White Matter Development from Birth to 6 Years of Age: A Longitudinal Study.

Human white matter development in the first years of life is rapid, setting the foundation for later development. Microstructural properties of white matter are linked to many behavioral and psychiatric outcomes; however, little is known about when in development individual differences in white matter microstructure are established. The aim of the current study is to characterize longitudinal development of white matter microstructure from birth through 6 years to determine when in development individual differences are established. Two hundred and twenty-four children underwent diffusion-weighted imaging after birth and at 1, 2, 4, and 6 years. Diffusion tensor imaging data were computed for 20 white matter tracts (9 left-right corresponding tracts and 2 commissural tracts), with tract-based measures of fractional anisotropy and axial and radial diffusivity. Microstructural maturation between birth and 1 year are much greater than subsequent changes. Further, by 1 year, individual differences in tract average values are consistently predictive of the respective 6-year values, explaining, on average, 40% of the variance in 6-year microstructure. Results provide further evidence of the importance of the first year of life with regard to white matter development, with potential implications for informing early intervention efforts that target specific sensitive periods.

Common and heritable components of white matter microstructure predict cognitive function at 1 and 2 y.

Previous studies indicate that the microstructure of individual white matter (WM) tracts is related to cognitive function. More recent studies indicate that the microstructure of individual tracts is highly correlated and that a property common across WM is related to overall cognitive function in adults. However, little is known about whether these common WM properties exist in early childhood development or how they are related to cognitive development. In this study, we used diffusion tensor imaging (DTI) to investigate common underlying factors in 12 fiber tracts, their relationship with cognitive function, and their heritability in a longitudinal sample of healthy children at birth (n = 535), 1 y (n = 322), and 2 y (n = 244) of age. Our data show that, in neonates, there is a highly significant correlation between major WM tracts that decreases from birth to 2 y of age. Over the same period, the factor structure increases in complexity, from one factor at birth to three factors at age 2 y, which explain 50% of variance. The identified common factors of DTI metrics in each age group are significantly correlated with general cognitive scores and predict cognitive ability in later childhood. These factors are moderately heritable. These findings illustrate the anatomical differentiation of WM fiber from birth to 2 y of age that correlate with cognitive development. Our results also suggest that the common factor approach is an informative way to study WM development and its relationship with cognition and is a useful approach for future imaging genetic studies.

Development of thalamocortical connectivity during infancy and its cognitive correlations.

Although commonly viewed as a sensory information relay center, the thalamus has been increasingly recognized as an essential node in various higher-order cognitive circuits, and the underlying thalamocortical interaction mechanism has attracted increasing scientific interest. However, the development of thalamocortical connections and how such development relates to cognitive processes during the earliest stages of life remain largely unknown. Leveraging a large human pediatric sample (N = 143) with longitudinal resting-state fMRI scans and cognitive data collected during the first 2 years of life, we aimed to characterize the age-dependent development of thalamocortical connectivity patterns by examining the functional relationship between the thalamus and nine cortical functional networks and determine the correlation between thalamocortical connectivity and cognitive performance at ages 1 and 2 years. Our results revealed that the thalamus-sensorimotor and thalamus-salience connectivity networks were already present in neonates, whereas the thalamus-medial visual and thalamus-default mode network connectivity emerged later, at 1 year of age. More importantly, brain-behavior analyses based on the Mullen Early Learning Composite Score and visual-spatial working memory performance measured at 1 and 2 years of age highlighted significant correlations with the thalamus-salience network connectivity. These results provide new insights into the understudied early functional brain development process and shed light on the behavioral importance of the emerging thalamocortical connectivity during infancy.

Diffusion tensor imaging-based characterization of brain neurodevelopment in primates.

