from early childhood to young adulthood. We cover studies of cortical volume, thickness, area, gyrification, T1-weighted (T1w) tissue contrasts such a grey/white matter contrast, T1w/T2w ratio, magnetization transfer and myelin water fraction. Finally, we integrate imaging studies with cortical gene expression findings to further our understanding of the underlying neurobiology of the developmental changes, bridging the gap between ex vivo histological- and in vivo MRI studies.

Maturation of cortical microstructure and cognitive development in childhood and adolescence: A T1w/T2w ratio MRI study.

The restructuring and optimization of the cerebral cortex from early childhood and through adolescence is an essential feature of human brain development, underlying immense cognitive improvements. Beyond established morphometric cortical assessments, the T1w/T2w ratio quantifies partly separate biological processes, and might inform models of typical neurocognitive development and developmental psychopathology. In the present study, we computed vertex-wise T1w/T2w ratio across the cortical surface in 621 youths (3-21 years) sampled from the Pediatric Imaging, Neurocognition, and Genetics (PING) study and tested for associations with individual differences in age, sex, and both general and specific cognitive abilities. The results showed a near global linear age-related increase in T1w/T2w ratio across the brain surface, with a general posterior to anterior increasing gradient in association strength. Moreover, results indicated that boys in late adolescence had regionally higher T1w/T2w ratio as compared to girls. Across individuals, T1w/T2w ratio was negatively associated with general and several specific cognitive abilities mainly within anterior cortical regions. Our study indicates age-related differences in T1w/T2w ratio throughout childhood, adolescence, and young adulthood, in line with the known protracted myelination of the cortex. Moreover, the study supports T1w/T2w ratio as a promising surrogate measure of individual differences in intracortical brain structure in neurodevelopment.

Testing relationships between multimodal modes of brain structural variation and age, sex and polygenic scores for neuroticism in children and adolescents.

Human brain development involves spatially and temporally heterogeneous changes, detectable across a wide range of magnetic resonance imaging (MRI) measures. Investigating the interplay between multimodal MRI and polygenic scores (PGS) for personality traits associated with mental disorders in youth may provide new knowledge about typical and atypical neurodevelopment. We derived independent components across cortical thickness, cortical surface area, and grey/white matter contrast (GWC) (n = 2596, 3-23 years), and tested for associations between these components and age, sex and-, in a subsample (n = 878), PGS for neuroticism. Age was negatively associated with a single-modality component reflecting higher global GWC, and additionally with components capturing common variance between global thickness and GWC, and several multimodal regional patterns. Sex differences were found for components primarily capturing global and regional surface area (boys > girls), but also regional cortical thickness. For PGS for neuroticism, we found weak and bidirectional associations with a component reflecting right prefrontal surface area. These results indicate that multimodal fusion is sensitive to age and sex differences in brain structure in youth, but only weakly to polygenic load for neuroticism.

Probing Brain Developmental Patterns of Myelination and Associations With Psychopathology in Youths Using Gray/White Matter Contrast.

BACKGROUND: Cerebral myeloarchitecture shows substantial development across childhood and adolescence, and aberrations in these trajectories are relevant for a range of mental disorders. Differential myelination between intracortical and subjacent white matter can be approximated using signal intensities in T1-weighted magnetic resonance imaging. METHODS: To test the sensitivity of gray/white matter contrast (GWC) to age and individual differences in psychopathology and general cognitive ability in youths (8-23 years), we formed data-driven psychopathology and cognitive components using a large population-based sample, the Philadelphia Neurodevelopmental Cohort (N = 6487, 52% female). We then tested for associations with regional GWC defined by an independent component analysis in a subsample with available magnetic resonance imaging data (n = 1467, 53% female). RESULTS: The analyses revealed a global GWC component, which showed an age-related decrease from late childhood and across adolescence. In addition, we found regional anatomically meaningful components with differential age associations explaining variance beyond the global component. When accounting for age and sex, both higher symptom levels of anxiety or prodromal psychosis and lower cognitive ability were associated with higher GWC in insula and cingulate cortices and with lower GWC in pre- and postcentral cortices. We also found several additional regional associations with anxiety, prodromal psychosis, and cognitive ability. CONCLUSIONS: Independent modes of GWC variation are sensitive to global and regional brain developmental processes, possibly related to differences between intracortical and subjacent white matter myelination, and individual differences in regional GWC are associated with both mental health and general cognitive functioning.

