Association of prenatal substance exposure and the development of the amygdala, hippocampus, and parahippocampus.

CONTEXT: Prenatal substance exposure (PSE) can lead to various harmful outcomes for the developing fetus and is linked to many emotional, behavioral, and cognitive difficulties later in life. Therefore, examination of the relationship between the development of associated brain structures and PSE is important for the development of more specific or new preventative methods. OBJECTIVES: Our study's primary objective was to examine the relationship between the physical development of the amygdala, hippocampus, and parahippocampus following prenatal alcohol, tobacco, and prescription opioid exposure. METHODS: We conducted a cross-sectional analysis of the Adolescent Brain and Cognitive Development (ABCD) Study, a longitudinal neuroimaging study that measures brain morphometry from childhood throughout adolescence. Data were collected from approximately 12,000 children (ages 9 and 10) and parents across 22 sites within the United States. Prenatal opioid, tobacco, and alcohol use was determined through parent self-report of use during pregnancy. We extracted variables assessing the volumetric size (mm3) of the amygdala, hippocampus, and parahippocampal gyrus as well as brain volume, poverty level, age, sex, and race/ethnicity for controls within our adjusted models. We reported sociodemographic characteristics of the sample overall and by children who had PSE. We calculated and reported the means of each of the specific brain regions by substance exposure. Finally, we constructed multivariable regression models to measure the associations between different PSE and the demographic characteristics, total brain volume, and volume of each brain structure. RESULTS: Among the total sample, 24.6% had prenatal alcohol exposure, 13.6% had prenatal tobacco exposure, and 1.2% had prenatal opioid exposure. On average, those with prenatal tobacco exposure were found to have a statistically significant smaller parahippocampus. CONCLUSIONS: We found a significant association between prenatal tobacco exposure and smaller parahippocampal volume, which may have profound impacts on the livelihood of individuals including motor delays, poor cognitive and behavioral outcomes, and long-term health consequences. Given the cumulative neurodevelopmental effects associated with PSE, we recommend that healthcare providers increase screening rates, detection, and referrals for cessation. Additionally, we recommend that medical associations lobby policymakers to address upstream barriers to the effective identification of at-risk pregnant individuals, specifically, eliminating or significantly reducing punitive legal consequences stemming from state laws concerning prenatal substance use.

Pediatric Primary Care of Children With Intrauterine Opioid Exposure: Survey of Academic Teaching Practices.

OBJECTIVE: Intrauterine opioid exposure (IOE) has increased over the last 2 decades and is associated with additional needs after birth. To date, no clinical guidelines address the primary care of children with IOE. We aimed to characterize clinician-reported screening and referral practices, barriers to effective primary care for children with IOE, and clinician- and practice-level characteristics associated with perceived barriers. METHODS: We conducted a cross-sectional survey of pediatric residents, pediatricians, and advanced practitioners at 28 primary care clinics affiliated with 7 pediatric residency programs (April-June 2022). We assessed screening and other clinical practices related to IOE and perceived barriers to addressing parental opioid use disorder (OUD). We used descriptive statistics to analyze survey responses, assessed the distribution of reported barriers, and applied a 2-stage cluster analysis to assess response patterns. RESULTS: Of 1004 invited clinicians, 329 (32.8%) responses were returned, and 325 pediatric residents and pediatricians were included in the final analytic sample. Almost all (99.3%) reported parental substance use screening as important, but only 11.6% screened routinely. Half of the respondents routinely refer children with IOE to early intervention services and social work. Lack of standard screening for substance use was the most frequently selected barrier to addressing parental OUD. Participants reporting fewer barriers to addressing parental OUD identified having greater access to OUD treatment programs and home visiting programs. CONCLUSIONS: Pediatricians report variations in primary care screenings and referrals for children with IOE. Access to parental OUD treatment programs may mitigate perceived barriers to addressing parental OUD in the pediatric office.

The effects of prenatal exposure to opioids on early childhood development: context matters most.

