Long-term Behavioral Outcomes Research Articles

How does family functioning contribute to child externalizing and internalizing behavior problems after childhood TBI? Evidence from a prospective cohort study.

Despite a well-documented association between childhood traumatic brain injury and elevated risk for internalizing and externalizing behavior problems, the mechanisms through which family functioning contributes to individual variation in these behavioral outcomes remains poorly understood. This prospective cohort study aimed to assess the respective contribution of family functioning and child emotion regulation (ER) to post-injury behavior problems at 1-year follow-up, with a specific focus on evaluating the role of emotional dysregulation in mediating the effects of familial affective responsiveness and communication on child behavioral outcomes. The study included 129 participants, comprising 86 children with medically confirmed mild-to-severe TBI, identified from consecutive hospital admissions, and 43 typically developing (TD) control children, of similar age and sex. Participants ranged in age from 6 to 15 years (mean age = 11.2 years). Parents completed validated assessments of post-acute family functioning and child emotion regulation difficulties at 6 months post-injury, as well as measures of child behavior problems at 1-year post-injury. Although group differences in internalizing behaviors did not reach statistical significance, the TBI group exhibited significantly higher overall externalizing symptoms and was significantly more likely to display clinically elevated symptoms than TD controls at 1-year post-injury. Compared to TD controls, the TBI group displayed significantly greater ER problems, which mediated the effects of lower familial affective responsiveness and communication on child behavior problems 1-year-post-injury. Evidence for these robust, prospective associations suggests that child emotional dysregulation plays a key role in mediating the effect of post-acute family functioning on long-term behavior problems in children with TBI. Early assessment and screening for relevant risk factors may help identify those children and families who could benefit from therapeutic interventions designed to address emotional dysregulation and mitigate risk for post-injury behavioral problems. Importantly, these findings underscore the value of adopting family-centred care approaches in rehabilitation, where involving families in therapeutic processes and addressing family dynamics may enhance child emotion regulation and improve long-term behavioral outcomes.

Maternal Nutrition during Pregnancy and Offspring Brain Development: Insights from Neuroimaging.

Maternal nutrition during pregnancy is known to be important for offspring growth and health and has also been increasingly recognized for shaping offspring brain development. On the other hand, recent advancements in brain imaging technology have provided unprecedented insights into fetal, neonatal, and pediatric brain morphometry and function. This review synthesizes the current literature regarding the impact of maternal nutrition on offspring brain development, with a specific focus on findings from neuroimaging studies. The diverse effects of maternal nutrients intake or status during pregnancy on neurodevelopmental outcomes in children are discussed. Neuroimaging evidence showed associations between maternal nutrition such as food categories, macronutrients, and micronutrients including vitamins and minerals during pregnancy and child brain imaging features measured using imaging techniques such as ultrasound, magnetic resonance imaging (MRI), electroencephalography (EEG), and magnetoencephalography (MEG). This review demonstrates the capability of neuroimaging in characterizing how maternal nutrition during pregnancy impacts structure and function of the developing brain that may further influence long-term neuropsychological, cognitive, and behavioral outcomes in children. It aims to inspire future research utilizing neuroimaging to deepen our understanding of the critical impacts of maternal nutrition during pregnancy on offspring brain development.

Peripheral, but not central, IGF-1 treatment attenuates stroke-induced cognitive impairment in middle-aged female Sprague Dawley rats: The gut as a therapeutic target