Primate neuroimaging provides a critical opportunity for understanding neurodevelopment. Yet the lack of a normative description has limited the direct comparison with changes in humans. This paper presents for the first time a cross-sectional diffusion tensor imaging (DTI) study characterizing primate brain neurodevelopment between 1 and 6 years of age on 25 healthy undisturbed rhesus monkeys (14 male, 11 female). A comprehensive analysis including region-of-interest, voxel-wise, and fiber tract-based approach demonstrated significant changes of DTI properties over time. Changes in fractional anisotropy (FA), mean diffusivity, axial diffusivity (AD), and radial diffusivity (RD) exhibited a heterogeneous pattern across different regions as well as along fiber tracts. Most of these patterns are similar to those from human studies yet a few followed unique patterns. Overall, we observed substantial increase in FA and AD and a decrease in RD for white matter (WM) along with similar yet smaller changes in gray matter (GM). We further observed an overall posterior-to-anterior trend in DTI property changes over time and strong correlations between WM and GM development. These DTI trends provide crucial insights into underlying age-related biological maturation, including myelination, axonal density changes, fiber tract reorganization, and synaptic pruning processes.

Maternal prenatal lead levels and neonatal brain volumes: Testing moderations by maternal depressive symptoms and family income.

There is considerable evidence that prenatal lead exposure is detrimental to child cognitive and socio-emotional development. Further evidence suggests that the effects of prenatal lead on developmental outcomes may be conditional upon exposure to social stressors, such as maternal depression and low socioeconomic status. However, no studies have examined associations between these co-occurring stressors during pregnancy and neonatal brain volumes. Leveraging a sample of 101 mother-infant dyads followed beginning in mid-pregnancy, we examined the main effects of prenatal urinary lead levels on neonatal lateralized brain volumes (left and right hippocampus, amygdala, cerebellum, frontal lobes) and total gray matter. We additionally tested for moderations between lead and depressive symptoms and between lead and family income relative to the federal poverty level (FPL) on the same neurodevelopmental outcomes. Analyses of main effects indicated that prenatal lead was significantly (ps < 0.05) associated with reduced right and left amygdala volumes (ßs = -0.23- -0.20). The testing and probing of cross-product interaction terms using simple slopes indicated that the negative effect of lead on the left amygdala was conditional upon mothers having low depressive symptoms or high income relative to the FPL. We interpret the results in the context of trajectories of prenatal and postnatal brain development and susceptibility to low levels of prenatal lead in the context of other social stressors.

Perceptions of mindfulness practices as a support for individuals managing caregiving responsibilities and chronic disease: A qualitative study.

OBJECTIVES: Explore the lived experience of individuals managing and/or caregiving for someone with a chronic disease and their perceptions of developing a mindfulness program for stress reduction. METHODS: Sixteen participants with chronic disease and/or caregivers participated. Participants completed eligibility screening, demographic questionnaires, and semi-structured interviews (30-60 min each) online or by phone. Interviews (n = 16) were audio recorded, transcribed, and analyzed using thematic analysis and NVivo® 12. Survey data were analyzed using SPSS® 28. RESULTS: Four themes emerged: (a) Chronic disease management and stress-perspectives on life's stressors; (b) Stress reduction techniques/perceptions of mindfulness-knowledge and implementation of stress reduction practices and familiarity with mindfulness; (c) Mindfulness program acceptability, barriers, and facilitators-interest, barriers, and facilitators to attending; (d) Mindfulness program structure-logistics to increase access and appeal to diverse audiences. DISCUSSION: Mindfulness has the potential for addressing the complexities of stress associated with disease management. Targeting mindfulness programs for populations with chronic disease management and caregiving responsibilities should include: Consideration of group formats with participation limited to this population, structuring programs to overcome barriers (i.e., culturally appropriate location), and equipping members of the community being served as instructors to ensure culturally relevant instruction.

Associations between white matter microstructure and infants' working memory.