Cerebral blood flow changes after a day of wake, sleep, and sleep deprivation.

Elucidating the neurobiological effects of sleep and wake is an important goal of the neurosciences. Whether and how human cerebral blood flow (CBF) changes during the sleep-wake cycle remain to be clarified. Based on the synaptic homeostasis hypothesis of sleep and wake, we hypothesized that a day of wake and a night of sleep deprivation would be associated with gray matter resting CBF (rCBF) increases and that sleep would be associated with rCBF decreases. Thirty-eight healthy adult males (age 22.1 ±â€¯2.5 years) underwent arterial spin labeling perfusion magnetic resonance imaging at three time points: in the morning after a regular night's sleep, the evening of the same day, and the next morning, either after total sleep deprivation (n = 19) or a night of sleep (n = 19). All analyses were adjusted for hematocrit and head motion. rCBF increased from morning to evening and decreased after a night of sleep. These effects were most prominent in bilateral hippocampus, amygdala, thalamus, and in the occipital and sensorimotor cortices. Group × time interaction analyses for evening versus next morning revealed significant interaction in bilateral lateral and medial occipital cortices and in bilateral insula, driven by rCBF increases in the sleep deprived individuals and decreases in the sleepers, respectively. Furthermore, group × time interaction analyses for first morning versus next morning showed significant effects in medial and lateral occipital cortices, in anterior cingulate gyrus, and in the insula, in both hemispheres. These effects were mainly driven by CBF increases from TP1 to TP3 in the sleep deprived individuals. There were no associations between the rCBF changes and sleep characteristics, vigilant attention, or subjective sleepiness that remained significant after adjustments for multiple analyses. Altogether, these results encourage future studies to clarify mechanisms underlying sleep-related rCBF changes.

Evidence for cortical structural plasticity in humans after a day of waking and sleep deprivation.

Sleep is an evolutionarily conserved process required for human health and functioning. Insufficient sleep causes impairments across cognitive domains, and sleep deprivation can have rapid antidepressive effects in mood disorders. However, the neurobiological effects of waking and sleep are not well understood. Recently, animal studies indicated that waking and sleep are associated with substantial cortical structural plasticity. Here, we hypothesized that structural plasticity can be observed after a day of waking and sleep deprivation in the human cerebral cortex. To test this hypothesis, 61 healthy adult males underwent structural magnetic resonance imaging (MRI) at three time points: in the morning after a regular night's sleep, the evening of the same day, and the next morning, either after total sleep deprivation (N=41) or a night of sleep (N=20). We found significantly increased right prefrontal cortical thickness from morning to evening across all participants. In addition, pairwise comparisons in the deprived group between the two morning scans showed significant thinning of mainly bilateral medial parietal cortices after 23h of sleep deprivation, including the precuneus and posterior cingulate cortex. However, there were no significant group (sleep vs. sleep deprived group) by time interactions and we can therefore not rule out that other mechanisms than sleep deprivation per se underlie the bilateral medial parietal cortical thinning observed in the deprived group. Nonetheless, these cortices are thought to subserve wakefulness, are among the brain regions with highest metabolic rate during wake, and are considered some of the most sensitive cortical regions to a variety of insults. Furthermore, greater thinning within the left medial parietal cluster was associated with increased sleepiness after sleep deprivation. Together, these findings add to a growing body of data showing rapid structural plasticity within the human cerebral cortex detectable with MRI. Further studies are needed to clarify whether cortical thinning is one neural substrate of sleepiness after sleep deprivation.

