Changes In Brain Development Research Articles

Developmental and Behavioral Phenotypes in a Mouse Model of DDX3X Syndrome

BackgroundMutations in the X-linked gene DDX3X account for approximately 2% of intellectual disability in females, often comorbid with behavioral problems, motor deficits, and brain malformations. DDX3X encodes an RNA helicase with emerging functions in corticogenesis and synaptogenesis. MethodsWe generated a Ddx3x haploinsufficient mouse (Ddx3x+/− females) with construct validity for DDX3X loss-of-function mutations. We used standardized batteries to assess developmental milestones and adult behaviors, as well as magnetic resonance imaging and immunostaining of cortical projection neurons to capture early postnatal changes in brain development. ResultsDdx3x+/− females showed physical, sensory, and motor delays that evolved into behavioral anomalies in adulthood, including hyperactivity, anxiety-like behaviors, cognitive impairments in specific tasks (e.g., contextual fear memory but not novel object recognition memory), and motor deficits. Motor function declined with age but not if mice were previously exposed to behavioral training. Developmental and behavioral changes were associated with a reduction in brain volume, with some regions (e.g., cortex and amygdala) disproportionally affected. Cortical thinning was accompanied by defective cortical lamination, indicating that Ddx3x regulates the balance of glutamatergic neurons in the developing cortex. ConclusionsThese data shed new light on the developmental mechanisms driving DDX3X syndrome and support construct and face validity of this novel preclinical mouse model.

ADHD: Reviewing the Causes and Evaluating Solutions.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder in which patients present inattention, hyperactivity, and impulsivity. The etiology of this condition is diverse, including environmental factors and the presence of variants of some genes. However, a great diversity exists among patients regarding the presence of these ADHD-associated factors. Moreover, there are variations in the reported neurophysiological correlates of ADHD. ADHD is often treated pharmacologically, producing an improvement in symptomatology, albeit there are patients who are refractory to the main pharmacological treatments or present side effects to these drugs, highlighting the importance of developing other therapeutic options. Different non-pharmacological treatments are in this review addressed, finding diverse results regarding efficacy. Altogether, ADHD is associated with different etiologies, all of them producing changes in brain development, leading to the characteristic symptomatology of this condition. Given the heterogeneous etiology of ADHD, discussion is presented about the convenience of personalizing ADHD treatment, whether pharmacological or non-pharmacological, to reach an optimum effect in the majority of patients. Approaches to personalizing both pharmacological therapy and neurofeedback are presented.

Maternal use of hormonal contraception and epilepsy in offspring.

Is maternal use of hormonal contraception associated with the development of epilepsy in the offspring? We found that maternal use of hormonal contraception was associated with a slightly increased risk of epilepsy in the offspring. Foetal exposure to exogenous hormones has been associated with changes in brain development. However, little is known about maternal hormonal contraception use and development of epilepsy in the offspring. A nationwide cohort of all live born children born in Denmark between 1 January 1998 and 31 December 2014, was followed from day 29 after birth for epilepsy (first diagnosis of epilepsy or first redeemed prescription for anti-epileptic medication) to censoring (emigration, death) or 31 December 2015, whichever occurred first. Diagnoses of epilepsy were obtained from the National Patient Registry. The Danish National Prescription Registry supplied information on redeemed prescriptions for hormonal contraception and anti-epileptic medication. Maternal hormonal contraception use was categorized as never use (reference group), previous use (prescriptions redeemed >3 months before pregnancy start) and recent use (prescriptions redeemed ≤3 months before or during pregnancy). The data show that 17 585 children developed epilepsy during a median follow-up of 9.2 years (9 732 635 person-years). The hazard ratio (HR) for epilepsy was 1.07 (95% CI 1.02-1.13) in children of mothers who had used any type of hormonal contraception recently, compared with children of mothers who had not used hormonal contraception. The HR was similar for recent use of oral combined products, while the HRs for recent or previous use of non-oral combined products were 1.32 (95% CI 0.98-1.77) and 1.16 (95% CI 1.02-1.32), respectively. For non-oral progestin-only products, the HRs were 1.19 (95% CI 1.04-1.38) and 1.53 (95% CI 1.31-1.80), respectively, for recent and previous use. There may be some misclassification of maternal hormonal contraception use, as some women may not have used the redeemed prescriptions or used them at a different point in time; potentially leading to an attenuation of the estimates. In addition, although we were able to account for known risk factors for epilepsy, unknown or residual confounding cannot be ruled out. Our findings are based on nationwide population-based data and can therefore be applied to other similar populations. However, as this is the first study in this field, further studies are needed to confirm our findings. No specific funding was obtained for this study, which was supported by internal funding at the Unit of Virus, Lifestyle and Genes. All authors report no conflicts of interest. N/A.