Stroke results in immediate sensory or motor disability and increases the risk for long term cognitive-affective impairments. Thus, therapies are urgently needed to improve quality of life for stroke survivors, especially women who are at a greater risk for severe stroke after menopause. Most current research on stroke therapies target the central nervous system; however, stroke also impacts peripheral organ systems. Our studies using acyclic (estrogen-deficient) middle aged female Sprague Dawley rats show that this group not only displays worse outcomes after stroke as compared to adult females, but also has lower levels of the neuroprotective peptide Insulin-like Growth Factor (IGF1) in circulation. Intracerebroventricular (ICV) administration of IGF1 to this group decreases infarct volume and improves sensory motor performance in the acute phase. In this study, we show that, despite this neuroprotection, ICV-IGF1 did not reduce peripheral inflammation or improve post stroke cognitive impairment in the chronic phase. In view of the evidence that stroke induces rapid gut dysfunction, we tested whether systemic delivery of IGF1 (intraperitoneal, IP) would promote gut health and consequently improve long-term behavioral outcomes. Surprisingly, while IP-IGF1, delivered 4 h and 24 h after ischemic stroke, did not reduce infarct volume or acute sensory motor impairment, it significantly attenuated circulating levels of pro-inflammatory cytokines, and attenuated stroke-induced cognitive impairment. In addition, IP-IGF1 treatment reduced gut dysmorphology and gut dysbiosis. Our data support the conclusion that therapeutics targeting peripheral targets are critical for long-term stroke recovery, and that gut repair is a novel therapeutic target to improve brain health in aging females.

The Effectiveness of an Exercise Program on Muscle Strength and Range of Motion on Upper Limbs, Functional Ability and Depression at Early Stage of Dementia.

Background: Dementia involves the loss of cognitive abilities and represents a decline from the prior level of function, which impairs functional abilities in day-to-day life. The purpose of the present study is to examine the effectiveness of an exercise program on the muscle strength and range of motion of the upper limbs, the functional status, and the depression of elderly people with early stage dementia. Methods: The sample consisted of 60 elderly people with early stage dementia who were randomly divided into a control and an experimental group of 30 participants each. The experimental group received a 12-week Otago exercise program with 45 min duration of each session. The control group received usual care without doing exercise. The outcome measures of muscle strength and range of motion of the upper limbs, the functional status, and the depression were assessed by valid instruments and tests at the beginning and at the end of the intervention program. Repeated measures one-way ANOVA and Mann-Whitney tests examined the differences between the two groups at the end of the 12-week exercise program. Results: Statistically significant differences were found between the experimental and control groups in the entire outcome measures (functional ability F = 9.35 p < 0.05; muscle strength right hand F = 32.33, p < 0.05 left hand U = 95.50 p < 0.01; e.g., range of motion shoulder extension U = 104.00 p < 0.01), except depression. Conclusions: Both muscle strength and range of motion of the upper limbs, as well as the functional ability, were improved by the exercise program. Further research is needed to investigate the present results, in particular to explore the long-term cognitive, behavioral, and functional status outcomes of exercise in the early stages of dementia.

Constructing maternal responsibility: narratives of “motherly love” and maternal blame in epigenetics research

Research in epigenetics is demonstrating the importance of maternal care towards offspring early in life for long-term health and behavioral outcomes. Although most of this research has been conducted in rodents, these findings are increasingly framing broader debates about mothers’ moral responsibilities for the health of their offspring. In this paper, I investigate the implications of scientific narratives and research agendas of maternal care for current discourses surrounding maternal epigenetic responsibility. I show how despite clear differences between rodent and human contexts of care, researchers tend to construct rodent maternal care as a form of love or emotional commitment. This construction, which ignores fathers’ care for their offspring, reflects widespread social assumptions about mothers’ particular or “natural” capacities to love their children. This has important implications for how we assign moral blame. Because love is important to our widespread understandings of parental virtues, mothers who act “unlovingly” are prone to being judged in an especially harsh manner. By embedding simplistic and gendered assumptions about mothers’ love for their children, then, epigenetics research perpetuates the tendency to consider mothers especially blameworthy where they are perceived as failing to sufficiently care for or love their children.

Long-term effects of Preweaning environmental impoverishment on neurobehavioral and neurocognitive outcomes in Sprague Dawley rats: An early environmental stress model

