Faculty Bibliography

Toxicity of prenatal ethanol leading to fetal alcohol spectrum disorders (FASDs) has been linked to disturbances in retinoic acid (RA) signaling necessary for embryonic development. While ethanol exposure in the postnatal day 7 (P7) mice, which induces immediate neurodegeneration and long-lasting GABAergic cell loss and behavioral deficits, has been used for the third trimester FASD model, involvement of RA signaling in the process has not been well explored. Using RARE-LacZ reporter mice that express β-galactosidase (β-Gal) under the control of retinoic acid response element (RARE), we examined RA signaling activity of the forebrains of P8 and P30 mice with or without P7 ethanol treatment. In all experimental groups, β-Gal was expressed mainly in the hippocampus with the strongest expression in the granule cell layer of dentate gyrus. In addition, β-Gal was expressed in pyramidal neurons and parvalbumin (PV) neurons in CA1-3 pyramidal layer and in astrocytes scattered around the CA1-3 region although PV neurons were only examined at P30 because of the low PV expression at P8. β-Gal was also expressed in the anteroventral/anteromedial (AV/AM) thalamus and the retrosplenial (Rs) and Tbr1-positive (+) layer 6 cortices. β-Gal-expressing PV neurons were also found in the cortex such as Rs, while β-Gal was barely detected in somatostatin neurons in any brain regions examined. Such region and cell specific β-Gal expression was significantly higher in P8 brains than P30 brains in various brain regions. P7 ethanol reduced β-Gal expression in the CA1-3 pyramidal layer, Tbr1 + cortical layer 6, and the AV/AM thalamus at P8 or P30 or both. Although P7 ethanol decreased PV cells in CA2-3 pyramidal layers as reported, it decreased β-Gal+ PV cells more drastically. The active RA signaling found in PV neurons and the effects of P7 ethanol on the signaling suggest that reduced RA signaling by P7 ethanol may disturb PV cell maturation and enhance long-lasting brain abnormalities.

BACKGROUND/UNASSIGNED:This paper provides an overview of adapting a micro-savings program originally developed in the United States to a resource-limited setting in Uganda, highlighting this specific case of adapting a program from one country to another. The program involved opening Child Development Accounts (CDAs) to support saving among adolescents girls and their families. Guided by the asset theory and institutional theory, the paper discusses the challenges and opportunities faced during the adaptation and implementation process. The findings offer insights that can inform efforts to expand similar micro-savings programs in other resource-limited communities. METHODS/UNASSIGNED:This paper utilizes data from the Suubi4Her study (2017-2022), a longitudinal intervention involving 1,260 adolescent girls in Southern Uganda. The analysis focused on saving behaviors among the entire sample and a subsample of 690 participants who opened CDAs. We examined self-reported and administrative savings outcomes over 30 months, encompassing bank savings behavior and savings beyond the initial deposit. Analyses also addressed key sociodemographic and psychosocial factors. A mixed-effect and adjusted logistic regression model were applied. RESULTS/UNASSIGNED:At enrollment, the participant's mean age was 15.37 years. The intervention improved bank saving behavior, evidenced by significant intervention-by-time interaction effects [χ2(2) = 43.38, p < 0.01], demonstrating a substantial increase in the odds of bank saving behavior in the intervention group at Wave 2 (OR = 78.85, 95% CI: 18.76, 331.51, p < 0.01) and Wave 3 (OR = 80.95, 95% CI: 19.31, 339.26, p < 0.01) compared to baseline within the control group. In the analysis of additional saving beyond the initial deposit, participants whose schools were located within 2 km of their home had significantly higher odds of saving (OR = 2.74, 95% CI: 1.72-4.37, p < 0.01), while older participants had lower odds (OR = 0.83, 95% CI: 0.68-0.99, p = 0.04). Living nearer to a bank was associated with increased odds of additional saving (OR = 1.74, 95% CI: 0.84-3.62, p = 0.13), though this association did not reach statistical significance. CONCLUSIONS AND IMPLICATIONS/UNASSIGNED:These findings suggest that, overall, CDA-based micro-saving programs implementation is possible even in resource limited communities like Uganda, and when given the opportunity, families living in low-income households can utilize the CDA "infrastructure" to save. Overall, for the saving intervention to yield its intended benefits, institutional barriers need to be addressed, including bringing the bank services to the people and providing financial literacy training to instill the culture of saving from a young age.

