Adam K. Walker

Background: Prenatal opioid exposure (POE) induces long-term neurodevelopmental, behavioral and cognitive deficits for which no targeted treatments are available. The mechanisms underlying POE deficits are poorly understood, but have been linked to a range of central, peripheral, and enteric nervous system changes. Emerging evidence indicates that maternal microbiota changes may also contribute to these long-term offspring deficits. Here we test the efficacy of the short-chain fatty acid sodium butyrate (NaB) to mitigate POE-induced deficits in a rat model. Method: 26 pregnant rat dams received methadone via mini-osmotic pump and/or NaB via drinking water in a 2 × 2 design. We then performed a battery of developmental, behavioral, microbiome and neurobiological assessments across offspring infancy, adolescence and adulthood. Results: Both methadone and sodium butyrate treatments altered dam microbiota composition and function: notably methadone disrupted microbial gene expression of enzymes critical for butyrate production and reduced faecal butyric acid levels. In pups, methadone increased infant gut barrier permeability that was reversed with NaB, and induced infant microbial enzymatic disruption that resolved in adulthood. POE induced anxiety-like behavior in adolescence, and adulthood working spatial memory and attentional processing deficits that were partially rescued by prenatal NaB treatment. POE decreased myelination in the hippocampus, and this was partially reversed by NaB. Conclusions: Together, these results highlight the role for the microbiota-gut-brain axis in animal models of POE. Furthermore, they provide evidence for NaB as a simple yet effective treatment to significantly improve the outcomes of children born with POE.

Background: Prenatal opioid exposure (POE) induces long-term neurodevelopmental, behavioral and cognitive deficits for which no targeted treatments are available. The mechanisms underlying POE deficits are poorly understood, but have been linked to a range of central, peripheral, and enteric nervous system changes. Emerging evidence indicates that maternal microbiota changes may also contribute to these long-term offspring deficits. Here we test the efficacy of the short-chain fatty acid sodium butyrate (NaB) to mitigate POE-induced deficits in a rat model. Method: 26 pregnant rat dams received methadone via mini-osmotic pump and/or NaB via drinking water in a 2 x 2 design. We then performed a battery of developmental, behavioral, microbiome and neurobiological assessments across offspring infancy, adolescence and adulthood. Results: Both methadone and sodium butyrate treatments altered dam microbiota composition and function: notably methadone disrupted microbial gene expression of enzymes critical for butyrate production and reduced faecal butyric acid levels. In pups, methadone increased infant gut barrier permeability that was reversed with NaB, and induced infant microbial enzymatic disruption that resolved in adulthood. POE induced anxiety-like behavior in adolescence, and adulthood working spatial memory and attentional processing deficits that were partially rescued by prenatal NaB treatment. POE decreased myelination in the hippocampus, and this was partially reversed by NaB. Conclusions: Together these results highlight for the first time the link between the gut-brain axis in animal models of POE. Furthermore, they provide evidence for NaB as a simple yet effective treatment to significantly improve the outcomes of children born with POE.

Purpose: Cognitive and psychological symptoms in neuropsychiatric disorders have been linked to blood cell parameters, including neutrophil-to-lymphocyte ratios (NLRs), systemic immune-inflammation indices (SIIs), and platelet-to-lymphocyte ratios (PLRs). It remains unclear whether cognitive impairments in haematological cancers are associated with biological vulnerabilities reflected in these parameters. We examined whether cognitive and psychological morbidity correlated with blood cell parameters before, during, and after chemotherapy in individuals with aggressive lymphoma. Methods: Neuropsychological testing and self-reported questionnaires were administered at diagnosis, mid-chemotherapy, and 6–8 weeks post-treatment ( n = 30). Regression models assessed associations between cognition and blood cell parameters. Bootstrapped Pearson correlations examined relationships between NLRs, SIIs, PLRs, and psychological symptoms. To test specificity, similar analyses were conducted in healthy controls ( n = 72). Results: In individuals with aggressive lymphoma, NLRs, SIIs, and PLRs correlated with impairments in inhibitory control, cognitive flexibility, delayed recall, and working memory across time points ( p < 0.05). A disconnect emerged between these parameters and subjective self-reports. At diagnosis, lower NLRs, SIIs, and PLRs were associated with worse objective cognitive performance but better perceived cognition. Mid-chemotherapy, higher NLRs correlated with worse delayed recall but fewer reported depression and anxiety symptoms ( p < 0.05). No significant associations were observed in healthy controls. Conclusion: Cognitive impairment was associated with blood cell parameters in individuals with aggressive lymphoma, indicating distinct biological patterns of dysfunction before, during, and after chemotherapy. The disconnect between objective neuropsychological performance and subjective self-reports reinforces the value of incorporating biomarkers into cognitive assessments in this population.

Background/Objectives: In utero exposure to painkillers has raised concerns regarding its potential impact on neurodevelopmental disorders, such as autism spectrum disorder (ASD). This study investigates the association between in utero exposure to painkillers and trajectories of hyperactivity and emotional problems in children with and without ASD, separately. Methods: Data were drawn from 5107 participants enrolled in the Longitudinal Study of Australian Children. Emotional and behavioral problems were assessed using the Strengths and Difficulties Questionnaire at ages 4, 6, and 8 years. ASD diagnosis was determined based on parental self-report by age 12. To examine the association between the exposure and the outcomes, mixed linear models were applied to assess the impact of in utero exposure to painkillers on hyperactivity and emotional problems, controlling for sex, time, and other perinatal risk factors. The interaction term between exposure and time was included to evaluate the effect of exposure on the trajectory over time. Results: In utero exposure to painkillers did not significantly affect hyperactivity or emotional problem trajectories in children with ASD. However, in non-ASD children, painkiller exposure was associated with worsening emotional problems by age 8, with males being affected to a greater extent than females. Further, emotional problem scores increased over time by gender, reflecting developmental challenges in early childhood. Conclusions: These findings indicate that prenatal painkiller exposure is unlikely to be a major determinant of the severity of neurodevelopmental outcomes in autistic children, but its role in neurodevelopmental outcomes among neurotypical children warrants further investigation. Future research should prioritize precise exposure assessments and integrate multi-environment interactions to further elucidate the long-term impacts of prenatal painkiller use.