Working memory emerges in infancy and plays a privileged role in subsequent adaptive cognitive development. The neural networks important for the development of working memory during infancy remain unknown. We used diffusion tensor imaging (DTI) and deterministic fiber tracking to characterize the microstructure of white matter fiber bundles hypothesized to support working memory in 12-month-old infants (n=73). Here we show robust associations between infants' visuospatial working memory performance and microstructural characteristics of widespread white matter. Significant associations were found for white matter tracts that connect brain regions known to support working memory in older children and adults (genu, anterior and superior thalamic radiations, anterior cingulum, arcuate fasciculus, and the temporal-parietal segment). Better working memory scores were associated with higher FA and lower RD values in these selected white matter tracts. These tract-specific brain-behavior relationships accounted for a significant amount of individual variation above and beyond infants' gestational age and developmental level, as measured with the Mullen Scales of Early Learning. Working memory was not associated with global measures of brain volume, as expected, and few associations were found between working memory and control white matter tracts. To our knowledge, this study is among the first demonstrations of brain-behavior associations in infants using quantitative tractography. The ability to characterize subtle individual differences in infant brain development associated with complex cognitive functions holds promise for improving our understanding of normative development, biomarkers of risk, experience-dependent learning and neuro-cognitive periods of developmental plasticity.

Longitudinal development of cortical and subcortical gray matter from birth to 2 years.

Very little is known about cortical development in the first years of life, a time of rapid cognitive development and risk for neurodevelopmental disorders. We studied regional cortical and subcortical gray matter volume growth in a group of 72 children who underwent magnetic resonance scanning after birth and at ages 1 and 2 years using a novel longitudinal registration/parcellation approach. Overall, cortical gray matter volumes increased substantially (106%) in the first year of life and less so in the second year (18%). We found marked regional differences in developmental rates, with primary motor and sensory cortices growing slower in the first year of life with association cortices growing more rapidly. In the second year of life, primary sensory regions continued to grow more slowly, while frontal and parietal regions developed relatively more quickly. The hippocampus grew less than other subcortical structures such as the amygdala and thalamus in the first year of life. It is likely that these patterns of regional gray matter growth reflect maturation and development of underlying function, as they are consistent with cognitive and functional development in the first years of life.

Environmental Toxicants and the Developing Brain.

Early life represents the most rapid and foundational period of brain development and a time of vulnerability to environmental insults. Evidence indicates that greater exposure to ubiquitous toxicants like fine particulate matter (PM2.5), manganese, and many phthalates is associated with altered developmental, physical health, and mental health trajectories across the lifespan. Whereas animal models offer evidence of their mechanistic effects on neurological development, there is little research that evaluates how these environmental toxicants are associated with human neurodevelopment using neuroimaging measures in infant and pediatric populations. This review provides an overview of 3 environmental toxicants of interest in neurodevelopment that are prevalent worldwide in the air, soil, food, water, and/or products of everyday life: fine particulate matter (PM2.5), manganese, and phthalates. We summarize mechanistic evidence from animal models for their roles in neurodevelopment, highlight prior research that has examined these toxicants with pediatric developmental and psychiatric outcomes, and provide a narrative review of the limited number of studies that have examined these toxicants using neuroimaging with pediatric populations. We conclude with a discussion of suggested directions that will move this field forward, including the incorporation of environmental toxicant assessment in large, longitudinal, multimodal neuroimaging studies; the use of multidimensional data analysis strategies; and the importance of studying the combined effects of environmental and psychosocial stressors and buffers on neurodevelopment. Collectively, these strategies will improve ecological validity and our understanding of how environmental toxicants affect long-term sequelae via alterations to brain structure and function.

Racial differences in the associations between adiposity, placental growth hormone and inflammatory cytokines in pregnant women.