INTRODUCTION: The opioid crisis has brought an increasing focus on the long-term outcomes of children following prenatal opioid exposure. Evidence to date has been conflicting, which has caused confusion and concern amongst parents, caregivers, social service providers, medical providers and policy makers. METHODS: This review systematically evaluated the highest quality studies relating prenatal exposure to opioids with early childhood developmental outcomes. It focused on developmental outcomes as measured by the Bayley Scales of Infant and Toddler Development, encompassing cognitive, motor, and psychosocial domains of child development. RESULTS: Although several articles reported correlations between prenatal opioid exposure and poor early childhood developmental outcomes, these relationships were no longer statistically significant after adjusting for socio-environmental factors. CONCLUSION: Additional research is needed to determine the extent of any relationship of socio-environmental factors with early childhood development in children prenatally exposed to opioids. This review suggests that socio-environmental factors may be significantly related to poor early childhood outcomes in the presence of prenatal opioid exposure.

Abnormal Morphology and Synaptogenic Signaling in Astrocytes Following Prenatal Opioid Exposure.

In recent decades, there has been a dramatic rise in the rates of children being born after in utero exposure to drugs of abuse, particularly opioids. Opioids have been shown to have detrimental effects on neurons and glia in the central nervous system (CNS), but the impact of prenatal opioid exposure (POE) on still-developing synaptic circuitry is largely unknown. Astrocytes exert a powerful influence on synaptic development, secreting factors to either promote or inhibit synapse formation and neuronal maturation in the developing CNS. Here, we investigated the effects of the partial µ-opioid receptor agonist buprenorphine on astrocyte synaptogenic signaling and morphological development in cortical cell culture. Acute buprenorphine treatment had no effect on the excitatory synapse number in astrocyte-free neuron cultures. In conditions where neurons shared culture media with astrocytes, buprenorphine attenuated the synaptogenic capabilities of astrocyte-secreted factors. Neurons cultured from drug-naïve mice showed no change in synapses when treated with factors secreted by astrocytes from POE mice. However, this same treatment was synaptogenic when applied to neurons from POE mice, indicating a complex neuroadaptive response in the event of impaired astrocyte signaling. In addition to promoting morphological and connectivity changes in neurons, POE exerted a strong influence on astrocyte development, disrupting their structural maturation and promoting the accumulation of lipid droplets (LDs), suggestive of a maladaptive stress response in the developing CNS.

Investigating the neurobiology of maternal opioid use disorder and prenatal opioid exposure using brain organoid technology.

Over the past two decades, Opioid Use Disorder (OUD) among pregnant women has become a major global public health concern. OUD has been characterized as a problematic pattern of opioid use despite adverse physical, psychological, behavioral, and or social consequences. Due to the relapsing-remitting nature of this disorder, pregnant mothers are chronically exposed to exogenous opioids, resulting in adverse neurological and neuropsychiatric outcomes. Collateral fetal exposure to opioids also precipitates severe neurodevelopmental and neurocognitive sequelae. At present, much of what is known regarding the neurobiological consequences of OUD and prenatal opioid exposure (POE) has been derived from preclinical studies in animal models and postnatal or postmortem investigations in humans. However, species-specific differences in brain development, variations in subject age/health/background, and disparities in sample collection or storage have complicated the interpretation of findings produced by these explorations. The ethical or logistical inaccessibility of human fetal brain tissue has also limited direct examinations of prenatal drug effects. To circumvent these confounding factors, recent groups have begun employing induced pluripotent stem cell (iPSC)-derived brain organoid technology, which provides access to key aspects of cellular and molecular brain development, structure, and function in vitro. In this review, we endeavor to encapsulate the advancements in brain organoid culture that have enabled scientists to model and dissect the neural underpinnings and effects of OUD and POE. We hope not only to emphasize the utility of brain organoids for investigating these conditions, but also to highlight opportunities for further technical and conceptual progress. Although the application of brain organoids to this critical field of research is still in its nascent stages, understanding the neurobiology of OUD and POE via this modality will provide critical insights for improving maternal and fetal outcomes.

Sex differences in neonatal outcomes following prenatal opioid exposure.

The impact of the opioid epidemic on pregnant people and children is a growing public health crisis. Understanding how opioids affect the developing brain during pregnancy and postnatally remains a critical area of investigation. Biological sex plays a crucial role in all physiologic processes, with the potential for a significant impact on neonatal outcomes, including those infants with opioid exposure. Here, we aim to explore current literature on the effect of sex on neonatal outcomes following prenatal opioid exposure. Sex differences in adults with opioid use disorder have been well studied, including increased mortality among males and higher rates of psychiatric comorbidities and likelihood of relapse in females. However, such differences are not yet well understood in neonates. Emerging clinical data suggest sex-specific effects in infants with prenatal opioid exposure on the expression of genes related to feeding regulation and reward signaling pathways. Increased susceptibility to white matter injury has also been noted in female infants following prenatal opioid exposure. Understanding the impact of sex as a biological variable on neonatal outcomes following prenatal opioid exposure is paramount to improving the health and well-being of infants, children, and adults impacted by the opioid epidemic.

