Impact of sociodemographic disadvantage on neurobehavioral outcomes in children with newly diagnosed seizures and their unaffected siblings over 36 months.

OBJECTIVE: This study was undertaken to determine the short-term and longer term impact of sociodemographic disadvantage on the emotional-behavioral status of youths with new onset epilepsy and their unaffected siblings at the time of diagnosis and the subsequent 3 years. METHODS: Three hundred twelve youths with newly diagnosed epilepsies and 223 unaffected siblings, aged 6-16 years, were independently assessed regarding their emotional and behavioral status by their parents and teachers at baseline, and at 18 at 36 months later; youths with seizures also completed self-report measures of depression, anxiety, and hostility at those three time points. A sociodemographic disadvantage score was computed for each family (children with newly diagnosed seizures and their siblings), and families were separated into four categories from most disadvantaged to least disadvantaged. RESULTS: In both children and siblings, the least disadvantaged group exhibited the lowest level of neurobehavioral problems, whereas the most disadvantaged group showed a higher level of neurobehavioral problems across all the same behavior metrics. Findings remained stable and significant across all informants (parent, teacher, child) and across all time periods (throughout the 3-year period). Furthermore, both corrected and uncorrected linear regression analyses indicated that disadvantage was a more constant and stable predictor of behavioral and emotional problems over time compared to clinical seizure characteristics and abnormalities in magnetic resonance imaging and electroencephalographic testing. SIGNIFICANCE: Sociodemographic disadvantage bears a strong relationship to youths with emotional and behavioral problems both at the time of diagnosis as well as prospectively. The relationship is robust and reflected in reports from multiple informants (parent, teacher, child self-report), evident in siblings as well, and possibly more explanatory than traditional clinical seizure variables. Future studies will be needed to determine whether this disadvantage factor is modifiable with early intervention.

Neurobehavioral outcomes in patients with myelomeningocele.

This paper describes some of the more common patterns in neurobehavioral deficits and their underlying neuroanatomical basis in myelomeningocele (MMC). Patients with MMC can face a lifetime of specific organ system dysfunction, chief among them spinal cord malformations, orthopedic issues, hydrocephalus, and urological disabilities. In addition, patients can experience specific patterns of neurobehavioral difficulties due to the changes in neuroanatomy associated with the open spinal defect. Although there is variability in these patterns, some trends have been described among MMC patients. It is thought that early recognition of these potential neurobehavioral deficits by treating neurosurgeons and other members of the treatment team could lead to earlier intervention and positively impact the overall outcome for patients. Neurodevelopmental and neurobehavioral follow-up assessments are recommended to help guide planning for relevant treatments or accommodations.

Infant regulatory behavior problems during first month of life and neurobehavioral outcomes in early childhood.

Whether infant regulatory behavior problems already in the first month of life indicate an increased risk of childhood neurobehavioral problems, and whether maternal depression in the postpartum and early childhood underpins these associations remain unclear. Altogether, 2049-2364 mothers from the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study completed the Neonatal Perception Inventory on regulatory behavior problems at the infant's age of 15.6 days (SD 3.2, range 1-30), the Infant Behavior Questionnaire-Revised on temperament at 6.5 months (SD 0.9, range 4.2-12.4), and the Ages and Stages Questionnaire-3 on developmental milestones and the Child Behavior Checklist on behavioral problems at 3.5 years (SD 0.7, range 1.9-6.0). Maternal depressive symptoms were measured by the Center for Epidemiological Studies Depression Scale (infancy follow-ups) and Beck Depression Inventory-II (childhood follow-up). Father-rated infant temperament and paternal depressive symptoms were also available (n = 1474). Higher levels of infant regulatory behavior problems predicted higher levels of mother- and father-rated negative affectivity temperament (0.13 SD units per SD unit, 95% confidence interval 0.09-0.17; and 0.09, 0.04-0.14, respectively), lower levels of mother-rated orienting/regulation temperament (- 0.09, - 0.13 to - 0.05) and problem-solving skills (- 0.12, - 0.21 to - 0.04), and higher levels of Externalizing (0.07, 0.03-0.11) and Total behavioral problems (0.07, 0.03-0.11). Regulatory behaviors partially mediated the effect of maternal depressive symptoms. Regulatory behavior problems already during the first month of life predict neurobehavioral outcomes, and partially mediate the effect of maternal depressive symptoms. Our study may inform design of interventions aimed at timely prevention in children at risk.

