Mapping Early Brain-Body Interactions: Associations of Fetal Heart Rate Variation with Newborn Brainstem, Hypothalamic, and Dorsal Anterior Cingulate Cortex Functional Connectivity.

The autonomic nervous system (ANS) regulates the body's physiology, including cardiovascular function. As the ANS develops during the second to third trimester, fetal heart rate variability (HRV) increases while fetal heart rate (HR) decreases. In this way, fetal HR and HRV provide an index of fetal ANS development and future neurobehavioral regulation. Fetal HR and HRV have been associated with child language ability and psychomotor development behavior in toddlerhood. However, their associations with postbirth autonomic brain systems, such as the brainstem, hypothalamus, and dorsal anterior cingulate cortex (dACC), have yet to be investigated even though brain pathways involved in autonomic regulation are well established in older individuals. We assessed whether fetal HR and HRV were associated with the brainstem, hypothalamic, and dACC functional connectivity in newborns. Data were obtained from 60 pregnant individuals (ages 14-42) at 24-27 and 34-37 weeks of gestation using a fetal actocardiograph to generate fetal HR and HRV. During natural sleep, their infants (38 males and 22 females) underwent a fMRI scan between 40 and 46 weeks of postmenstrual age. Our findings relate fetal heart indices to brainstem, hypothalamic, and dACC connectivity and reveal connections with widespread brain regions that may support behavioral and emotional regulation. We demonstrated the basic physiologic association between fetal HR indices and lower- and higher-order brain regions involved in regulatory processes. This work provides the foundation for future behavioral or physiological regulation research in fetuses and infants.

A systematic review of MRI studies on the effects of maternal obesity on offspring brain structure and function.

Maternal obesity before or during pregnancy has been associated previously in offspring with a wide range of poor neurodevelopmental outcomes and mental health problems. The effects of maternal obesity on offspring brain structure and function that may be responsible for these poor outcomes are not well understood. We, therefore, undertook a systematic review of magnetic resonance imaging (MRI) studies that have assessed the associations of maternal obesity with brain measures in offspring. A systematic search was conducted in PubMed, Web of Science, Scopus, and PsycINFO on August 20, 2023. Of 15 eligible studies, seven employed functional MRI (fMRI), five diffusion tensor imaging (DTI), and four anatomical MRI (one used both DTI and anatomical MRI) in the offspring. The ages of offspring varied widely: one was a study of fetuses in utero, five of neonates, one of infants, five of school-aged children, two of both neonates and infants, and one of both children and adults. Collectively, 12 studies reported significant associations of maternal obesity with structural or functional alterations of the offspring's brain, most frequently in the prefrontal cortex and limbic system. In conclusion, maternal obesity appears to have a profound influence on offspring brain development, particularly within the prefrontal and limbic networks that regulate emotion and behavior. Further studies are needed to identify how changes in brain structure and function mediate the effects of maternal obesity on long-term emotional and behavioral outcomes, as well as the molecular pathways through which maternal obesity alters offspring brain development.

Maternal prenatal immune activation associated with brain tissue microstructure and metabolite concentrations in newborn infants.

Few human studies have assessed the association of prenatal maternal immune activation (MIA) with measures of brain development and psychiatric risk in newborn offspring. Our goal was to identify the effects of MIA during the 2nd and 3rd trimesters of pregnancy on newborn measures of brain metabolite concentrations, tissue microstructure, and motor development. This was a prospective longitudinal cohort study conducted with nulliparous pregnant women who were aged 14 to 19 years and recruited in their 2nd trimester, as well as their children who were followed through 14 months of age. MIA was indexed by maternal interleukin-6 (IL-6) and C-reactive protein (CRP) in both trimesters of pregnancy. Primary outcomes included: (1) newborn brain metabolite concentrations as ratios to creatine (N-acetylaspartate (NAA)/creatine (Cr) and choline (Cho)/Cr) measured using Magnetic Resonance Spectroscopy; (2) newborn fractional anisotropy and mean diffusivity, measured using Diffusion Tensor Imaging; and (3) indices of motor development, assessed prenatally and postnatally at ages 4- and 14-months. Maternal IL-6 and CRP levels associated significantly with both metabolites in the putamen, thalamus, insula, and the internal capsule. Maternal IL-6 associated significantly with fractional anisotropy in the putamen, caudate, thalamus, insula, and precuneus, and with mean diffusivity in the inferior parietal and middle temporal gyrus. CRP associated significantly with fractional anisotropy in the thalamus, insula, and putamen. Significant associations were found in common regions across imaging modalities, though the direction of associations differed by immune marker. In addition, both maternal IL-6 and CRP (in both trimesters) prenatally associated significantly with offspring motor development at 4- and 14-months of age. The left thalamus mediated effects of IL-6 on postnatal motor development. These findings demonstrate that levels of MIA in mid- to late pregnancy in a generally healthy sample associate with tissue characteristics in newborn brain regions that primarily support motor integration and coordination, as well as behavioral regulation. Those brain effects may contribute to differences in motor development.

