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Background About 69% of the 299,000 Americans living with spinal cord injury (SCI) experience long-term debilitating neuropathic pain. New treatments are needed because current treatments do not provide enough pain relief. We have found that insular-opercular brain network alterations may contribute to neuropathic pain and that restoring this network could reduce neuropathic pain. Here, we outline a study protocol using a physical therapy approach, cognitive multisensory rehabilitation (CMR), which has been shown to restore OP1/OP4 connections in adults post stroke, to test our hypothesis that CMR can normalize pain perception through restoring OP1/OP4 connectivity in adults with SCI and relieve neuropathic pain. Objectives To compare baseline brain function via resting-state and task-based functional magnetic resonance imaging in adults with SCI versus uninjured controls, and to identify changes in brain function and behavioral pain outcomes after CMR in adults with SCI. Methods In this phase I randomized controlled trial, adults with SCI will be randomized into two groups: Group A will receive 6 weeks of CMR followed by 6 weeks of standard of care (no therapy) at home. Group B will start with 6 weeks of standard of care (no therapy) at home and then receive 6 weeks of CMR. Neuroimaging and behavioral measures are collected at baseline, after the first 6 weeks (A: post therapy, B: post waitlist), and after the second 6 weeks (A: post-therapy follow-up, B: post therapy), with follow-up of both groups up to 12 months. Conclusion The successful outcome of our study will be a critical next step toward implementing CMR in clinical care to improve health in adults with SCI.

SUMMARYBackgroundChronic low back pain (cLBP) affects the quality of life of 52 million Americans and leads to an enormous personal and economic burden. A multidisciplinary approach to cLBP management is recommended. Since medication has limited efficacy and there are mounting concerns about opioid addiction, the American College of Physicians and American Pain Society recommend non-pharmacological interventions, such as mind and body approaches (e.g., Qigong, yoga, Tai Chi) before prescribing medications. Of those, Qigong practice might be most accessible given its gentle movements and because it can be performed standing, sitting, or lying down. The three available Qigong studies in adults with cLBP showed that Qigong reduced pain more than waitlist and equally well than exercise. Yet, the duration and/or frequency of Qigong practice were low (MethodsWe conducted a feasibility Phase I Randomized Clinical Trial. Of the 36 adults with cLBP recruited between January 2020 and June 2021, 32 were enrolled and randomized to either 12 weeks of remote Spring Forest Qigong™ practice or remote P.Volve low-intensity exercises. Participants practiced at least 3x/week for 41min/session with online videos. Our main outcome measures were the Numeric Pain Rating Scale (highest, average, and lowest cLBP pain intensity levels in the prior week), assessed weekly and fMRI data (resting-state and task-based fMRI tasks: pain imagery, kinesthetic imagery of a Qigong movement, and robot-guided shape discrimination). We compared baseline resting-state connectivity and brain activation during fMRI tasks in adults with cLBP with data from a healthy control group (n=28) acquired in a prior study. Secondary outcomes included measures of function, disability, body awareness, kinesiophobia, balance, self-efficacy, core muscle strength, and ankle proprioceptive acuity with a custom-build device.ResultsFeasibility of the study design and methods was demonstrated with 30 participants completing the study (94% retention) and reporting high satisfaction with the programs; 96% adherence to P.Volve low-intensity exercises, and 128% of the required practice intensity for Spring Forest Qigong™ practice. Both groups saw promising reductions in low back pain (effect sizes Cohen’sd=1.01-2.22) and in most other outcomes (d=0.90-2.33). Markers of ankle proprioception were not significantly elevated in the cLBP group after the interventions. Brain imaging analysis showed weaker parietal operculum and insula network connectivity in adults with cLBP (n=26), compared to data from a healthy control group (n=28). The pain imagery task elicited lower brain activation of insula, parietal operculum, angular gyrus and supramarginal gyrus at baseline in adults with cLBP than in healthy adults. Adults with cLBP had lower precentral gyrus activation than healthy adults for the Qigong movement and robot task at baseline. Pre-post brain function changes showed individual variability: Six (out of 13) participants in the Qigong group showed increased activation in the parietal operculum, angular gyrus, supramarginal gyrus, and precentral gyrus during the Qigong fMRI task.InterpretationOur data indicate the feasibility and acceptability of using Spring Forest Qigong™ practice or P.Volve low-intensity exercises for cLBP relief showing promising results in terms of pain relief and associated symptoms. Our brain imaging results indicated brain function improvements after 12 weeks of Qigong practice in some participants, pointing to the need for further investigation in larger studies.Trial registration numberClinicalTrials.gov:NCT04164225.

