Aberrant Maturation of the Uncinate Fasciculus Follows Exposure to Unpredictable Patterns of Maternal Signals.

Across species, unpredictable patterns of maternal behavior are emerging as novel predictors of aberrant cognitive and emotional outcomes later in life. In animal models, exposure to unpredictable patterns of maternal behavior alters brain circuit maturation and cognitive and emotional outcomes. However, whether exposure to such signals in humans alters the development of brain pathways is unknown. In mother-child dyads, we tested the hypothesis that exposure to more unpredictable maternal signals in infancy is associated with aberrant maturation of corticolimbic pathways. We focused on the uncinate fasciculus, the primary fiber bundle connecting the amygdala to the orbitofrontal cortex and a key component of the medial temporal lobe-prefrontal cortex circuit. Infant exposure to unpredictable maternal sensory signals was assessed at 6 and 12 months. Using high angular resolution diffusion imaging, we quantified the integrity of the uncinate fasciculus using generalized fractional anisotropy (GFA). Higher maternal unpredictability during infancy presaged greater uncinate fasciculus GFA in children 9-11 years of age (n = 69, 29 female). In contrast to the uncinate, GFA of a second corticolimbic projection, the hippocampal cingulum, was not associated with maternal unpredictability. Addressing the overall functional significance of the uncinate and cingulum relationships, we found that the resulting imbalance of medial temporal lobe-prefrontal cortex connectivity partially mediated the association between unpredictable maternal sensory signals and impaired episodic memory function. These results suggest that unbalanced maturation of corticolimbic circuits is a mechanism by which early unpredictable sensory signals may impact cognition later in life.SIGNIFICANCE STATEMENT Our prior work across species demonstrated that unpredictable patterns of maternal care are associated with compromised memory function. However, the neurobiological mechanisms by which this occurs in humans remain unknown. Here, we identify an association of exposure to unpredictable patterns of maternal sensory signals with the integrity of corticolimbic circuits involved in emotion and cognition using state-of-the-art diffusion imaging techniques and analyses. We find that exposure to early unpredictability is associated with higher integrity of the uncinate fasciculus with no effect on a second corticolimbic pathway, the cingulum. The resulting imbalance of corticolimbic circuit development is a novel mediator of the association between unpredictable patterns of maternal care and poorer episodic memory.

The role of parental health and distress in assessing children's health status.

PURPOSE: The purpose of the study was to examine the contributions of parents' health and distress to parent's and children's assessments of children's health. METHODS: We used baseline data from a longitudinal study of 364 children (ages 4-12) about to undergo surgery and their parents in a Southern California pediatric hospital. We used the 20-item child self-reported CHRIS 2.0 general health and the parallel parent-reported measure of the child's health, along with a measure of parental distress about the child's health were administered in the perioperative period. Other measures included parents' physical and mental health, quality of life, distress over their child's health, and number and extent of other health problems of the child and siblings. RESULTS: On average, parents' reports about the child were consistently and statistically significantly higher than children's self-reports across all sub-dimensions of the CHRIS 2.0 measure. Parents' personal health was positively associated with their reports of the child's health. More distressed parents were closer to the child's self-reports, but reported poorer personal health. CONCLUSION: Parent-child differences in this study of young children's health were related to parental distress. Exploring the nature of the gap between parents and children in assessments of children's health could improve effective clinical management for the child and enhance family-centered pediatric care. Future studies are needed to assess the generalizability of CHRIS 2.0 to other health settings and conditions and to other racial/ethnic groups.

Integrity of the uncinate fasciculus is associated with emotional pattern separation-related fMRI signals in the hippocampal dentate and CA3.

