Maternal stress and development of infant attention to threat-related facial expressions.

Attentional biases to threat-related stimuli, such as fearful and angry facial expressions, are important to survival and emerge early in development. Infants demonstrate an attentional bias to fearful facial expressions by 5-7 months of age and an attentional bias toward anger by 3 years of age that are modulated by experiential factors. In a longitudinal study of 87 mother-infant dyads from families predominantly experiencing low income, we examined whether maternal stress and depressive symptoms were associated with trajectories of attentional biases to threat, assessed during an attention disengagement eye-tracking task when infants were 6-, 9-, and 12-month old. By 9 months, infants demonstrated a generalized bias toward threat (both fearful and angry facial expressions). Maternal perceived stress was associated with the trajectory of the bias toward angry facial expressions between 6 and 12 months. Specifically, infants of mothers with higher perceived stress exhibited a greater bias toward angry facial expressions at 6 months that decreased across the next 6 months, compared to infants of mothers with lower perceived stress who displayed an increased bias to angry facial expressions over this age range. Maternal depressive symptoms and stressful life events were not associated with trajectories of infant attentional bias to anger or fear. These findings highlight the role of maternal perceptions of stress in shaping developmental trajectories of threat-alerting systems.

Quantifying Therapists' Activities during Sensory Integration Treatment for Young Children with Autism.

AIMS: There is limited research on the type and quantity of actions (activities) occupational therapy practitioners utilize when providing sensory integration treatment to children with Autism Spectrum Disorders (ASD). METHODS: A coding scheme identifying specific aspects of sensory integration treatment was developed and used to analyze 34 videos of 9 children with ASD, aged between 18 and 56 months, treated by 8 occupational therapists. Occupational therapists providing sensory integration treatment to children with ASD were behaviorally coded and rated using Observer XT, a software package designed for analysis of behavioral processes. RESULTS: Verbal communications, including offers, positive commands, and feedback, to facilitate engagement were the most frequent actions enacted by therapists. Proprioceptive activities were the most frequent sensory opportunities presented. Therapists received high ratings for sensitivity qualities. CONCLUSIONS: The number of sensory opportunities and interactions the therapists provided suggest concordance with sensory integration treatment components in the clinical setting. General impression ratings indicate engagement between child and therapist may be an important aspect of sensory integration treatment for young children with ASD. Quantification of therapists' actions can provide insight into the moment-to-moment decision-making and relationships between therapist and child during daily practice of sensory integration treatment.

Adapting social conditioned place preference for use in young children.

OBJECTIVE: Social-emotional processing is key to daily interactions and routines, yet a challenging construct to quantify. Measuring social and emotional processing in young children, children with language impairments, or non-verbal children, presents additional challenges. This study addresses a pressing need for tools to probe internal responses such as feelings, drives, and motivations that do not rely on intact language skills. METHODS: In this study, we extend our recent success of inducing conditioned place preference (CPP) in children to demonstrate the success of using a social unconditioned stimulus in the CPP paradigm in both typically developing children (n = 36) and in children with a diagnosis of autism spectrum disorder (n = 14). RESULTS: This is the first study to demonstrate successful social conditioned place preference in the human population. Both typically developing children and children with autism spectrum disorder demonstrate significant social conditioned place preference by spending significantly more time in the room paired with social interaction following training. CONCLUSIONS: Significant heterogeneity of CPP scores in both groups of children indicates that social motivation is expressed along a continuum, and that the CPP paradigm may provide a more comprehensive characterization of social motivation beyond a diagnosis of an autism spectrum disorder for each child.

Prenatal exposure to drugs: effects on brain development and implications for policy and education.