The Gut-Brain Axis in Autism Spectrum Disorder: A Focus on the Metalloproteases ADAM10 and ADAM17.

Autism Spectrum Disorder (ASD) is a spectrum of disorders that are characterized by problems in social interaction and repetitive behavior. The disease is thought to develop from changes in brain development at an early age, although the exact mechanisms are not known yet. In addition, a significant number of people with ASD develop problems in the intestinal tract. A Disintegrin And Metalloproteases (ADAMs) include a group of enzymes that are able to cleave membrane-bound proteins. ADAM10 and ADAM17 are two members of this family that are able to cleave protein substrates involved in ASD pathogenesis, such as specific proteins important for synapse formation, axon signaling and neuroinflammation. All these pathological mechanisms are involved in ASD. Besides the brain, ADAM10 and ADAM17 are also highly expressed in the intestines. ADAM10 and ADAM17 have implications in pathways that regulate gut permeability, homeostasis and inflammation. These metalloproteases might be involved in microbiota-gut–brain axis interactions in ASD through the regulation of immune and inflammatory responses in the intestinal tract. In this review, the potential roles of ADAM10 and ADAM17 in the pathology of ASD and as targets for new therapies will be discussed, with a focus on the gut–brain axis.

Association of Poor Family Functioning From Pregnancy Onward With Preadolescent Behavior and Subcortical Brain Development

The association of poor family functioning, a potent stressor, with child behavior is potentially long term and relevant for a person's well-being later in life. Whether changes in brain development underlie the associations with preadolescent behavior and help identify periods of vulnerability is unclear. To assess the associations of poor family functioning from pregnancy onward with cortical, white matter, and subcortical volumes, and to examine the extent to which, in particular, hippocampal volume mediates the association of prenatal parental environmental exposures with child problem behavior in preadolescence. This population-based cohort study, conducted from April 2002 to January 2006, was embedded in Generation R, a multiethnic population-based cohort from fetal life onward. All pregnant women living in Rotterdam, the Netherlands, with an expected delivery date between April 2002 and January 2006 were invited to participate. Of the 8879 pregnant women enrolled during pregnancy, 1266 mothers with no partner data and 490 with missing family functioning data were excluded, as well as 1 sibling of 32 twin pairs. After excluding an additional 657 children with poor imaging data quality or incidental findings, the final sample consisted of 2583 mother-child pairs. Data analysis was performed from March 1, 2019, to June 28, 2019. Mother- and father-rated poor family functioning was repeatedly measured by the General Functioning subscale of the Family Assessment Device. Our primary hypothesis, formulated after data collection but before analysis, was that poor prenatal family functioning would be associated with smaller hippocampal and amygdala volumes in late childhood. High-resolution structural neuroimaging data of children aged 10 years were collected with a single 3-T magnetic resonance imaging system. Child emotional and behavioral problems were assessed with the Child Behavior Checklist. Data were available for 2583 children (mean [SD] age, 10.1 [0.6] years; 1315 girls [50.9%]). Data for parents included 2583 mothers (mean [SD] age, 31.1 [4.7] years; 1617 Dutch race/ethnicity [62.6%]) and 1788 fathers (mean [SD] age, 33.5 [5.3] years; 1239 Dutch race/ethnicity [69.3%]). Children exposed to prenatal maternal-reported poor family functioning had smaller hippocampal (B = -0.08; 95% CI, -0.13 to -0.02) and occipital lobe (B = -0.70; 95% CI, -1.19 to -0.21) volumes in preadolescence. There was no evidence for an association of exposure to poor family functioning at mid- or late childhood with brain morphology. Hippocampal volumes partially mediated the association of prenatal maternal-reported poor family functioning with preadolescent problem behavior (B = 0.08; 95% CI, 0.03-0.13), even after adjusting for prior child problems at age 1.5 years. Analyses of combined maternal and paternal family functioning ratings showed similar results, but associations were largely driven by maternal family functioning reports. In this population-based cohort study, prenatal maternal-reported poor family functioning was associated with a smaller hippocampus in preadolescents. This difference in brain structure may underlie behavioral problems and is a possible neurodevelopmental manifestation of the long-term consequences of poor family functioning for the child.

