Subcortical volume in middle-aged adults with fetal alcohol spectrum disorders.

Studies of youth and young adults with prenatal alcohol exposure (PAE) have most consistently reported reduced volumes of the corpus callosum, cerebellum and subcortical structures. However, it is unknown whether this continues into middle adulthood or if individuals with PAE may experience premature volumetric decline with aging. Forty-eight individuals with fetal alcohol spectrum disorders (FASD) and 28 healthy comparison participants aged 30 to 65 participated in a 3T MRI session that resulted in usable T1-weighted and T2-weighted structural images. Primary analyses included volumetric measurements of the caudate, putamen, pallidum, cerebellum and corpus callosum using FreeSurfer software. Analyses were conducted examining both raw volumetric measurements and subcortical volumes adjusted for overall intracranial volume (ICV). Models tested for main effects of age, sex and group, as well as interactions of group with age and group with sex. We found the main effects for group; all regions were significantly smaller in participants with FASD for models using raw volumes (P's < 0.001) as well as for models using volumes adjusted for ICV (P's < 0.046). Although there were no significant interactions of group with age, females with FASD had smaller corpus callosum volumes relative to both healthy comparison females and males with FASD (P's < 0.001). As seen in children and adolescents, adults aged 30 to 65 with FASD showed reduced volumes of subcortical structures relative to healthy comparison adults, suggesting persistent impact of PAE. Moreover, the observed volumetric reduction of the corpus callosum in females with FASD could suggest more rapid degeneration, which may have implications for cognition as these individuals continue to age.

Brain Volume in Fetal Alcohol Spectrum Disorders Over a 20-Year Span.

Importance: Anomalous brain development and mental health problems are prevalent in fetal alcohol spectrum disorders (FASD), but there is a paucity of longitudinal brain imaging research into adulthood. This study presents long-term follow-up of brain volumetrics in a cohort of participants with FASD. Objective: To test whether brain tissue declines faster with aging in individuals with FASD compared with control participants. Design, Setting, and Participants: This cohort study used magnetic resonance imaging (MRI) data collected from individuals with FASD and control individuals (age 13-37 years at first magnetic resonance imaging [MRI1] acquired 1997-2000) compared with data collected 20 years later (MRI2; 2018-2021). Participants were recruited for MRI1 through the University of Washington Fetal Alcohol Syndrome (FAS) Follow-Up Study. For MRI2, former participants were recruited by the University of Washington Fetal Alcohol and Drug Unit. Data were analyzed from October 2022 to August 2023. Main Outcomes and Measures: Intracranial volume (ICV) and regional cortical and cerebellar gray matter, white matter, and cerebrospinal fluid volumes were quantified automatically and analyzed, with group and sex as between-participant factors and age as a within-participant variable. Results: Of 174 individuals with MRI1 data, 48 refused participation, 36 were unavailable, and 24 could not be located. The remaining 66 individuals (37.9%) were rescanned for MRI2, including 26 controls, 18 individuals with nondysmorphic heavily exposed fetal alcohol effects (FAE; diagnosed prior to MRI1), and 22 individuals with FAS. Mean (SD) age was 22.9 (5.6) years at MRI1 and 44.7 (6.5) years at MRI2, and 35 participants (53%) were male. The FAE and FAS groups exhibited enduring stepped volume deficits at MRI1 and MRI2; volumes among control participants were greater than among participants with FAE, which were greater than volumes among participants with FAS (eg, mean [SD] ICV: control, 1462.3 [119.3] cc at MRI1 and 1465.4 [129.4] cc at MRI2; FAE, 1375.6 [134.1] cc at MRI1 and 1371.7 [120.3] cc at MRI2; FAS, 1297.3 [163.0] cc at MRI1 and 1292.7 [172.1] cc at MRI2), without diagnosis-by-age interactions. Despite these persistent volume deficits, the FAE participants and FAS participants showed patterns of neurodevelopment within reference ranges: increase in white matter and decrease in gray matter of the cortex and decrease in white matter and increase in gray matter of the cerebellum. Conclusions and Relevance: The findings of this cohort study support a nonaccelerating enduring, brain structural dysmorphic spectrum following prenatal alcohol exposure and a diagnostic distinction based on the degree of dysmorphia. FASD was not a progressive brain structural disorder by middle age, but whether accelerated decline occurs in later years remains to be determined.