Developmental stress, including low socioeconomic status (SES), can induce dysregulation of the hypothalamic-pituitary-adrenal axis and result in long-term changes in stress reactivity. Children in lower SES conditions often experience more stress than those in other SES groups. There are multiple model systems of early environmental stress (EES), one of which is reduced cage bedding. Here we tested the effects of both prenatal and lactational EES in rats on a range of long-term behavioral and cognitive outcomes. There were persistent reductions in body weight in the EES rats in both sexes. The behavioral results showed no effects on learning and memory using tests of spatial learning or cognitive flexibility in the Morris water maze, egocentric learning in the Cincinnati water maze, or working memory in the radial-arm maze. There were no effects on basic open-field activity, elevated zero-maze, or forced swim test, but EES rats had reduced time in the dark side of the light/dark test. When rats were drug challenged in the open-field with d-amphetamine or MK-801, there were no differential responses to d-amphetamine, but the EES group under responded compared with the drug-induced hyperactivity in the control group in both males and females. The objective was to establish a developmental stress model that induced cognitive deficits and to the extent that this method did not cause such effects it was not the model we sought. However, the data showed several long-term effects of EES, including the reduced response to the irreversible NMDA antagonist MK-801. This effect merits further investigation.

Executive functioning, behavior, and white matter microstructure in the chronic phase after pediatric mild traumatic brain injury: results from the adolescent brain cognitive development study.

Mild traumatic brain injury (mTBI) is common in children. Long-term cognitive and behavioral outcomes as well as underlying structural brain alterations following pediatric mTBI have yet to be determined. In addition, the effect of age-at-injury on long-term outcomes is largely unknown. Children with a history of mTBI (n = 406; Mage = 10 years, SDage = 0.63 years) who participated in the Adolescent Brain Cognitive Development (ABCD) study were matched (1:2 ratio) with typically developing children (TDC; n = 812) and orthopedic injury (OI) controls (n = 812). Task-based executive functioning, parent-rated executive functioning and emotion-regulation, and self-reported impulsivity were assessed cross-sectionally. Regression models were used to examine the effect of mTBI on these domains. The effect of age-at-injury was assessed by comparing children with their first mTBI at either 0-3, 4-7, or 8-10 years to the respective matched TDC controls. Fractional anisotropy (FA) and mean diffusivity (MD), both MRI-based measures of white matter microstructure, were compared between children with mTBI and controls. Children with a history of mTBI displayed higher parent-rated executive dysfunction, higher impulsivity, and poorer self-regulation compared to both control groups. At closer investigation, these differences to TDC were only present in one respective age-at-injury group. No alterations were found in task-based executive functioning or white matter microstructure. Findings suggest that everyday executive function, impulsivity, and emotion-regulation are affected years after pediatric mTBI. Outcomes were specific to the age at which the injury occurred, suggesting that functioning is differently affected by pediatric mTBI during vulnerable periods. Groups did not differ in white matter microstructure.

Evaluating Effectiveness of an Online LGBTQIA+ Health Course for Medical Students.

Despite the increasing number of sexual and gender minority (SGM) patients in the United States and designation by the National Institutes of Health as a population with health disparities, available tools are lacking to train medical students on appropriate care for this population. Therefore, we developed and implemented a novel, self-directed, 2-week online elective for undergraduate medical students. The objective of our study was to evaluate the effectiveness of this course in increasing medical students' competency and confidence in caring for SGM patients. We developed the curriculum using Kern's six-step model for curriculum development. We created anonymous pre- and postcourse surveys using the standardized Lesbian, Gay, Bisexual, Transgender Development of Clinical Skills Survey (LGBT-DOCSS) questionnaire to assess cultural competence, as well as a 5-point Likert-scored survey to assess self-perceived confidence in the care of SGM patients. We tested the statistical significance in pre- and postsurvey scores via paired sample t tests in R (R Project for Statistical Computing). We found statistically significant increases in the LGBT-DOCSS categories of clinical preparedness (P&lt;.001), basic knowledge (P&lt;.001), overall competency (P&lt;.001), and self-perceived confidence in caring for SGM patients (P&lt;.001, N=33). The course represents an effective solution for increasing medical students' self-perceived competence and confidence in caring for SGM patients. The flexibility and ease of the online format may be appealing to both students and institutions, and ultimately can serve to increase access to crucial content that is largely absent from current undergraduate medical education. Future evaluation efforts will be required to determine whether the course impacts long-term behavioral changes and outcomes.

Toward a more holistic approach to the study of exposures and child outcomes.