Lessons From Zika and Other Virus Induced Skull Deformity

Objective: Viral infections during pregnancy can cause disturbance in normal craniofacial morphogenesis. While some pathogens such as cytomegalovirus and herpes simplex are familiar to us, others remain obscure. This review examines the arbovirus-induced cranial deformities and combines biomechanics with growth dynamics to gain a deeper appreciation of this complex morphogenetic process. Materials and Methods: Using Wolfram Alpha, we analyzed the impact of cell population changes. The growth dynamics of the brain, and thus the size of the calvarium, followed 2 potential logistic curves: compensated and uncompensated. To understand the potential mechanism of cell loss, we performed literature review on maternal immune activation and viral tropism for neurons and glial cells. Results: With arboviral infections such as Zika, uncompensated loss of cells during the critical phases of fetal brain development reduces the intracranial mass and therefore decreases the tensile stress across the cranial sutures. The deflationary effect produces microcephaly by subduction and reduced osteogenesis seen clinically in these infants. Conclusion: Many viral infections cause intense maternal immune activation, some have neurotropism and can result in cell loss within the developing cranium. Unable to overcome this loss, the cranium assumes a new, abnormal shape and volume. Secondary calvarial deformities is due to, and should not cause, changes in brain development.

Perinatal fluoxetine exposure disrupts the circadian response to a phase-shifting challenge in female rats

RationaleSelective serotonin reuptake inhibitor (SSRI) antidepressants are increasingly prescribed during pregnancy. Changes in serotonergic signaling during human fetal development have been associated with changes in brain development and with changes in affective behavior in adulthood. The suprachiasmatic nucleus (SCN) is known to be modulated by serotonin and it is therefore assumed that SSRIs may affect circadian rhythms. However, effects of perinatal SSRI treatment on circadian system functioning in the offspring are largely unknown.ObjectiveOur aim was to investigate the effects of perinatal exposure to the SSRI fluoxetine (FLX) on circadian behavior, affective behavior, and 5-HT1A receptor sensitivity in female rats. In addition, we studied the expression of clock genes and the 5-HT1A receptor in the SCN, as they are potentially involved in underlying mechanisms contributing to changes in circadian rhythms.ResultsPerinatal FLX exposure shortened the free-running tau in response to the 5-HT1A/7 agonist 8-OH-DPAT. However, FLX exposure did not alter anxiety, stress coping, and 5-HT1A receptor sensitivity. No differences were found in 5-HT1A receptor and clock genes Per1, Per2, Cry1, and Cry2 SCN gene expression.ConclusionsPerinatal FLX exposure altered the response to a phase-shifting challenge in female rats, whether this may pose health risks remains to be investigated.