Current considerations for fetal alcohol spectrum disorders: identification to intervention.

PURPOSE OF REVIEW: This review highlights recent findings regarding the prevalence, public health impact, clinical presentation, intervention access and conceptualization of fetal alcohol spectrum disorders (FASDs). Despite ongoing work in prevention and identification of this population, the rates of drinking during pregnancy have increased and significant gaps remain in diagnosis and intervention. RECENT FINDINGS: Prenatal alcohol exposure is the most common preventable cause of developmental disability in the world. Research has focused on improving diagnostic clarity, utilizing technology and neuroimaging to facilitate identification, engaging broader stakeholders (including self-advocates) to inform understanding and needs, and increasing access to effective interventions. There is an emerging focus on developmental trajectories and experiences in young and middle adulthood. Public policy advocacy has also made great strides in recent years. SUMMARY: Increases in public awareness, greater concordance of diagnostic schema, leveraged use of novel technology, and the development of targeted interventions within a holistic, strengths-based conceptualization are important considerations for this population.

Tertiary Survey in the Days of Modern Imaging: Assessing the Detection Rate of Clinically Significant Injuries on Tertiary Survey in a Level 2 Trauma Centre.

AIM: To determine the utility of tertiary survey (TS) in patients subjected to whole-body CT (WBCT) or selective CT (SCT) following trauma. METHODS: A retrospective analysis was performed on trauma patients admitted to a level 2 trauma centre following the introduction of a standardised TS form in 2017. The initial imaging protocol (WBCT versus selective CT versus x-ray), subsequently requested imaging, standardised injury data, and length of stay (LOS) were recorded. Clinically significant injuries were defined as those with an Injury Severity Score (ISS) of 1 on the Abbreviated Injury Scale (AIS). RESULTS: Five hundred and seven patients were included. The rate of additional significant injuries at the time of TS was 1.18% (n=6), each requiring conservative management only. There was no significant difference in injury detection based on the initial imaging protocol; however, there were three near-misses identified. Of these patients, two underwent selective CT and one was subjected to a plain film series, with clinically significant injuries identified early upon completion of trauma imaging. Overall, 2.9% (n=15) of patients had completed trauma imaging during the same admission. WBCT was associated with higher ISS and length of stay (p<0.05). After controlling for ISS, there was no difference in length of stay between imaging modalities except in those patients with an ISS of 0 (no clinically significant injuries), who appeared to have longer admissions if subject to WBCT (p<0.001). CONCLUSION: The rate of missed injuries identified at TS is low. The imaging modality did not alter this. This may allow for the omission of the tertiary survey and earlier discharge in many trauma patients.

Neurodevelopmental Trajectories Following Prenatal Alcohol Exposure.

Prenatal alcohol exposure (PAE) interferes with neurodevelopment. The brain is particularly susceptible to the adverse consequences of prenatal alcohol exposure, and numerous studies have documented changes to brain anatomy and function, as well as consequences for cognition, behavior, and mental health. Studies in typically developing individuals have shown that the brain undergoes dynamic developmental processes over an individual's lifespan. Furthermore, magnetic resonance imaging (MRI) studies in other neurodevelopmental and psychiatric disorders have shown that their developmental trajectories differ from the typical pattern. Therefore, to understand long-term clinical outcomes of fetal alcohol spectrum disorders (FASD), it is necessary to investigate changes in neurodevelopmental trajectories in this population. Here we review studies that have used MRI to evaluate changes in brain structure and function over time via cross-sectional or longitudinal methods in individuals with PAE. Research demonstrates that individuals with PAE have atypical cortical and white matter microstructural developmental trajectories through childhood and adolescence. More research is needed to understand how factors such as sex and postnatal experiences may further mediate these trajectories. Furthermore, nothing is known about the trajectories beyond young adulthood.

Cross-Sectional Analysis of Spatial Working Memory Development in Children with Histories of Heavy Prenatal Alcohol Exposure.