SUMMARYBackgroundNeuropathic pain after spinal cord injury (SCI) is notoriously hard to treat. Mechanisms of neuropathic pain are unclear, which makes finding effective treatments challenging. Prior studies have shown that adults with SCI have body awareness deficits. Recent imaging studies, including ours, point to the parietal operculum and insula as key areas for both pain perception and body awareness. Cognitive multisensory rehabilitation (CMR) is a physical therapy approach that helps improve body awareness for pain reduction and sensorimotor recovery. Based on our prior brain imaging work in CMR in stroke, we hypothesized that improving body awareness through restoring parietal operculum network connectivity leads to neuropathic pain relief and improved sensorimotor and daily life function in adults with SCI. Thus, the objectives of this study were to (1) determine baseline differences in resting-state and task-based functional magnetic resonance imaging (fMRI) brain function in adults with SCI compared to healthy controls and (2) identify changes in brain function and behavioral pain and pain-associated outcomes in adults with SCI after CMR.MethodsHealthy adults underwent a one-time MRI scan and completed questionnaires. We recruited community-dwelling adults with SCI-related neuropathic pain, with complete or incomplete SCI >3 months, and highest neuropathic pain intensity level of >3 on the Numeric Pain Rating Scale (NPRS). Participants with SCI were randomized into two groups, according to a delayed treatment arm phase I randomized controlled trial (RCT): Group A immediately received CMR intervention, 3x/week, 45 min/session, followed by a 6-week and 1-year follow-up. Group B started with a 6-week observation period, then 6 weeks of CMR, and a 1-year follow-up. Highest, average, and lowest neuropathic pain intensity levels were assessed weekly with the NPRS as primary outcome. Other primary outcomes (fMRI resting-state and functional tasks; sensory and motor function with the INSCI AIS exam), as well as secondary outcomes (mood, function, spasms, and other SCI secondary conditions), were assessed at baseline, after the first and second 6-week period. The INSCI AIS exam and questionnaires were repeated at the 1-year follow-up.FindingsThirty-six healthy adults and 28 adults with SCI were recruited between September 2020 and August 2021, and of those, 31 healthy adults and 26 adults with SCI were enrolled in the study. All 26 participants with SCI completed the intervention and pre-post assessments. There were no study-related adverse events. Participants were 52±15 years of age, and 1-56 years post-SCI. During the observation period, group B did not show any reductions in neuropathic pain and did not have any changes in sensation or motor function (INSCI ASIA exam).However, both groups experienced a significant reduction in neuropathic pain after the 6-week CMR intervention. Their highest level ofneuropathic painof 7.81±1.33 on the NPRS at baseline was reduced to 2.88±2.92 after 6 weeks of CMR. Their change scores were 4.92±2.92 (large effect size Cohen’sd=1.68) for highest neuropathic pain, 4.12±2.23 (d=1.85) for average neuropathic pain, and 2.31±2.07 (d=1.00) for lowest neuropathic pain. Nine participants out of 26 were pain-free after the intervention (34.62%).The results of the INSCI AIS testing also showed significant improvements in sensation, muscle strength, and function after 6 weeks of CMR. Their INSCI AIS exam increased by 8.81±5.37 points (d=1.64) for touch sensation, 7.50±4.89 points (d=1.53) for pin prick sensation, and 3.87±2.81 (d=1.38) for lower limb muscle strength. Functional improvements after the intervention included improvements in balance for 17 out of 18 participants with balance problems at baseline; improved transfers for all of them and a returned ability to stand upright with minimal assistance in 12 out of 20 participants who were unable to stand at baseline. Those improvements were maintained at the 1-year follow-up.With regard to brain imaging, we confirmed that the resting-state parietal operculum and insula networks had weaker connections in adults with SCI-related neuropathic pain (n=20) compared to healthy adults (n=28). After CMR, stronger resting-state parietal operculum network connectivity was found in adults with SCI. Also, at baseline, as expected, right toe sensory stimulation elicited less brain activation in adults with SCI (n=22) compared to healthy adults (n=26). However, after CMR, there was increased brain activation in relevant sensorimotor and parietal areas related to pain and mental body representations (i.e., body awareness and visuospatial body maps) during the toe stimulation fMRI task. These brain function improvements aligned with the AIS results of improved touch sensation, including in the feet.InterpretationAdults with chronic SCI had significant neuropathic pain relief and functional improvements, attributed to the recovery of sensation and movement after CMR. The results indicate the preliminary efficacy of CMR for restoring function in adults with chronic SCI. CMR is easily implementable in current physical therapy practice. These encouraging impressive results pave the way for larger randomized clinical trials aimed at testing the efficacy of CMR to alleviate neuropathic pain in adults with SCI.Clinical Trial registrationClinicalTrials.govIdentifier:NCT04706208FundingAIRP2-IND-30: Academic Investment Research Program (AIRP) University of Minnesota School of Medicine. National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR002494; the Biotechnology Research Center: P41EB015894, the National Institute of Neurological Disorders & Stroke Institutional Center Core Grants to Support Neuroscience Research: P30 NS076408; and theHigh-Performancee Connectome Upgrade for Human 3T MR Scanner: 1S10OD017974.