The effects of prenatal exposure to drugs on brain development are complex and are modulated by the timing, dose and route of drug exposure. It is difficult to assess these effects in clinical cohorts as these are beset with problems such as multiple exposures and difficulties in documenting use patterns. This can lead to misinterpretation of research findings by the general public, the media and policy makers, who may mistakenly assume that the legal status of a drug correlates with its biological impact on fetal brain development and long-term clinical outcomes. It is important to close the gap between what science tells us about the impact of prenatal drug exposure on the fetus and the mother and what we do programmatically with regard to at-risk populations.

Exploring development of infant gaze, affect, and object exploration in a primarily Latino sample.

Infants demonstrate rapid development across the first years of life, which underlies increased human interactions that promote social-emotional development. In particular, gaze, affect, and object exploration are early indicators of engagement and show rapid changes in the first year of life. However, current understanding on developmental trajectories during infancy often comes from majority white, non-Hispanic/Latino samples. This longitudinal study explored the development of infant gaze, affect, and object exploration across 2-18 months of age in a sample of primarily Latino infants drawn from a pediatric community clinic. Videos of mother-infant play when infants were 2, 6, 9, 12 and 18 months were coded for durations of three types of behaviors: gaze, affect, and object exploration. Additionally, mother-infant play videos when the infant was 24 months of age were coded for joint engagement. Descriptive statistics for the three behavior types were obtained at each timepoint, and repeated measures analysis of covariance investigated the development of behaviors from timepoint to timepoint. Latent growth curve analyses were conducted to analyze developmental trajectories of capacities across 2-18 months, as well as development in relation to joint engagement at 24 months. Results indicate an important development period from 2 to 6 months of infants' life, unique developmental patterns of specific behaviors, and heterogeneity in gaze development in the sample and across ages. Overall, this study provides an important description of development within mother-infant play in a primarily Latino sample.

Analysis and novel methods for capture of normative eye-tracking data in 2.5-month old infants.

Development of attention systems is essential for both cognitive and social behavior maturation. Visual behavior has been used to assess development of these attention systems. Yet, given its importance, there is a notable lack of literature detailing successful methods and procedures for using eye-tracking in early infancy to assess oculomotor and attention dynamics. Here we show that eye-tracking technology can be used to automatically record and assess visual behavior in infants as young as 2.5 months, and present normative data describing fixation and saccade behavior at this age. Features of oculomotor dynamics were analyzed from 2.5-month old infants who viewed videos depicting live action, cartoons, geometric shapes, social and non-social scenes. Of the 54 infants enrolled, 50 infants successfully completed the eye-tracking task and high-quality data was collected for 32 of those infants. We demonstrate that modifications specifically tailored for the infant population allowed for consistent tracking of pupil and corneal reflection and minimal data loss. Additionally, we found consistent fixation and saccade behaviors across the entire six-minute duration of the videos, indicating that this is a feasible task for 2.5-month old infants. Moreover, normative oculomotor metrics for a free-viewing task in 2.5-month old infants are documented for the first time as a result of this high-quality data collection.

Environmental Epigenetics of Diesel Particulate Matter Toxicogenomics.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by disruptions in social communication and behavioral flexibility. Both genetic and environmental factors contribute to ASD risk. Epidemiologic studies indicate that roadway vehicle exhaust and in utero exposure to diesel particulate matter (DPM) are associated with ASD. Using the Comparative Toxicogenomics Database (CTD), we identified genes connected to DPM exposure and ASD, extracted the known enhancers/promoters of the identified genes, and integrated this with Assay for Transposase Accessible Chromatin (ATAC-seq) data from DPM-exposed human neural progenitor cells. Enhancer/promoter elements with significantly different chromosome accessibility revealed enriched DNA sequence motifs with transcription factor binding sites for EGR1. Variant extraction for linkage disequilibrium blocks of these regions followed by analysis through Genome Wide Association Studies (GWAS) revealed multiple neurological trait associations including exploratory eye movement and brain volume measurement. This approach highlights the effects of pollution on the regulatory regions of genes implicated in ASD by genetic studies, indicating convergence of genetic and environmental factors on molecular networks that contribute to ASD. Integration of publicly available data from the CTD, cell culture exposure studies, and phenotypic genetics synergize extensive evidence of chemical exposures on gene regulation for altered brain development.