BACKGROUND: In children with prenatal alcohol exposure, spatial working memory is affected and brain regions important for spatial working memory performance exhibit atypical neurodevelopment. We therefore hypothesized that children with prenatal alcohol exposure may also have atypical development of spatial working memory ability. METHODS: We examined the relation between spatial working memory and age using a cross-sectional developmental trajectory approach in youth with and without histories of heavy prenatal alcohol exposure. The Cambridge Neuropsychological Test Automated Battery Spatial Working Memory subtest was administered to children 5.0 to 16.9 years old. RESULTS: While the controls and children with prenatal alcohol exposure showed similar performance at younger ages, larger group differences were observed in older children. This effect was replicated in a separate sample. CONCLUSIONS: The atypical brain development that has previously been reported in children with heavy prenatal alcohol exposure may have clinically relevant implications for cognitive development; however, longitudinal cognitive analyses are needed.

Mortality of patients with COVID-19 who undergo an elective or emergency surgical procedure: a systematic review and meta-analysis.

BACKGROUND: There have been several reports that co-infection with the novel coronavirus severe acute respiratory syndrome coronavirus 2 at the time of surgery increases mortality. The aim of this study was to estimate the effect size of coronavirus disease 2019 (COVID-19) on post-operative mortality by performing a systematic review and meta-analysis of the literature. METHODS: A systematic review and meta-analysis of the literature was performed. A search was undertaken using electronic bibliographic databases MEDLINE, EMBASE, PubMed and Cochrane Library to identify eligible studies published from 1 November 2019 until 21 August 2020. Eligible papers for meta-analysis were those that provided mortality rates following elective and emergency surgery in both COVID-19 positive and negative patients. Forest plots and estimates of odds of death related to having COVID-19 were formed using MedCalc version 9.6 software. Funnel plots to assess for publication bias and heterogeneity were formed in Meta-Essentials. RESULTS: There were 140 records screened for inclusion. Full texts of 39 articles were reviewed, and 36 articles were included in the qualitative synthesis. There were eight studies eligible for meta-analysis. There was a total of 193 operations performed on patients with a concurrent COVID-19 infection and 910 performed on patients who were COVID-19 negative. The odds ratio for mortality in patients who underwent a surgical procedure while COVID-19 positive was 7.9 (95% confidence interval: 3.2-19.4). CONCLUSION: This meta-analysis confirms that concurrent COVID-19 infection increases the risk of surgical mortality. The magnitude of this risk mandates that strategies are developed to mitigate the risk at both an individual and system level.

Analysis of Financial Risk Protection Indicators in Myanmar for Paediatric Surgery.

PURPOSE: To estimate proportion of Myanmar paediatric population at risk of impoverishment and catastrophic expenditure due to emergency surgical intervention. METHODS: Prospective data were collected at two tertiary surgical centres including income, household expenses, expenses related to surgery. Data analysis was performed to estimate out-of-pocket (OOP) direct medical costs and OOP total costs. Catastrophic expenditure: expense exceeded 10% of household income. Risk of impoverishment: net income drops were below an impoverishment threshold (PPP-purchasing power parity): I$ 2.00 PPP/day, I$ 1.25/day PPP, national poverty line. Distribution of income was estimated using a gamma distribution. Comparison to an adult cohort was performed using Chi-square test with a p value of <0.05 being significant. RESULTS: A total of 145 surveys were collected, and 119 (82.1%) contained sufficient data: Paediatric Centre (n = 99) and Adult Centre (n = 20). Overall average per patient direct medical and non-medical OOP costs was I$493: Centre 1: I$540 PPP (range I$41-6,588 PPP) and Centre 2: I$437 PPP (range I$ 36-1,405 PPP). 64% experienced catastrophic expense. There is no significant difference between the centres in the risks of impoverishment or catastrophic expenditure (p = 0.05). Up to 44% are at risk of catastrophic expenditure should surgery be required. Most of the risk (90%) is derived from direct non-medical costs. A high proportion were at the national poverty line threshold (36.1%). Seeking surgical treatment would imperil up to 37% at the national poverty line threshold, and up to 5.7% at the I$2 PPP per day limit. CONCLUSIONS: A large proportion of the Myanmar population are at risk of impoverishment or catastrophic expenditure should they require surgery. Financial risk protection mechanisms are needed.