Aim: The current work was designed to demonstrate the application of the exposome framework in examining associations between exposures and children's long-term neurodevelopmental and behavioral outcomes. Methods: Longitudinal data werecollected from birth through age 6 from 402 preterm infants. Three statistical methods were utilized to demonstrate the exposome framework: exposome-wide association study, cumulative exposureand machine learning models, with and without epigenetic data. Results: Each statistical approach answered a distinct research question regarding the impact of exposures on longitudinal child outcomes. Findings highlight associations between exposures, epigenetics and executive function. Conclusion: Findings demonstrate how an exposome-based approach can be utilized to understand relationships between internal (e.g., DNA methylation) and external (e.g., prenatal risk) exposures and long-term developmental outcomes in preterm children.

The Long Shadow of Early Poverty: Poverty at Birth, Epigenetic Changes at Age 15, And Youth Outcomes at Age 22.

Early life socioeconomic conditions and race/ethnicity are critical determinants of long-term health and behavioral outcomes. Epigenetic changes, particularly those measured by the GrimAge biomarker, may mediate the impact of these early adversities on later life outcomes. This study investigates the relationships between race/ethnicity, poverty at birth, epigenetic aging at age 15, and subsequent self-rated health, school discipline, depression, and school dropout at age 22. We explored sex differences in these paths. Data were drawn from the Fragile Families and Child Wellbeing Study (FFCWS), which included 733 youth with comprehensive follow-up data up to age 22. Structural Equation Modeling (SEM) was employed to assess the pathways from race/ethnicity and poverty at birth to epigenetic aging (GrimAge) at age 15, and subsequently to self-rated health and school discipline at age 22. The model controlled for potential confounders including sex, family structure, and parental education. Race/ethnicity and poverty at birth were significantly associated with higher GrimAge scores at age 15 (p < 0.05). Higher GrimAge scores were predictive of poorer self-rated health (β = -0.08, p < 0.05) and increased instances of school discipline (β = 0.13, p < 0.01) at age 22. The indirect effects of race/ethnicity and poverty at birth on self-rated health and school discipline through GrimAge were also significant (p < 0.05), suggesting that epigenetic aging partially mediates these relationships. Sex differences were also observed. Poverty at birth predicted faster epigenetic aging at age 15 for males not females. We also observed that faster epigenetic aging at age 15 was predictive of school discipline of male not female participants at age 22. In contrast, faster epigenetic aging at age 15 was predictive of self-rated health (SRH) of female not male participants at age 22. This study provides evidence that with some sex differences, race/ethnicity and poverty at birth contribute to accelerated epigenetic aging (GrimAge) by age 15, which in turn predicts poorer self-rated health and increased school discipline issues by age 22. These findings emphasize the importance of early interventions targeting social determinants to mitigate long-term health and behavioral disparities. Addressing these early life conditions is crucial for improving health equity and outcomes in young adulthood.

Accuracy of Reticulocyte Hemoglobin for Diagnosing Iron Deficiency in Very Preterm Infants: A Population-Based Cohort Study