0334 Hippocampal Development, Slow Wave Activity, and Nap-Dependent Memory Consolidation in Early Childhood

Abstract Introduction Naps support memory consolidation in early childhood. In adults, nap-dependent declarative consolidation is associated with SWA. SWA increases from early childhood into adulthood, and the shift of SWA from occipital to frontal distribution (F/O-ratio) is a marker of brain maturation. Thus, we explored how electrophysiological and structural characteristics of brain development relate to nap-dependent declarative learning in early childhood. Methods Twelve preschool-age children (8 female, M=48 months, SD=0.44) have completed three sessions (~1wk apart) within a larger study. In the first two sessions, children completed a visuo-spatial task before and after a 2-hr nap or wake interval. During the third visit, children underwent MRI assessment. Using PSG, SWA was measured in the delta band over frontal and occipital regions for nREM2 and nREM3 sleep. Results While F/O-ratio of SWA does not currently predict the F/O-ratio of cortical thickness (r(12)=.383, p=.219), right parahippocampal thickness positively correlates with F/O-ratio of SWA in nREM2 (r(12)=.591, p=.043). Nonetheless, children’s performance change following the nap was not associated with either parahippocampal thickness or F/O-ratio of SWA in any sleep stage (all ps>.538). However, performance in children who showed a post-nap benefit (n=5) positively correlated with right parahippocampal thickness (r(5)=.915, p=.029). This was not the case for children who did not show a post-nap benefit (r(7)=-.199, p=.668). Conclusion Although the F/O-ratio of SWA did not predict a similar ratio of cortical thickness, the association between right parahippocampal thickness and F/O-ratio of SWA is evidence that development of SWA parallels cortical development. While there is no overall association between post-nap performance and brain development characteristics, the relation between performance and right parahippocampal thickness in children showing a nap benefit suggests that memory during this age may depend on structural (rather than electrophysiological) brain development changes. Support NIH R21 HD094758 & NSF BCS 1749280

Painful procedures experienced by preterm newborns and evidence-based non-pharmacological methods

Preterm newborns are defined as babies born alive before 37 weeks of pregnancy are completed. Prolonged or frequent pain in the early stages of life can prevent the baby’s behaviour, feeding patterns, adaptation to the outside world, as well as changes in brain development and adversely affect growth. Preterm newborns are known to be more sensitive to pain due to immature pain mechanisms. Therefore, preterm newborns need more support during painful procedures. The aim of this review is to provide information about the painful procedures encountered by preterm newborns in neonatal intensive care units and the evidence-based non-pharmacological methods for these painful procedures. This study used English–Turkish language articles and a search was conducted in PubMed, Scopus, Cochrane and Google Scholar, using a combination of key words like ‘painful procedures’, ‘preterm newborn’, ‘non-pharmacological methods’ and ‘pain and newborn’. These terms are frequently used in non-pharmacological methods as well as pharmacological methods in pain relief. Non-pharmacologic methods used in pain management in preterm neonates are massage, kangaroo care, music, oral sucrose, pacifier, aromatherapy, swaddling, facilitated tucking, prone position, mother’s touch, mother’s voice and smell and breastfeeding method. Facilitated tucking, kangaroo care, swaddling, breast milk and oral sucrose are effective in heel blood collection and venous blood collection in newborns. It has been reported in the literature that the smell of glucose, breast milk, vanilla and lavender reduces pain. It is stated in the literature that breast milk, sucrose and kangaroo care used during the retinopathy of premature retinopathy reduces pain during and after the procedure. The aim of newborn pain management is to help reduce pain and help the baby cope with pain. Therefore, further research on evidence-based non-pharmacological methods is essential, and it is essential for all health professionals to be aware, know and practice non-pharmacological methods.
 
 Keywords: Newborn; pain; non-pharmacological methods; preterm;

The effect of facilitated tucking position during painful procedure in pain management of preterm infants in neonatal intensive care unit: a systematic review and meta-analysis.