How will increasing surgical volume affect mortality in the Pacific, Papua New Guinea and Timor Leste?

BACKGROUND: Nine South Pacific nations, Papua New Guinea and Timor Leste, have collaborated to report and publish their surgical metrics as recommended by the Lancet Commission on Global Surgery (LCoGS). Currently, these countries experience about 750 postoperative deaths per year, representing 1% of crude mortality in the region. Given that more than 400 000 annual procedures are needed in the nine nations to reach the LCoGS target of 5000/100 000, we aimed to calculate the potential contribution of perioperative mortality to national mortality where these procedures are performed. METHODS: We utilized reported surgical metrics with current rates for surgical volume (SV) and perioperative mortality (POMR), as well as World Bank/WHO mortality statistics, to predict the likely impact of surgical scale-up to recommended targets by 2030. We tested correlations between SV and POMR in countries from our region using Pearson's r statistic. Funnel plots were used to evaluate the dataset for outliers. RESULTS: Surgical scale up would result in perioperative mortality contributing on average to 3.3% of all national crude mortality. This prediction assumes POMR stays the same, which is challenging to predict. In our region countries that achieved the LCoGS target (n = 5) had a lower POMR than countries that did not (n = 8). CONCLUSIONS: Surgical volumes in the South Pacific region must increase to meet the LCoGS target. Postoperative mortality as a proportion of all mortality may increase with the surgical scale up, however, the overall number of premature deaths is expected to reduce with better access to timely and safe surgical care.

Graded Cerebellar Lobular Volume Deficits in Adolescents and Young Adults with Fetal Alcohol Spectrum Disorders (FASD).

The extensive prenatal developmental growth period of the cerebellum renders it vulnerable to unhealthy environmental agents, especially alcohol. Fetal alcohol spectrum disorders (FASD) is marked by neurodysmorphology including cerebral and cerebellar volume deficits, but the cerebellar lobular deficit profile has not been delineated. Legacy MRI data of 115 affected and 59 unaffected adolescents and young adults were analyzed for lobular gray matter volume and revealed graded deficits supporting a spectrum of severity. Graded deficits were salient in intracranial volume (ICV), where the fetal alcohol syndrome (FAS) group was smaller than the fetal alcohol effects (FAE) group, which was smaller than the controls. Adjusting for ICV, volume deficits were present in VIIB and VIIIA of the FAE group and were more widespread in FAS and included lobules I, II, IV, V, VI, Crus II, VIIB, and VIIIA. Graded deficits (FAS < FAE) were consistently present in lobules VI; neither group showed volume deficits in Crus I or IX. Neuroradiological readings blind to diagnosis identified 20 anomalies, 8 involving the cerebellum, 5 of which were in the FAS group. We speculate that the regional cerebellar FASD-related volume deficits may contribute to diagnostically characteristic functional impairment involving emotional control, visuomotor coordination, and postural stability.

The Economic Value of the Delivery of Primary Cleft Surgery in Timor Leste 2000-2017.

BACKGROUND: Plastic and reconstructive surgical teams visiting from Australia, a high-income country, have delivered cleft surgical services to Timor Leste since 2000 on a volunteer basis. This paper aims to estimate the economic benefit of correcting cleft deformities in this new nation as it evolved its healthcare delivery service from independence in 1999. METHODS: We have utilised a prospective database of all cleft surgical interventions performed during 44 plastic surgical missions over the last 18 years. The disability-adjusted life year (DALY) framework was used to calculate the total DALYs averted by primary cleft lip and palate repair. The 2004 global burden of disease disability weights were used. Economic benefits were calculated using the gross national income (GNI) and the value of a statistical life (VSL) methods for Timor Leste. Estimates were adjusted for treatment effectiveness, counterfactual cases, and complications. Cost estimates included the local hospitalisation costs, the foregone salaries of the visiting surgeons and nurses, other costs associated with providing surgical care, and an estimate for foregone wages of the patients or their carers. Sensitivity analysis was performed with income elasticity set to 0.55, 1.0, and 1.5. RESULTS: During 44 visiting plastic surgical missions to Timor Leste, 1500 procedures were performed, including 843 primary cleft lip and palate operations. The cleft procedures resulted in the aversion of 842 DALYs and an economic return to Timor Leste of USD 2.2 million (GNI-based) or USD 197,917 (VSL-based). Our programme cost USD 705 per DALY averted. The economic return on investment was 0.3:1 (VSL-based) or 3.8:1 (GNI-based). CONCLUSION: A sustained and consistent visiting team approach providing repair of cleft lip and palate defects has resulted in considerable economic gain for Timor Leste over an 18-year period. The training of a local surgeon and multidisciplinary team with ongoing support to the in-country cleft service is expected to reduce the cost per DALY averted once the surgeon and team are able to manage clefts independently.

