Neurobehavioral Outcomes Research Articles

0295 Subjective alertness, behavioral alertness, and perception-action coupling reflect distinct aspects of neurobehavioral resilience during simulated military operational stress

Abstract Introduction Despite exposure to operational stressors (e.g., sleep loss, caloric restriction), military personnel must maintain different aspects of neurobehavioral function (i.e., subjective alertness, behavioral alertness, perception-action coupling) to operate safely within military environments. It is unclear whether perception-action coupling, which refers to the ability to ‘read and react’ to ever-changing circumstances, reflects a distinct aspect of neurobehavioral resilience from subjective and behavioral alertness. Further, prior sleep may enhance resilience during subsequent exposure to operational stressors. Therefore, we examined resilience across different neurobehavioral tasks during exposure to simulated military operational stress (SMOS) and examined differences in baseline sleep between resilient and vulnerable participants. Methods Forty-nine military personnel (11 females, 26.6 ± 5.8 years) completed a 5-day SMOS protocol that included two days of sleep restriction and disruption (sleep opportunities: 01:00-03:00 and 05:00-07:00) accompanied by caloric restriction (50% caloric need). Participants completed tasks of subjective alertness (Profile of Mood States Vigor subscale, POMS), behavioral alertness (Psychomotor Vigilance Task) and perception-action coupling (Perception-Action Coupling Task) at baseline and at 04:00 across the two nights of sleep disruption. For each neurobehavioral outcome, a two-step decision-making process defined resilient and vulnerable participants: resilient participants demonstrated high alertness/performance during sleep disruption and minimal change from baseline during sleep disruption. Kappa coefficients were calculated to determine agreement in resilience classification across different neurobehavioral outcomes. Further, differences between resilient and vulnerable participants in baseline sleep questionnaires (Pittsburgh Sleep Quality Index; Epworth Sleepiness Scale) and polysomnography (sleep efficiency; sleep fragmentation; and slow wave activity, SWA) were examined with independent t-tests. Results Classification of participants as resilient or vulnerable differed across neurobehavioral outcomes, as indicated by kappa values <0.60. Resilient participants, defined by POMS, had lower baseline SWA than vulnerable participants (t = 2.06, p = .04). No other differences in sleep were observed between groups. Conclusion Subjective alertness, behavioral alertness, and perception-action coupling reflect distinct aspects of neurobehavioral resilience, highlighting the importance of understanding the operational relevance of different neurobehavioral measures when assessing fatigue risk. Further, more baseline SWA, indicating higher baseline sleep need, may reflect vulnerability to SMOS and subsequent sleep loss. Support (If Any) Department of Defense Award #W81XWH-17-2-0070

La Crosse Virus Neuroinvasive Disease in Children: A Contemporary Analysis of Clinical/Neurobehavioral Outcomes and Predictors of Disease Severity.

La Crosse virus (LACV) is the most common neuroinvasive arboviral infection in children in the United States. However, data regarding predictors of disease severity and neurologic outcome are limited. Additionally, long-term neurologic and neurobehavioral outcomes remain relatively sparse. This was a single-center, retrospective cohort study, followed by recruitment for a cross-sectional analysis of long-term neurobehavioral outcomes, among children aged 0-18 years with proven or probable LACV neuroinvasive disease (LACV-ND) between January 2009 and December 2018. Case ascertainment was assured by International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification codes cross-referenced with laboratory results detecting LACV. Demographics, diagnostics, radiographs, and outcomes were evaluated. Recruitment of patients with prior diagnosis of LACV-ND occurred from January 2020 to March 2020, with assessment performed by validated pediatric questionnaires. One-hundred fifty-two children (83 males; median age, 8 years [interquartile range, 5-11.5 years]) were diagnosed with proven (n = 61 [47%]) and probable (n = 91 [60%]) LACV-ND. Sixty-five patients (43%) had severe disease. Altered mental status (AMS) (odds ratio [OR], 6.36 [95% confidence interval {CI}, 2.03-19.95]; P = .0002) and seizures at presentation (OR, 10.31 [95% CI, 3.45-30.86]; P = .0001) were independent predictors of severe disease. Epileptiform discharges on electroencephalogram (EEG) were independently associated with epilepsy diagnosis at follow-up (OR, 13.45 [95% CI, 1.4-128.77]; P = .024). Fifty-four patients were recruited for long-term neurobehavioral follow-up, with frequent abnormal assessments identified (19%-54%) irrespective of disease severity. Severe disease was observed frequently among children with LACV-ND. Seizures and AMS at presentation were independent predictors of severe disease. EEG may help determine long-term epilepsy risk. Long-term neurobehavioral issues are frequent and likely underrecognized among children with LACV-ND.