Alterations in white matter integrity have been demonstrated in a number of psychiatric disorders involving emotional disruptions. One such pathway - the uncinate fasciculus - connects the orbitofrontal cortex (OFC) to the medial temporal lobes (MTL) and has been associated with early life adversity, maltreatment, anxiety, and depression. While it is purported to play a role in episodic memory and discrimination, its exact function remains poorly understood. We have previously described the role of the amygdala and dentate (DG)/CA3 fields of the hippocampus in the mnemonic discrimination of emotional experiences (i.e. emotional pattern separation). However, how this computation may be modulated by connectivity with the orbitofrontal cortex remains unknown. Here we asked if the uncinate fasciculus plays a role in influencing MTL subregional activity during emotional pattern separation. By combining diffusion imaging with high-resolution fMRI, we found that reduced integrity of the UF is related to elevated BOLD fMRI activation of the DG/CA3 subregions of the hippocampus during emotional lure discrimination. We additionally report that higher levels of DG/CA3 activity are associated with poorer memory performance, suggesting that greater activation in this network (possibly driven by CA3 recurrent collaterals) is associated with memory errors. Based on this work we suggest that the UF is one pathway that may allow the OFC to exert control on this network and improve discrimination of emotional experiences, although further work is necessary to fully evaluate this possibility. This work provides novel insight into the role of prefrontal interactions with the MTL, particularly in the context of emotional memory.

Development and initial validation of self-report measures of general health, preoperative anxiety, and postoperative pain in young children using computer-administered animation.

BACKGROUND: For young children, existing measures of children's health-related quality of life must be parent-reported or interviewer-administered for those who cannot read or complete measures independently. Parents' and childrens' reports about the child's health have been shown to disagree. AIMS: (a) To test the reliability and validity of an animated, computer-administered Child Health Rating Inventories (CHRIS2.0) among children aged 4-12 undergoing surgery; and (b) to develop and test two CHRIS measures of preoperative anxiety and postoperative pain management. METHODS: We conducted a longitudinal cohort study of a diverse group of 542 children aged 4-12 undergoing surgery. We compared the CHRIS measures to Pediatric Quality of Life Inventory (PedsQL), the Functional Disabilities Inventory (FDI), State-Trait Anxiety Inventory for children (STAI-CH), and the Parent Postoperative Pain Measure (PPPM). RESULTS: Factor analyses supported the construct validity of the 12-item general physical health and the 8-item mental health CHRIS scales, as well as a composite 20-item scale, and the CHRIS preoperative anxiety and postoperative pain scales. Internal consistency reliability for all CHRIS scales exceeded the standard for group comparisons (Cronbach's α ≥0.70). The CHRIS general health composite was significantly correlated with composite PedsQL and FDI (r = 0.28, P < .001 and r = 0.43, P < .001, respectively). The CHRIS peri-operative anxiety measure was significantly correlated with the STAI-CH (r = 0.44, P < .001), as was the CHRIS postoperative pain scale with the PPPM (r = 0.52, P < .001). CONCLUSIONS: The CHRIS measures were reliable and valid in this diverse sample of young children (4-12). Because CHRIS measures are self-administered, scored in real time, and run on multiple different platforms, this approach provides a feasible method for the collection of health-related quality of life in young children and those with limited literacy. Our data indicate that this approach is psychometrically sound and has the potential for adding the child's voice to pediatric outcomes.

Exposure to unpredictable maternal sensory signals influences cognitive development across species.

Maternal care is a critical determinant of child development. However, our understanding of processes and mechanisms by which maternal behavior influences the developing human brain remains limited. Animal research has illustrated that patterns of sensory information is important in shaping neural circuits during development. Here we examined the relation between degree of predictability of maternal sensory signals early in life and subsequent cognitive function in both humans (n = 128 mother/infant dyads) and rats (n = 12 dams; 28 adolescents). Behaviors of mothers interacting with their offspring were observed in both species, and an entropy rate was calculated as a quantitative measure of degree of predictability of transitions among maternal sensory signals (visual, auditory, and tactile). Human cognitive function was assessed at age 2 y with the Bayley Scales of Infant Development and at age 6.5 y with a hippocampus-dependent delayed-recall task. Rat hippocampus-dependent spatial memory was evaluated on postnatal days 49-60. Early life exposure to unpredictable sensory signals portended poor cognitive performance in both species. The present study provides evidence that predictability of maternal sensory signals early in life impacts cognitive function in both rats and humans. The parallel between experimental animal and observational human data lends support to the argument that predictability of maternal sensory signals causally influences cognitive development.

Unpredictable maternal behavior is associated with a blunted infant cortisol response.