Fear overgeneralization is a potential pathogenic mechanism of anxiety-related disorders. A dominant model posits that overgeneralization occurs when the hippocampus fails to distinctly encode benign stimuli with insufficient similarity to previously encountered fear cues, triggering excessive retrieval of stored fear representations. This model has cross-species support but has not been causally tested in humans. A developing literature demonstrates that hippocampal network targeted transcranial magnetic stimulation (HNT-TMS) can strengthen hippocampal-dependent memory encoding. Building on this literature, we hypothesized that HNT-TMS would strengthen encoding of perceptually similar stimuli and thereby reduce retrieval errors (i.e., sharpen discrimination) in participants with post-traumatic stress symptoms. We predicted that this effect would emerge for fear stimuli as measured by the Farmer Task and neutral stimuli as measured by the Mnemonic Similarity Task. Continuous theta-burst stimulation (cTBS) was delivered to individualized left posterior-parietal targets derived via precision functional mapping, seed-based connectivity, and electric-field modeling methods. A vertex control target was also stimulated in a within-subject design (final N = 25). Multilevel models did not reveal significant interactions between stimulation target and fear or neutral stimulus discrimination. However, HNT-TMS strengthened fear discrimination in participants with lower sensitization, indexed by responsivity to a control stimulus perceptually unrelated to the CS+. Sensitization reflects indiscriminate fear responding unrelated to CS + similarity and is not expected to engage the hippocampal CS + matching function. Our findings therefore indicate that HNT-TMS may selectively sharpen fear discrimination when the hippocampal CS + matching function is more strongly engaged.

Nonsuicidal self-injury (NSSI) is a common but poorly understood phenomenon in adolescents. This study examined the Sustained Threat domain in female adolescents with a continuum of NSSI severity (N = 142). Across NSSI lifetime frequency and NSSI severity groups (No + Mild NSSI, Moderate NSSI, Severe NSSI), we examined physiological, self-reported and observed stress during the Trier Social Stress Test; amygdala volume; amygdala responses to threat stimuli; and resting-state functional connectivity (RSFC) between amygdala and medial prefrontal cortex (mPFC). Severe NSSI showed a blunted pattern of cortisol response, despite elevated reported and observed stress during TSST. Severe NSSI showed lower amygdala–mPFC RSFC; follow-up analyses suggested that this was more pronounced in those with a history of suicide attempt for both moderate and severe NSSI. Moderate NSSI showed elevated right amygdala activation to threat; multiple regressions showed that, when considered together with low amygdala–mPFC RSFC, higher right but lower left amygdala activation predicted NSSI severity. Patterns of interrelationships among Sustained Threat measures varied substantially across NSSI severity groups, and further by suicide attempt history. Study limitations include the cross-sectional design, missing data, and sampling biases. Our findings highlight the value of multilevel approaches in understanding the complexity of neurobiological mechanisms in adolescent NSSI.

Theoretical models of addiction suggest that alterations in addiction domains including incentive salience, negative emotionality, and executive control lead to relapse in alcohol use disorder (AUD). To determine whether the functional organization of neural networks underlying these domains predict subsequent relapse, we generated theoretically defined addiction networks. We collected resting functional magnetic resonance imaging data from 45 individuals with AUD during early abstinence (number of days abstinent M = 25.40, SD = 16.51) and calculated the degree of resting-state functional connectivity (RSFC) within these networks. Regression analyses determined whether the RSFC strength in domain-defined addiction networks measured during early abstinence predicted subsequent relapse (dichotomous or continuous relapse metrics). RSFC within each addiction network measured during early abstinence was significantly lower in those that relapsed (vs. abstained) and predicted subsequent time to relapse. Lower incentive salience RSFC during early abstinence increased the odds of relapsing. Neither RSFC in a control network nor clinical self-report measures predicted relapse. The association between low incentive salience RSFC and faster relapse highlights the need to design timely interventions that enhance RSFC in AUD individuals at risk of relapsing faster.