Background: The prevalence of obesity among women of child-bearing age has contributed to an increased risk of pregnancy complications with a disproportional impact on women of lower socioeconomic status and among certain racial groups. In particular, socio-demographic and historical factors have resulted in higher rates of premature births and small-for-gestational age infants among Black women, which may be associated with placental function during pregnancy. The current study investigated the influence of maternal pre-pregnancy adiposity and race on the associations between inflammatory proteins, placental growth hormone (PGH), and infant birthweight. This information was collected for a subsample of 109 participants (Black, n = 39 vs. White, n = 70) from the Brain and Early Experiences (BEE) study. Methods: Serum samples were acquired late in the second trimester to assess PGH levels, C-reactive protein (CRP), interleukin 6 (IL-6), interleukin 8 (IL-8), and interleukin-1 receptor antagonist (IL-1Ra). Participant questionnaire responses provided information on pre-pregnancy BMI, health, race, educational attainment, and infant birthweight. Bivariate correlations and multiple linear regression models were utilized to evaluate associations by race between preconception adiposity, inflammatory markers and PGH. Results: After controlling for covariates including maternal age and education, gestational age, and fetal sex, regression models indicated that pre-pregnancy BMI was negatively associated with PGH (ß=-0.42, p<0.05) and IL-8 was positively associated with PGH (ß=0.35, p<0.05) among the Black mothers only; neither were significantly associated with PGH in the White mothers. When extending models to birth outcomes, BMI was positively associated with birthweight corrected for gestational age (BWz) (ß=0.24, p<0.05) and educational attainment was negatively associated with BWz (ß=0.28, p<0.05) for infants of White women. In contrast, neither variable was predictive of BWz for infants of Black mothers. Conclusion: Future work is needed to investigate racial differences in the association between adiposity and placental functioning, which are likely to contribute to differential effects on pregnancy outcomes and fetal growth.

The Brain and Early Experience Study: Protocol for a Prospective Observational Study.

BACKGROUND: Children raised in conditions of poverty (or near poverty) are at risk for nonoptimal mental health, educational, and occupational outcomes, many of which may be precipitated by individual differences in executive function (EF) skills that first emerge in early childhood. OBJECTIVE: The Brain and Early Experience study considers prenatal and postnatal experiences that may mediate the association between poverty and EF skills, including neural substrates. This paper described the study rationale and aims; research design issues, including sample size determination, the recruitment strategy, and participant characteristics; and a summary of developmental assessment points, procedures, and measures used to test the study hypotheses. METHODS: This is a prospective longitudinal study examining multiple pathways by which poverty influences normative variations in EF skills in early childhood. It is funded by the National Institute of Child Health and Human Development and approved by the institutional review board. RESULTS: Recruitment is complete with a sample of 203 participants, and data collection is expected to continue from September 2018 to February 2024. Of those recruited as low socioeconomic status (SES), 71% (55/78) reported income-to-needs (ITN) ratios of <2.0, and 35% (27/78) reported ITN ratios of <1.0. Among participants recruited into the not-low SES stratum, only 8.8% (11/125) reported ITN ratios of <2.0, and no participant reported ITN ratios of <1.0. The average ITN ratio for participants recruited into the low-income stratum was significantly lower than the average for the high-income recruitment cell (P<.001). Comparable recruitment outcomes were observed for both Black and non-Black families. Overall, the sample has adequate diversity for testing proposed hypotheses, with 13.3% (27/203) of participants reporting ITN ratios of <1 and >32.5% (66/203) reporting ratios of <2.0. CONCLUSIONS: Preliminary results indicate that the recruitment strategy for maximizing variation in family SES was successful, including variation within race. The findings of this study will help elucidate the complex interplay between prenatal and postnatal risk factors affecting critical neurocognitive developmental outcomes in early childhood. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/34854.

Diffusion Tensor Based White Matter Tract Atlases for Pediatric Populations.

Diffusion Tensor Imaging (DTI) is a non-invasive neuroimaging method that has become the most widely employed MRI modality for investigations of white matter fiber pathways. DTI has proven especially valuable for improving our understanding of normative white matter maturation across the life span and has also been used to index clinical pathology and cognitive function. Despite its increasing popularity, especially in pediatric research, the majority of existing studies examining infant white matter maturation depend on regional or white matter skeleton-based approaches. These methods generally lack the sensitivity and spatial specificity of more advanced functional analysis options that provide information about microstructural properties of white matter along fiber bundles. DTI studies of early postnatal brain development show that profound microstructural and maturational changes take place during the first two years of life. The pattern and rate of these changes vary greatly throughout the brain during this time compared to the rest of the life span. For this reason, appropriate image processing of infant MR imaging requires the use of age-specific reference atlases. This article provides an overview of the pre-processing, atlas building, and the fiber tractography procedures used to generate two atlas resources, one for neonates and one for 1- to 2-year-old populations. Via the UNC-NAMIC DTI Fiber Analysis Framework, our pediatric atlases provide the computational templates necessary for the fully automatic analysis of infant DTI data. To the best of our knowledge, these atlases are the first comprehensive population diffusion fiber atlases in early pediatric ages that are publicly available.