Neurodevelopment in adolescents and adults with fetal alcohol spectrum disorders (FASD): A magnetic resonance region of interest analysis.

The neurodevelopmental trajectory in individuals with fetal alcohol spectrum disorders (FASD) has not been well characterized. We examined age-related differences in the volume of the corpus callosum, basal ganglia, and cerebellum across adolescence and young adulthood, due to the sensitivity of these regions to prenatal alcohol exposure. T1-weighted anatomical magnetic resonance images (MRI) were acquired from a cross-sectional sample of subjects 13-30 years old who had received an alcohol-related diagnosis (FASD, n = 107) and typically developing controls (CON, n = 56). FreeSurfer v5.3 was used to obtain volumetric data for the corpus callosum, caudate, putamen, pallidum, and cerebellum. Analysis of variance (ANOVA) was used to examine the effects of group (FASD, CON), sex, and age on region volume. Data were analyzed with and without correction for intracranial volume (ICV). All subregions were significantly smaller in the FASD group compared to controls, and these findings persisted even after ICV correction. Furthermore, the FASD and control groups differed in their relationship between age and total volume of the corpus callosum, caudate, and cerebellum. Specifically, older FASD individuals had smaller total volume in these regions; this relationship was not seen in the control group. Control males demonstrated larger volumes than control females in all regions prior to ICV correction; however, sex differences were attenuated in the FASD group in both the pallidum and cerebellum. Sex differences remained after ICV correction in the pallidum and cerebellum. These cross-sectional findings suggest that at least some brain regions may become smaller at an earlier than expected age in individuals with FASD, and that sex is an important factor to consider when examining neural structures in FASD. Further evaluation is necessary using longitudinal methods and including older ages.

Universal access to safe, affordable, timely surgical and anaesthetic care in Papua New Guinea: the six global health indicators.

BACKGROUND: The unmet global burden of surgical disease is substantial. The Lancet Commission on Global Surgery (LCoGS) estimated that 5 billion people do not have access to safe, affordable and timely surgical care, with 80% of those without access living in low- and middle-income countries. The Milne Bay Province (pop 331 000) of Papua New Guinea, with an archipelago of islands up to 750 km from its capital, Alotau, has only one hospital capable of performing Caesarean Section, Emergency Laparotomy and managing an open fracture, the three Bellwether procedures. This paper aims to report the six Lancet Commission on Global Surgery metrics for Milne Bay Province. METHODS: The study was conducted between January and August 2019. Bellwether access was investigated by a prospective study on 115 patients presenting to hospital. The surgical, anaesthesia and obstetric (SAO) workforce, surgical volume and perioperative mortality rate, were calculated for 2012-2018 from hospital records and operation registers. Financial risk metrics were calculated by surveying 50 patients at discharge from hospital. RESULTS: Bellwether access: Only 27.8% (n = 32) of the study population (n = 115) experienced less than 2-hours second delay (journey time to hospital). The average SAO provider density was 1.8 per 100 000 population. There were 606 procedures performed per 100 000 with a mean annual perioperative mortality rate of 0.3%. Catastrophic expenditure is a risk for 29% of the population. CONCLUSION: Milne Bay Province can perform surgery safely, but there is limited access to timely surgical care when needed with a significant proportion put at financial risk by requiring it.

Male urethral stricture disease in a regional centre: 10 years of experience.