Highlights • Brain networks in mTBI remain plastic decades after injury. • Global integration increased over time in mTBI group to the level of Controls. • mTBI networks became more clustered and less segregated into modules over time., Background In mild traumatic brain injury (mTBI), diffuse axonal injury results in disruption of functional networks in the brain and is thought to be a major contributor to cognitive dysfunction even years after trauma. Objective Few studies have assessed longitudinal changes in network topology in chronic mTBI. We utilized a graph theoretical approach to investigate alterations in global network topology based on resting-state functional connectivity in veterans with chronic mTBI. Methods 50 veterans with chronic mTBI (mean of 20.7 yrs. from trauma) and 40 age-matched controls underwent two functional magnetic resonance imaging scans 18 months apart. Graph theory analysis was used to quantify network topology measures (density, clustering coefficient, global efficiency, and modularity). Hierarchical linear mixed models were used to examine longitudinal change in network topology. Results With all network measures, we found a significant group × time interaction. At baseline, brain networks of individuals with mTBI were less clustered (p = 0.03) and more modular (p = 0.02) than those of HC. Over time, the mTBI networks became more densely connected (p = 0.002), with increased clustering (p = 0.001) and reduced modularity (p

Motivated by a study on adolescent mental health, we conduct a dynamic connectivity analysis using resting-state functional magnetic resonance imaging (fMRI) data. A dynamic connectivity analysis investigates how the interactions between different regions of the brain, represented by the different dimensions of a multivariate time series, change over time. Hidden Markov models (HMMs) and hidden semi-Markov models (HSMMs) are common analytic approaches for conducting dynamic connectivity analyses. However, existing approaches for HSMMs are limited in their ability to incorporate covariate information. In this work, we approximate an HSMM using an HMM for modeling multivariate time series data. The approximate HSMM model allows one to explicitly model dwell-time distributions that are available to HSMMs, while maintaining the theoretical and methodological advances that are available to HMMs. We conducted a simulation study to show the performance of the approximate HSMM relative to other approaches. Finally, we used the approximate HSMM to conduct a dynamic connectivity analysis, where we showed how dwell-time distributions vary across the severity of non-suicidal self-injury (NSSI) in female adolescents, and how those with moderate or severe NSSI have greater state-switching frequency.

Cognitive Multisensory Rehabilitation (CMR) is a promising therapy for upper limb recovery in stroke, but the brain mechanisms are unknown. We previously demonstrated that the parietal operculum (parts OP1/OP4) is activated with CMR exercises. In this exploratory study, we assessed the baseline difference between OP1/OP4 functional connectivity (FC) at rest in stroke versus healthy adults to then explore whether CMR affects OP1/OP4 connectivity and sensorimotor recovery after stroke. We recruited 8 adults with chronic stroke and left hemiplegia/paresis and 22 healthy adults. Resting-state FC with the OP1/OP4 region-of-interest in the affected hemisphere was analysed before and after 6 weeks of CMR. We evaluated sensorimotor function and activities of daily life pre- and post-CMR, and at 1-year post-CMR. At baseline, we found decreased FC between the right OP1/OP4 and 34 areas distributed across all lobes in stroke versus healthy adults. After CMR, only four areas had decreased FC compared to healthy adults. Compared to baseline (pre-CMR), participants improved on motor function (MESUPES arm p = 0.02; MESUPES hand p = 0.03; MESUPES total score p = 0.006); on stereognosis (p = 0.03); and on the Frenchay Activities Index (p = 0.03) at post-CMR and at 1-year follow-up. These results suggest enhanced sensorimotor recovery post-stroke after CMR. Our results justify larger-scale studies.