Early-life adversity and long-term neurobehavioral outcomes: epigenome as a bridge?

Accumulating evidence suggests that adversities at critical periods in early life, both pre- and postnatal, can lead to neuroendocrine perturbations, including hypothalamic-pituitary-adrenal axis dysregulation and inflammation persisting up to adulthood. This process, commonly referred to as biological embedding, may cause abnormal cognitive and behavioral functioning, including impaired learning, memory, and depressive- and anxiety-like behaviors, as well as neuropsychiatric outcomes in later life. Currently, the regulation of gene activity by epigenetic mechanisms is suggested to be a key player in mediating the link between adverse early-life events and adult neurobehavioral outcomes. Role of particular genes, including those encoding glucocorticoid receptor, brain-derived neurotrophic factor, as well as arginine vasopressin and corticotropin-releasing factor, has been demonstrated in triggering early adversity-associated pathological conditions. This review is focused on the results from human studies highlighting the causal role of epigenetic mechanisms in mediating the link between the adversity during early development, from prenatal stages through infancy, and adult neuropsychiatric outcomes. The modulation of epigenetic pathways involved in biological embedding may provide promising direction toward novel therapeutic strategies against neurological and cognitive dysfunctions in adult life.

Does Apolipoprotein e4 Status Moderate the Association of Family Environment with Long-Term Child Functioning following Early Moderate to Severe Traumatic Brain Injury? A Preliminary Study.

OBJECTIVES: To examine whether apolipoprotein e4 (APOE) status moderates the association of family environment with child functioning following early traumatic brain injury (TBI). METHODS: Sixty-five children with moderate to severe TBI and 70 children with orthopedic injury (OI) completed assessments 6, 12, 18 months, and 3.5 and 6.8 years post injury. DNA was extracted from saliva samples and genotyped for APOE e4 status. Linear mixed models examined moderating effects of APOE e4 status on associations between two family environment factors (parenting style, home environment) and three child outcomes (executive functioning, behavioral adjustment, adaptive functioning). RESULTS: Children with TBI who were carriers of the e4 allele showed poorer adaptive functioning relative to non-carriers with TBI and children with OI in the context of low authoritarianism. At high levels of authoritarianism, non-carriers with TBI showed the poorest adaptive functioning among groups. There were no main effects or interactions involving APOE and executive functioning or behavioral adjustment. CONCLUSIONS: The APOE e4 allele was detrimental for long-term adaptive functioning in the context of positive parenting, whereas in less optimal parenting contexts, being a non-carrier was detrimental. We provide preliminary evidence for an interaction of APOE e4 status and parenting style in predicting long-term outcomes following early TBI. (JINS, 2016, 22, 859-864).

Toddler temperament and prenatal exposure to lead and maternal depression.

BACKGROUND: Temperament is a psychological construct that reflects both personality and an infant's reaction to social stimuli. It can be assessed early in life and is stable over time Temperament predicts many later life behaviors and illnesses, including impulsivity, emotional regulation and obesity. Early life exposure to neurotoxicants often results in developmental deficits in attention, social function, and IQ, but environmental predictors of infant temperament are largely unknown. We propose that prenatal exposure to both chemical and non-chemical environmental toxicants impacts the development of temperament, which can itself be used as a marker of risk for maladaptive neurobehavior in later life. In this study, we assessed associations among prenatal and early life exposure to lead, mercury, poverty, maternal depression and toddler temperament. METHODS: A prospective cohort of women living in the Mexico City area were followed longitudinally beginning in the second trimester of pregnancy. Prenatal exposure to lead (blood, bone), mercury, and maternal depression were assessed repeatedly and the Toddler Temperament Scale (TTS) was completed when the child was 24 months old. The association between each measure of prenatal exposure and performance on individual TTS subscales was evaluated by multivariable linear regression. Latent profile analysis was used to classify subjects by TTS performance. Multinomial regression models were used to estimate the prospective association between prenatal exposures and TTS performance. RESULTS: 500 mother-child pairs completed the TTS and had complete data on exposures and covariates. Three latent profiles were identified and categorized as predominantly difficult, intermediate, or easy temperament. Prenatal exposure to maternal depression predicted increasing probability of difficult toddler temperament. Maternal bone lead, a marker of cumulative exposure, also predicted difficult temperament. Prenatal lead exposure modified this association, suggesting that joint exposure in pregnancy to both was most toxic. CONCLUSIONS: Maternal depression predicts difficult temperament and concurrent prenatal exposure to maternal depression and lead predicts a more difficult temperament phenotype in 2 year olds. The role of temperament as an intermediate variable in the path from prenatal exposures to neurobehavioral deficits and other health effects deserves further study.