BACKGROUND: Male urethral stricture disease is a challenging condition with a propensity for recurrence following endoscopic management. In recent years, earlier definitive urethral reconstruction has been advocated through international guidelines, prompted by series suggesting the underutilization of urethroplasty at rates of 0.6-0.8%. However, little local data exists to characterize our urethral stricture patients and we aimed to characterize the management of patients with urethral stricture disease presenting over a 10-year period to a single regional centre. METHODS: Patients with urethral stricture disease and admitted to a regional health service were identified. Retrospective chart review was undertaken for patients detailing basic demographics, stricture characteristics, clinical management and follow up. RESULTS: We identified 360 patients with median age 69 years (interquartile range 56-77). A total of 191 (53%) presented with lower urinary tract symptoms, 122 (34%) urethral strictures were incidental, and 13% presented in urinary retention. Bulbar urethral strictures were the commonest strictures at 40% with most being spontaneous or idiopathic (67%). A total of 339 patients had treatment during their first admission, 48% of patients had subsequent treatment on a second episode, and over 20% had a third or subsequent treatment. Only 21 (5.8%) underwent urethroplasty. Urethral dilatation and optical urethrotomy were most commonly performed (54%). With follow up 19 months (interquartile range 2-56), 205 (57%) were voiding, 38 (11%) were performing intermittent catheterization, and 59 were catheterized permanently. CONCLUSION: Definitive urethral reconstruction appears underutilized in our cohort of patients. A high proportion of incidentally presenting urethral strictures emphasizes the importance of wider education to optimize patient outcomes.

Executive Functioning Correlates With Communication Ability in Youth With Histories of Heavy Prenatal Alcohol Exposure.

OBJECTIVES: Caregivers of youth with heavy prenatal alcohol exposure report impaired communication, which can significantly impact quality of life. Using data collected as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD), we examined whether cognitive variables predict communication ability of youth with histories of heavy prenatal alcohol exposure. METHODS: Subjects (ages 10-16 years) comprised two groups: adolescents with heavy prenatal alcohol exposure (AE) and non-exposed controls (CON). Selected measures of executive function (NEPSY, Delis-Kaplan Executive Function System), working memory (CANTAB), and language were tested in the child, while parents completed communication ratings (Vineland Adaptive Behavior Scales - Second Edition). Separate multiple regression analyses determined which cognitive domains predicted communication ability. A final, global model of communication comprised the three cognitive models. RESULTS: Spatial Working Memory and Inhibition significantly contributed to communication ability across groups. Twenty Questions performance related to communication ability in the CON group only while Word Generation performance related to communication ability in the AE group only. Effects remained significant in the global model, with the exception of Spatial Working Memory. CONCLUSIONS: Both groups displayed a relation between communication and Spatial Working Memory and Inhibition. Stronger communication ability related to stronger verbal fluency in the AE group and Twenty Questions performance in the CON group. These findings suggest that alcohol-exposed adolescents may rely more heavily on learned verbal storage or fluency for daily communication while non-exposed adolescents may rely more heavily on abstract thinking and verbal efficiency. Interventions aimed at aspects of executive function may be most effective at improving communication ability of these individuals. (JINS, 2018, 24, 1026-1037).

Post-Operative Cognitive Dysfunction: An exploration of the inflammatory hypothesis and novel therapies.

Post-Operative Cognitive Dysfunction (POCD) is a highly prevalent condition with significant clinical, social and financial impacts for patients and their communities. The underlying pathophysiology is becoming increasingly understood, with the role of neuroinflammation and oxidative stress secondary to surgery and anaesthesia strongly implicated. This review aims to describe the putative mechanisms by which surgery-induced inflammation produces cognitive sequelae, with a focus on identifying potential novel therapies based upon their ability to modify these pathways.

Neural correlates of verbal memory in youth with heavy prenatal alcohol exposure.