Defining Longer-Term Outcomes in an Ovine Model of Moderate Perinatal Hypoxia-Ischemia

Hypoxic-ischemic encephalopathy (HIE) is the leading cause of neonatal morbidity and mortality worldwide. Approximately 1 million infants born with HIE each year survive with cerebral palsy and/or serious cognitive disabilities. While infants born with mild and severe HIE frequently result in predictable outcomes, infants born with moderate HIE exhibit variable outcomes that are highly unpredictable. Here, we describe an umbilical cord occlusion (UCO) model of moderate HIE with a 6-day follow-up. Near-term lambs (n = 27) were resuscitated after the induction of 5 min of asystole. Following recovery, lambs were assessed to define neurodevelopmental outcomes. At the end of this period, lambs were euthanized, and brains were harvested for histological analysis. Compared with prior models that typically follow lambs for 3 days, the observation of neurobehavioral outcomes for 6 days enabled identification of animals that recover significant neurological function. Approximately 35% of lambs exhibited severe motor deficits throughout the entirety of the 6-day course and, in the most severely affected lambs, developed spastic diparesis similar to that observed in infants who survive severe neonatal HIE (severe, UCOs). Importantly, and similar to outcomes in human neonates, while initially developing significant acidosis and encephalopathy, the remainder of the lambs in this model recovered normal motor activity and exhibited normal neurodevelopmental outcomes by 6 days of life (improved, UCOi). The UCOs group exhibited gliosis and inflammation in both white and gray matters, oligodendrocyte loss, neuronal loss, and cellular death in the hippocampus and cingulate cortex. While the UCOi group exhibited more cellular death and gliosis in the parasagittal cortex, they demonstrated more preserved white matter markers, along with reduced markers of inflammation and lower cellular death and neuronal loss in Ca3 of the hippocampus compared with UCOs lambs. Our large animal model of moderate HIE with prolonged follow-up will help further define pathophysiologic drivers of brain injury while enabling identification of predictive biomarkers that correlate with disease outcomes and ultimately help support development of therapeutic approaches to this challenging clinical scenario.

Associations of prenatal phthalate exposure with neurobehavioral outcomes in 4.5- and 7.5-month-old infants

Phthalates are ubiquitous endocrine-disrupting chemicals, and research indicates that prenatal exposure to some phthalates may affect neurodevelopment. In a prospective birth cohort study, five first-morning urine samples collected across pregnancy were pooled and the following phthalate biomarkers assessed: sum of di-(2-ethylhexyl) phthalate metabolites (ΣDEHP), sum of diisononyl phthalate metabolites (ΣDINP), sum of dibutyl phthalate metabolites (ΣDBP), sum of anti-androgenic metabolites (ΣAA), monoethyl phthalate (MEP), and sum of all phthalate metabolites (ΣAll). The Ages & Stages Questionnaires® (ASQ), a standardized parent-reported, age-adapted screening tool, measured communication, personal-social, problem solving, and motor domains in infants at 4.5 and 7.5 months (n = 123). Adjusting for maternal age, annual household income, gestational age at birth, infant age at assessment, and sex, repeated-measures generalized linear regression models were used to examine associations between prenatal phthalate urine biomarker concentrations and domain scores (assuming a Poisson distribution). Beta estimates were exponentiated back to the domain scale for ease of interpretation. Mothers were mostly white and college-educated, and most reported an annual household income of ≥$60,000. Associations of phthalate concentrations with ASQ outcomes are presented as follows: (1) anti-androgenic phthalate metabolites (ΣDEHP, ΣDINP, ΣDBP, and ΣAA), (2) MEP, which is not anti-androgenic, and (3) ΣAll. Overall, anti-androgenic phthalates were associated with higher (i.e., better) scores. However, there were exceptions, including the finding that a one-unit increase in ΣDBP was associated with a 12% increase in problem solving scores in 4.5-month-old females (β = 1.12; 95% CI: 0.99, 1.28; p = 0.067) but a 85% decrease for 7.5-month-old females (β = 0.54; 95% CI: 0.3, 0.99; p = 0.047). In contrast, MEP was associated with poorer scores on several outcomes. Sex- and timepoint-specific estimates demonstrated a one-unit increase in MEP was associated with: a 52% decrease in personal-social scores in 7.5-month-old males (β = 0.66; 95% CI: 0.46, 0.95; p = 0.02), a 39% decrease in fine motor scores in 7.5-month-old males (β = 0.72; 95% CI: 0.52, 0.98; p = 0.035), and a 6% decrease in fine motor scores in 4.5-month-old females (β = 0.94; 95% CI: 0.88, 0.99; p = 0.03). A one-unit increase in ΣAll was associated with a 4% increase in personal-social scores in 4.5-month-old males (β = 1.04; 95% CI: 0.99, 1.1; p = 0.08) but a 17% decrease in 7.5-month-old males (β = 0.85; 95% CI: 0.73, 0.99; p = 0.03). These data suggest age- and sex-specific associations of prenatal phthalates with infant neurobehavior. The current findings should be confirmed by longitudinal studies with larger sample sizes.