We performed a systematic review and meta-analysis to investigate the effects of facilitated tucking position during painful procedure in pain management of preterm infants. We searched MEDLINE, PEDro, SciELO and the Cochrane Library (until June 2019) for randomized controlled trials. An α value ≤ 0.05 was considered significant. Heterogeneity among studies was examined with Cochran's Q and I2 statistic, in which values greater than 40% were considered indicative of high heterogeneity and random-effects model was chosen. Analyses were performed with Review Manager 5.3. Fifteen studies met the eligibility criteria, including 664 preterm infants. The meta-analyses showed a significant reduction in pain of - 1.02 (95% CI - 1.7 to - 0.4, N = 216) during endotraqueal suctioning for participants in the facilitated tucking position group (FTPG) compared with routine care group. The meta-analyses showed a non-significant difference in pain - 0.3 (95% CI - 2.05 to - 1.4, N = 88) during heel stick for participants in the FTPG compared with oral glucose group. The meta-analyses showed a non-significant difference in pain for participants in the FTPG compared with oral opioid group 0.2 (95% CI - 1.4 to 1.8, N = 140).Conclusion: Facilitated tucking position may improve the pain during painful procedures.What is Known:• Exposure of premature babies to painful procedures is associated with changes in brain development, regardless of other factors.• Facilitated tucking reduces the expression of pain in premature infants.What is New:• Facilitated tucking position was efficient in pain management of preterm infants when compared to routine care.• Facilitated tucking compared to opioid or oral glucose did not achieve a significant reduction in pain intensity.

Adolescent microglia play a role in executive function in male mice exposed to perinatal high fat diet

In humans, excessive gestational weight gain during pregnancy is associated with an increased risk for executive function deficits in the offspring. Our previous work has confirmed this finding in mice, as offspring from dams fed a 60% high fat (HF) diet during breeding, gestation, and lactation demonstrate impulsive-like behavior in the 5 choice serial reaction time task (5CSRTT). Because the prefrontal cortex (PFC), which plays a key role in executive function, undergoes substantial postnatal adolescent pruning and microglia are actively involved in synaptic refinement, we hypothesized that microglia may play a role in mediating changes in brain development after maternal HF diet, with a specific focus on microglial activity during adolescence. Therefore, we treated male and female offspring from HF or control diet (CD) dams with PLX3397-formulated diet (PLX) to ablate microglia during postnatal days 23–45. After PLX removal and microglial repopulation, adult mice underwent testing to evaluate executive function. Adolescent PLX treatment did increase the control male dropout rate in learning the basic FR1 task, but otherwise had a minimal effect on behavior in control offspring. In males, HF offspring learned faster and performed better on a simple operant task (fixed ratio 1) without an effect of PLX. However, in HF offspring this increase in FR1 responding was associated with more impulsive errors in the 5CSRTT while PLX eliminated this association and decreased impulsive errors specifically in HF offspring. This suggests that adolescent PLX treatment improves executive function and particularly impulsive behavior in adult male HF offspring, without an overall effect of perinatal diet. In females, maternal HF diet impaired reversal learning but PLX had no effect on performance. We then measured gene expression in adult male PFC, nucleus accumbens (NAC), and amygdala (AMG), examining targets related to synaptic function, reward, and inflammation. Maternal HF diet increased PFC synaptophysin and AMG psd95 expression. PFC synaptophysin expression was correlated with more impulsive errors in the 5CSRTT in the HF offspring only and PLX treatment eliminated this correlation. These data suggest that adolescent microglia may play a critical role in mediating executive function after perinatal high fat diet in males.

16.2 STRUCTURAL BRAIN DEVELOPMENT IN THE FIRST 2 YEARS IN ASD

Longitudinal, prospective imaging studies of infants at high risk for ASD reveal disorder-specific and age-specific effects that emerge during the first few years of life. These changes in brain development have important implications for understanding the underlying brain mechanisms that will have implications for clinical practice in the near future.