Progression of brain injuries associated with methotrexate chemotherapy in childhood acute lymphoblastic leukemia.

BACKGROUND: Brain bases and progression of methotrexate-associated neurotoxicity and cognitive disturbances remain unknown. We tested whether brain abnormalities worsen in proportion to intrathecal methotrexate(IT-MTX) doses. METHODS: In this prospective, longitudinal study, we recruited 19 patients with newly diagnosed acute lymphoblastic leukemia 4-to-20 years of age and 20 matched controls. We collected MRI and neuropsychological assessments at a pre-methotrexate baseline and at week 9, week 22, and year 1 during treatment. RESULTS: Patients had baseline abnormalities in cortical and subcortical gray matter(GM), white matter(WM) volumes and microstructure, regional cerebral blood flow, and neuronal density. Abnormalities of GM, blood flow, and metabolites worsened in direct proportions to IT-MTX doses. WM abnormalities persisted until week 22 but normalized by year 1. Brain injuries were localized to dorsal and ventral attentional and frontoparietal cognitive networks. Patients had cognitive deficits at baseline that persisted at 1-year follow-up. CONCLUSIONS: Baseline abnormalities are likely a consequence of neuroinflammation and oxidative stress. Baseline abnormalities in WM microstructure and volumes, and blood flow persisted until week 22 but normalized by year 1, likely due to treatment and its effects on reducing inflammation. The cytotoxic effects of IT-MTX, however, likely contributed to continued, progressive cortical thinning and reductions in neuronal density, thereby contributing to enduring cognitive deficits. IMPACT: Brain abnormalities at a pre-methotrexate baseline likely are due to acute illness. The cytotoxic effects of intrathecal MTX contribute to progressive cortical thinning, reductions in neuronal density, and enduring cognitive deficits. Baseline white matter abnormalities may have normalized via methotrexate treatment and decreasing neuroinflammation. Corticosteroid and leucovorin conferred neuroprotective effects. Our findings suggest that the administration of neuroprotective and anti-inflammatory agents should be considered even earlier than they are currently administered. The neuroprotective effects of leucovorin suggest that strategies may be developed that extend the duration of this intervention or adapt it for use in standard risk patients.

Cerebrovascular responses to a 90° tilt in healthy neonates.

BACKGROUND: Tilts can induce alterations in cerebral hemodynamics in healthy neonates, but prior studies have only examined systemic parameters or used small tilt angles (<90°). The healthy neonatal population, however, are commonly subjected to large tilt angles (≥90°). We sought to characterize the cerebrovascular response to a 90° tilt in healthy term neonates. METHODS: We performed a secondary descriptive analysis on 44 healthy term neonates. We measured cerebral oxygen saturation (rcSO2), oxygen saturation (SpO2), heart rate (HR), breathing rate (BR), and cerebral fractional tissue oxygen extraction (cFTOE) over three consecutive 90° tilts. These parameters were measured for 2-min while neonates were in a supine (0°) position and 2-min while tilted to a sitting (90°) position. We measured oscillometric mean blood pressure (MBP) at the start of each tilt. RESULTS: rcSO2 and BR decreased significantly in the sitting position, whereas cFTOE, SpO2, and MBP increased significantly in the sitting position. We detected a significant position-by-time interaction for all physiological parameters. CONCLUSION: A 90° tilt induces a decline in rcSO2 and an increase in cFTOE in healthy term neonates. Understanding the normal cerebrovascular response to a 90° tilt in healthy neonates will help clinicians to recognize abnormal responses in high-risk infant populations. IMPACT: Healthy term neonates (≤14 days old) had decreased cerebral oxygen saturation (~1.1%) and increased cerebral oxygen extraction (~0.01) following a 90° tilt. We detected a significant position-by-time interaction with all physiological parameters measured, suggesting the effect of position varied across consecutive tilts. No prior study has characterized the cerebral oxygen saturation response to a 90° tilt in healthy term neonates.