Prenatal alcohol exposure can impact both brain development and neurobehavioral function, including verbal learning and recall, although the relation between verbal recall and brain structure in this population has not been examined fully. We aimed to determine the structural neural correlates of verbal learning and recall in youth with histories of heavy prenatal alcohol exposure using a region of interest (ROI) approach. As part of an ongoing multisite project, subjects (age 10-16 years) with prenatal alcohol exposure (AE, n = 81) and controls (CON, n = 81) were tested using the CVLT-C and measures of cortical volume, surface area, and thickness as well as hippocampal volume were derived from MRI. Group differences in brain and memory indices were tested with ANOVA. Multiple regression analyses tested whether brain ROIs significantly predicted memory performance. The AE group had lower scores than the CON group on all CVLT-C variables (ps ≤ .001) and volume and surface area (ps < .025), although results varied by ROI. No group differences in cortical thickness were found. The relations between cortical structure and memory performance differed between group among some ROIs, particularly those in the frontal cortex, generally with smaller surface area and/or thinner cortex predicting better performance in CON but worse performance in AE. Cortical surface area appears to be the most sensitive index to the effects of prenatal alcohol exposure, while cortical thickness appears to be the least sensitive. These findings also indicate that the neural correlates of verbal memory are altered in youth with heavy prenatal alcohol exposure compared to controls.

Altered functional connectivity during spatial working memory in children with heavy prenatal alcohol exposure.

Individuals prenatally exposed to alcohol often have impaired spatial working memory (SWM). This study examines functional connections of frontal and parietal regions that support SWM in children with and without prenatal alcohol exposure. Children ages 10 to 16 with histories of heavy prenatal alcohol exposure (AE group; n = 18) and controls (CON group; n = 19) underwent functional magnetic resonance imaging (fMRI) while performing a SWM task. Whole brain task-related functional connectivity of bilateral dorsolateral prefrontal cortex (DLPFC) and posterior parietal cortex (PPC) seed regions were estimated for each participant using a psychophysiological interaction approach. Children in the AE group were less accurate than children in the CON group when performing the SWM task (p = 0.008). Positive coupling between bilateral DLPFC seeds and regions within the fronto-parietal network was observed in the CON group, whereas the AE group showed negative connectivity. In contrast to the CON group, the AE group showed positive connectivity between PPC seeds and frontal lobe regions. Across seeds, decreased negative coupling with regions outside the fronto-parietal network (e.g., left middle occipital gyrus) were observed in the AE group relative to the CON group. Functional data clusters were considered significant at p < 0.05. Overall findings suggest that localized alterations in neural activity, aberrant fronto-parietal network synchrony, and poor coordination of neural responses with regions outside of this network may help explain SWM deficits in individuals with a history of heavy prenatal alcohol exposure.

Activation of extrasynaptic δ-GABAA receptors globally or within the posterior-VTA has estrous-dependent effects on consumption of alcohol and estrous-independent effects on locomotion.

Recent reports support higher than expected rates of binge alcohol consumption among women and girls. Unfortunately, few studies have assessed the mechanisms underlying this pattern of intake in females. Studies in males suggest that alcohol concentrations relevant to the beginning stages of binge intoxication may selectively target tonic GABAergic inhibition mediated by GABAA receptor subtypes expressing the δ-subunit protein (δ-GABAARs). Indeed, administration of agonists that interact with these δ-GABAARs prior to alcohol access can abolish binge drinking behavior in male mice. These δ-GABAARs have also been shown to exhibit estrous-dependent plasticity in regions relevant to drug taking behavior, like the hippocampus and periaqueductal gray. The present experiments were designed to determine whether the estrous cycle would alter binge drinking, or our ability to modulate this pattern of alcohol use with THIP, an agonist with high selectivity and efficacy at δ-GABAARs. Using the Drinking-in-the-Dark (DID) binge-drinking model, regularly cycling female mice were given 2h of daily access to alcohol (20%v/v). Vaginal cytology or vaginal impedance was assessed after drinking sessions to track estrous status. There was no fluctuation in binge drinking associated with the estrous cycle. Both Intra-posterior-VTA administration of THIP and systemic administration of the drug was also associated with an estrous cycle dependent reduction in drinking behavior. Pre-treatment with finasteride to inhibit synthesis of 5α-reduced neurosteroids did not disrupt THIP's effects. Analysis of δ-subunit mRNA from posterior-VTA enriched tissue samples revealed that expression of this GABAA receptor subunit is elevated during diestrus in this region. Taken together, these studies demonstrate that δGABAARs in the VTA are an important target for binge drinking in females and confirm that the estrous cycle is an important moderator of the pharmacology of this GABAA receptor subtype.