Background: Preterm born infants are at an increased risk of developing iron deficiency (ID) despite preventative iron supplementation, which can lead to long-term negative neurodevelopmental and behavioral outcomes. Serum ferritin (SF) is the commonly used test for diagnosing ID. However, SF is influenced by infection and inflammation, making it an unreliable marker in such situations. An alternative, reticulocyte hemoglobin equivalent (Ret-He), measures the iron content in newly produced red blood cells, providing an immediate assessment of iron availability. Unlike SF, Ret-He tests are automated, can be performed on the same blood sample as a complete blood count, and is not influenced by infection or inflammation like SF. However, there is limited literature on the reliability of Ret-He as an ID marker in very preterm infants (VPI) during their first year of life. This study aims to evaluate the diagnostic accuracy of Ret-He as an ID indicator in VPI at 4-6 months of corrected age (CA) compared to SF levels. Objective: To investigate the accuracy of Ret-He in detecting ID in VPI at 4-6 months CA Methods: A retrospective population-based cohort study was conducted using a population-based Provincial Perinatal Follow-Up (PFUP) database on all live VPIs born in Nova Scotia between 2012 and 2018. Infants with hematological disorders, chromosomal abnormalities, or major congenital anomalies were excluded. Prophylactic iron supplementation (2-3 mg/kg/day) starting at 2-4 weeks of chronological age was a standard of care for all included infants. Iron supplementation was recommended until 9-12 months CA. All infants underwent SF and CBC testing at either 4- or 6-months CA to assess iron stores and guide supplementation. In 2012, Ret-He was added as an additional marker of ID for clinical decision-making. Two definitions of ID were used. Definition one defined ID as SF level &amp;lt;20 mcg/L. Definition two defined ID as SF level &amp;lt;20 mcg/L at 4 months and &amp;lt;12 mcg/L at 6 months CA. Receiver operating characteristic curves were performed and the areas under the curves (AUC) were calculated to assess the accuracy of Ret-He in classifying patients with ID. The optimal cut-off point for Ret-He was determined using Youden's index, from which sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. The Spearman correlation coefficient was calculated between SF and Ret-He. Statistical significance was set at a two-sided P value of &amp;lt; 0.05. Results: A total of 156 patients were included. Under definition one, 62 (39.7%) met the criteria for ID. Under definition two, 39 (25.0%) patients had ID. Baseline characteristics are provided in Table 1. The Spearman correlation coefficient between SF and Ret-He was 0.23 (p=0.004). Under definition one, the AUC of Ret-He for diagnosing ID was 0.64 (p=0.002) and 0.69 (p&amp;lt;0.001) under definition two (Figure 1). The optimal cut-off value for Ret-He in ID diagnosis was 29.4 pg irrespective of the definition. Sensitivity, specificity, PPV, and NPV for both definitions are reported in Table 1. Conclusion: Regardless of the ID definition used, the AUCs indicated a weak discriminatory ability of Ret-He for ID diagnosis. The study indicated a weak positive relationship between SF and Ret-He. Ret-He's low diagnostic accuracy in this study is comparable to other studies involving healthy pediatric populations but lower than studies involving children with chronic health conditions. Clinicians should use caution when relying on Ret-He alone to diagnose ID in VPI. Further research is needed to determine the optimal diagnostic approach for identifying ID in VPI as well as explore the clinical utility of Ret-He in combination with other ID biomarkers such as SF and transferrin saturation.

What Is Food Noise? A Conceptual Model of Food Cue Reactivity.

As GLP-1 receptor agonists, like semaglutide, emerge as effective treatments for weight management, anecdotal reports from patients and clinicians alike point to a reduction in what has been colloquially termed "food noise", as patients report experiencing less rumination and obsessive preoccupation about food. In this narrative review, we discuss concepts used in studies to investigate human eating behavior that can help elucidate and define food noise, particularly food cue reactivity. We propose a conceptual model that summarizes the main factors that have been shown to determine the magnitude of the reactivity elicited by external and internal food cues and how these factors can affect short- and long-term behavioral and clinical outcomes. By integrating key research conducted in this field, the Cue-Influencer-Reactivity-Outcome (CIRO) model of food cue reactivity provides a framework that can be used in future research to design studies and interpret findings related to food noise and food cue reactivity.

Effects of different types of neonatal pain on somatosensory and cognitive development in male juvenile rats.

Premature infants are inevitably exposed to painful events, including repetitive procedures, inflammation, or mixed stimulation that may induce long-term behavioral outcomes. Here, we set up three neonatal painful models to investigate their long-term effect on somatosensation and cognition. Three types of neonatal pain models in rat were set up. Rat pups were randomly assigned to four groups. The needling pain (NP) group received repetitive needle pricks on the paws from the day of birth (PD0) to postnatal day 7 (PD7) to mimic the diagnostic and therapeutic procedures. The inflammatory pain (IP) group received the injection of carrageenan into the left hindpaw at PD3 to induce IP in peripheral tissues. The mixed pain group received a combination of the NP and IP (NIP). The control (CON) group was untreated. We performed behavioral and biochemical testing of juvenile rats (PD21-PD26). The NIP group showed a longer hypersensitivity than the NP group, when given a secondary inflammatory stimulation. NP led to insensitivity to anxiety-causing stimuli and impairment of fear memory both aggravated by NIP. NP reduced the expression of synapse-related molecules (GluN1/PSD95/GFAP) in the medial prefrontal cortex, and NIP exacerbated this decrease. The corticosterone secretion in the NIP group increased after the behavioral task, compared with those in other three groups. A combination of NP with inflammation occurring in the neonatal period might aggravate the adverse effects of each on somatosensory and cognitive development of rats, the mechanism of which might be associated with the increase of corticosterone secretion and the dysregulation of synaptic molecules.