Associations of a toenail metal mixture with attention and memory in the Gulf long-term follow-up (GuLF) study.

BACKGROUND: Research on metal-associated neurodegeneration has largely focused on single metals. Since metal exposures typically co-occur as combinations of both toxic and essential elements, a mixtures framework is important for identifying risk and protective factors. This study examined associations between toenail levels of an eight-metal mixture and attention and memory in men living in US Gulf states. METHODS: We measured toenail concentrations of toxic (arsenic, chromium, lead, and mercury) and essential (copper, manganese, selenium, and zinc) metals in 413 non-smoking men (23-69 years, 46 % Black) from the Gulf Long-Term Follow-Up (GuLF) Study. Sustained attention and working memory were assessed at the time of toenail sample collection using the continuous performance test (CPT) and digit span test (DST), respectively. Associations between toenail metal concentrations and performance on neurobehavioral tests were characterized using co-pollutant adjusted general linear models and Bayesian Kernel Machine Regression. RESULTS: Adjusting for other metals, one interquartile range (IQR) increase in toenail chromium was associated with a 0.19 (95 % CI: -0.31, -0.07) point reduction in CPT D Prime score (poorer ability to discriminate test signals from noise). One IQR increase in toenail manganese was associated with a 0.20 (95 % CI, -0.41, 0.01) point reduction on the DST Reverse Count (fewer numbers recalled). Attention deficits were greater among Black participants compared to White participants for the same increase in toenail chromium concentrations. No evidence of synergistic interaction between metals or adverse effect of the overall metal mixture was observed for either outcome. CONCLUSIONS: Our findings support existing studies of manganese-related memory deficits and are some of the first to show chromium related attention deficits in adults. Longitudinal study of cognitive decline is needed to verify chromium findings. Research into social and chemical co-exposures is also needed to explain racial differences in metal-associated neurobehavioral deficits observed in this study.

Occupational exposure to pesticides and neurobehavioral outcomes. Impact of different original and recalled exposure measures on the associations.

BACKGROUND: Several measures of occupational exposure to pesticides have been used to study associations between exposure to pesticides and neurobehavioral outcomes. This study assessed the impact of different exposure measures for glyphosate and mancozeb on the association with neurobehavioral outcomes based on original and recalled self-reported data with 246 smallholder farmers in Uganda. METHODS: The association between the 6 exposure measures and 6 selected neurobehavioral test scores was investigated using linear multivariable regression models. Exposure measures included original exposure measures for the previous year in 2017: (i) application status (yes/no), (ii) number of application days, (iii) average exposure-intensity scores (EIS) of an application and (iv) number of EIS-weighted application days. Two additional measures were collected in 2019: (v) recalled application status and (vi) recalled EIS for the respective periods in 2017. RESULTS: Recalled applicator status and EIS were between 1.2 and 1.4 times more frequent and higher for both pesticides than the original application status and EIS. Adverse associations between the different original measures of exposure to glyphosate and 4 neurobehavioral tests were observed. Glyphosate exposure based on recalled information and all mancozeb exposure measures were not associated with the neurobehavioral outcomes. CONCLUSIONS: The relation between the different original self-reported glyphosate exposure measures and neurobehavioral test scores appeared to be robust. When based on recalled exposure measures, associations observed with the original exposure measures were no longer present. Therefore, future epidemiological studies on self-reported exposure should critically evaluate the potential bias towards the null in observed exposure-response associations.

The impact of phosphodiesterase inhibition on neurobehavioral outcomes in preclinical models of traumatic and non-traumatic spinal cord injury: a systematic review.