Risk factors for food insecurity and association with prenatal care utilization among women who took opioids during pregnancy.

Background: Food insecurity during pregnancy is associated with poorer outcomes for both mothers and their newborns. Given the ongoing opioid crisis in the United States, mothers who take opioids during pregnancy may be at particular risk of experiencing food insecurity. Methods: This research utilized data from 254 biological mothers of infants in the Advancing Clinical Trials in Neonatal Opioid Withdrawal Syndrome (ACT NOW) Outcomes of Babies with Opioid Exposure (OBOE) Study. We examined factors associated with food insecurity among mothers of infants with antenatal opioid exposure and their unexposed (control) counterparts. Chi-square tests and logistic regression were used to compare food insecurity by sociodemographic characteristics, opioid use, prior traumatic experiences, and housing instability. Similar analyses were conducted to examine the relationship between food insecurity during pregnancy and receipt of adequate prenatal care. Results: Overall, 58 (23%) of the mothers screened positive for food insecurity. Food insecurity was more common among mothers who took opioids during pregnancy (28% vs. 14%; p =0.007), had public insurance (25% vs. 8%; p = 0.027), had housing instability (28% vs. 11%, p = 0.002), experienced three or more adverse experiences in their childhood (37% vs. 17%; p < 0.001), and reported physical or emotional abuse during their pregnancy (44% vs. 17%; p < 0.001). Mothers with food insecurity during pregnancy were less likely to have received adequate prenatal care (78% vs. 90%; p = 0.020). This difference remained after controlling for demographic characteristics (AOR (95% CI) = 0.39 (0.16, 1.00), p = 0.049). Conclusions: This study adds to the body of evidence supporting the need for screening and development of interventions to address food insecurity during pregnancy, particularly among mothers of infants with antenatal opioid exposure, for which limited data are available. The findings revealed that food insecurity frequently co-occurs with housing instability and prior trauma, indicating that a multifaceted intervention incorporating principles of trauma-informed health care is needed. Although those with food insecurity are at increased risk for poor pregnancy outcomes, they were less likely to have received adequate prenatal care despite high levels of public insurance coverage among study participants, suggesting additional strategies are needed to address barriers to health care among this population. Trial registration: The Outcomes of Babies with Opioid Exposure (OBOE) Study is registered at Clinical Trials.gov (NCT04149509) (04/11/2019).

Comparative study of oral microbiota in the experimental long-term opioid exposure, after its withdrawal and the use of complex drug correction.

OBJECTIVE: Aim: To study changes of dental biofilm microbiota composition during experimental opioid exposure, after its withdrawal and when using of complex drug correction.. PATIENTS AND METHODS: Materials and Methods: Microbiological studies (48 rats) included microscopic and bacteriological methods, as well as determination of antibiotic susceptibility of microbial isolates. Ceftriaxone and pentoxifylline were used to correction the changes. RESULTS: Results: The action of opioid for 10 weeks caused considerable changes in the microbiocenosis, which was illustrated by a significant increasing of the opportunistic pathogens quantitative indicators and the emergence of pathogenic microbiota. Changes in the microbiocenosis at 6 weeks of opioid exposure and after its withdrawal for 4 weeks were expressed in the appearance of pathogenic microbiota and the absence of significant differences in quantitative indicators of saprophytic and opportunistic microflora compared to similar indicators in animals with 10 weeks opioid exposure. This indicated a slow progression of dysbiotic changes and the inflammatory process in the oral cavity of rats. CONCLUSION: Conclusions: After 10 weeks of experiment with opioid administration for 6 weeks and the use of ceftriaxone and pentoxifylline on the background of 4-week opioid withdrawal, a significant reduction of quantitative indicators of opportunistic bacteria and elimination of pathogenic species of microorganisms was determined. The use of complex drug correction on the background of 10 weeks of opioid exposure led to a significant reduction in the quantitative indicators of opportunistic pathogens and contributed to the elimination of most pathogenic species of microbiota under the action of ceftriaxone.

Limited bedding and nesting increases ethanol drinking in female rats.