BACKGROUND: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with poor physical and mental health. Early-life adversity may dysregulate cortisol response to subsequent stress. This study examines the association between patterns of maternal behavior and infant stress response to a challenge. Specifically, we test whether infant exposure to unpredictable maternal sensory signals is related to the cortisol response to a painful stressor. METHOD: Participants were 102 mothers and their children enrolled in a longitudinal study. Patterns of maternal sensory signals were evaluated at 6 and 12 months during a 10-min mother-infant play episode. Entropy rate was calculated as a quantitative measure of the degree of unpredictability of maternal sensory signals (visual, auditory, and tactile) exhibited during the play episode. Infant saliva samples were collected for cortisol analysis before and after inoculation at 12 months. RESULTS: Unpredictable patterns of maternal sensory signals were associated with a blunted infant cortisol response to a painful stressor. This relation persisted after evaluation of covariates including maternal sensitivity and maternal psychological distress. CONCLUSIONS: This study provides evidence that unpredictable patterns of maternal sensory signals are one process through which caregiving affects the function of infant stress response systems.

Why Temporal Persistence of Biometric Features, as Assessed by the Intraclass Correlation Coefficient, Is So Valuable for Classification Performance.

It is generally accepted that relatively more permanent (i.e., more temporally persistent) traits are more valuable for biometric performance than less permanent traits. Although this finding is intuitive, there is no current work identifying exactly where in the biometric analysis temporal persistence makes a difference. In this paper, we answer this question. In a recent report, we introduced the intraclass correlation coefficient (ICC) as an index of temporal persistence for such features. Here, we present a novel approach using synthetic features to study which aspects of a biometric identification study are influenced by the temporal persistence of features. What we show is that using more temporally persistent features produces effects on the similarity score distributions that explain why this quality is so key to biometric performance. The results identified with the synthetic data are largely reinforced by an analysis of two datasets, one based on eye-movements and one based on gait. There was one difference between the synthetic and real data, related to the intercorrelation of features in real data. Removing these intercorrelations for real datasets with a decorrelation step produced results which were very similar to that obtained with synthetic features.

The Function Biomedical Informatics Research Network Data Repository.

The Function Biomedical Informatics Research Network (FBIRN) developed methods and tools for conducting multi-scanner functional magnetic resonance imaging (fMRI) studies. Method and tool development were based on two major goals: 1) to assess the major sources of variation in fMRI studies conducted across scanners, including instrumentation, acquisition protocols, challenge tasks, and analysis methods, and 2) to provide a distributed network infrastructure and an associated federated database to host and query large, multi-site, fMRI and clinical data sets. In the process of achieving these goals the FBIRN test bed generated several multi-scanner brain imaging data sets to be shared with the wider scientific community via the BIRN Data Repository (BDR). The FBIRN Phase 1 data set consists of a traveling subject study of 5 healthy subjects, each scanned on 10 different 1.5 to 4 T scanners. The FBIRN Phase 2 and Phase 3 data sets consist of subjects with schizophrenia or schizoaffective disorder along with healthy comparison subjects scanned at multiple sites. In this paper, we provide concise descriptions of FBIRN's multi-scanner brain imaging data sets and details about the BIRN Data Repository instance of the Human Imaging Database (HID) used to publicly share the data.

A Test by Any Other Name: P Values, Bayes Factors, and Statistical Inference.

Procedures used for statistical inference are receiving increased scrutiny as the scientific community studies the factors associated with insuring reproducible research. This note addresses recent negative attention directed at p values, the relationship of confidence intervals and tests, and the role of Bayesian inference and Bayes factors, with an eye toward better understanding these different strategies for statistical inference. We argue that researchers and data analysts too often resort to binary decisions (e.g., whether to reject or accept the null hypothesis) in settings where this may not be required.

Reliability of ordinal outcomes in forensic black-box studies.