Study design: Systematic review. Objective: The objective of this study was to evaluate the impact of phosphodiesterase (PDE) inhibitors on neurobehavioral outcomes in preclinical models of traumatic and non-traumatic spinal cord injury (SCI). Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and was registered with PROSPERO (CRD42019150639). Searches were performed in MEDLINE and Embase. Studies were included if they evaluated the impact of PDE inhibitors on neurobehavioral outcomes in preclinical models of traumatic or non-traumatic SCI. Data were extracted from relevant studies, including sample characteristics, injury model, and neurobehavioral assessment and outcomes. Risk of bias was assessed using the SYRCLE checklist. Results: The search yielded a total of 1,679 studies, of which 22 met inclusion criteria. Sample sizes ranged from 11 to 144 animals. PDE inhibitors used include rolipram (n = 16), cilostazol (n = 4), roflumilast (n = 1), and PDE4-I (n = 1). The injury models used were traumatic SCI (n = 18), spinal cord ischemia (n = 3), and degenerative cervical myelopathy (n = 1). The most commonly assessed outcome measures were Basso, Beattie, Bresnahan (BBB) locomotor score (n = 13), and grid walking (n = 7). Of the 22 papers that met the final inclusion criteria, 12 showed a significant improvement in neurobehavioral outcomes following the use of PDE inhibitors, four papers had mixed findings and six found PDE inhibitors to be ineffective in improving neurobehavioral recovery following an SCI. Notably, these findings were broadly consistent across different PDE inhibitors and spinal cord injury models. Conclusion: In preclinical models of traumatic and non-traumatic SCI, the administration of PDE inhibitors appeared to be associated with statistically significant improvements in neurobehavioral outcomes in a majority of included studies. However, the evidence was inconsistent with a high risk of bias. This review provides a foundation to aid the interpretation of subsequent clinical trials of PDE inhibitors in spinal cord injury. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=150639, identifier: CRD42019150639.

Structural and pragmatic language in young children with sex chromosome trisomy (XXX, XXY, XYY): Predictive value for neurobehavioral problems one year later.

Objective: To investigate pragmatic language abilities in young children with an increased risk for adverse neurobehavioral and neurocognitive outcomes due to an extra X or Y chromosome (sex chromosome trisomy; SCT) and to investigate to what degree early structural and pragmatic language abilities are predictive of neurobehavioral problems one year later. Method: In total, 72 children with SCT and 71 controls aged 3-7 years were included. Language assessments included parent-reported pragmatic language skills and direct assessment of structural language abilities. Parent-reported behavioral outcomes were measured one year after the initial language assessment. Results: Children with SCT demonstrated weaker pragmatic language skills compared to controls. These differences were not driven by karyotype, time of diagnosis, or ascertainment bias and irrespective of the presence of structural language impairment. Odds of having pragmatic difficulties was 23 times higher in the SCT group, with 25% of the children not meeting age-expectations. In addition, language, in particular pragmatic language, was an important predictor for later affective, oppositional defiant, pervasive developmental, attention deficit, and social-emotional problems in young children with SCT. Conclusions: This study is one of the first studies that directly illustrates the relationship between language and behavioral outcomes in children with SCT. Our results stress the importance to closely monitor pragmatic language in addition to structural language in clinical care of children with SCT, as pragmatic language abilities could serve as an early marker for children at risk for developing behavioral problems.

Non-Invasive Vagus Nerve Stimulation Improves Brain Lesion Volume and Neurobehavioral Outcomes in a Rat Model of Traumatic Brain Injury.