Prenatal opioid exposure (POE) and postnatal adverse experiences are early life adversities (ELA) that often co-occur and increase problematic alcohol (EtOH) drinking during adolescence. We investigated the relationship between POE, postnatal adversity, and adolescent EtOH drinking in rats. We also sought to determine whether ELAs affect alpha-adrenoceptor density in the brain because the noradrenergic system is involved in problematic alcohol drinking and its treatment. We hypothesized that the combination of POE and postnatal adversity will increase alcohol drinking in rats compared to rats with exposure to either adversity alone or to control. We also predicted that POE and postnatal adversity would increase α1-adrenoceptor density and decrease α2-adrenoceptor density in brain to confer a stress-responsive phenotype. Pregnant rats received morphine (15 mg/kg/day) or saline via subcutaneous minipumps from gestational day 9 until birth. Limited bedding and nesting (LBN) procedures were introduced from postnatal day (PD) 3-11 to mimic early life adversity-scarcity. Offspring rats (PD 31-33) were given opportunities to drink EtOH (20 %, v/v) using intermittent-access, two-bottle choice (with water) procedures. Rats given access to EtOH were assigned into sub-groups that were injected with either yohimbine (1 mg/kg, ip) or vehicle (2 % DMSO, ip) 30 min prior to each EtOH access session to determine the effects of α2-adrenoceptor inhibition on alcohol drinking. We harvested cortices, brainstems, and hypothalami from EtOH-naïve littermates on either PD 30 or PD 70 and conducted radioligand receptor binding assays to quantify α1- and α2-adrenoceptor densities. Contrary to our hypothesis, only LBN alone increased EtOH intake in female adolescent rats compared to female rats with POE. Neither POE nor LBN affected α1- or α2-adrenoceptor densities in the cortex, brainstem, or hypothalamus of early- or late-aged adolescent rats. These results suggest a complex interaction between ELA type and sex on alcohol drinking.

[Formula: see text] Neural and behavioral indicators of cognitive control in preschoolers with and without prenatal opioid exposure.

Prenatal opioid exposure is one consequence of the opioid epidemic, but effects on child development remain poorly understood. There is emerging evidence that children exposed to opioids in utero exhibit elevated emotional and behavioral problems, which may be partially due to alterations in cognitive control. Using multiple methods (i.e., neuropsychological, behavioral, and event-related potential [ERP] assessments), the present study examined differences in emotional, behavioral, and cognitive control difficulties in preschool-aged children with (n = 21) and without (n = 23) prenatal opioid exposure (Mage = 4.30, SD = 0.77 years). Child emotional and behavioral problems were measured with a caregiver questionnaire, indicators of cognitive control were measured using developmentally appropriate behavioral (i.e., delay discounting, Go/No-Go) and neuropsychological (i.e., Statue) tasks, and electroencephalogram was recorded to error and correct responses in a Go/No-Go task. ERP analyses focused on the error-related negativity (ERN), an ERP that reflects error monitoring, and correct-response negativity (CRN), a component reflecting performance monitoring more generally. Opioid exposure was associated with elevated difficulties across domains and a blunted ERN, reflecting altered cognitive control at the neural level, but groups did not significantly differ on behavioral measures of cognitive control. These result replicate prior studies indicating an association between prenatal opioid exposure and behavioral problems in preschool-aged children. Further, our findings suggest these differences may be partially due to children with prenatal opioid exposure exhibiting difficulties with cognitive control at the neural level. The ERN is a potential target for future research and intervention efforts to address the sequelae of prenatal opioid exposure.

Effects of prenatal opioid exposure on infant sympathetic and parasympathetic nervous system activity.

Prenatal opioid exposure has been associated with developmental problems, including autonomic nervous system dysregulation. However, little is known about the effects of prenatal opioid exposure on the autonomic nervous system beyond the first days of life, particularly across both the parasympathetic and sympathetic branches, and when accounting for exposure to other substances. The present study examined the effects of prenatal exposure to opioid agonist therapy (OAT, e.g., methadone) and other opioids on infant autonomic nervous system activity at rest and in response to a social stressor (the Still-Face Paradigm) at six months among 86 infants varying in prenatal opioid and other substance exposure. Results indicated that OAT and other opioids have unique effects on the developing autonomic nervous system that may further depend on subtype (i.e., methadone versus buprenorphine) and timing in gestation. Results are discussed in the context of theoretical models of the developing stress response system.

Motion Robust MR Fingerprinting Scan to Image Neonates With Prenatal Opioid Exposure.