Forensic science disciplines such as latent print examination, bullet and cartridge case comparisons, and shoeprint analysis, involve subjective decisions by forensic experts throughout the examination process. Most of the decisions involve ordinal categories. Examples include a three-category outcome for latent print comparisons (exclusion, inconclusive, identification) and a seven-category outcome for footwear comparisons (exclusion, indications of non-association, inconclusive, limited association of class characteristics, association of class characteristics, high degree of association, identification). As the results of the forensic examinations of evidence can heavily influence the outcomes of court proceedings, it is important to assess the reliability and accuracy of the underlying decisions. "Black box" studies are the most common approach for assessing the reliability and accuracy of subjective decisions. In these studies, researchers produce evidence samples consisting of a sample of questioned source and a sample of known source where the ground truth (same source or different source) is known. Examiners provide assessments for selected samples using the same approach they would use in actual casework. These studies often have two phases; the first phase comprises of decisions on samples of varying complexities by different examiners, and the second phase involves repeated decisions by the same examiner on a (usually) small subset of samples that were encountered by examiners in the first phase. We provide a statistical method to analyze ordinal decisions from black-box trials with the objective of obtaining inferences for the reliability of these decisions and quantifying the variation in decisions attributable to the examiners, the samples, and statistical interaction effects between examiners and samples. We present simulation studies to judge the performance of the model on data with known parameter values and apply the model to data from a handwritten signature complexity study, a latent fingerprint examination black-box study, and a handwriting comparisons black-box study.

How signature complexity affects expert and lay ability to distinguish genuine, disguised and simulated signatures.

This study examined how variations in signature complexity affected the ability of forensic document examiners (FDEs) and laypeople to determine whether signatures are authentic or simulated (forged), as well as whether they are disguised. Forty-five FDEs from nine countries evaluated nine different signature comparisons in this online study. Receiver Operating Characteristic (ROC) analyses revealed that FDEs performed in excess of chance levels, but performance varied as a function of signature complexity: Sensitivity (the true-positive rate) did not differ much between complexity levels (i.e., 65% vs. 79% vs. 79% for low vs medium vs high complexity), but specificity (the true-negative rate) was the highest (95%) for the medium complexity signatures and lowest (73%) for low complexity signatures. The specificity of high-complexity signatures (83%) was between these values. The sensitivity for disguised comparisons was only 11% and did not vary across complexity levels. One hundred-one novices also completed the study. A comparison of the area under the ROC curve (AUCs) revealed that FDEs outperformed novices in medium and high-complexity signatures but not low-complexity signatures. Novices also struggled to detect disguised signatures. While these findings elucidate the role of signature complexity in lay and expert evaluations, the error rates observed here may differ from those in forensic practice due to differences in the experimental stimuli and circumstances under which they were evaluated. This investigation of the role of signature complexity in the evaluation process was not intended to estimate error rates in forensic practice.

Individual longitudinal changes in DNA-methylome identify signatures of early-life adversity and correlate with later outcome.

Adverse early-life experiences (ELA) affect a majority of the world's children. Whereas the enduring impact of ELA on cognitive and emotional health is established, there are no tools to predict vulnerability to ELA consequences in an individual child. Epigenetic markers including peripheral-cell DNA-methylation profiles may encode ELA and provide predictive outcome markers, yet the interindividual variance of the human genome and rapid changes in DNA methylation in childhood pose significant challenges. Hoping to mitigate these challenges we examined the relation of several ELA dimensions to DNA methylation changes and outcome using a within-subject longitudinal design and a high methylation-change threshold. DNA methylation was analyzed in buccal swab/saliva samples collected twice (neonatally and at 12 months) in 110 infants. We identified CpGs differentially methylated across time for each child and determined whether they associated with ELA indicators and executive function at age 5. We assessed sex differences and derived a sex-dependent 'impact score' based on sites that most contributed to methylation changes. Changes in methylation between two samples of an individual child reflected age-related trends and correlated with executive function years later. Among tested ELA dimensions and life factors including income to needs ratios, maternal sensitivity, body mass index and infant sex, unpredictability of parental and household signals was the strongest predictor of executive function. In girls, high early-life unpredictability interacted with methylation changes to presage executive function. Thus, longitudinal, within-subject changes in methylation profiles may provide a signature of ELA and a potential predictive marker of individual outcome.

Infant hedonic/anhedonic processing index (HAPI-Infant): Assessing infant anhedonia and its prospective association with adolescent depressive symptoms.