Diurnal Variation and Twenty-Four Hour Sleep Deprivation Do Not Alter Supine Heart Rate Variability in Healthy Male Young Adults.

Heart rate variability (HRV) has become an increasingly popular index of cardiac autonomic control in the biobehavioral sciences due to its relationship with mental illness and cognitive traits. However, the intraindividual stability of HRV in response to sleep and diurnal disturbances, which are commonly reported in mental illness, and its relationship with executive function are not well understood. Here, in 40 healthy adult males we calculated high frequency HRV-an index of parasympathetic nervous system (PNS) activity-using pulse oximetry during brain imaging, and assessed attentional and executive function performance in a subsequent behavioral test session at three time points: morning, evening, and the following morning. Twenty participants were randomly selected for total sleep deprivation whereas the other 20 participants slept as normal. Sleep deprivation and morning-to-night variation did not influence high frequency HRV at either a group or individual level; however, sleep deprivation abolished the relationship between orienting attention performance and HRV. We conclude that a day of wake and a night of laboratory-induced sleep deprivation do not alter supine high frequency HRV in young healthy male adults.

The brain functional connectome is robustly altered by lack of sleep.

Sleep is a universal phenomenon necessary for maintaining homeostasis and function across a range of organs. Lack of sleep has severe health-related consequences affecting whole-body functioning, yet no other organ is as severely affected as the brain. The neurophysiological mechanisms underlying these deficits are poorly understood. Here, we characterize the dynamic changes in brain connectivity profiles inflicted by sleep deprivation and how they deviate from regular daily variability. To this end, we obtained functional magnetic resonance imaging data from 60 young, adult male participants, scanned in the morning and evening of the same day and again the following morning. 41 participants underwent total sleep deprivation before the third scan, whereas the remainder had another night of regular sleep. Sleep deprivation strongly altered the connectivity of several resting-state networks, including dorsal attention, default mode, and hippocampal networks. Multivariate classification based on connectivity profiles predicted deprivation state with high accuracy, corroborating the robustness of the findings on an individual level. Finally, correlation analysis suggested that morning-to-evening connectivity changes were reverted by sleep (control group)-a pattern which did not occur after deprivation. We conclude that both, a day of waking and a night of sleep deprivation dynamically alter the brain functional connectome.

Widespread changes in white matter microstructure after a day of waking and sleep deprivation.

BACKGROUND: Elucidating the neurobiological effects of sleep and waking remains an important goal of the neurosciences. Recently, animal studies indicated that sleep is important for cell membrane and myelin maintenance in the brain and that these structures are particularly susceptible to insufficient sleep. Here, we tested the hypothesis that a day of waking and sleep deprivation would be associated with changes in diffusion tensor imaging (DTI) indices of white matter microstructure sensitive to axonal membrane and myelin alterations. METHODS: Twenty-one healthy adult males underwent DTI in the morning [7:30AM; time point (TP)1], after 14 hours of waking (TP2), and then after another 9 hours of waking (TP3). Whole brain voxel-wise analysis was performed with tract based spatial statistics. RESULTS: A day of waking was associated with widespread increases in white matter fractional anisotropy, which were mainly driven by radial diffusivity reductions, and sleep deprivation was associated with widespread fractional anisotropy decreases, which were mainly explained by reductions in axial diffusivity. In addition, larger decreases in axial diffusivity after sleep deprivation were associated with greater sleepiness. All DTI changes remained significant after adjusting for hydration measures. CONCLUSIONS: This is the first DTI study of sleep deprivation in humans. Although previous studies have observed localized changes in DTI indices of cerebral microstructure over the course of a few hours, further studies are needed to confirm widespread DTI changes within hours of waking and to clarify whether such changes in white matter microstructure serve as neurobiological substrates of sleepiness.