Thioredoxin 1 regulates the pentose phosphate pathway via ATM phosphorylation after experimental subarachnoid hemorrhage in rats

Subarachnoid hemorrhage (SAH), a type of hemorrhagic stroke, is a neurological emergency with high morbidity and mortality. Early brain injury (EBI) after SAH is the leading cause of poor prognosis in SAH patients. TRX system is a NADPH-dependent antioxidant system which is composed of thioredoxin reductase (TRXR), thioredoxin (TRX). The pentose phosphate pathway (PPP), a pathway through which glucose can be metabolized, is a major source of NADPH. Thioredoxin 1 (TRX1) is a member of thioredoxin system mainly located in cytoplasm. Serine/threonine kinases ataxia telangiectasia mutated (ATM) is an important oxidative stress receptor, and TRX1 can regulate ATM phosphorylation and then affect the activity of PPP key enzyme glucose 6-phosphate dehydrogenase (G6PD). However, whether TRX1 is involved in the regulation of PPP pathway after subarachnoid hemorrhage remains unclear. The results showed that after SAH, the level of TRX1 and phosphor-ATM decreased while the level of TRXR1 increased. G6PD protein level remained unchanged but the activity decreased, and the NADPH contents decreased. Overexpression of TRX1 by lentivirus upregulates the level of phosphor-ATM, G6PD activity and NADPH content. TRX1 overexpression improved short-term and long-term neurobehavioral outcomes and alleviated neuronal impairment in rats. Nissl staining showed that upregulation of TRX1 reduced cortical neuron injury. Our study shows that TRX1 participates in the PPP pathway by regulating phosphorylation ATM, which is accomplished by affecting G6PD activity. TRX1 may be an important target for EBI intervention after SAH.

Roflumilast, a cyclic nucleotide phosphodiesterase 4 inhibitor, protects against cerebrovascular endothelial injury following cerebral ischemia/reperfusion by activating the Notch1/Hes1 pathway

The loss of tight junction (TJ) and adherens junction (AJ) proteins leads to the damage of the blood-brain barrier (BBB) during cerebral ischemia. Inhibition of cyclic nucleotide phosphodiesterase 4 (PDE4) by roflumilast (Roflu) protects against ischemic stroke-induced neuronal damage. However, the effects of Roflu on vascular endothelial injury and BBB integrity remain unknown. Here, we investigated whether and how Roflu protects against cerebrovascular endothelial injury caused by cerebral ischemia/reperfusion. We demonstrated that PDE4B knocking-down increased the expression of TJ and AJ proteins in human brain microvascular endothelial cells (HBMECs) subjected to oxygen-glucose deprivation reperfusion (OGD/R). Inhibition of PDE4 by Roflu (1.0 μM) showed similar effects as PDE4B knocking-down. We then found that Roflu activated Notch1/Hairy and enhancer of split 1 (Hes1) signaling. Consistently, the effects of Roflu on TJ and AJ proteins were reversed by the γ-secretase inhibitor DAPT or Hes1 knocking-down. Furthermore, Roflu (1.0 mg/kg) improved neurobehavioral outcomes and ameliorated BBB disruption in rats following ischemic stroke. Roflu also increased the levels of TJ proteins and AJ proteins in vivo. Collectively, these data suggest that Roflu is a promising compound for the prevention of BBB damage. The protective effects of Roflu are mediated through activation of the Notch1/Hes1 pathway.