BACKGROUND: Anhedonia, an impairment in the motivation for or experience of pleasure, is a well-established transdiagnostic harbinger and core symptom of mental illness. Given increasing recognition of early life origins of mental illness, we posit that anhedonia should, and could, be recognized earlier if appropriate tools were available. However, reliable diagnostic instruments prior to childhood do not currently exist. METHODS: We developed an assessment instrument for anhedonia/reward processing in infancy, the Infant Hedonic/Anhedonic Processing Index (HAPI-Infant). Exploratory factor and psychometric analyses were conducted using data from 6- and 12-month-old infants from two cohorts (N = 188, N = 212). Then, associations were assessed between infant anhedonia and adolescent self-report of depressive symptoms. RESULTS: The HAPI-Infant (47-items), exhibited excellent psychometric properties. Higher anhedonia scores at 6 (r = 0.23, p < .01) and 12 months (r = 0.19, p < .05) predicted elevated adolescent depressive symptoms, and these associations were stronger than for established infant risk indicators such as negative affectivity. Subsequent analyses supported the validity of short (27-item) and very short (12-item) versions of this measure. LIMITATIONS: The primary limitations of this study are that the HAPI-Infant awaits additional tests of generalizability and of its ability to predict clinical diagnosis of depression. CONCLUSIONS: The HAPI-Infant is a novel, psychometrically strong diagnostic tool suitable for recognizing anhedonia during the first year of life with strong predictive value for later depressive symptoms. In view of the emerging recognition of increasing prevalence of affective disorders in children and adolescents, the importance of the HAPI-Infant in diagnosing anhedonia is encouraging. Early recognition of anhedonia could target high-risk individuals for intervention and perhaps prevention of mental health disorders.

Across ages and places: Unpredictability of maternal sensory signals and child internalizing behaviors.

BACKGROUND: Patterns of sensory inputs early in life play an integral role in shaping the maturation of neural circuits, including those implicated in emotion and cognition. In both experimental animal models and observational human research, unpredictable sensory signals have been linked to aberrant developmental outcomes, including poor memory and effortful control. These findings suggest that sensitivity to unpredictable sensory signals is conserved across species and sculpts the developing brain. The current study provides a novel investigation of unpredictable maternal sensory signals in early life and child internalizing behaviors. We tested these associations in three independent cohorts to probe the generalizability of associations across continents and cultures. METHOD: The three prospective longitudinal cohorts were based in Orange, USA (n = 163, 47.2 % female, Mage = 1 year); Turku, Finland (n = 239, 44.8 % female, Mage = 5 years); and Irvine, USA (n = 129, 43.4 % female, Mage = 9.6 years). Unpredictability of maternal sensory signals was quantified during free-play interactions. Child internalizing behaviors were measured via parent report (Orange & Turku) and child self-report (Irvine). RESULTS: Early life exposure to unpredictable maternal sensory signals was associated with greater child fearfulness/anxiety in all three cohorts, above and beyond maternal sensitivity and sociodemographic factors. The association between unpredictable maternal sensory signals and child sadness/depression was relatively weaker and did not reach traditional thresholds for statistical significance. LIMITATIONS: The correlational design limits our ability to make causal inferences. CONCLUSIONS: Findings across the three diverse cohorts suggest that unpredictable maternal signals early in life shape the development of internalizing behaviors, particularly fearfulness and anxiety.

Prenatal Exposure to Maternal Mood Entropy Is Associated With a Weakened and Inflexible Salience Network in Adolescence.

BACKGROUND: Fetal exposure to maternal mood dysregulation influences child cognitive and emotional development, which may have long-lasting implications for mental health. However, the neurobiological alterations associated with this dimension of adversity have yet to be explored. Here, we tested the hypothesis that fetal exposure to entropy, a novel index of dysregulated maternal mood, would predict the integrity of the salience network, which is involved in emotional processing. METHODS: A sample of 138 child-mother pairs (70 females) participated in this prospective longitudinal study. Maternal negative mood level and entropy (an index of variable and unpredictable mood) were assessed 5 times during pregnancy. Adolescents engaged in a functional magnetic resonance imaging task that was acquired between 2 resting-state scans. Changes in network integrity were analyzed using mixed-effect and latent growth curve models. The amplitude of low frequency fluctuations was analyzed to corroborate findings. RESULTS: Prenatal maternal mood entropy, but not mood level, was associated with salience network integrity. Both prenatal negative mood level and entropy were associated with the amplitude of low frequency fluctuations of the salience network. Latent class analysis yielded 2 profiles based on changes in network integrity across all functional magnetic resonance imaging sequences. The profile that exhibited little variation in network connectivity (i.e., inflexibility) consisted of adolescents who were exposed to higher negative maternal mood levels and more entropy. CONCLUSIONS: These findings suggest that fetal exposure to maternal mood dysregulation is associated with a weakened and inflexible salience network. More broadly, they identify maternal mood entropy as a novel marker of early adversity that exhibits long-lasting associations with offspring brain development.