Abstract Traumatic brain injury (TBI) continues to be a major cause of death and disability worldwide. This study assessed the effectiveness of non-invasive vagus nerve stimulation (nVNS) in reducing brain lesion volume and improving neurobehavioral performance in a rat model of TBI. Animals were randomized into three experimental groups: (1) TBI with sham stimulation treatment (Control), (2) TBI treated with five lower doses (2-min) nVNS, and (3) TBI treated with five higher doses (2 × 2-min) nVNS. We used the gammaCore nVNS device to deliver stimulations. Magnetic resonance imaging studies were performed 1 and 7 days post-injury to confirm lesion volume. We observed smaller brain lesion volume in the lower dose nVNS group compared with the control group on days 1 and 7. The lesion volume for the higher dose nVNS group was significantly smaller than either the lower dose nVNS or the control groups on days 1 and 7 post-injury. The apparent diffusion coefficient differences between the ipsilateral and contralateral hemispheres on day 1 were significantly smaller for the higher dose (2 × 2 min) nVNS group than for the control group. Voxel-based morphometry analysis revealed an increase in the ipsilateral cortical volume in the control group caused by tissue deformation and swelling. On day 1, these abnormal volume changes were 13% and 55% smaller in the lower dose and higher dose nVNS groups, respectively, compared with the control group. By day 7, nVNS dampened cortical volume loss by 35% and 89% in the lower dose and higher dose nVNS groups, respectively, compared with the control group. Rotarod, beam walking, and anxiety performances were significantly improved in the higher-dose nVNS group on day 1 compared with the control group. The anxiety indices were also improved on day 7 post-injury compared with the control and the lower-dose nVNS groups. In conclusion, the higher dose nVNS (five 2 × 2-min stimulations) reduced brain lesion volume to a level that further refined the role of nVNS therapy for the acute treatment of TBI. Should nVNS prove effective in additional pre-clinical TBI models and later in clinical settings, it would have an enormous impact on the clinical practice of TBI in both civilian and military settings, as it can easily be adopted into routine clinical practice.

Effects of Perinatal Stroke on Executive Functioning and Mathematics Performance in Children.

The goal of this study was to examine executive functioning, math performance, and visuospatial processing skills of children with perinatal stroke, which have not been well explored in this population. Participants included 18 children with perinatal stroke (aged 6-16 years old) and their primary caregiver. Each child completed standardized tests of executive function and visuospatial processing skills, Intelligence Quotient (IQ), and math achievement. Performance on executive function, IQ, math, and visuospatial processing tests was significantly lower in children with perinatal stroke when compared to normative means. Poorer inhibitory control was associated with worse math performance. Increased age at testing was associated with better performance on visuospatial ability (using standardized scores), and females performed better than males on a test of inhibitory control. Children with perinatal stroke displayed a range of neuropsychological impairments, and difficulties with executive function (inhibition) may contribute to math difficulties in this population.

Transcranial focused ultrasound stimulation reduces vasogenic edema after middle cerebral artery occlusion in mice.

Blood-brain barrier (BBB) disruption underlies the vasogenic edema and neuronal cell death induced by acute ischemic stroke. Reducing this disruption has therapeutic potential. Transcranial focused ultrasound stimulation has shown neuromodulatory and neuroprotective effects in various brain diseases including ischemic stroke. Ultrasound stimulation can reduce inflammation and promote angiogenesis and neural circuit remodeling. However, its effect on the BBB in the acute phase of ischemic stroke is unknown. In this study of mice subjected to middle cerebral artery occlusion for 90 minutes, low-intensity low-frequency (0.5 MHz) transcranial focused ultrasound stimulation was applied 2, 4, and 8 hours after occlusion. Ultrasound stimulation reduced edema volume, improved neurobehavioral outcomes, improved BBB integrity (enhanced tight junction protein ZO-1 expression and reduced IgG leakage), and reduced secretion of the inflammatory factors tumor necrosis factor-α and activation of matrix metalloproteinase-9 in the ischemic brain. Our results show that low-intensity ultrasound stimulation attenuated BBB disruption and edema formation, which suggests it may have therapeutic use in ischemic brain disease as a protector of BBB integrity.

Positive Effects of Kangaroo Mother Care on Long-Term Breastfeeding Rates, Growth, and Neurodevelopment in Preterm Infants.

Background and Objectives: Kangaroo mother care (KMC) benefits preterm infants' health through increasing breastfeeding, but the longitudinal effects of KMC remain unknown. This study investigates the impact of KMC on breastfeeding and health outcomes in Chinese preterm infants. Methods: A longitudinal randomized controlled study was conducted with 79 preterm infant-mother dyads. The KMC group (n = 36) was provided 2.5 hours/day KMC during the neonatal intensive care unit (NICU) hospitalization, while the control group (n = 43) received standard care. Infant's feeding regimens and physical growth were documented daily at NICU. Physical growth and Neonatal Behavioral Neurological Assessment were measured at 40 weeks, 3 months, and 6 months of corrected age (CA). Breastfeeding outcomes were documented at 6 months of CA. Results: Compared with the control group, KMC infants received higher mothers' milk proportion during hospitalization (B = 0.16, confidence interval [CI] = [0.11-0.21]) and less feeding intolerance at discharge (odds ratio [OR] = 0.11, CI = [0.02-0.43]); and higher exclusive breastfeeding proportion (OR = 14.6, CI = [3.5-60.9]) at 6 months CA. KMC infants also had significant increased body weight and body length at hospital discharge; and more increases of body weight, body length, and head circumference in follow-ups. The neurobehavioral score was also higher in the KMC group compared to the control group over time. Conclusions: Longitudinal KMC effects are significant in promoting preterm infants' breastfeeding outcomes, growth, and neurodevelopment. Early initiation of KMC practice is highly recommended to the parent-infant population in Chinese NICUs to promote breastfeeding and developmental outcomes.