Advancing the treatment of anxiety disorders in transition-age youth: a review of the therapeutic effects of unconscious exposure.

BACKGROUND: The real-world effectiveness of exposure-based therapies for youth depends on the willingness and ability of young people to tolerate confronting their fears, which can be experienced as highly aversive and create problems with treatment engagement and acceptance. Recently, neuroscientific research on the nonconscious basis of fear has been translated into novel exposure interventions that bypass conscious processing of feared stimuli and that thus do not cause phobic youth to experience distress. We present a review of these unconscious exposure interventions. METHODS: A PRISMA-based search yielded 20 controlled experiments based on three paradigms that tested if fear-related responses could be reduced without conscious awareness in highly phobic, transition-age youth: 14 randomized controlled trials (RCTs), 5 fMRI studies (1 was also an RCT), 4 psychophysiological studies (3 were also RCTs), and 1 ERP study. We conducted meta-analyses of outcomes where feasible. RESULTS: Unconscious exposure interventions significantly (1) reduced avoidance behavior (range of Cohen's d = 0.51-0.95) and self-reported fear (d = 0.45-1.25) during in vivo exposure to the feared situation; (2) reduced neurobiological indicators of fear (d = 0.54-0.62) and concomitant physiological arousal (d = 0.55-0.64); (3) activated neural systems supporting fear regulation more strongly than visible exposure to the same stimuli (d = 1.2-1.5); (4) activated regions supporting fear regulation that mediated the reduction of avoidance behavior (d = 0.70); (5) evoked ERPs suggesting encoding of extinction memories (d = 2.13); and (6) had these effects without inducing autonomic arousal or subjective fear. CONCLUSIONS: Unconscious exposure interventions significantly reduce a variety of symptomatic behaviors with mostly moderate effect sizes in transition-age youth with specific phobias. fMRI and physiological findings establish a neurophysiological basis for this efficacy, and suggest it occurs through extinction learning. Unconscious exposure was well tolerated, entirely unassociated with drop out, and is highly scalable for clinical practice. However, a number of limitations must be addressed to assess potential clinical impacts, including combining unconscious exposure with exposure therapy to boost treatment acceptance and efficacy.

A Scoping Review of the Mechanisms Underlying Developmental Anesthetic Neurotoxicity.

Although anesthesia makes painful or uncomfortable diagnostic and interventional health care procedures tolerable, it may also disrupt key cellular processes in neurons and glia, harm the developing brain, and thereby impair cognition and behavior in children. Many years of studies using in vitro, animal behavioral, retrospective database studies in humans, and several prospective clinical trials in humans have been invaluable in discerning the potential toxicity of anesthetics. The objective of this scoping review was to synthetize the evidence from preclinical studies for various mechanisms of toxicity across diverse experimental designs and relate their findings to those of recent clinical trials in real-world settings.

"All we have to fear is fear itself": Paradigms for reducing fear by preventing awareness of it.