Common mental health disorders and cognitive decline in a longitudinal Down syndrome cohort.

Down syndrome is the most common genetic cause of intellectual disability and Alzheimer's disease. In the general population, common mental disorders (CMDs), including anxiety, depression and obsessive-compulsive disorder, are linked to cognitive decline and higher risk for dementia. It is not known how CMDs affect longer-term cognitive outcomes in Down syndrome, and there is often diagnostic uncertainty in older people with Down syndrome and psychiatric comorbidity. To study the influence of CMDs on cognitive ability and whether they are related longitudinally to development of clinical signs of Alzheimer's disease in Down syndrome. We followed 115 individuals with Down syndrome, 27 of whom were diagnosed with a CMD, over approximately 3 years. Changes in cognitive and behavioural outcomes between baseline and follow-up assessment were analysed, with comparisons made between those with and without a comorbid CMD. Age, gender, apolipoprotein E status and level of intellectual disability were included as covariates. No significant association between presence of a CMD and poorer performance on cognitive tasks or informant-rated decline over time was observed (P > 0.05). Our results suggest that a diagnosis of a CMD does not have a significant negative effect on long-term cognitive or behavioural outcomes in individuals with Down syndrome. In individuals with stable or treated CMD, subsequent cognitive decline is likely indicative of Alzheimer's disease rather than a consequence of mental disorder.

Receptor-interacting protein kinase 2 (RIPK2) profoundly contributes to post-stroke neuroinflammation and behavioral deficits with microglia as unique perpetrators

BackgroundReceptor-interacting protein kinase 2 (RIPK2) is a serine/threonine kinase whose activity propagates inflammatory signaling through its association with pattern recognition receptors (PRRs) and subsequent TAK1, NF-κB, and MAPK pathway activation. After stroke, dead and dying cells release a host of damage-associated molecular patterns (DAMPs) that activate PRRs and initiate a robust inflammatory response. We hypothesize that RIPK2 plays a damaging role in the progression of stroke injury by enhancing the neuroinflammatory response to stroke and that global genetic deletion or microglia-specific conditional deletion of Ripk2 will be protective following ischemic stroke.MethodsAdult (3–6 months) male mice were subjected to 45 min of transient middle cerebral artery occlusion (tMCAO) followed by 24 h, 48 h, or 28 days of reperfusion. Aged male and female mice (18–24 months) were subjected to permanent ischemic stroke and sacrificed 48 h later. Infarct volumes were calculated using TTC staining (24–48 h) or Cresyl violet staining (28d). Sensorimotor tests (weight grip, vertical grid, and open field) were performed at indicated timepoints. Blood–brain barrier (BBB) damage, tight junction proteins, matrix metalloproteinase-9 (MMP-9), and neuroinflammatory markers were assessed via immunoblotting, ELISA, immunohistochemistry, and RT-qPCR. Differential gene expression profiles were generated through bulk RNA sequencing and nanoString®.ResultsGlobal genetic deletion of Ripk2 resulted in decreased infarct sizes and reduced neuroinflammatory markers 24 h after stroke compared to wild-type controls. Ripk2 global deletion also improved both acute and long-term behavioral outcomes with powerful effects on reducing infarct volume and mortality at 28d post-stroke. Conditional deletion of microglial Ripk2 (mKO) partially recapitulated our results in global Ripk2 deficient mice, showing reductive effects on infarct volume and improved behavioral outcomes within 48 h of injury. Finally, bulk transcriptomic profiling and nanoString data demonstrated that Ripk2 deficiency in microglia decreases genes associated with MAPK and NF-κB signaling, dampening the neuroinflammatory response after stroke injury by reducing immune cell activation and peripheral immune cell invasion.ConclusionsThese results reveal a hitherto unknown role for RIPK2 in the pathogenesis of ischemic stroke injury, with microglia playing a distinct role. This study identifies RIPK2 as a potent propagator of neuroinflammatory signaling, highlighting its potential as a therapeutic target for post-stroke intervention.