A history of low dose ethanol modulates ventral hippocampus activity during motivated behavior

More than half of the 130 million people in the U.S. who consumed alcohol within the last month did so at a level that did not meet diagnostic criteria for an alcohol binge. However, even these sub diagnostic drinking levels can have neurobehavioral outcomes. Clinical studies have shown that low levels of acute ethanol drinking soon after learning can enhance task consolidation and memory recall. Our preclinical data in C57BL6J mice show that a history of repeated, low dose ethanol (0.5g/kg) exposure increases sucrose reward motivation as measured by progressive ratio. The ventral hippocampus (vHPC) is increasingly considered a critical contributor to reward seeking and has been shown to be sensitive to chronic ethanol exposure at higher doses. The present study sought to determine whether daily, post‐training, low dose ethanol exposure can modulate vHPC activity during motivated behavior. To investigate this, we implanted mice with an electrode array to record vHPC neural activity during performance of a progressive ratio task. We also investigated vHPC activity around important behavioral events in the task, including lever pressing (when the animal is seeking the reward) and magazine entries (when the animal is checking for reward delivery). Our results demonstrate that saline control mice show suppression of vHPC activity following a lever press, while mice with a history of low dose ethanol exposure exhibit this suppression prior to a lever press. In contrast, both saline and ethanol‐exposed mice exhibit similar vHPC activity patterns surrounding magazine entry. These results suggest that a history of post‐training low dose ethanol exposure modulates vHPC activity during reward seeking. Further, this shift in vHPC suppression around a lever press may be associated with the enhanced motivation for sucrose observed in ethanol‐exposed mice. Future studies will use optogenetics to determine whether this shift in activity contributes to heightened reward motivation in ethanol exposed mice. A greater understanding of the neurobiological substrates impacted by ethanol exposure can help identify factors placing casual drinkers at risk for transition to alcohol use disorder.

P358. Preschool Depression and Hippocampal Volume: The Moderating Role of Family Income

Depression and low socioeconomic status have both been associated with hippocampal volume alterations. Whether these factors interact to predict neurobehavioral outcomes has not been adequately studied. The authors investigated family income as a moderator of the relationship between depression and hippocampal volume in a longitudinal sample.

Sex-specific neurobehavioural outcomes and brain stimulation pattern in adult offspring paternally exposed to methamphetamine.

Paternal methamphetamine (METH) exposure results in long-term behavioural deficits in the sub-generations with a sex difference. Here, we aim to investigate the sex-specific neurobehavioural outcomes in the first-generation offspring mice (F1 mice) paternally exposed to METH prior to conception and explore the underlying brain mechanisms. We found that paternal METH exposure increased anxiety-like behaviours and spatial memory deficits only in female F1 mice and caused depression-like behaviours in the offspring without sex-specific differences. In parallel, METH-sired F1 mice exhibited sex-specific brain activity pattern in response to mild stimulus (in water at room temperature for 3 min). Overall, paternal METH exposure caused a blunting phenomenon of prelimbic cortex (PrL), infralimbic cortex (IL) and nucleus accumbens (NAc) core in both male and female F1 mice, as indicated by the decreased c-Fos levels under mild stimulus. Of note, the activity of central nucleus of the amygdala (CeA) by mild stimulus was triggered in male but suppressed in female F1 mice, whereas the neurons of orbitofrontal cortex (OFC), cingulate cortex (Cg1), NAc shell, medial habenula (mHb), dorsal hippocampal CA1 (dCA1) and ventral hippocampal CA1 (vCA1) were only blunted in female F1 mice. Taken together, the distinct brain stimulation patterns between male and female F1 mice might contribute to the sex-specific behavioural outcomes by paternal METH exposure, which indicate that sex differences should be considered in the treatment of offspring paternally exposed drugs.