Research on unconscious fear responses has recently been translated into experimental paradigms for reducing fear that bypass conscious awareness of the phobic stimulus and thus do not induce distress. These paradigms stand in contrast to exposure therapies for anxiety disorders, which require direct confrontation of feared situations and thus are distressing. We systematically review these unconscious exposure paradigms. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-based search yielded 39 controlled experiments based on 10 paradigms that tested whether exposure without awareness can reduce fear-related responses. In randomized controlled trials of phobic participants, unconscious exposure interventions: (a) reduced behavioral avoidance (weighted mean d = 0.77, N = 469) and self-reported fear (d = 0.78, N = 329) during in vivo exposure to feared situations; (b) reduced neurobiological indicators of fear and enhanced such indicators of fear regulation (d = 0.81, N = 205); (c) had significantly stronger effects on reducing symptomatic behaviors and enhancing neurobiological indicators of fear regulation than did conscious exposure (d = 0.78, N = 342); and (d) produced these effects without inducing subjective fear. In fear-conditioned participants, unconscious exposureinduced extinction learning (d = 0.80, N = 420), even during sleep, and yielded somewhat stronger extinction learning than conscious exposure did (d = 0.44, N = 438). We organize these findings within a neuroscientific framework and evaluate alternative mechanisms for unconscious exposure. The use of incommensurate outcome measures across exposure paradigms and nonreporting of relevant statistics limited meta-analyses. Despite steps taken to address publication bias, 25.6% of included studies came from a single laboratory. We propose potential clinical applications of these findings. Future research should clarify underlying mechanisms, use common outcome measures, and explore effects on other anxiety disorders. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Craniofacial chondrogenesis in organoids from human stem cell-derived neural crest cells.

Knowledge of cell signaling pathways that drive human neural crest differentiation into craniofacial chondrocytes is incomplete, yet essential for using stem cells to regenerate craniomaxillofacial structures. To accelerate translational progress, we developed a differentiation protocol that generated self-organizing craniofacial cartilage organoids from human embryonic stem cell-derived neural crest stem cells. Histological staining of cartilage organoids revealed tissue architecture and staining typical of elastic cartilage. Protein and post-translational modification (PTM) mass spectrometry and snRNA-seq data showed that chondrocyte organoids expressed robust levels of cartilage extracellular matrix (ECM) components: many collagens, aggrecan, perlecan, proteoglycans, and elastic fibers. We identified two populations of chondroprogenitor cells, mesenchyme cells and nascent chondrocytes, and the growth factors involved in paracrine signaling between them. We show that ECM components secreted by chondrocytes not only create a structurally resilient matrix that defines cartilage, but also play a pivotal autocrine cell signaling role in determining chondrocyte fate.

Treatments for ADHD in Children and Adolescents: A Systematic Review.

CONTEXT: Effective treatment of attention-deficit/hyperactivity disorder (ADHD) is essential to improving youth outcomes. OBJECTIVES: This systematic review provides an overview of the available treatment options. DATA SOURCES: We identified controlled treatment evaluations in 12 databases published from 1980 to June 2023; treatments were not restricted by intervention content. STUDY SELECTION: Studies in children and adolescents with clinically diagnosed ADHD, reporting patient health and psychosocial outcomes, were eligible. Publications were screened by trained reviewers, supported by machine learning. DATA EXTRACTION: Data were abstracted and critically appraised by 1 reviewer and checked by a methodologist. Data were pooled using random-effects models. Strength of evidence and applicability assessments followed Evidence-based Practice Center standards. RESULTS: In total, 312 studies reported in 540 publications were included. We grouped evidence for medication, psychosocial interventions, parent support, nutrition and supplements, neurofeedback, neurostimulation, physical exercise, complementary medicine, school interventions, and provider approaches. Several treatments improved ADHD symptoms. Medications had the strongest evidence base for improving outcomes, including disruptive behaviors and broadband measures, but were associated with adverse events. LIMITATIONS: We found limited evidence of studies comparing alternative treatments directly and indirect analyses identified few systematic differences across stimulants and nonstimulants. Identified combination of medication with youth-directed psychosocial interventions did not systematically produce better results than monotherapy, though few combinations have been evaluated. CONCLUSIONS: A growing number of treatments are available that improve ADHD symptoms and other outcomes, in particular for school-aged youth. Medication therapies remain important treatment options but are associated with adverse events.

Tools for the Diagnosis of ADHD in Children and Adolescents: A Systematic Review.