PURPOSE: To explore whether MR fingerprinting (MRF) scans provide motion-robust and quantitative brain tissue measurements for non-sedated infants with prenatal opioid exposure (POE). STUDY TYPE: Prospective. POPULATION: 13 infants with POE (3 male; 12 newborns (age 7-65 days) and 1 infant aged 9-months). FIELD STRENGTH/SEQUENCE: 3T, 3D T1-weighted MPRAGE, 3D T2-weighted TSE and MRF sequences. ASSESSMENT: The image quality of MRF and MRI was assessed in a fully crossed, multiple-reader, multiple-case study. Sixteen image quality features in three types-image artifacts, structure and myelination visualization-were ranked by four neuroradiologists (8, 7, 5, and 8 years of experience respectively), using a 3-point scale. MRF T1 and T2 values in 8 white matter brain regions were compared between babies younger than 1 month and babies between 1 and 2 months. STATISTICAL TESTS: Generalized estimating equations model to test the significance of differences of regional T1 and T2 values of babies under 1 month and those older. MRI and MRF image quality was assessed using Gwet's second order auto-correlation coefficient (AC2) with confidence levels. The Cochran-Mantel-Haenszel test was used to assess the difference in proportions between MRF and MRI for all features and stratified by the type of features. A P value <0.05 was considered statistically significant. RESULTS: The MRF of two infants were excluded in T1 and T2 value analysis due to severe motion artifact but were included in the image quality assessment. In infants under 1 month of age (N = 6), the T1 and T2 values were significantly higher compared to those between 1 and 2 months of age (N = 4). MRF images showed significantly higher image quality ratings in all three feature types compared to MRI images. CONCLUSIONS: MR Fingerprinting scans have potential to be a motion-robust and efficient method for nonsedated infants. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

Opioid-induced dysbiosis of maternal gut microbiota during gestation alters offspring gut microbiota and pain sensitivity.

There has been a rapid increase in neonates born with a history of prenatal opioid exposure. How prenatal opioid exposure affects pain sensitivity in offspring is of interest, as this may perpetuate the opioid epidemic. While few studies have reported hypersensitivity to thermal pain, potential mechanisms have not been described. This study posits that alterations in the gut microbiome may underly hypersensitivity to pain in prenatally methadone-exposed 3-week-old male offspring, which were generated using a mouse model of prenatal methadone exposure. Fecal samples collected from dams and their offspring were subjected to 16s rRNA sequencing. Thermal and mechanical pain were assessed using the tail flick and Von Frey assays. Transcriptomic changes in whole brain samples of opioid or saline-exposed offspring were investigated using RNA-sequencing, and midbrain sections from these animals were subjected to qPCR profiling of genes related to neuropathic and inflammatory pain pathways. Prenatal methadone exposure increased sensitivity to thermal and mechanical pain and elevated serum levels of IL-17a. Taxonomical analysis revealed that prenatal methadone exposure resulted in significant alterations in fecal gut microbiota composition, including depletion of Lactobacillus, Bifidobacterium, and Lachnospiracea sp and increased relative abundance of Akkermansia, Clostridium sensu stricto 1, and Lachnoclostridium. Supplementation of the probiotic VSL#3 in dams rescued hypersensitivity to thermal and mechanical pain in prenatally methadone-exposed offspring. Similarly, cross-fostering prenatally methadone-exposed offspring to control dams also attenuated hypersensitivity to thermal pain in opioid-exposed offspring. Modulation of the maternal and neonatal gut microbiome with probiotics resulted in transcriptional changes in genes related to neuropathic and immune-related signaling in whole brain and midbrain samples of prenatally methadone-exposed offspring. Together, our work provides compelling evidence of the gut-brain-axis in mediating pain sensitivity in prenatally opioid-exposed offspring.

A Systematic Review of Clinical Practice Guidelines for Neonatal Abstinence Syndrome.