An exploratory study of predictors of cognition in two low-income samples of infants across the first year of life.

OBJECTIVE: In this exploratory longitudinal study we assessed cognitive development in a community sample of infants born into predominantly low-income families from two different urban sites, to identify family and community factors that may associate with outcomes by 1 year of age. METHOD: Infant-mother dyads (n = 109) were recruited in Boston and Los Angeles community pediatric practices. Infant cognition was measured using the Mullen Scales of Early Learning when the infant was aged 2, 6, 9, and 12 months. Longitudinal linear mixed effects modeling and linear regression models explored potential predictors of cognitive outcomes. RESULTS: Cognitive scores were lower than the reference population mean at both 6 and 12 months. There were site differences in demographics and cognitive performance. Maternal education predicted expressive language in Boston, and speaking Spanish and lower rates of community poverty were associated with greater increases in overall cognition in Los Angeles. CONCLUSION: This exploratory study identified a number of drivers of child development that are both shared across cohorts and unique to specific community samples. Factors influencing heterogeneity within and across populations both may be important contributors to prevention and intervention in supporting healthy development among children.

Pleiotropic effects of neurotransmission during development: modulators of modularity.

The formation and function of the mammalian cerebral cortex relies on the complex interplay of a variety of genetic and environmental factors through protracted periods of gestational and postnatal development. Biogenic amine systems are important neuromodulators, both in the adult nervous system, and during critical epochs of brain development. Abnormalities in developmental programming likely contribute to developmental delays and multiple neurological and psychiatric disorders, often with symptom onset much later than the actual induction of pathology. We review several genetic and pharmacological models of dopamine, norepinephrine and serotonin modulation during development, each of which produces permanent changes in cerebral cortical structure and function. These models clearly illustrate the ability of these neurotransmitters to function beyond their classic roles and show their involvement in the development and modulation of fine brain circuitry that is sensitive to numerous effectors. Furthermore, these studies demonstrate the need to consider not only gene by environment interactions, but also gene by environment by developmental time interactions.

Association of Perceived Maternal Stress During the Perinatal Period With Electroencephalography Patterns in 2-Month-Old Infants.

Importance: Variation in child responses to adversity creates a clinical challenge to identify children most resilient or susceptible to later risk for disturbances in cognition and health. Advances in establishing scalable biomarkers can lead to early identification and mechanistic understanding of the association of early adversity with neurodevelopment. Objectives: To examine whether maternal reports of stress are associated with patterns in resting electroencephalography at 2 months of age and whether unique electroencephalographic profiles associated with risk and resiliency factors can be identified. Design, Setting, and Participants: For this cohort study, a population-based sample of 113 mother-infant dyads was recruited from January 1, 2016, to March 1, 2018, during regularly scheduled pediatric visits before infants were 2 months of age from 2 primary care clinics in Boston, Massachusetts, and Los Angeles, California, that predominantly serve families from low-income backgrounds. Data are reported from a single time point, when infants were aged 2 months, of an ongoing cohort study longitudinally following the mother-infant dyads. Exposures: Maternal reported exposure to stressful life events and perceived stress. Main Outcomes and Measures: Spectral power (absolute and relative) in different frequency bands (Δ, θ, low and high α, ß, and γ) from infant resting electroencephalography (EEG) and EEG profiles across frequency bands determined by latent profile analysis. Results: Of 113 enrolled infants, 70 (mean [SD] age, 2.42 [0.37] months; 35 girls [50%]) provided usable EEG data. In multivariable hierarchical linear regressions, maternal perceived stress was significantly and negatively associated with absolute ß (ß = -0.007; 95% CI, -0.01 to -0.001; semipartial r = -0.25) and γ power (ß = -0.008; 95% CI, -0.01 to -0.002; semipartial r = -0.28). Maternal educational level was significantly and positively associated with power in high α, ß, and γ bands after adjusting for covariates (high school: γ: ß = 0.108; 95% CI, 0.014-0.203; semipartial r = -0.236; associate's degree or higher: high α: ß = 0.133; 95% CI, 0.018-0.248; semipartial r = 0.241; ß: ß = 0.167; 95% CI, 0.055-0.279; semipartial r = 0.309; and γ: ß = 0.183; 95% CI, 0.066-0.299; semipartial r = 0.323). Latent profile analysis identified 2 unique profiles for absolute and relative power. Maternal perceived stress (ß = 0.13; 95% CI, 0.01-0.25; adjusted odds ratio [AOR], 1.14; 95% CI, 1.01-1.28) and maternal educational level (high school: ß = 3.00; 95% CI, 0.35-5.65; AOR, 20.09; 95% CI, 1.42-283.16; associate's degree or higher: ß = 4.12; 95% CI, 1.45-6.79; AOR, 61.56; 95% CI, 4.28-885.01) were each associated with unique profile membership. Conclusions and Relevance: These findings suggest that unique contributions of caregiver stress and maternal educational level on infant neurodevelopment are detectable at 2 months; EEG might be a promising tool to identify infants most susceptible to parental stress and to reveal mechanisms by which neurodevelopment is associated with adversity. Additional studies validating subgroups across larger cohorts with different stressors and at different ages are required before use at the individual level in clinical settings.