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.

Residence in an Area with Environmental Exposure to Heavy Metals and Neurobehavioral Performance in Children 9-11 Years Old: An Explorative Study.

We explored the association between residence in an area polluted with metals and neurobehavioral performance in children aged 9 to 11. A cross-sectional study was conducted with thirty boys and thirty girls aged 9 to 11 from public schools in a heavily industrialized area, matched by age (±4 months) and gender with 15 boys and 15 girls from public schools in cities without relevant industrial activity. Neurobehavioral performance was assessed with the Behavioral Assessment and Research System. Linear regression models were used, adjusting for age, sex, social class and multimedia activities to predict each of the neurobehavioral outcome variables. No differences in neurobehavioral performance were found when all children with residence in areas with environmental exposure to metals were classified as exposed and the children from the other provinces as unexposed. However, when we compared children living <1 km from an industrial area with respect to those living more than 1 km away, significant differences were found. Children living <1 km away had lower scores on Finger Tapping (p = 0.03), Symbol-Digit (p = 0.07) and Continuous Performance (p = 0.02) than those living farther away. Our results support the hypothesis that residing close to an area with industrial activity (<1 km) is associated with deficits in neurobehavioral performance among children aged 9 to 11.

Efficacy of melatonin in term neonatal models of perinatal hypoxia-ischaemia.

ObjectiveNeonatal encephalopathy (NE) is an important cause of mortality and disability worldwide. Therapeutic hypothermia (HT) is an effective therapy, however not all babies benefit. Novel agents are urgently needed to improve outcomes. Melatonin in preclinical studies has promising neuroprotective properties. This meta‐analysis assessed the efficacy of melatonin in term animal models of NE on cerebral infarct size, neurobehavioural tests and cell death.MethodsA literature search was carried out using Embase, MEDLINE and Web of Science (31 May 2021). We identified 14 studies and performed a meta‐analysis with a random effects model using standardised mean difference (SMD) as the effect size. The risk of bias was assessed using the Systematic Review Centre for Laboratory animal Experimentation tool and publication bias was assessed with funnel plots, and adjusted using trim and fill analysis. Subgroup and meta‐regression analyses were performed to assess the effects of study design variables.ResultsWe observed significant reduction in brain infarct size (SMD −2.05, 95% CI [−2.93, −1.16]), improved neurobehavioural outcomes (SMD −0.86, 95% CI [−1.23, −0.53]) and reduction in cell death (SMD −0.60, 95% CI [−1.06, −0.14]) favouring treatment with melatonin. Neuroprotection was evident as a single therapy and combined with HT. Subgroup analysis showed greater efficacy with melatonin given before or immediately after injury and with ethanol excipients. The overall effect size remained robust even after adjustment for publication bias.InterpretationThese studies demonstrate a significant neuroprotective efficacy of melatonin in term neonatal models of hypoxia‐ischaemia, and suggest melatonin is a strong candidate for translation to clinical trials in babies with moderate–severe NE.

Neurogenesis and chronic neurobehavioral outcomes are partially improved by vagus nerve stimulation in a mouse model of Gulf War illness

Gulf War illness (GWI) is a chronic, multi-symptom disorder that has impacted approximately one third of Gulf War veterans. GWI and its symptoms have been linked to the exposure to neurological chemicals, including the anti-nerve gas drug pyridostigmine bromide (PB) and the insecticide permethrin (PER), among others. Mouse models utilizing these chemicals have reported symptomology analogous to human GWI. These changes include behavioral and cognitive impairment, neuroinflammation and hippocampal pathogenesis. Disease modifying interventions that target these pathological components are desperately needed. Vagus nerve stimulation (VNS) is FDA approved for drug-resistant epilepsy and depression. VNS has also been used off-label to target a myriad of symptoms, some of which are encompassed within the Kansas and CDC definitions of clinical GWI symptomology. A GWI animal model in which mice are exposed to a daily injection of PB and PER for 10 consecutive days has been shown to exhibit cognitive impairment and hippocampal pathology. The purpose of this study was to determine if 2–4 weeks of continuous vagus nerve stimulation initiated at 32 weeks after exposure to PB and PER would improve cognitive performance and hippocampal pathology. The results of the study revealed that exposure to PB and PER produces long-term cognitive deficits and reduced hippocampal neurogenesis. The results also showed that the VNS treatment was anxiolytic, improved some aspects of pattern separation deficits, and mitigated the reduced hippocampal neurogenesis. Thus, VNS improves outcomes in a mouse model of GWI and should be examined as a potential therapeutic strategy for mitigating some symptomology associated with GWI.