Background Prenatal alcohol exposure (PAE) is associated with a variety of structural abnormalities in the brain, including several within the para-limbic system. Children with PAE have higher rates of internalizing disorders, including depression and anxiety, which may be related to underlying limbic system anomalies. Methods Children aged 8 to 16 with PAE (n = 41) or without PAE (n = 36) underwent an magnetic resonance imaging of the brain and parents completed behavioral questionnaires about their children. Semi-automated procedures (FreeSurfer) were used to derive para-limbic volumes from T1-weighted anatomical images. Results There were significant group differences (PAE vs. nonexposed controls) in the caudate, hippocampus, and the putamen; children with PAE had smaller volumes in these regions even after controlling for total intracranial volume. A trend-level association was seen between caudate volume and internalizing symptoms in children with PAE; smaller caudate volumes (presumably reflecting less optimal neurodevelopment) were associated with higher levels of anxiety and depression symptoms in these children. Conclusions Caudate structure may be disproportionately affected by PAE and may be associated with the later development of internalizing symptoms in those affected by PAE.

Objectives: Cortical abnormalities in prenatal alcohol exposure (PAE) are known, including in gyrification (LGI), thickness (CT), volume (CV), and surface area (CS). This study provides longitudinal and developmental context to the PAE cortical development literature. Experimental design: Included: 58 children with PAE and 52 controls, ages 6–17 at enrollment, from four Collaborative Initiative on FASD (CIFASD) sites. Participants underwent a formal evaluation of physical anomalies and dysmorphic facial features associated with PAE. MRI data were collected on three platforms (Siemens, GE, and Philips) at four sites. Scans were spaced two years apart. Change in LGI, CT, CS, and CV were examined. Principal observations: Several significant regional age-by-diagnosis linear and quadratic interaction effects in LGI, CT, and CV were found, indicating atypical developmental trajectories in PAE. No significant correlations were observed between cortical measures and IQ. Conclusions: Regional differences were seen longitudinally in CT, CV, and LGI in those with PAE. The findings represent important insights into developmental trajectories and may have implications for the timing of assessments and interventions in this population. It is noteworthy that cortical metrics did not correlate with IQ, suggesting that more specific aspects of cognitive development may need to be explored to provide further context. Keywords: Cerebral cortex, Fetal alcohol spectrum disorder, Longitudinal MRI, Neuropsychology, Pediatric

IMPACT: Our research has the potential to impact human health by identifying gender specific neural markers of emotion regulation in alcohol use disorder. OBJECTIVES/GOALS: Emotion dysregulation is known to be mediated by altered functional organization of the limbic system in addiction. This preliminary study sought to identify gender effects in the association between emotion regulation and resting-state functional connectivity (rsFC) of a negative affect network. METHODS/STUDY POPULATION: 55 individuals receiving treatment for alcohol use disorder (˜2 weeks of abstinence) were recruited for this study and included in this analysis (N=55; Age: M=41.78, SD=10.66; 21 females). RsFC within a network involved in the withdrawal/negative affect stage of addiction and Personality Inventory for DSM-5 (PID-5) metrics were collected from all participants. RsFC data were preprocessed using the Human Connectome Project pipelines. Correlations between (a) rsFC within the withdrawal/negative affect network and the (b) scores of the negative affect subscale of the PID-5 instrument were conducted for each gender separately. RESULTS/ANTICIPATED RESULTS: Independent samples t-test showed a statistically significant gender difference in the PID-5 negative affect scores (Males: M=1.02, SD=0.66; Females: M=1.53, SD=0.51); t(55)=-3.002, p=0.004. Only females showed a significant correlation between rsFC within the withdrawal/negative affect network and negative affect scores of the PID-5 (r=0.51, p

Objectives Prenatal alcohol exposure (PAE) adversely affects early brain development. Previous studies have shown a wide range of structural and functional abnormalities in children and adolescents with PAE. The current study adds to the existing literature specifically on cortical development by examining cortical gyrification in a large sample of children with PAE compared to controls. Relationships between cortical development and intellectual functioning are also examined. Experimental design Included were 92 children with PAE and 83 controls ages 9–16 from four sites in the Collaborative Initiative on FASD (CIFASD). All PAE participants had documented heavy PAE. All underwent a formal evaluation of physical anomalies and dysmorphic facial features. MRI data were collected using modified matched protocols on three platforms (Siemens, GE, and Philips). Cortical gyrification was examined using a semi-automated procedure. Principal observations Whole brain group comparisons using Monte Carlo z-simulation for multiple comparisons showed significantly lower cortical gyrification across a large proportion of the cerebral cortex amongst PAE compared to controls. Whole brain comparisons and ROI based analyses showed strong positive correlations between cortical gyrification and IQ (i.e. less developed cortex was associated with lower IQ). Conclusions Abnormalities in cortical development were seen across the brain in children with PAE compared to controls. Cortical gyrification and IQ were strongly correlated, suggesting that examining mechanisms by which alcohol disrupts cortical formation may yield clinically relevant insights and potential directions for early intervention., Highlights • Children exposed to alcohol prenatally have widespread abnormalities in the development of cortical gyrification. • Abnormally smooth cortex occurs in developmental insults that interfere with cell proliferation and neuronal migration. • In FASD, we observed that abnormally smooth cortex was strongly associated with lower IQ.