Global and Regional Changes in Cortical Development Assessed by MRI in Fetuses with Isolated Nonsevere Ventriculomegaly Correlate with Neonatal Neurobehavior.

Fetuses with isolated nonsevere ventriculomegaly (INSVM) are at risk of presenting neurodevelopmental delay. However, the currently used clinical parameters are insufficient to select cases with high risk and determine whether subtle changes in brain development are present and might be a risk factor. The aim of this study was to perform a comprehensive evaluation of cortical development in INSVM by magnetic resonance (MR) imaging and assess its association with neonatal neurobehavior. Thirty-two INSVM fetuses and 29 healthy controls between 26-28 weeks of gestation were evaluated using MR imaging. We compared sulci and fissure depth, cortical maturation grading of specific areas and sulci and volumes of different brain regions obtained from 3D brain reconstruction of cases and controls. Neonatal outcome was assessed by using the Neonatal Behavioral Assessment Scale at a mean of 4 ± 2 weeks after birth. Fetuses with INSVM showed less profound and underdeveloped sulcation, including the Sylvian fissure (mean depth: controls 16.8 ± 1.9 mm, versus INSVM 16.0 ± 1.6 mm; P = .01), and reduced global cortical grading (mean score: controls 42.9 ± 10.2 mm, versus INSVM: 37.8 ± 9.9 mm; P = .01). Fetuses with isolated nonsevere ventriculomegaly showed a mean global increase of gray matter volume (controls, 276.8 ± 46.0 ×10 mm3, versus INSVM 277.5 ± 49.3 ×10 mm3, P = .01), but decreased mean cortical volume in the frontal lobe (left: controls, 53.2 ± 8.8 ×10 mm3, versus INSVM 52.4 ± 5.4 ×10 mm3; P = < .01). Sulcal depth and brain volumes were significantly associated with the Neonatal Behavioral Assessment Scale severity (P = .005, Nagelkerke R2 = 0.732). INSVM fetuses showed differences in cortical development, including regions far from the lateral ventricles, that are associated with neonatal neurobehavior. These results suggest the possible use of these parameters to identify cases at higher risk of altered neurodevelopment.

Developing a brain atlas through deep learning

Neuroscientists have devoted significant effort into the creation of standard brain reference atlases for high-throughput registration of anatomical regions of interest. However, variability in brain size and form across individuals poses a significant challenge for such reference atlases. To overcome these limitations, we introduce a fully automated deep neural network-based method (SeBRe) for registration through Segmenting Brain Regions of interest with minimal human supervision. We demonstrate the validity of our method on brain images from different mouse developmental time points, across a range of neuronal markers and imaging modalities. We further assess the performance of our method on images from MR-scanned human brains. Our registration method can accelerate brain-wide exploration of region-specific changes in brain development and, by simply segmenting brain regions of interest for high-throughput brain-wide analysis, provides an alternative to existing complex brain registration techniques.

System-level matching of structural and functional connectomes in the human brain

The brain can be considered as an information processing network, where complex behavior manifests as a result of communication between large-scale functional systems such as visual and default mode networks. As the communication between brain regions occurs through underlying anatomical pathways, it is important to define a “traffic pattern” that properly describes how the regions exchange information. Empirically, the choice of the traffic pattern can be made based on how well the functional connectivity between regions matches the structural pathways equipped with that traffic pattern. In this paper, we present a multimodal connectomics paradigm utilizing graph matching to measure similarity between structural and functional connectomes (derived from dMRI and fMRI data) at node, system, and connectome level. Through an investigation of the brain's structure-function relationship over a large cohort of 641 healthy developmental participants aged 8–22 years, we demonstrate that communicability as the traffic pattern describes the functional connectivity of the brain best, with large-scale systems having significant agreement between their structural and functional connectivity patterns. Notably, matching between structural and functional connectivity for the functionally specialized modular systems such as visual and motor networks are higher as compared to other more integrated systems. Additionally, we show that the negative functional connectivity between the default mode network (DMN) and motor, frontoparietal, attention, and visual networks is significantly associated with its underlying structural connectivity, highlighting the counterbalance between functional activation patterns of DMN and other systems. Finally, we investigated sex difference and developmental changes in brain and observed that similarity between structure and function changes with development.