Educational initiatives that address the gap between basic/preclinical and clinical practices are important to effectively translate basic science discoveries to benefit patients. The ILAE Neurobiology Commission conducted a pilot project aimed at exposing basic and preclinical scientists engaged in epilepsy research to general clinical issues pertaining to the diagnosis and care of people with epilepsy. This aim was addressed through a two-week-long, on-site clinical training program for 50 basic scientists in 21 epilepsy centers across 18 countries in the six ILAE regions (with a maximum of 3 basic scientists per center). The learning objectives and the training module were discussed and defined by the project organizing committee, which consisted of Neurobiology Commission members and a team of epileptologists representing different geographical regions. The training activities were conducted at each epilepsy center under the local supervision of clinical tutors. Each basic scientist was exposed to 50.3 ± 23.3 (range 16-89) hours of intensive and dedicated clinical training, coordinated by 2-3 tutors per center, assisted by 6.8 ± 3.6 colleagues. A structured test consisting of 17 general clinical epilepsy questions was completed by the trainees before and after the training activity. The learning assessment was based on the comparison between responses to the exit and entry tests. After the on-site clinical exposure, the proportion of correct answers increased to 87% compared to 61% in the entry test. Structured post-training questionnaires demonstrated very high satisfaction of trainees and all involved tutors across the different aspects of the training module. This global pilot study demonstrated that on-site attendance by basic scientists in specialized clinical settings up-scaled their knowledge of clinical epileptology and facilitated networking with clinicians. Expansion of this pilot to further centers should be considered to understand how exposure to clinical practice affects research direction and quality of translational epilepsy research. PLAIN LANGUAGE SUMMARY: Epilepsy research has long benefitted from collaboration between scientists and clinicians. Early exposure of researchers to people with epilepsy and their care teams may strengthen future impact. This pilot study tested a two-week immersive experience where small teams of basic scientists shadowed clinicians during their work at hospitals around the world. Questionnaires showed high satisfaction among both groups. Results support expanding such training, with the backing of the International League Against epilepsy and aligned centers, to build understanding, interest, and long-term commitment, ensuring bench research is informed by and translates to clinical practice and improved quality of life for patients.

IntroductionBipolar depression is disabling and often inadequately responsive to medication alone. The current efficacy evidence of transcranial magnetic stimulation (TMS) for bipolar depression is conflicting. Therefore, we synthesized randomized controlled trials (RCTs) that tested the efficacy, safety, and tolerability of TMS for bipolar depression.MethodsWe searched MEDLINE/EMBASE/Cochrane/PsycINFO/gray literature (01/10/2025) for RCTs comparing any TMS protocol with sham. Co-primary outcomes were depressive symptoms, all-cause discontinuation; secondary outcomes were response, remission. Risk of bias (RoB) was assessed with RoB-2. Random-effects models estimated standardized mean differences (SMDs) and risk ratios (RRs) with 95% confidence intervals (95%CI), alongside sensitivity, subgroup, and meta-regression analyses.ResultsNineteen comparisons from 17 RCTs (N = 563; TMS = 293, sham = 270; mean N TMS = 15.4, sham = 15.9; mean duration = 2.40 weeks; RoB "low" = 35%, "some concerns" = 65%) were included. Among trials reporting subtypes (k = 13), 41.8% of participants had bipolar I disorder, and 58.2% had bipolar II disorder. The left dorsolateral prefrontal cortex was the most common target (k = 12). TMS reduced depressive symptoms versus sham (SMD = -0.34; 95%CI = -0.58 to -0.11), with no difference in all-cause discontinuation. TMS was favoured for response (RR = 1.41; 95%CI = 1.10 to 1.80) and remission (RR = 1.54; 95%CI = 1.06 to 2.23). However, these effects were not consistently confirmed in sensitivity or subgroup analyses by RoB, TMS type, stimulation site, or treatment resistance. Overall, 15 comparisons (88.2%) did not show superiority of TMS over sham for depressive symptoms at the individual trial level. No seizures or serious adverse events occurred; adverse events did not differ from sham. Meta-regression suggested a greater number of total pulses was associated with greater depressive symptom reduction (β = -0.018; p = .00017).ConclusionsTMS shows a small meta-analytic antidepressant effect and acceptable tolerability in bipolar depression despite most individual trials being negative. However, subgroups and sensitivity findings did not support TMS as an efficacious treatment at current doses. Further testing via larger RCTs with higher-dose protocols is warranted.

Murine studies show that the gut microbiota-the collection of the microbes residing in the large intestine-affects memory performance in the host. However, whether commensal gut bacteria are linked to human episodic memory remains unknown. Here, we investigated whether individual differences in episodic memory performance were associated with differences in the indigenous gut microbiota composition between individuals. We show that greater gut microbiota α diversity was associated with better item recognition and that gut microbiota dissimilarity index (β diversity) between participants was associated with differences in their performance. Finally, our results suggest that Prevotella copri might play a role in the relationship between gut microbiota and human item recognition in healthy individuals. In a sample size larger than previous human studies and examining unmanipulated gut microbiota, we provide evidence that episodic memory in healthy humans is linked to their gut microbiota composition.

[This corrects the article DOI: 10.3389/fpsyt.2025.1623358.].