Maturational trajectories of cortical brain development through the pubertal transition: unique species and sex differences in the monkey revealed through structural magnetic resonance imaging.

Characterizing normal brain development in the rhesus macaque is a necessary prerequisite for establishing better nonhuman primate models of neuropathology. Structural magnetic resonance imaging scans were obtained on 37 rhesus monkeys (20 Male, 17 Female) between 10 and 64 months of age. Effects of age and sex were analyzed with a cross-sectional design. Gray matter (GM) and white matter (WM) volumes were determined for total brain and major cortical regions using an automatic segmentation and parcellation pipeline. Volumes of major subcortical structures were evaluated. Unlike neural maturation in humans, GM volumes did not show a postpubertal decline in most cortical regions, with the notable exception of the prefrontal cortex. Similar to humans, WM volumes increased through puberty with less change thereafter. Caudate, putamen, amygdala, and hippocampus increased linearly as did the corpus callosum. Males and females showed similar maturational patterns, although males had significantly larger brain volumes. Females had a proportionately larger caudate, putamen, and hippocampus, whereas males had both an absolute and relatively larger corpus callosum. The authors discuss the possible implications of these findings for research using the rhesus macaque as a model for neurodevelopmental disorders.

Parent-Child Mindfulness-Based Training: A Feasibility and Acceptability Study.

Stress in young children can interfere with academic achievement. To help address stress and aid in developing beneficial lifelong coping skills, educational systems are more widely incorporating programs that teach social and emotional regulation, such as mindfulness-based programs. The effects of these programs may be strengthened through parental support in the home environment. This study examined the feasibility and acceptability of a new Parent-Child Mindfulness-Based Training (PC-MBT) program, which delivered mindfulness-based training to parents and children simultaneously in the home environment. This study also implemented a working memory training after PC-MBT to assess the feasibility of completing two trainings sequentially. Healthy children, ages 8-10 (n = 14), and their parents participated in the PC-MBT program. They met with an instructor at home and online each week for 6 weeks and were provided resources including books, worksheets, audio recordings, and daily practices to reinforce mindfulness skills. A control group (n = 8) participated in the working memory training only. All PC-MBT and control children, except one, participated in the working memory training. All PC-MBT assigned families completed the PC-MBT program, and a majority utilized all types of the mindfulness training materials. A majority of participants also reported high levels of enjoyment and understanding of the PC-MBT program. This study establishes the feasibility and acceptability of the PC-MBT program and lays the foundation for future studies to assess program efficacy in healthy and clinical populations as well as the utility of PC-MBT to improve engagement and outcomes of other cognitive training programs.

Altering expectancy dampens neural response to aversive taste in primary taste cortex.

The primary taste cortex consists of the insula and operculum. Previous work has indicated that neurons in the primary taste cortex respond solely to sensory input from taste receptors and lingual somatosensory receptors. Using functional magnetic resonance imaging, we show here that expectancy modulates these neural responses in humans. When subjects were led to believe that a highly aversive bitter taste would be less distasteful than it actually was, they reported it to be less aversive than when they had accurate information about the taste and, moreover, the primary taste cortex was less strongly activated. In addition, the activation of the right insula and operculum tracked online ratings of the aversiveness for each taste. Such expectancy-driven modulation of primary sensory cortex may affect perceptions of external events.

Mindfulness-based interventions for children and adolescents across all settings: a scoping review protocol.