Exposure to multiple pesticides and neurobehavioral outcomes among smallholder farmers in Uganda.

BACKGROUND: Multiple epidemiological studies have shown that exposure to single pesticide active ingredients or chemical groups is associated with adverse neurobehavioral outcomes in farmers. In agriculture, exposure to multiple pesticide active ingredients is the rule, rather than exception. Therefore, occupational studies on neurobehavioral effects of pesticides should account for potential co-exposure confounding. METHODS: We conducted a cross-sectional study of 288 Ugandan smallholder farmers between September and December 2017. We collected data on self-reported use of pesticide products during the 12 months prior to survey and estimated yearly exposure-intensity scores for 14 pesticide active ingredients using a semi-quantitative exposure algorithm. We administered 11 neurobehavioral tests to assess five neurobehavioral domains. We implemented a Bayesian Model-Averaging (BMA) approach to examine the association between exposure to multiple pesticides and neurobehavioral outcomes, while accounting for multiple testing. We applied two levels of inference to determine (1) which neurobehavioral outcomes were associated with overall pesticide exposure (marginal inclusion probability (MIP) for covariate-only models <0.5) and (2) which specific pesticide active ingredients were associated with these outcomes (MIP for models where active ingredient was included >0.5). RESULTS: Seventy-two percent of farmers reported use of pesticide products that contained at least one of 14 active ingredients, while the applicators used in median three different active ingredients (interquartile range (IQR) 4) in the 12 months prior to the study. The most widely used active ingredients were glyphosate (79%), cypermethrin (60%), and mancozeb (55%). We found that overall pesticide exposure was associated with impaired visual memory (Benton Visual Retention Test (BVRT)), language (semantic verbal fluency test), perceptual-motor function (Finger tapping test), and complex attention problems (Trail making A test and digit symbol test). However, when we looked at the associations for individual active ingredients, we only observed a positive association between glyphosate exposure and impaired visual memory (-0.103 [95% Bayesian Credible Interval (BCI)] [-0.24, 0] units in BVRT scores per interquartile range (IQR) increase in annual exposure to glyphosate, relative to a median [IQR] of 6 [3] units in BVRT across the entire study population). CONCLUSIONS: We found that overall pesticide exposure was associated with several neurobehavioral outcome variables. However, when we examined individual pesticide active ingredients, we observed predominantly null associations, except for a positive association between glyphosate exposure and impaired visual memory. Additional epidemiologic studies are needed to evaluate glyphosate's neurotoxicity, while accounting for co-pollutant confounding.

E2-BSA and G1 exert neuroprotective effects and improve behavioral abnormalities following traumatic brain injury: The role of classic and non-classic estrogen receptors.

The role of classical and non-classical estrogen receptors (ERs) in mediating the neuroprotective effects of this hormone on brain edema and long-term behavioral disorders was evaluated after traumatic brain injury (TBI). Ovariectomized rats were divided as follows: E2 (17 ß-estradiol), E2-BSA (E2 conjugated to bovine serum albumin), G1 [G-protein-coupled estrogen receptor agonist (GPER)] or their vehicle was injected following TBI, whereas ICI (classical estrogen receptor antagonist), G15 (GPER antagonist), ICI + G15, and their vehicle were injected before the induction of TBI and the injection of E2 and E2-BSA. Brain water (BWC) and Evans blue (EB) contents were measured 24 h and 5 h after TBI, respectively. Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were measured before and at different times after TBI. Locomotor activity, anxiety-like behavior, and spatial memory were assessed on days 3, 7, 14, and 21 after injury. E2, E2-BSA, and G1 prevented the increase of BWC and EB content after TBI, and these effects were inhibited by ICI and G15. ICI and G15 also inhibited the beneficial effects of E2, E2-BSA on ICP, as well as CPP, after trauma. E2, E2-BSA, and G1 prevented the cognitive deficiency and behavioral abnormalities induced by TBI. Similar to the above parameters, ICI and G15 also reversed this E2 and E2-BSA effects on days 3, 7, 14, and 21. Our findings indicated that the beneficial effects of E2-BSA and E2 were inhibited by both ICI and G15, suggesting that GPER and classic ERs were involved in mediating the long-term effects of E2.