Abstract 32 Expanded Umbilical Cord Blood CD34+ Cells Are Immunomodulatory in a Rat Model of Neonatal Brain Injury

Abstract Introduction Hypoxic ischemic (HI) insults during pregnancy and birth can result in neurodevelopmental disorders, including cerebral palsy. We have previously shown that multiple doses of umbilical cord blood (UCB) cells are needed to effectively reduce long-term neuropathology and behavioural outcomes. Unfortunately, for multiple doses it is likely that UCB expansion will be required to increase the number of cells available for treatment. Objectives In this study, we aimed to investigate the efficacy of expanded UCB derived CD34+ cells in modulating perinatal brain injury. Methods UCB derived CD34+ cells were expanded over a 14-day period using a previously optimised expansion protocol. HI injury was induced in postnatal day (P) 10 rats by left carotid artery ligation, followed by 90min hypoxia (8% oxygen). Pups were administered 1 million expanded UCB cells (eUCB) on P11, 13 and 20. Rats underwent extensive behavioural testing and post-mortem was performed on either P17 or P50 where tissue was collected for flow cytometry or immunohistochemistry analysis. Results After the 14-day expansion there was a ~800-fold increase in cell number with 70.7±2.18% CD34+ cells. Flow cytometry at P17 showed a significant increase in peripheral regulatory T-cells following eUCB administration (P=0.047). At P50, HI brain injury resulted in significant behavioural deficits and adverse neuropathologies. Multiple doses of eUCB significantly reduced microglial activation compared to HI in the cortex (P=0.02) and the hippocampus (P=0.018). Discussion Results from this study show for the first time that expanded UCB-derived CD34+ cells are a promising treatment option for perinatal brain injury as they have significant anti-inflammatory properties.

Thalamocortical coherence predicts persistent postconcussive symptoms

The pathogenetic mechanism of persistent post-concussive symptoms (PCS) following concussion remains unclear. Thalamic damage is known to play a role in PCS prolongation while the evidence and biomarkers that trigger persistent PCS have never been elucidated. We collected longitudinal neuroimaging and behavior data from patients and rodents after concussion, complemented with rodents’ histological staining data, to unravel the early biomarkers of persistent PCS. Diffusion tensor imaging (DTI) were acquired to investigated the thalamic damage, while quantitative thalamocortical coherence was derived through resting-state functional MRI for evaluating thalamocortical functioning and predicting long-term behavioral outcome. Patients with prolonged symptoms showed abnormal DTI-derived indices at the boundaries of bilateral thalami (peri-thalamic regions). Both patients and rats with persistent symptoms demonstrated enhanced thalamocortical coherence between different thalamocortical circuits, which disrupted thalamocortical multifunctionality. In rodents, the persistent DTI abnormalities were validated in thalamic reticular nucleus (TRN) through immunohistochemistry, and correlated with enhanced thalamocortical coherence. Strong predictive power of these coherence biomarkers for long-term PCS was also validated using another patient cohort. Postconcussive events may begin with persistent TRN injury, followed by disrupted thalamocortical coherence and prolonged PCS. Functional MRI-based coherence measures can be surrogate biomarkers for early prediction of long-term PCS.

A consequence of immature breathing induces persistent changes in hippocampal synaptic plasticity and behavior: a role of prooxidant state and NMDA receptor imbalance.