BACKGROUND AND PURPOSE: Although mindfulness-based interventions (MBIs) are becoming increasingly popular, the application of MBIs with children and adolescents is still in its infancy. Mapping the existing literature is necessary to help guide pediatric mindfulness interventions. Our purpose is to synthesize the evidence of reported MBIs for children and adolescents with and without physical, mental, and cognitive disorders. Accordingly, we aim to identify trends and gaps in the literature, so that we can provide direction to researchers who seek to advance the evidence base for using MBIs in pediatric populations. METHODS: Our search strategy will be conducted following Arksey and O'Malley's methodological framework. It will include a comprehensive search of published studies in 7 databases, gray literature, conference proceedings, and citations of selected articles. Two independent reviewers will evaluate all abstracts and full articles that have a pediatric sample (children 2-17 years), use MBIs to promote development or to remediate underlying disorders, and are written in English or French. We will identify the definitions and concepts from MBIs, categorize accepted studies according to etiology and rehabilitation type, describe intervention methodology, and report outcomes of selected studies. DISCUSSION: Our review will provide a comprehensive overview of the pediatric mindfulness intervention literature to date, involving a range of mental, cognitive, and physical outcomes for healthy children and adolescents and for those with a variety of disorders in clinical and institutional settings. We will disseminate results to mindfulness practitioners and provide guidance to future pediatric researchers in their development and application of mindfulness interventions, thereby contributing to the scientific understanding of mindfulness for the ultimate betterment of child and adolescent well-being and life-long functioning. SYSTEMATIC REVIEW REGISTRATION: PROSPERO does not accept scoping review protocols.

Individual differences in neonatal white matter are associated with executive function at 3 years of age.

The development of executive function (EF) in early childhood contributes to social and academic aspects of school readiness and facilitates emerging self-regulatory competence. Numerous efforts are underway to identify aspects of early brain development that contribute to emerging EF. Existing research supports the importance of multiple white matter tracts for EF in older children and adults. However, this research has not been extended to young children. In this study, we consider neonatal white matter microstructure in relation to children's performance on a battery of EF tasks three years later. We obtained diffusion tensor imaging data from a sample of neonates (N = 27) shortly after birth. At 3 years of age, children completed a computerized battery of EF tasks. The primary data analyses involved regression models estimated for each white matter tract. Multiple demographic and measure-related covariates were included in each model. A follow-up analysis of tracts determined to be associated with EF examined individual data points along those fibers. Among the white matter tracts analyzed, the cingulum was significantly associated with EF at 3 years of age. Specifically, lower axial diffusivity values along the cingulum were associated with increased performance on the EF battery. Results are discussed as providing initial evidence that individual differences in neonatal brain structure may facilitate the acquisition of EF abilities in early childhood. These findings are consistent with previous research that supports the value of the cingulum for higher-order cognitive abilities. Cautions and implications of these results are considered.

Verbal and nonverbal predictors of executive function in early childhood.

The study of executive function (EF) has become increasingly popular in multiple areas of research. A wealth of evidence has supported the value of EF in shaping notable outcomes across typical and atypical development; however, little evidence has supported the cognitive contributors to early EF development. The current study used data from a large longitudinal sample of healthy children to investigate the differential influence of verbal and nonverbal cognition on later EF. Participants were assessed at 2 years of age using the Mullen Scales of Early Learning, and Mullen scores were used to calculate nonverbal and verbal developmental quotients. Executive function was measured at 6 years using assessments from the Stanford-Binet, Cambridge Neuropsychological Test Automated Battery, and the Behavior Rating Inventory of Executive Function. Results suggested that early nonverbal cognition was a better predictor of 6-year EF as measured by task-based laboratory assessments, whereas verbal cognition was a better predictor of parent-reported EF. Findings are discussed in regard to EF development and characteristics of EF measurement.

Association of Prenatal Maternal Depression and Anxiety Symptoms With Infant White Matter Microstructure.