Residential exposure to urban traffic is associated with the poorer neurobehavioral health of Ecuadorian schoolchildren.

PURPOSE: We investigated whether chronic traffic-generated air pollution containing fine and ultrafine particulate matter is associated with reduced neurobehavioral performance and behavioral dysfunction in urban Ecuadorian schoolchildren. Also, we examined the effect of child hemoglobin and sociodemographic risk factors on these neurocognitive outcomes. METHODS: A convenience sample of healthy children aged 8-14 years attending public schools were recruited in Quito, Ecuador. Child residential proximity to the nearest heavily trafficked road was used as a proxy for traffic-related pollutant exposure. These included high exposure (<100 m), medium exposure (100-199 m) and low exposure (≥ 200 m) from the nearest heavily trafficked road. The Behavioral Assessment and Research System (BARS), a computerized test battery assessing attention, memory, learning and motor function was used to evaluate child neurobehavioral performance. The Child Behavior Checklist (CBCL/6-18) was used to assess child behavioral dysfunction as reported by mothers. The data were analyzed using multiple linear regression. RESULTS: Children with the highest residential exposure to traffic pollutants (< 100 m) had significantly longer latencies as measured by match to sample (b = 410.27; p = 0.01) and continuous performance (b = 37.90; p = 0.02) compared to those living ≥ 200 m away. A similar but non-significant association was observed for reaction time latency. Children living within 100 m of heavy traffic also demonstrated higher scores across all CBCL subscales although only the relationship with thought problems (p = 0.05) was statistically significant in the adjusted model. CONCLUSION: The study findings suggest that children living within 100 m of heavy traffic appear to experience subtle neurobehavioral deficits that may result from fine and ultrafine particulate matter exposure.

Exposure to Pesticides and Health Effects on Farm Owners and Workers From Conventional and Organic Agricultural Farms in Costa Rica: Protocol for a Cross-Sectional Study.

BACKGROUND: Pesticide use is increasing in low- and middle-income countries (LMICs) including Costa Rica. This increase poses health risks to farm owners, farm workers, and communities living near agricultural farms. OBJECTIVE: We aimed to examine the health effects associated with occupational pesticide exposure in farm owners and workers from conventional and organic smallholder farms in Costa Rica. METHODS: We conducted a cross-sectional study involving 300 owners and workers from organic and conventional horticultural smallholder farms in Zarcero County, Costa Rica. During the baseline study visit, we administered a structured, tablet-based questionnaire to collect data on sociodemographic characteristics, pesticide exposure, and health conditions (eg, respiratory and allergic outcomes and acute pesticide intoxication symptoms) and administered a neurobehavioral test battery (eg, Finger Tapping Test and Purdue Pegboard); we measured blood pressure, anthropometry (height, weight, and waist circumference), and erythrocytic acetylcholinesterase activity and also collected urine samples. In addition, a functional neuroimaging assessment using near-infrared spectroscopy was conducted with a subset of 50 study participants. During the follow-up study visit (~2-4 weeks after the baseline), we administered participants a short questionnaire on recent pesticide exposure and farming practices and collected hair, toenail, and urine samples. Urine samples will be analyzed for various pesticide metabolites, whereas toenails and hair will be analyzed for manganese (Mn), a biomarker of exposure to Mn-containing fungicides. Self-reported pesticide exposure data will be used to develop exposure intensity scores using an exposure algorithm. Furthermore, exposure-outcome associations will be examined using linear and logistic mixed-effects regression models. RESULTS: Fieldwork for our study was conducted between May 2016 and August 2016. In total, 113 farm owners and 187 workers from 9 organic and 83 conventional horticultural smallholder farms were enrolled. Data analyses are ongoing and expected to be published between 2019 and 2020. CONCLUSIONS: This study is one of the first to examine differences in health effects due to pesticide exposure between farm owners and workers from organic and conventional smallholder farms in an LMIC. We expect that this study will provide critical data on farming practices, exposure pathways, and how occupational exposure to pesticides may affect farm owners and workers' health. Finally, we hope that this study will allow us to identify strategies to reduce pesticide exposure in farm owners and workers and will potentially lay the groundwork for a future longitudinal study of health outcomes in farm owners and workers exposed to pesticides. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/10914.