Outcomes of a Texas family medicine residency rural training track: 2000 through 2007.

Physician distribution nationally and in Texas trends away from rural toward more urban areas. Consequently, access to health care in rural areas is adversely affected. The University of Texas Medical Branch at Galveston (UTMB) Family Medicine Residency established a rural training track (RTT) in 2000 to combat this trend. This paper describes the graduate cohort to date, their practice locations, and strengths and limitations of the program as perceived by its participants. Data were collected from the UTMB Family Medicine Residency Alumni database and from focus group evaluations of the RTT conducted in 2004. Seven family medicine residents completed the RTT through 2007. Most graduates of the RTT (6 out of 7) entered practice in rural areas. Four of the 7 RTT graduates are Hispanic, reflecting the program's success in attracting underrepresented minority physicians.

Pharmacokinetic profile of cocaine following intravenous administration in the female rabbit.

Prenatal cocaine exposure in a rabbit intravenous model has revealed selective disruption of brain development and pharmacological responsiveness. We therefore examined the pharmacokinetic properties of cocaine in this model. Dutch-belted rabbits were surgically implanted with a catheter in the carotid artery, allowed to recover, and then injected intravenously with a cocaine bolus. Cocaine and benzoylecgonine concentrations were measured in arterial blood plasma and analyzed by nonlinear regression and noncompartmental analyses. Peak cocaine concentration occurred by 30s, was transient, and distribution was rapid. The profile of cocaine in the rabbit is similar to that observed in humans using cocaine at recreational doses.

Immediate-early gene expression in the central nucleus of the amygdala is not specific for anxiolytic or anxiogenic drugs.

The lateral, basal, and central nuclei of the amygdala are part of a circuitry that instantiates many fear and anxious behaviors. One line of support indicates that immediate-early gene (IEG) expression (e.g., c-fos and egr-1 (zif268)) is increased in these nuclei following fear conditioning. Other research finds that anxiogenic drugs working through various mechanisms induce IEG expression in the central nucleus of the amygdala (CeA) suggesting that expression is a neural marker for fear and anxiety. However, several studies have also found that anxiolytic drugs induce IEG expression in the CeA. Expression of egr-1 in the CeA and lateral nucleus of the amygdala following administration of anxiolytic and anxiogenic benzodiazepine and serotonin agonists and antagonists was investigated. The first experiment determined behaviorally active anxiolytic and anxiogenic doses for two anxiogenic drugs (FG 7142 and mCPP) and two anxiolytic drugs (diazepam and buspirone). The effects of anxiogenic and anxiolytic doses of these drugs on egr-1 expression in the amygdala were then tested in a second experiment. All four drugs increased egr-1 in the CeA indicating that increased egr-1 mRNA expression in the CeA is not specific to anxiolytic or anxiogenic effects of the drugs. We suggest that IEG expression in the CeA may be due to activation of circuits that are associated with systemic physiological homeostasis perturbed by a number of drugs including anxiogenic and anxiolytic compounds.