OBJECTIVE:To estimate associations of more than minimal prenatal nicotine, alcohol, cannabis, and opioid exposures with gestational age, birth weight, and birth weight for gestational age. METHODS:Data were drawn from the HEALthy Brain and Child Development (HBCD) Study, a multisite, longitudinal study in the United States. Predefined recruitment thresholds for each substance were assessed using maternal self-report, maternal toxicology results, and newborn substance exposure-related diagnoses. Birth outcomes included gestational age at delivery (weeks), birth weight (grams), and birth weight for gestational age (centiles). Mean differences and risk ratios for the associations between substance exposure and birth outcomes were estimated using multilevel mixed-effect linear regression or multilevel mixed-effect Poisson regression. RESULTS:Among 660 mother-infant dyads, 17% (n = 115) of participants met recruitment thresholds for prenatal cannabis, 15% for nicotine (n = 102), 13% for alcohol (n = 86), and 5% for opioids (n = 32). In adjusted models, prenatal cannabis and opioid exposures were each associated with lower birth weight (cannabis: -272.2 [95% CI -444.6 to -99.8] g; opioids: -295.4 [95% CI -574.9 to -15.9] g) and birth weight centiles (cannabis: -8.2 [95% CI -15.3 to -1.1] centiles; opioids: -14.4 [95% CI -25.5, -3.4] centiles), although the results were sensitive to model specifications. Prenatal nicotine and alcohol estimates were in similar directions but not statistically significant. No significant associations between exposures and gestational age at delivery were detected. CONCLUSIONS:In this initial HBCD Study data release, more than minimal exposure to cannabis and opioids was associated with smaller birth size, adding evidence to an inconsistent literature. Future studies from HBCD can more deeply interrogate timing and dose of each substance and expand to childhood outcomes.

While attention-deficit/hyperactivity disorder (ADHD) medications, particularly stimulants, are among the most effective treatments in psychiatry, there remains a need for novel alternatives, as not all individuals with ADHD respond to or tolerate currently available medications. We aimed to provide an up-to-date overview of randomised controlled trials (RCTs) of agents either not approved for ADHD or approved for ADHD but tested for off-label indications. We updated, using the same methodology, two previous reviews (Cortese et al, 2023 exploring agents in the pipeline for children with ADHD, and Veronesi et al, 2024, focusing on RCTs of novel compounds in adults with ADHD). For the update, we searched ClinicalTrials.gov and the European Union-based EU Clinical Trials registers up to December 14, 2025. Including the RCTs retrieved by the two previous reviews and those from the updated search, we identified a total of 53 eligible RCTs. Of these, 11 reported results in children and adolescents, and 11 in adults. Considering agents with at least two positive trials for ADHD core symptoms without negative trials, only dasotraline, in children, and centanafadine, in adults, emerged as promising (however, the dasotraline development programme was halted in 2020). This review also includes a discussion of opportunities for advancing the development of novel, effective agents and maximising the benefits of currently available options.

Executive function (EF), which includes inhibitory control, working memory, and cognitive flexibility, supports adaptive behavior and predicts long-term academic, social, and mental health outcomes. While EF-related neural networks mature throughout childhood, their earliest developmental origins remain unclear. Large-scale brain systems begin organizing in utero, but whether fetal connectivity prospectively relates to EF has not been tested. We collected resting-state fMRI from 113 fetuses (26-39 weeks gestation). Executive function at age 5 was assessed using the Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P), resulting in 52 cases with both usable imaging and outcome data after applying motion and birth-outcome criteria. Whole-brain functional connectivity matrices (197 ROIs) were parcellated into 15 networks, and enrichment analysis identified network pairs with a higher-than-expected density of brain-behavior associations. Six enriched network pairs were associated with global EF, including Frontal, Default Mode Network (DMN), Cerebellar, Salience, and Visual networks. Stronger positive connectivity in Frontal-Salience, DMN-Visual, and Cerebellar-DMN predicted poorer EF, whereas greater negative connectivity in Cerebellar-Visual and Salience-Salience predicted better EF. Subscale analyses revealed both shared and distinct associations across EF domains, with Cerebellar and Salience networks consistently implicated. These findings provide the first evidence linking fetal functional architecture to later EF, highlighting distributed, beyond-frontal systems as early scaffolds of executive control.

Higher predicted brain age difference has been associated with several psychiatric disorders. Generalized anxiety disorder (GAD) is associated with markers of accelerated aging. In this study, we determined brain predicted age difference (PAD) in individuals with GAD and healthy controls (HC) as well as group differences in PAD variability using voxel-wise structural MRI. The training dataset included 3511 controls, and the testing dataset included 1595 individuals with GAD and 4552 HC from the ENIGMA-Anxiety GAD Working Group. A convolutional neural network model using four input modalities per subject and a model ensemble approach was used to predict brain age. The PAD was then calculated by subtracting chronological age from the predicted age. Model performance was consistent with other image-based brain age prediction models with similar accuracy across the training set (mean absolute error (MAE) = 2.95 years) and HC in the testing set (MAE = 2.94). We found no evidence of accelerated brain aging in individuals with GAD compared to individuals without GAD, though we did find evidence for greater variation in PAD for individuals with GAD (Levene's test: W = 442.98, p < 0.001) and evidence for greater variability in PAD of those with GAD over 25 years of age. In several exploratory analyses, we found that symptom severity related significantly to PAD, even after controlling for medication and comorbid diagnoses, echoing previous brain age research. These findings underscore the need for consideration of heterogeneity and dimensionality of psychopathology when examining brain age predicted differences.