Decoding the Synaptic Proteome with Long-Term Exposure to Midazolam during Early Development.

The intensive use of anesthetic and sedative agents in the neonatal intensive care unit (NICU) has raised controversial concerns about the potential neurodevelopmental risks. This study focused on midazolam (MDZ), a common benzodiazepine regularly used as a sedative on neonates in the NICU. Mounting evidence suggests a single exposure to MDZ during the neonatal period leads to learning disturbances. However, a knowledge gap that remains is how long-term exposure to MDZ during very early stages of life impacts synaptic alterations. Using a preclinical rodent model system, we mimicked a dose-escalation regimen on postnatal day 3 (P3) pups until day 21. Next, purified synaptosomes from P21 control and MDZ animals were subjected to quantitative mass-spectrometry-based proteomics, to identify potential proteomic signatures. Further analysis by ClueGO identified enrichment of proteins associated with actin-binding and protein depolymerization process. One potential hit identified was alpha adducin (ADD1), belonging to the family of cytoskeleton proteins, which was upregulated in the MDZ group and whose expression was further validated by Western blot. In summary, this study sheds new information on the long-term exposure of MDZ during the early stages of development impacts synaptic function, which could subsequently perturb neurobehavioral outcomes at later stages of life.

Association of Abnormal Findings on Neonatal Cranial Ultrasound With Neurobehavior at Neonatal Intensive Care Unit Discharge in Infants Born Before 30 Weeks’ Gestation

Cranial ultrasound (CUS) findings are routinely used to identify preterm infants at risk for impaired neurodevelopment, and neurobehavioral examinations provide information about early brain function. The associations of abnormal findings on early and late CUS with neurobehavior at neonatal intensive care unit (NICU) discharge have not been reported. To examine the associations between early and late CUS findings and infant neurobehavior at NICU discharge. This prospective cohort study included infants enrolled in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants Study between April 2014 and June 2016. Infants born before 30 weeks' gestational age were included. Exclusion criteria were maternal age younger than 18 years, maternal cognitive impairment, maternal inability to read or speak English or Spanish, maternal death, and major congenital anomalies. Overall, 704 infants were enrolled. The study was conducted at 9 university-affiliated NICUs in Providence, Rhode Island; Grand Rapids, Michigan; Kansas City, Missouri; Honolulu, Hawaii; Winston-Salem, North Carolina; and Torrance and Long Beach, California. Data were analyzed from September 2019 to September 2021. Early CUS was performed at 3 to 14 days after birth and late CUS at 36 weeks' postmenstrual age or NICU discharge. Abnormal findings were identified by consensus of standardized radiologists' readings. Neurobehavioral examination was performed using the NICU Network Neurobehavioral Scale (NNNS). Among the 704 infants enrolled, 675 had both CUS and NNNS data (135 [20.0%] Black; 368 [54.5%] minority race or ethnicity; 339 [50.2%] White; 376 [55.7%] male; mean [SD] postmenstrual age, 27.0 [1.9] weeks). After covariate adjustment, lower attention (adjusted mean difference, -0.346; 95% CI, -0.609 to -0.083), hypotonicity (mean difference, 0.358; 95% CI, 0.055 to 0.662), and poorer quality of movement (mean difference, -0.344; 95% CI, -0.572 to -0.116) were observed in infants with white matter damage (WMD). Lower attention (mean difference, -0.233; 95% CI, -0.423 to -0.044) and hypotonicity (mean difference, 0.240; 95% CI, 0.014 to 0.465) were observed in infants with early CUS lesions. In this cohort study of preterm infants, certain early CUS lesions were associated with hypotonicity and lower attention around term-equivalent age. WMD was associated with poor attention, hypotonicity, and poor quality of movement. Infants with these CUS lesions might benefit from targeted interventions to improve neurobehavioral outcomes during their NICU hospitalization.