Compulsivity and impulsivity traits linked to attenuated developmental frontostriatal myelination trajectories.

The transition from adolescence into adulthood is a period when ongoing brain development coincides with a substantially increased risk of psychiatric disorders. The developmental brain changes accounting for this emergent psychiatric symptomatology remain obscure. Capitalising on a unique longitudinal dataset that includes in-vivo myelin-sensitive magnetization transfer (MT) MRI, we show that this developmental period is characterised by brain-wide growth in MT, within both gray matter and adjacent juxta-cortical white matter. In this healthy population the expression of common developmental traits, namely compulsivity and impulsivity, is tied to a reduced growth of these MT trajectories in fronto-striatal regions. This reduction is most marked in dorsomedial and dorsolateral prefrontal regions for compulsivity, and in lateral and medial prefrontal regions for impulsivity. The findings highlight that psychiatric traits of compulsivity and impulsivity are linked to regionally specific reduction in myelin-related growth in late adolescent brain development.

Management of Self-injurious Behaviors in Children with Neurodevelopmental Disorders: A Pharmacotherapy Overview.

Neurodevelopmental disorders (NDDs), a group of disorders affecting ~1-2% of the general population, are caused by changes in brain development that result in behavioral and cognitive alterations, sensory and motor changes, and speech and language deficits. Neurodevelopmental disorders encompass a heterogeneous group of disorders including, but not limited to, Smith-Magenis syndrome, Lesch-Nyhan disease, cri du chat syndrome, Prader-Willi syndrome, pervasive developmental disorders, fragile X syndrome, Rett syndrome, Cornelia de Lange syndrome, and Down syndrome. Self-injurious behaviors (SIBs) are common in children with NDDs; depending on the specific NDD, the incidence of SIBs is nearly 100%. The management of SIBs in this population is complex, and little high-quality data exist to guide a consistent approach to therapy. However, managing SIBs is of the utmost importance for the child as well as the family and caregivers. Behavior therapies must be implemented as first-line therapy. If behavioral interventions alone fail, pharmacotherapy becomes an essential part of management plans. The limited available evidence for the use of common pharmacologic agents, such as second-generation antipsychotics, and less common agents, such as clonidine, n-acetylcysteine, riluzole, naltrexone, and topical anesthetics, is reviewed. Additional data from well-designed studies in children with NDDs are needed to gain a better understanding of this common and troublesome problem including efficacy and safety implications associated with pharmacotherapy. Until then, clinicians must rely on the limited available data, clinical expertise, and ongoing systematic monitoring when managing SIBs in children with NDDs.

A preliminary study on prenatal polybrominated diphenyl ether serum concentrations and intrinsic functional network organization and executive functioning in childhood.

The prenatal period is a period of vulnerability during which neurotoxic exposures exert persistent changes in brain development and behavior. Polybrominated diphenyl ethers (PBDEs), used as flame retardants in commercial products, are known to be developmental neurotoxicants. PBDEs were phased out of use in the United States a decade ago, but exposure remains widespread due to their release from existing products and biopersistence. Despite consistent animal and epidemiological evidence of developmental neurotoxicity, the neural substrates linking prenatal PBDE serum concentrations to impaired neurodevelopment are poorly understood. In the present study, we used resting state functional magnetic resonance imaging (fMRI) to examine associations between prenatal PBDE concentrations measured in maternal serum and intrinsic functional network organization (i.e., global and local efficiency; estimated using agraph-theoretical approach) in 5-year-old children (n=34). We explored whether PBDE serum concentrations were associated with executive functioning (EF) assessed using a parent-report questionnaire (BRIEF-P) (n=106) and whether changes in intrinsic functional network organization linked the association between prenatal PBDE serum concentrations and EF problems. Children with higher prenatal PBDE serum concentrations showed: (a) increased global efficiency of brain areas involved in visual attention (e.g., inferior occipital gyrus) (β's=.01, FDR-corrected p's≤.05); (b) more reported EF problems (β's=.001, FDR-corrected p's≤.05). Higher global efficiency of brain areas involved in visual attention was associated with more EF problems (β's=.01, FDR-corrected p's<.05). Intrinsic functional network organization of visual attention brain areas linked prenatal PBDE concentrations to EF problems in childhood. Visual attention may contribute to the development of higher-order cognitive functions, such as EF, which could be explored in future studies.