Underdeveloped breathing results from premature birth and causes intermittent hypoxia during the early neonatal period. Neonatal intermittent hypoxia (nIH) is a condition linked to the increased risk of neurocognitive deficit later in life. However, the mechanistic basis of nIH-induced changes to neurophysiology remains poorly resolved. We investigated the impact of nIH on hippocampal synaptic plasticity and NMDA receptor (NMDAr) expression in neonatal mice. Our findings indicate that nIH induces a prooxidant state that leads to an imbalance in NMDAr subunit composition favoring GluN2B over GluN2A expression and impairs synaptic plasticity. These consequences persist in adulthood and coincide with deficits in spatial memory. Treatment with an antioxidant, manganese (III) tetrakis (1-methyl-4-pyridyl)porphyrin (MnTMPyP), during nIH effectively mitigated both immediate and long-term effects of nIH. However, MnTMPyP treatment post-nIH did not prevent long-lasting changes in either synaptic plasticity or behavior. In addition to demonstrating that the prooxidant state has a central role in nIH-mediated neurophysiological and behavioral deficits, our results also indicate that targeting the prooxidant state during a discrete therapeutic window may provide a potential avenue for mitigating long-term neurophysiological and behavioral outcomes that result from unstable breathing during early postnatal life.

Mindful Coping Power Effects on Children's Autonomic Nervous System Functioning and Long-Term Behavioral Outcomes.

Mindful Coping Power (MCP) was developed to enhance the effects of the Coping Power (CP) preventive intervention on children's reactive aggression by integrating mindfulness training into CP. In prior pre-post analyses in a randomized trial of 102 children, MCP improved children's self-reported anger modulation, self-regulation, and embodied awareness relative to CP but had fewer comparative effects on parent- and teacher-reported observable behavioral outcomes, including reactive aggression. It was hypothesized that MCP-produced improvements in children's internal awareness and self-regulation, if maintained or strengthened over time with ongoing mindfulness practice, would yield improvements in children's observable prosocial and reactive aggressive behavior at later time points. To appraise this hypothesis, the current study examined teacher-reported child behavioral outcomes at a one-year follow-up. In the current subsample of 80 children with one-year follow-up data, MCP produced a significant improvement in children's social skills and a statistical trend for a reduction in reactive aggression compared with CP. Further, MCP produced improvements in children's autonomic nervous system functioning compared with CP from pre- to post-intervention, with a significant effect on children's skin conductance reactivity during an arousal task. Mediation analyses found that MCP-produced improvements in inhibitory control at post-intervention mediated program effects on reactive aggression at the one-year follow-up. Within-person analyses with the full sample (MCP and CP) found that improvements in respiratory sinus arrhythmia reactivity were associated with improvements in reactive aggression at the one-year follow-up. Together, these findings indicate that MCP is an important new preventive tool to improve embodied awareness, self-regulation, stress physiology, and observable long-term behavioral outcomes in at-risk youth. Further, children's inhibitory control and autonomic nervous system functioning emerged as key targets for preventive intervention.

Key Competencies of Pediatric Disaster Medicine as Determined by a Systematic Review of Gray Literature

Introduction:Children are often disproportionately impacted by disasters, and yet pediatric specific considerations are not properly emphasized during disaster planning and training, resulting in the desperate needs of children falling through the cracks during disasters. Children differ from adults developmentally, physiologically, and psychologically, and are more vulnerable to negative long-term medical, social, and behavioral outcomes. Additionally, children lack autonomy and rely on adults to gain access to the healthcare system and other resources. Despite the distinctions between adults and children, time and curricula for pediatric disaster training is insufficient, and workforce capacity and competency to plan for and respond to the disaster related needs of children are inadequate; this is especially true for both physicians and other healthcare responders who do not complete a specific pediatric residency. Our study seeks to determine the key core competencies of pediatric disaster medicine that should be included in the training of responders.Method:A systematic gray literature review of existing pediatric disaster medicine curricula was performed, from which a list of the most commonly present key core competencies was created.Results:Data collection and analysis is expected to be completed by April 2023 and will yield a ranked list of core competencies.Conclusion:There is a need for improved pediatric disaster training that addresses the specific considerations of children; this is especially true for non-pediatricians who may be treating children following a disaster. The gray literature review will identify key components of pediatric disaster medicine, which should be applied to all such training curricula to ensure that the care of children who suffer during and after disasters is equitable across the globe.