Importance: Maternal depression and anxiety can have deleterious and lifelong consequences on child development. However, many aspects of the association of early brain development with maternal symptoms remain unclear. Understanding the timing of potential neurobiological alterations holds inherent value for the development and evaluation of future therapies and interventions. Objective: To examine the association between exposure to prenatal maternal depression and anxiety symptoms and offspring white matter microstructure at 1 month of age. Design, Setting, and Participants: This cohort study of 101 mother-infant dyads used a composite of depression and anxiety symptoms measured in mothers during the third trimester of pregnancy and measures of white matter microstructure characterized in the mothers' 1-month offspring using diffusion tensor imaging and neurite orientation dispersion and density imaging performed from October 1, 2014, to November 30, 2016. Magnetic resonance imaging was performed at an academic research facility during natural, nonsedated sleep. Main Outcomes and Measures: Brain mapping algorithms and statistical models were used to evaluate the association between maternal depression and anxiety and 1-month infant white matter microstructure as measured by diffusion tensor imaging and neurite orientation dispersion and density imaging findings. Results: In the 101 mother-infant dyads (mean [SD] age of mothers, 33.22 [3.99] years; mean age of infants at magnetic resonance imaging, 33.07 days [range, 18-50 days]; 92 white mothers [91.1%]; 53 male infants [52.5%]), lower 1-month white matter microstructure (decreased neurite density and increased mean, radial, and axial diffusivity) was associated in right frontal white matter microstructure with higher prenatal maternal symptoms of depression and anxiety. Significant sex × symptom interactions with measures of white matter microstructure were also observed, suggesting that white matter development may be differentially sensitive to maternal depression and anxiety symptoms in males and females during the prenatal period. Conclusions and Relevance: These data highlight the importance of the prenatal period to early brain development and suggest that the underlying white matter microstructure is associated with the continuum of prenatal maternal depression and anxiety symptoms.

Correspondence between hair cortisol concentrations and 30-day integrated daily salivary and weekly urinary cortisol measures.

Characterization of cortisol production, regulation and function is of considerable interest and relevance given its ubiquitous role in virtually all aspects of physiology, health and disease risk. The quantification of cortisol concentration in hair has been proposed as a promising approach for the retrospective assessment of integrated, long-term cortisol production. However, human research is still needed to directly test and validate current assumptions about which aspects of cortisol production and regulation are reflected in hair cortisol concentrations (HCC). Here, we report findings from a validation study in a sample of 17 healthy adults (mean±SD age: 34±8.6 yrs). To determine the extent to which HCC captures cumulative cortisol production, we examined the correspondence of HCC, obtained from the first 1cm scalp-near hair segment, assumed to retrospectively reflect 1-month integrated cortisol secretion, with 30-day average salivary cortisol area-under-the curve (AUC) based on 3 samples collected per day (on awakening, +30min, at bedtime) and the average of 4 weekly 24-h urinary free cortisol (UFC) assessments. To further address which aspects of cortisol production and regulation are best reflected in the HCC measure, we also examined components of the salivary measures that represent: (1) production in response to the challenge of awakening (using the cortisol awakening response [CAR]), and (2) chronobiological regulation of cortisol production (using diurnal slope). Finally, we evaluated the test-retest stability of each cortisol measure. Results indicate that HCC was most strongly associated with the prior 30-day integrated cortisol production measure (average salivary cortisol AUC) (r=0.61, p=0.01). There were no significant associations between HCC and the 30-day summary measures using CAR or diurnal slope. The relationship between 1-month integrated 24-h UFC and HCC did not reach statistical significance (r=0.30, p=0.28). Lastly, of all cortisol measures, test-retest correlations of serial measures were highest for HCC (month-to-month: r=0.84, p<0.001), followed by 24-h UFC (week-to-week: r's between 0.59 and 0.68, ps<0.05) and then integrated salivary cortisol concentrations (week-to-week: r's between 0.38 and 0.61, p's between 0.13 and 0.01). These findings support the contention that HCC provides a reliable estimate of long-term integrated free cortisol production that is aligned with integrated salivary cortisol production measured over a corresponding one-month period.