Prenatal cocaine exposure specifically alters spontaneous alternation behavior.

Our laboratory has previously characterized a rabbit model of gestational cocaine exposure in which permanent alterations in neuronal morphology, cell signaling and psychostimulant-induced behavior are observed. The cellular and molecular neuroadaptations produced by prenatal cocaine occur in brain regions involved in executive function and attention, such as the anterior cingulate and medial prefrontal cortices. Therefore, in the present study, we have measured the effects of prenatal cocaine exposure on specific behavioral tasks in adult offspring whose mothers were treated with cocaine (3mg/kg, twice a day, E16-E25). We assessed non-spatial, short-term memory in a two-object recognition task and found no deficits in memory or exploratory behaviors in cocaine-exposed offspring in this paradigm. We also evaluated a different memory task with a more robust attentional component, using spontaneous alternation in a Y maze. In this task, young adult rabbits exposed to cocaine prenatally exhibited a significant deficit in performance. Deficits in spontaneous alternation can be induced by a wide variety of behavioral and cognitive dysfunctions, but taken together with previous findings in this and other animal models, we hypothesize that prenatal exposure to cocaine alters highly specific aspects of cognitive and emotional development.

Expression of egr-1 (zif268) mRNA in select fear-related brain regions following exposure to a predator.

Research has demonstrated that immediate-early genes/inducible transcriptional factors (e.g., c-fos, egr-1) are increased in amygdala nuclei (lateral, basal and central nuclei) known to be involved in fear conditioning, footshock stress and novelty. Although these data suggest that expression of inducible transcriptional factors are involved in fear, other non-shock ethologically based paradigms (predator or predator odor exposure) do not appear to increase c-fos in the lateral and basal nuclei. While the lack of c-fos expression may indicate that predator stress does not engage the lateral and basal amygdala nuclei, it may be that c-fos in the amygdala is not responsive to predator exposure. Therefore, egr-1, which increases in the lateral nucleus following fear conditioning, footshock and novelty, was assessed to determine if its expression is induced in rats exposed to a cat. Five minutes of cat exposure did not increase expression of egr-1 mRNA in the lateral nucleus of the amygdala. egr-1 was increased in the paraventricular nucleus of the hypothalamus, indicating cat-induced stress, and visual cortex compared to rats that were either confined for 5 min or handled. In the lateral periaqueductal gray, handled rats displayed a left hemisphere dominance, which disappeared in both the cat-exposed and confined group, suggesting that immobility, induced by either cat-induced stress or unstressed confinement, increased right hemisphere egr-1 expression. The results are discussed in a context of differences and similarities in neural circuitry for conditioned and unconditioned fear.

Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior.