Childhood unpredictability is associated with increased risk for long- and short-term depression and anhedonia symptoms following combat deployment.

High unpredictability has emerged as a dimension of early-life adversity that may contribute to a host of deleterious consequences later in life. Early-life unpredictability affects development of limbic and reward circuits in both rodents and humans, with a potential to increase sensitivity to stressors and mood symptoms later in life. Here, we examined the extent to which unpredictability during childhood was associated with changes in mood symptoms (anhedonia and general depression) after two adult life stressors, combat deployment and civilian reintegration, which were assessed ten years apart. We also examined how perceived stress and social support mediated and /or moderated links between childhood unpredictability and mood symptoms. To test these hypotheses, we leveraged the Marine Resiliency Study, a prospective longitudinal study of the effects of combat deployment on mental health in Active-Duty Marines and Navy Corpsman. Participants (N = 273) were assessed for depression and anhedonia before (pre-deployment) and 3-6 months after (acute post-deployment) a combat deployment. Additional assessment of depression and childhood unpredictability were collected 10 years post-deployment (chronic post-deployment). Higher childhood unpredictability was associated with higher anhedonia and general depression at both acute and chronic post-deployment timepoints (ßs ≥ 0.16, ps ≤.007). The relationship between childhood unpredictability and subsequent depression at acute post-deployment was partially mediated by lower social support (b = 0.07, 95% CI [0.03, 0.15]) while depression at chronic post-deployment was fully mediated by a combination of lower social support (b = 0.14, 95% CI [0.07, 0.23]) and higher perceived stress (b = 0.09, 95% CI [0.05, 0.15]). These findings implicate childhood unpredictability as a potential risk factor for depression in adulthood and suggest that increasing the structure and predictability of childhood routines and developing social support interventions after life stressors could be helpful for preventing adult depression.

Experiences of COVID-19-Related Racism and Impact on Depression Trajectories Among Racially/Ethnically Minoritized Adolescents.

PURPOSE: In 2020, racially/ethnically minoritized (REMD) youth faced the "dual pandemics" of COVID-19 and racism, both significant stressors with potential for adverse mental health effects. The current study tested whether short- and long-term trajectories of depressive symptoms from before to during the COVID-19 pandemic differed between REMD adolescents who did and did not endorse exposure to COVID-19-era-related racism (i.e., racism stemming from conditions created or exacerbated by the COVID-19 pandemic). METHODS: A community sample of 100 REMD adolescents enrolled in an ongoing longitudinal study of mental health was assessed before and during the COVID-19 pandemic. Participants were 51% girls, mean age = 16, standard deviation = 2.7, and identified as Latinx/Hispanic (48%), Multiethnic (34%), Asian American (12%), and Black (6%). RESULTS: REMD adolescents' depressive symptoms were elevated during the COVID-19 pandemic compared to pre-pandemic levels, and increases were more pronounced over time for those who endorsed exposure to COVID-19-era-related racism. In general, Asian American participants endorsed racism experiences at the highest rates compared to others, including being called names (42%), people acting suspicious around them (33%), and being verbally threatened (17%). Additionally, more than half of Black and Asian American participants reported worry about experiencing racism related to the COVID-19 pandemic, even if they had not experienced it to date. DISCUSSION: REMD adolescents are at increased risk for depressive symptoms related to converging stressors stemming from the COVID-19 pandemic and pandemic-related racism, which has the potential to widen racial/ethnic mental health disparities faced by the REMD youth.

Within-subject changes in methylome profile identify individual signatures of early-life adversity, with a potential to predict neuropsychiatric outcome.