BACKGROUND: The prevalence of neonatal abstinence syndrome is increasing, but the number and quality of clinical practice guidelines available are unknown. This systematic review aimed to identify, appraise and evaluate clinical practice guidelines for neonatal abstinence syndrome. METHODS: A systematic search of databases and the grey literature was conducted between 1 June and 1 July 2022. Full-text guidelines published by national or state-wide institutions were included. The recommendations from each guideline were extracted. The AGREE-II instrument was used to assess guideline quality. Sufficient-quality scores were defined as >60 and good-quality scores were >80 for each domain of AGREE-II. RESULTS: A total of 1703 records were identified, and 22 guidelines from the United States, Australia, Canada and the United Kingdom, published between 2012 to 2021, were included. The quality scores were low, with median scores of 37/100 for stakeholder involvement, 33/100 for methodology, 34/100 for applicability and 0 for editorial independence. Scope and purpose scored 72/100, and presentation scored 85/100. Sixteen (73%) guidelines did not meet the cut-offs for clinical use. CONCLUSION: Many guidelines were of insufficient quality to guide clinical practice for neonatal abstinence syndrome. This emphasises the need for high-quality studies to inform clinical practice guidelines, improve care and reduce the risk of poor outcomes in these high-risk infants.

Developmental implications of prenatal opioid exposure among school-aged children: a mixed methods and community-initiated analysis.

BACKGROUND: Growing research points to potential long-term developmental implications of prenatal opioid exposure for children. Yet, polysubstance use and adverse childhood experiences are raised as potential confounders. Further, there is a lack of data on school-age children and the children's strengths. METHODS: Parents and caregivers of children with prenatal opioid exposure worked with the study team to design, collect, and descriptively analyze mixed method data. Data were collected through survey (n = 148) and two focus groups (n = 15) from a convenience sample in mostly West Virginia and Massachusetts. RESULTS: Nearly half of the children in the sample were diagnosed with multiple developmental delays, behavioral health conditions, and specific learning disorders. Roughly 85% of children have behavioral challenges. Associations between prenatal opioid exposure and negative developmental outcomes did not vary by type of opioid nor by polysubstance use, while controlling for adverse childhood experiences. Importantly, over 80% of families also reported their child's strengths, including empathy, social magnetism, and their resilience. CONCLUSIONS: The challenges for children born with prenatal opioid exposure may extend into school-age. The results are consistent with prior research on younger children, suggesting a need for best practices for caring for these children beyond the neonatal stage.

Comparisons of stress-related neuronal activation induced by restraint in adult male rat offspring with prenatal exposure to buprenorphine, methadone, or morphine.

Prenatal opioid exposure may impede the development of adaptive responses to environmental stimuli by altering the stress-sensitive brain circuitry located at the paraventricular nucleus of the hypothalamus (PVH) and locus coeruleus (LC). Corticotropin-releasing factor (CRF) released from neurons in the PVH has emerged as a key molecule to initiate and integrate the stress response. Methadone (Meth) and buprenorphine (Bu) are two major types of synthetic opioid agonists for first-line medication-assisted treatment of opioid (e.g., morphine, Mor) use disorder in pregnant women. No studies have compared the detrimental effects of prenatal exposure to Meth versus Bu on the stress response of their offspring upon reaching adulthood. In this study, we aimed to compare stress-related neuronal activation in the PVH and LC induced by restraint (RST) stress in adult male rat offspring with prenatal exposure to the vehicle (Veh), Bu, Meth, or Mor. CFos-immunoreactive cells were used as an indicator for neuronal activation. We found that RST induced less neuronal activation in the Meth or Mor exposure groups compared with that in the Bu or Veh groups; no significant difference was detected between the Bu and Veh exposure groups. RST-induced neuronal activation was completely prevented by central administration of a CRF receptor antagonist (α-helical CRF9-41, 10 µg/3 µL) in all exposure groups, suggesting the crucial role of CRF in this stress response. In offspring without RST, central administration of CRF (0.5 µg/3 µL)-induced neuronal activation in the PVH and LC. CRF-induced neuronal activation was lessened in the Meth or Mor exposure groups compared with that in the Bu or Veh groups; no significant difference was detected between the Bu and Veh exposure groups. Moreover, RST- or CRF-induced neuronal activation in the Meth exposure group was comparable with that in the Mor exposure group. Further immunohistochemical analysis revealed that the Meth and Mor exposure groups displayed less CRF neurons in the PVH of offspring with or without RST compared with the Bu or Veh groups. Thus, stress-induced neuronal activation in the PVH and LC was well preserved in adult male rat offspring with prenatal exposure to Bu, but it was substantially lessened in those with prenatal exposure to Meth or Mor. Lowered neuronal activation found in the Meth or Mor exposure groups may be, at least in part, due to the reduction in the density of CRF neurons in the PVH.

A 12-month follow-up of infant neurodevelopmental outcomes of prenatal opioid exposure and polysubstance use.