CONTEXT: Correct diagnosis is essential for the appropriate clinical management of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. OBJECTIVE: This systematic review provides an overview of the available diagnostic tools. DATA SOURCES: We identified diagnostic accuracy studies in 12 databases published from 1980 through June 2023. STUDY SELECTION: Any ADHD tool evaluation for the diagnosis of ADHD, requiring a reference standard of a clinical diagnosis by a mental health specialist. DATA EXTRACTION: Data were abstracted and critically appraised by 1 reviewer and checked by a methodologist. Strength of evidence and applicability assessments followed Evidence-based Practice Center standards. RESULTS: In total, 231 studies met eligibility criteria. Studies evaluated parental ratings, teacher ratings, youth self-reports, clinician tools, neuropsychological tests, biospecimen, EEG, and neuroimaging. Multiple tools showed promising diagnostic performance, but estimates varied considerably across studies, with a generally low strength of evidence. Performance depended on whether ADHD youth were being differentiated from neurotypically developing children or from clinically referred children. LIMITATIONS: Studies used different components of available tools and did not report sufficient data for meta-analytic models. CONCLUSIONS: A valid and reliable diagnosis of ADHD requires the judgment of a clinician who is experienced in the evaluation of youth with and without ADHD, along with the aid of standardized rating scales and input from multiple informants across multiple settings, including parents, teachers, and youth themselves.

Pre-pregnancy maternal obesity and infant neurodevelopmental outcomes in Latino infants.

OBJECTIVE: This study explores the impact of maternal pre-pregnancy BMI on infant neurodevelopment at 24 months in low-income Latino families. It also investigates whether infant diet mediates this relationship. METHODS: Latino mother-infant pairs (n = 163) were enrolled at 1 month post partum and were followed for 2 years, with assessments at 6-month intervals. Maternal pre-pregnancy anthropometrics were self-reported at baseline, and child neurodevelopment was assessed at 24 months using the Bayley Scales of Infant Development. Diet quality of infants was measured using the Healthy Eating Index (HEI)-2015 and HEI-Toddlers-2020 scores at multiple time points. Mediation and regression models that adjust for maternal factors were used to examine the associations. RESULTS: Pre-pregnancy BMI showed significant negative associations with child cognitive scores (ß = -0.1, 95% CI: -0.2 to -0.06, p < 0.001) and language scores (ß = -0.1, 95% CI: -0.2 to -0.03, p = 0.01) at 24 months. Infant HEI-2015 scores at 24 months partly mediated these associations, explaining 23% and 30% of the total effect on cognitive and language subscales, respectively. No specific dietary components in infants mediated the relationship, except for the total HEI-2015 score. CONCLUSIONS: Managing maternal obesity pre-pregnancy is crucial for improving infant neurodevelopmental outcomes, especially in low-income Latino families. Promoting healthy weight and enhancing infant diet quality can enhance neurodevelopment in these populations.

A multi-site 99mTc-HMPAO SPECT study of cerebral blood flow in a community sample of patients with major depression.

Prior regional Cerebral Blood Flow (rCBF) studies in Major Depressive Disorder (MDD) have been limited by small, highly selective, non-representative samples that have yielded variable and poorly replicated findings. The aim of this study was to compare rCBF measures in a large, more representative community sample of adults with MDD and healthy control participants. This is a cross-sectional, retrospective multi-site cohort study in which clinical data from 338 patients 18-65 years of age with a primary diagnosis of MDD were retrieved from a central database for 8 privately owned, private-pay outpatient psychiatric centers across the United States. Two 99mTc-HMPAO SPECT brain scans, one at rest and one during performance of a continuous performance task, were acquired as a routine component of their initial clinical evaluation. In total, 103 healthy controls, 18-65 years old and recruited from the community were also assessed and scanned. Depressed patients had significantly higher rCBF in frontal, anterior cingulate, and association cortices, and in basal ganglia, thalamus, and cerebellum, after accounting for significantly higher overall CBF. Depression severity associated positively with rCBF in the basal ganglia, hippocampus, cerebellum, and posterior white matter. Elevated rCBF was especially prominent in women and older patients. Elevated rCBF likely represents pathogenic hypermetabolism in MDD, with its magnitude in direct proportion to depression severity. It is brain-wide, with disproportionate increases in cortical and subcortical attentional networks. Hypermetabolism may be a reasonable target for novel therapeutics in MDD.