IMPACT: Our research has the potential to impact human health by identifying a neural network that can be used to predict time to relapse in individuals with alcohol use disorder. OBJECTIVES/GOALS: Preoccupation towards alcohol use (e.g. craving, rumination, and poor executive control) is a maladaptive behavior associated with relapse risk. We investigated whether alterations in resting state networks known to mediate preoccupation could predict time to relapse in alcohol use disorder (AUD). METHODS/STUDY POPULATION: 50 participants with alcohol use disorder (AUD) (Age: M=41.76, SD=10.22, 19 females) were recruited from an addiction treatment program at ˜2 weeks of abstinence. fMRI data were preprocessed with the Human Connectome Project pipeline. Strength of resting state functional connectivity (RSFC) within two networks known to mediate the ‘Preoccupation go’ (PG) and ‘Preoccupation stop’ (PS) stages of addiction were calculated. T-tests were conducted to compare RSFC between subsequent abstainers and relapsers (after 4 months). Linear regressions were conducted to determine whether RSFC (of PG and PS networks) can predict time to relapse. Craving measures were included in the model. RESULTS/ANTICIPATED RESULTS: 19 AUD relapsed during the 4-month follow-up period. There were no RSFC group effects (subsequent abstainers and relapsers) in the PG or PS networks. Number of days to relapse could be predicted by PG RSFC (F(1,17)=14.90, p=0.001, r 2=0.47). Time to relapse increased by 13.19 days for each PG RSFC unit increase. Number of days to relapse could be predicted by PS RSFC (F(1,17)=9.39, p=0.002, r ²=0.36). Time to relapse increased by 12.94 days for each PS RSFC unit increase. After adding a self-report craving measure (i.e. Penn Alcohol Craving Scale) in the prediction model, both PG and PS RSFC still significantly predicted time to relapse. Craving metric did not predict time to relapse. DISCUSSION/SIGNIFICANCE OF FINDINGS: RSFC in preoccupation networks during short-term abstinence predicted time to relapse. These preliminary findings highlight promising targets for AUD neuromodulation interventions aimed to reduce relapse. Future larger scale studies that examine the effects of covariates and mediators are needed.

Background Prenatal alcohol exposure (PAE) affects early brain development and has been associated with hippocampal damage. Animal models of PAE have suggested that some subfields of the hippocampus may be more susceptible to damage than others. Recent advances in structural MRI processing now allow us to examine the morphology of hippocampal subfields in humans with PAE. Method Structural MRI scans were collected from 40 children with PAE and 39 typically developing children (ages 8–16). The images were processed using the Human Connectome Project Minimal Preprocessing Pipeline (v4.0.1) and the Hippocampal Subfields package (v21) from FreeSurfer. Using a large dataset of typically developing children enrolled in the Human Connectome Project in Development (HCP-D) for normative standards, we computed age-specific volumetric z-scores for our two samples. Using these norm-adjusted hippocampal subfield volumes, comparisons were performed between children with PAE and typically developing children, controlling for total intracranial volume. Lastly, we investigated whether subfield volumes correlated with episodic memory (i.e., Picture Sequence Memory test of the NIH toolbox). Results Five subfields had significantly smaller adjusted volumes in children with PAE than in typically developing controls: CA1, CA4, subiculum, presubiculum, and the hippocampal tail. Subfield volumes were not significantly correlated with episodic memory. Conclusions The results suggest that several regions of the hippocampus may be particularly affected by PAE. The finding of smaller CA1 volumes parallels previous reports in rodent models. The novel findings of decreased volume in the subicular cortex, CA4 and the hippocampal tail suggest avenues for future research.

3-Phenylbicyclo-octadiene (3) has undergone base-catalysed hydrogen-deuterium exchange at C-4 only slightly faster than the parent hydrocarbon, bicyclo-octadiene (4), thereby ruling out the presence of significant homoaromatic stabilization in the bicyclo-octadienyl anion (1).