Fetal brain development at 25-39 weeks gestational age: A preliminary study using intravoxel incoherent motion diffusion-weighted imaging.

The fetal brain developmental changes of water diffusivity and perfusion has not been extensively explored. To evaluate the fetal brain developmental changes of water diffusivity and perfusion using intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI). Prospective. Seventy-nine normal singleton fetuses were scanned without sedation of healthy pregnant women. 5 T MRI/T1 /2 -weighted image and IVIM-DWI. Pure diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) values were calculated in the frontal (FWM), temporal (TWM), parietal (PWM), and occipital white matter (OWM) as well as cerebellar hemisphere (CH), basal ganglia region (BGR), thalamus (TH), and pons using an IVIM model. One-way analysis of variable (ANOVA) followed by Bonferroni post-hoc multiple comparison was employed to reveal the difference of IVIM parameters among the investigated brain regions. The linear and the nonlinear polynomial regression analyses were utilized to reveal the correlation between gestational age (GA) and IVIM parameters. There were significant differences in both D (F(7,623) = 96.64, P = 0.000) and f values (F(7,623) = 2.361, P = 0.0219), but not D* values among the varied brain regions. D values from TWM (r2 = 0.1402, P = 0.0002), PWM (r2 = 0.2245, P = 0.0002), OWM (r2 = 0.2519, P = 0.0002), CH (r2 = 0.2245, P = 0.0002), BGR (r2 = 0.3393, P = 0.0001), TH (r2 = 0.1259, P = 0.0001), and D* value from pons (r2 = 0.2206, P = 0.0002) were significantly correlated with GA using linear regression analysis. Quadratic regression analysis led to results similar to those using the linear regression model. IVIM-DWI parameters may indicate fetal brain developmental alterations but the conclusion is far from reached due to the not as high-powered correlation between IVIM parameters and GA. 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;50:899-909.

Analysis of pain and free cortisol of newborns in intensive therapy with therapeutic procedures

ABSTRACT BACKGROUND AND OBJECTIVES: Newborns at high risk in the intensive care unit are exposed to painful, repetitive and prolonged procedures that may be related to changes in brain development and behavioral abnormalities. The objective of this study was to relate pain and free cortisol of premature newborns undergoing therapeutic procedures in intensive care units. METHODS: A quantitative, descriptive, cross-sectional study conducted with 32 premature newborns submitted to venipuncture, who were evaluated for pain and stress related to assisted ventilation; sedatives, prenatal corticoid, type of venipuncture, site, and the number of attempts. RESULTS: Preterm newborns undergoing invasive ventilation had a predominance of moderate pain in 12 (37.5%) and cortisol increase in 14 (43.8%) of them. Venipuncture triggered moderate and intense pain, 10 (31.3%), and in 17 (53.1) the cortisol levels increased. More than half was due to peripherally inserted central catheter placement, so that 10 (43.8) had moderate pain. The results of the research suggest that the exposure of newborns to invasive procedures is stressful, especially when repeated several times. CONCLUSION: Repeated venous puncture associated with therapeutic procedures intensified pain and altered cortisol, causing stress in premature newborns.