The impact of cumulative pain/stress on neurobehavioral development of preterm infants in the NICU.

BACKGROUND: Vulnerable preterm infants experience repeated and prolonged pain/stress stimulation during a critical period in their development while in the neonatal intensive care unit (NICU). The contribution of cumulative pain/stressors to altered neurodevelopment remains unclear. The study purpose was to investigate the impact of early life painful/stressful experiences on neurobehavioral outcomes of preterm infants in the NICU. METHODS: A prospective exploratory study was conducted with fifty preterm infants (28 0/7-32 6/7weeks gestational age) recruited at birth and followed for four weeks. Cumulative pain/stressors (NICU Infant Stressor Scale) were measured daily and neurodevelopmental outcomes (NICU Network Neurobehavioral Scale) were examined at 36-37weeks post-menstrual age. Data analyses were conducted on the distribution of pain/stressors experienced over time and the linkages among pain/stressors and neurobehavioral outcomes. RESULTS: Preterm infants experienced a high degree of pain/stressors in the NICU, both in numbers of daily acute events (22.97±2.30 procedures) and cumulative times of chronic/stressful exposure (42.59±15.02h). Both acute and chronic pain/stress experienced during early life significantly contributed to the neurobehavioral outcomes, particularly in stress/abstinence (p<0.05) and habituation responses (p<0.01), meanwhile, direct breastfeeding and skin-to-skin holding were also significantly associated with habituation (p<0.01-0.05). CONCLUSION: Understanding mechanisms by which early life experience alters neurodevelopment will assist clinicians in developing targeted neuroprotective strategies and individualized interventions to improve infant developmental outcomes.

Creative music therapy to promote brain structure, function, and neurobehavioral outcomes in preterm infants: a randomized controlled pilot trial protocol.

BACKGROUND: Preterm birth is associated with increased risk of neurological impairment and deficits in cognition, motor function, and behavioral problems. Limited studies indicate that multi-sensory experiences support brain development in preterm infants. Music appears to promote neurobiological processes and neuronal learning in the human brain. Creative music therapy (CMT) is an individualized, interactive therapeutic approach based on the theory and methods of Nordoff and Robbins. CMT may promote brain development in preterm infants via concurrent interaction and meaningful auditory stimulation. We hypothesize that preterm infants who receive creative music therapy during neonatal intensive care admission will have developmental benefits short- and long-term brain function. METHODS/DESIGN: A prospective, randomized controlled single-center pilot trial involving 60 clinically stable preterm infants under 32 weeks of gestational age is conducted in preparation for a multi-center trial. Thirty infants each are randomized to either standard neonatal intensive care or standard care with CMT. Music therapy intervention is approximately 20 min in duration three times per week. A trained music therapist sings for the infants in lullaby style, individually entrained and adjusted to the infant's rhythm and affect. Primary objectives of this study are feasibility of protocol implementation and investigating the potential mechanism of efficacy for this new intervention. To examine the effect of this new intervention, non-invasive, quantitative magnetic resonance imaging (MRI) methods at corrected age and standardized neurodevelopmental assessments using the Bayley Scales of Infant and Toddler Development third edition at a corrected age of 24 months and Kaufman Assessment Battery for Children at 5 years will be performed. All assessments will be performed and analyzed by blinded experts. DISCUSSION: To our knowledge, this is the first randomized controlled clinical trial to systematically examine possible effects of creative music therapy on short- and long-term brain development in preterm infants. This project lies at the interface of music therapy, neuroscience, and medical imaging. New insights into the potential role and impact of music on brain function and development may be elucidated. If such a low-cost, low-risk intervention is demonstrated in a future multi-center trial to be effective in supporting brain development in preterm neonates, findings could have broad clinical implications for this vulnerable patient population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02434224.