BACKGROUND: Prenatal opioid exposure has been associated with developmental deficits during infancy, but the literature is limited by simple group comparisons and lack of appropriate controls. Previously published research with the current sample documented unique associations between prenatal opioid exposure and developmental outcomes at three and six months, but less is known about associations later in infancy. METHOD: The current study examined pre- and postnatal opioid and polysubstance exposure as predictors of parent-reported developmental status at 12 months of age. Participants were 85 mother-child dyads, oversampled for mothers taking opioid treatment medications during pregnancy. Maternal opioid and polysubstance use were reported using the Timeline Follow-Back Interview during the third trimester of pregnancy or up to one month postpartum and updated through the child's first year of life. Seventy-eight dyads participated in a 12-month assessment, including 68 with parent-reported developmental status on Ages and Stages Questionnaire. RESULTS: At 12 months, average developmental scores fell within normal ranges and prenatal opioid exposure was not significantly related to any developmental outcomes. However, more prenatal alcohol exposure was significantly related to worse problem-solving scores, and this relationship remained after controlling for adjusted age and other substance exposure. CONCLUSION: Although findings await replication with larger samples and more comprehensive measures, results suggest that unique developmental risks of prenatal opioid exposure may not persist through the first year of life. Effects of prenatal exposure to co-occurring teratogens, such as alcohol, may become apparent as children exposed to opioids develop.

In utero methadone exposure permanently alters anatomical and functional connectivity: A preclinical evaluation.

The opioid epidemic is an ongoing public health crisis, and children born following prenatal opioid exposure (POE) have increased risk of long-term cognitive and behavioral sequelae. Clinical studies have identified reduced gray matter volume and abnormal white matter microstructure in children with POE but impacts on whole-brain functional brain connectivity (FC) have not been reported. To define effects of POE on whole brain FC and white matter injury in adult animals, we performed quantitative whole-brain structural and functional MRI. We used an established rat model of POE in which we have previously reported impaired executive function in adult rats analogous to persistent neurocognitive symptoms described in humans with POE. Pregnant Sprague-Dawley rat dams received continuous methadone (12 mg/kg/day) vs. saline infusion for 28 days via osmotic mini-pumps, exposing rats to pre- and postnatal opioid until weaning. At young adult age (P60), POE and saline exposed offspring underwent in vivo MRI included diffusion tensor imaging and functional MRI (fMRI). Results indicate that fractional anisotropy (FA) was decreased in adult animals with POE [n = 11] compared to animals that received saline [n = 9] in major white matter tracts, including the corpus callosum (p < 0.001) and external capsule (p < 0.01). This change in FA was concomitant with reduced axial diffusivity in the external capsule (p < 0.01) and increased radial diffusivity in the corpus callosum (p < 0.01). fMRI analyses reveal brainwide FC was diffusely lower in POE (p < 10-6; 10% of variance explained by group). Decreased connectivity in cortical-cortical and cortico-basal ganglia circuitry was particularly prominent with large effect sizes (Glass's Δ > 1). Taken together, these data confirm POE reduces brainwide functional connectivity as well as microstructural integrity of major white matter tracts. Altered neural circuitry, dysregulated network refinement, and diffuse network dysfunction have been implicated in executive function deficits that are common in children with POE. FC may serve as a translatable biomarker in children with POE.

Effects of prenatal opioid exposure on synaptic adaptations and behaviors across development.

In this review, we focus on prenatal opioid exposure (POE) given the significant concern for the mental health outcomes of children with parents affected by opioid use disorder (OUD) in the view of the current opioid crisis. We highlight some of the less explored interactions between developmental age and sex on synaptic plasticity and associated behavioral outcomes in preclinical POE research. We begin with an overview of the rich literature on hippocampal related behaviors and plasticity across POE exposure paradigms. We then discuss recent work on reward circuit dysregulation following POE. Additional risk factors such as early life stress (ELS) could further influence synaptic and behavioral outcomes of POE. Therefore, we include an overview on the use of preclinical ELS models where ELS exposure during key critical developmental periods confers considerable vulnerability to addiction and stress psychopathology. Here, we hope to highlight the similarity between POE and ELS on development and maintenance of opioid-induced plasticity and altered opioid-related behaviors where similar enduring plasticity in reward circuits may occur. We conclude the review with some of the limitations that should be considered in future investigations. This article is part of the Special Issue on 'Opioid-induced addiction'.