Neurobiology of Parental Regulation of the Infant and Its Disruption by Trauma Within Attachment.

The complex process of regulating physiological functions and homeostasis during external and internal disruptions develops slowly in altricial species, with parental care functioning as a co-regulator of infant physiological and emotional homeostasis. Here, we review our current understanding of the infant’s use of parental behaviors for neurobehavioral regulation and its disruption with harsh parental care. Taking a cross-species view, we briefly review the human developmental literature that highlights the importance of the caregiver in scaffolding the child’s physiological and emotional regulation, especially under threat and stress. We then use emerging corresponding animal literature within the phylogenetically preserved attachment system to help define neural systems supporting caregiver regulation and its supporting causal mechanism to provide translational bridges to inform causation and mechanisms impossible to define in children. Next, we briefly review animal research highlighting the impact of specific sensory stimuli imbedded in parental care as important for infant physiological and emotion regulation. We then highlight the importance of parental sensory stimuli gaining hedonic value to go beyond simple sensory stimuli to further impact neurobehavioral regulation, with poor quality of care compromising the infant’s ability to use these cues for regulation. Clinically, parental regulation of the infant is correlated with later-life neurobehavioral outcome and quality of life. We suggest an understanding of this parental regulation of the infant’s immediate neurobehavioral functioning within the context of attachment quality, that may provide insights into the complex processes during early life, initiating the pathway to pathology.

Association of maternal depression and anxiety with toddler social-emotional and cognitive development in South Africa: a prospective cohort study

ObjectiveA robust literature has identified associations between prenatal maternal depression and adverse child social-emotional and cognitive outcomes. The majority of prior research is from high-income countries despite increased reporting of...

Cerebral perfusion changes of the basal ganglia and thalami in full-term neonates with hypoxic-ischaemic encephalopathy: a three-dimensional pseudo continuous arterial spin labelling perfusion magnetic resonance imaging study.

Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the common causes of neurological injury in full-term neonates following perinatal asphyxia. The conventional magnetic resonance technique has low sensitivity in detecting variations in cerebral blood flow in patients with HIE. This article evaluates the clinical diagnostic value of three-dimensional pseudo-continuous arterial spin labelling (3-D pcASL) perfusion magnetic resonance imaging (MRI) for early prediction of neurobehavioral outcomes in full-term neonates with HIE. All neonates diagnosed with HIE underwent MRI (conventional and 3-D pcASL perfusion MRI). Cerebral blood flow values were measured in the basal ganglia (caudate nuclei, lenticular nuclei), thalami and white matter regions (frontal lobes, corona radiata). After 1-month follow-up, the Neonatal Behavioral Neurological Assessment scores were used to divide patients into favourable outcome group versus adverse outcome group. Twenty-three patients were enrolled in this study. There were no statistical differences between the symmetrical cerebral blood flow values of bilateral basal ganglia, thalami and white matter regions. However, the cerebral blood flow values of grey matter nuclei were higher than the white matter regions. The average value of cerebral blood flow in the basal ganglia and thalami in the adverse outcome group was 37.28±6.42ml/100g/min, which is greater than the favourable outcome group (22.55 ± 3.21ml/100g/min) (P<0.01). The area under the curve (AUC) of 3-D pcASL perfusion MRI was 0.992 with a cutoff value of 28.75ml/100g/min, with a Youden's index of 0.9231. The sensitivity and specificity were 92.3% and 100%, respectively. The 3-D pcASL demonstrated higher perfusion alteration in the basal ganglia and thalami of neonatal HIE with adverse outcomes. The 3-D pcASL perfusion MRI has the potential to predict neurobehavioral outcomes of neonates with HIE.