BACKGROUND: Our laboratory discovered that the gene encoding the receptor tyrosine kinase, MET, contributes to autism risk. Expression of MET is reduced in human postmortem temporal lobe in autism and Rett Syndrome. Subsequent studies revealed a role for MET in human and mouse functional and structural cortical connectivity. To further understand the contribution of Met to brain development and its impact on behavior, we generated two conditional mouse lines in which Met is deleted from select populations of central nervous system neurons. Mice were then tested to determine the consequences of disrupting Met expression. METHODS: Mating of Emx1 (cre) and Met (fx/fx) mice eliminates receptor signaling from all cells arising from the dorsal pallium. Met (fx/fx) and Nestin (cre) crosses result in receptor signaling elimination from all neural cells. Behavioral tests were performed to assess cognitive, emotional, and social impairments that are observed in multiple neurodevelopmental disorders and that are in part subserved by circuits that express Met. RESULTS: Met (fx/fx) /Emx1 (cre) null mice displayed significant hypoactivity in the activity chamber and in the T-maze despite superior performance on the rotarod. Additionally, these animals showed a deficit in spontaneous alternation. Surprisingly, Met (fx/fx; fx/+) /Nestin (cre) null and heterozygous mice exhibited deficits in contextual fear conditioning, and Met (fx/+) /Nestin (cre) heterozygous mice spent less time in the closed arms of the elevated plus maze. CONCLUSIONS: These data suggest a complex contribution of Met in the development of circuits mediating social, emotional, and cognitive behavior. The impact of disrupting developmental Met expression is dependent upon circuit-specific deletion patterns and levels of receptor activity.

Conditioned place preference successfully established in typically developing children.

Affective processing, known to influence attention, motivation, and emotional regulation is poorly understood in young children, especially for those with neurodevelopmental disorders characterized by language impairments. Here we faithfully adapt a well-established animal paradigm used for affective processing, conditioned place preference (CPP) for use in typically developing children between the ages of 30-55 months. Children displayed a CPP, with an average 2.4 fold increase in time spent in the preferred room. Importantly, associative learning as assessed with CPP was not correlated with scores on the Mullen Scales of Early Learning (MSEL), indicating that CPP can be used with children with a wide range of cognitive skills.

Partnering With Patients, Families, and Communities.

BACKGROUND AND OBJECTIVES: Collaborating with patients, families, and communities is a core principle of family medicine. However, the health care system in the United States has grown increasingly complex, fragmented, and difficult to navigate. This system, focused on disease-specific care delivered by specialists, often treats patients as the objects of care rather than as partners in care. Family Medicine for America's Health (FMAHealth) offers an opportunity to challenge the status quo in collaborative care through enhanced patient outreach and community engagement. With a central focus on improving health and achieving the Triple Aim, the FMAHealth initiative recognizes that successful transformation of the US health care system requires collaborative partnerships between clinicians, patients, families, and communities. Patient and population-level outcomes can be improved through shared decision making; application of new technology; and authentic partnerships with patient, families, and communities. Broader collaboration in practice transformation, research, and policymaking can lead to identification of common goals and mutually embraced transformation. The discipline of family medicine aspires to encourage patients, families, and communities to demand change as consumers, as citizens, and as voters.

Corticosterone facilitates retention of contextually conditioned fear and increases CRH mRNA expression in the amygdala.

The present study examined the effects of glucocorticoid administration on emotional memory and on corticotropin-releasing hormone (CRH) mRNA expression in the central nucleus of the amygdala (CeA) and the paraventricular nucleus of the hypothalamus (PVN). This was tested by administering repeated corticosterone (CORT) within a contextual fear conditioning paradigm. Rats received 2.5 mg/kg (s.c.) CORT or placebo twice a day for five and a half days and, 2 h after the last injection, rats were given one-trial contextual fear conditioning. When tested for retention of conditioned fear 6 days later, the CORT-treated rats displayed more fear-conditioned freezing in the retention test than vehicle-treated rats, which was not accounted for by an increase in footshock responsivity nor elevated plasma CORT. Another group of rats was fear conditioned prior to CORT administration, followed 24 h later by the five and a half days of CORT, and tested 6 days later; conditioned fear was not enhanced in these rats. Finally, CORT administration produced an increase of CRH mRNA in the CeA and a decrease in the PVN. The data suggest that repeated administration of CORT given before fear conditioning facilitates the acquisition of emotional memory, whereas CORT given after consolidation does not increase emotional memory.