Consumption of different combinations of human milk oligosaccharides in the first 6 mo of infancy is positively associated with early cognition at 2 y of age in a longitudinal cohort of Latino children.

BACKGROUND: Lactation has been widely associated with optimal neurocognitive development, but the underlying mechanism remains unknown. Human milk oligosaccharides (HMOs) are complex sugars that support brain development, but previous studies examining their associations with cognition have yielded inconsistent findings. OBJECTIVES: This study aimed to provide a broader understanding of how HMOs jointly influence cognition. METHODS: We used data from an ongoing longitudinal cohort of Latino mother-infant dyads. Human milk samples from 1 mo (n = 157) and 6 mo (n = 107) postpartum were assessed for the 19 most abundant HMOs. Cognitive performance was assessed at 2 y using the Bayley Scale of Infant and Toddler Development. A partial least squares model identified HMO combinations predictive of cognitive scores. RESULTS: At 1 mo, the combination of higher concentrations of lacto-N-neotetraose (LNnT), lacto-N-tetraose (LNT), lacto-N-fucopentaose (LNFP)-III, 6'-sialyllactose, and 2'-fucosyllactose (FL) with lower concentrations of sialyllacto-N-tetraose (LST) b, LNFP-II, fucodisialyllacto-N-hexaose, and 3-FL significantly predicted higher cognitive scores (ß: 0.61; 95% confidence interval [CI]: 0.30, 0.92), explaining an additional 8% of the variance over a model with only nuisance covariates (11%). Additional analyses revealed that the combination of higher LNFP-III and lower LSTb alone explained 5% more of the variation in cognitive scores (ß: 0.66; 95% CI: 0.24, 1.09). At 6 mo (n = 107), higher LNnT, LNT, and LNFP-III and lower 3FL and LSTb concentrations explained an extra 6% of the variance in cognitive scores (ß: 0.43; 95% CI: 0.12, 0.75). CONCLUSIONS: This study highlights specific HMO combinations in early life influencing cognitive performance at 2 y.

The potential role of early life feeding patterns in shaping the infant fecal metabolome: implications for neurodevelopmental outcomes.

Infant fecal metabolomics can provide valuable insights into the associations of nutrition, dietary patterns, and health outcomes in early life. Breastmilk is typically classified as the best source of nutrition for nearly all infants. However, exclusive breastfeeding may not always be possible for all infants. This study aimed to characterize associations between levels of mixed breastfeeding and formula feeding, along with solid food consumption and the infant fecal metabolome at 1- and 6-months of age. As a secondary aim, we examined how feeding-associated metabolites may be associated with early life neurodevelopmental outcomes. Fecal samples were collected at 1- and 6-months, and metabolic features were assessed via untargeted liquid chromatography/high-resolution mass spectrometry. Feeding groups were defined at 1-month as 1) exclusively breastfed, 2) breastfed >50% of feedings, or 3) formula fed ≥50% of feedings. Six-month groups were defined as majority breastmilk (>50%) or majority formula fed (≥50%) complemented by solid foods. Neurodevelopmental outcomes were assessed using the Bayley Scales of Infant Development at 2 years. Changes in the infant fecal metabolome were associated with feeding patterns at 1- and 6-months. Feeding patterns were associated with the intensities of a total of 57 fecal metabolites at 1-month and 25 metabolites at 6-months, which were either associated with increased breastmilk or increased formula feeding. Most breastmilk-associated metabolites, which are involved in lipid metabolism and cellular processes like cell signaling, were associated with higher neurodevelopmental scores, while formula-associated metabolites were associated with lower neurodevelopmental scores. These findings offer preliminary evidence that feeding patterns are associated with altered infant fecal metabolomes, which may be associated with cognitive development later in life.