Lithium upregulates growth-associated protein-43 (GAP-43) and postsynaptic density-95 (PSD-95) in cultured neurons exposed to oxygen-glucose deprivation and improves electrophysiological outcomes in rats subjected to transient focal cerebral ischemia following a long-term recovery period

ABSTRACT Objectives Lithium has numerous neuroplastic and neuroprotective effects in patients with stroke. Here, we evaluated whether delayed and short-term lithium treatment reduces brain infarction volume and improves electrophysiological and neurobehavioral outcomes following long-term recovery after cerebral ischemia and the possible contributions of lithium-mediated mechanisms of neuroplasticity. Methods Male Sprague Dawley rats were subjected to right middle cerebral artery occlusion for 90 min, followed by 28 days of recovery. Lithium chloride (1 mEq/kg) or vehicle was administered via intraperitoneal infusion once per day at 24 h after reperfusion onset. Neurobehavioral outcomes and somatosensory evoked potentials (SSEPs) were examined before and 28 days after ischemia-reperfusion. Brain infarction was assessed using Nissl staining. Primary cortical neuron cultures were exposed to oxygen-glucose deprivation (OGD) and treated with 2 or 20 μM lithium for 24 or 48 h; subsequent brain-derived neurotrophic factor (BDNF), growth-associated protein-43 (GAP-43), postsynaptic density-95 (PSD-95), and synaptosomal-associated protein-25 (SNAP-25) levels were analyzed using western blotting. Results Compared to controls, lithium significantly reduced infarction volume in the ischemic brain and improved electrophysiological and neurobehavioral outcomes at 28 days post-insult. In cultured cortical neurons, BDNF, GAP-43, and PSD-95 expression were enhanced by 24- and 48-h treatment with lithium after OGD. Conclusion Lithium upregulates BDNF, GAP-43, and PSD-95, which partly accounts for its improvement of neuroplasticity and provision of long-term neuroprotection in the ischemic brain. Abbreviations: BDNF: brain-derived neurotrophic factor; ECM: extracellular matrix; EDTA: ethylenediaminetetraacetic acid; GAP-43: growth-associated protein-43; GSK-3β: glycogen synthase kinase-3β; HBSS: Hank’s balanced salt solution; LCBF: local cortical blood perfusion; LDF: laser-Doppler flowmetry; MCAO: middle cerebral artery occlusion; MMP: matrix metalloproteinase; NMDA: N-methyl-D-aspartate; NMDAR: N-methyl-D-aspartate receptor; OCT: optimal cutting temperature compound; OGD: oxygen-glucose deprivation; PSD-95: postsynaptic density-95; SDS: sodium dodecyl sulfate; SNAP-25: synaptosomal-associated protein-25; SSEP: somatosensory evoked potential

Early-life factors associated with neurobehavioral outcomes in preterm infants during NICU hospitalization.

The aim of this study was to investigate the influence of early-life pain/stress and medical characteristics on neurobehavioral outcomes in preterm infants. A prospective cohort study was conducted with 92 preterm infants (28-32 weeks gestational age [GA]). Early-life pain/stress was measured via the Neonatal Infant Stressor Scale (NISS) during the first 28 days of NICU hospitalization. Neurobehavioral outcomes were evaluated using the NICU Network Neurobehavioral Scale at 36-38 weeks post-menstrual age. Functional regression and machine learning models were performed to investigate the predictors of neurobehavioral outcomes. Infants experienced daily acute pain/stress (24.99 ± 7.13 frequencies) and chronic events (41.13 ± 17.81 h). Up to 12 days after birth, both higher acute and chronic NISS scores were associated with higher stress scores; and higher chronic NISS scores were also related to lower self-regulation and quality of movement. Younger GA predicted worse neurobehavioral outcomes; GA < 31.57 weeks predicted worse stress/abstinence, self-regulation, and excitability; GA < 30.57 weeks predicted poor quality of movement. A higher proportion of maternal breastmilk intake predicted better self-regulation, excitability, and quality of movement in older GA infants. Preterm infants are vulnerable to the impact of early-life pain/stress. Neurobehavioral outcomes are positively associated with increased GA and higher maternal breastmilk intake. During the first 12 days of life, preterm infant neurobehavioral outcomes were vulnerable to the negative impact of acute and chronic pain/stress. Future research is warranted to investigate the long-term effects of early-life pain/stress on neurobehavioral outcomes. Gestational age remains one of the critical factors to predict neurobehavioral outcomes in preterm infants; older gestational age significantly predicted better neurobehavioral outcomes. Feeding with a higher proportion of maternal breastmilk predicted better neurobehavioral outcomes. Future research is warranted to investigate how maternal breastmilk may buffer the negative effects of early-life pain/stress on neurobehavioral outcomes.