Background: Adverse early-life experiences (ELA), including poverty, trauma and neglect, affect a majority of the world's children. Whereas the impact of ELA on cognitive and emotional health throughout the lifespan is well-established, it is not clear how distinct types of ELA influence child development, and there are no tools to predict for an individual child their vulnerability or resilience to the consequences of ELAs. Epigenetic markers including DNA-methylation profiles of peripheral cells may encode ELA and provide a predictive outcome marker. However, the rapid dynamic changes in DNA methylation in childhood and the inter-individual variance of the human genome pose barriers to identifying profiles predicting outcomes of ELA exposure. Here, we examined the relation of several dimensions of ELA to changes of DNA methylation, using a longitudinal within-subject design and a high threshold for methylation changes in the hope of mitigating the above challenges. Methods: We analyzed DNA methylation in buccal swab samples collected twice for each of 110 infants: neonatally and at 12 months. We identified CpGs differentially methylated across time, calculated methylation changes for each child, and determined whether several indicators of ELA associated with changes of DNA methylation for individual infants. We then correlated select dimensions of ELA with methylation changes as well as with measures of executive function at age 5 years. We examined for sex differences, and derived a sex-dependent 'impact score' based on sites that most contributed to the methylation changes. Findings: Setting a high threshold for methylation changes, we discovered that changes in methylation between two samples of an individual child reflected age-related trends towards augmented methylation, and also correlated with executive function years later. Among the tested factors and ELA dimensions, including income to needs ratios, maternal sensitivity, body mass index and sex, unpredictability of parental and household signals was the strongest predictor of executive function. In girls, an interaction was observed between a measure of high early-life unpredictability and methylation changes, in presaging executive function. Interpretation: These findings establish longitudinal, within-subject changes in methylation profiles as a signature of some types of ELA in an individual child. Notably, such changes are detectable beyond the age-associated DNA methylation dynamics. Future studies are required to determine if the methylation profile changes identified here provide a predictive marker of vulnerabilities to poorer cognitive and emotional outcomes.

Function biomedical informatics research network recommendations for prospective multicenter functional MRI studies.

This report provides practical recommendations for the design and execution of multicenter functional MRI (MC-fMRI) studies based on the collective experience of the Function Biomedical Informatics Research Network (FBIRN). The study was inspired by many requests from the fMRI community to FBIRN group members for advice on how to conduct MC-fMRI studies. The introduction briefly discusses the advantages and complexities of MC-fMRI studies. Prerequisites for MC-fMRI studies are addressed before delving into the practical aspects of carefully and efficiently setting up a MC-fMRI study. Practical multisite aspects include: (i) establishing and verifying scan parameters including scanner types and magnetic fields, (ii) establishing and monitoring of a scanner quality program, (iii) developing task paradigms and scan session documentation, (iv) establishing clinical and scanner training to ensure consistency over time, (v) developing means for uploading, storing, and monitoring of imaging and other data, (vi) the use of a traveling fMRI expert, and (vii) collectively analyzing imaging data and disseminating results. We conclude that when MC-fMRI studies are organized well with careful attention to unification of hardware, software and procedural aspects, the process can be a highly effective means for accessing a desired participant demographics while accelerating scientific discovery.

Genetic variations in the dopamine system and facial expression recognition in healthy chinese college students.

OBJECTIVE: This study investigated the relation between genetic variations in the dopamine system and facial expression recognition. METHODS: A sample of Chinese college students (n = 478) was given a facial expression recognition task. Subjects were genotyped for 98 loci [96 single-nucleotide polymorphisms (SNPs) and 2 variable number tandem repeats] in 16 genes involved in the dopamine neurotransmitter system, including its 4 subsystems: synthesis (TH, DDC, and DBH), degradation/transport (COMT,MAOA,MAOB, and SLC6A3), receptors (DRD1,DRD2,DRD3,DRD4, and DRD5), and modulation (NTS,NTSR1,NTSR2, and NLN). To quantify the total contributions of the dopamine system to emotion recognition, we used a series of multiple regression models. Permutation analyses were performed to assess the posterior probabilities of obtaining such results. RESULTS: Among the 78 loci that were included in the final analyses (after excluding 12 SNPs that were in high linkage disequilibrium and 8 that were not in Hardy-Weinberg equilibrium), 1 (for fear), 3 (for sadness), 5 (for anger), 13 (for surprise), and 15 (for disgust) loci exhibited main effects on the recognition of facial expressions. Genetic variations in the dopamine system accounted for 3% for fear, 6% for sadness, 7% for anger, 10% for surprise, and 18% for disgust, with the latter surviving a stringent permutation test. CONCLUSIONS: Genetic variations in the dopamine system (especially the dopamine synthesis and modulation subsystems) made significant contributions to individual differences in the recognition of disgust faces.