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OBJECTIVE Globus pallidus (GP) lesioning improves motor symptoms of Parkinson’s disease (PD) and is occasionally associated with nonmotor side effects. Although these variable clinical effects were shown to be site-specific within the GP, the motor and nonmotor subregions have not been distinguished radiologically in patients with PD. The GP was recently found to have a distinct radiological signature on diffusion MRI (dMRI), potentially related to its unique cellular content and organization (or tissue architecture). In this study, the authors hypothesize that the magnitude of water diffusivity, a surrogate for tissue architecture, will radiologically distinguish motor from nonmotor GP subregions in patients with PD. They also hypothesize that the therapeutic focused ultrasound pallidotomy lesions will preferentially overlap the motor subregion. METHODS Diffusion MRI from healthy subjects (n = 45, test-retest S1200 cohort) and PD patients (n = 33) was parcellated based on the magnitude of water diffusivity in the GP, as measured orientation distribution function (ODF). A clustering algorithm was used to identify GP parcels with distinct ODF magnitude. The individual parcels were used as seeds for tractography to distinguish motor from nonmotor subregions. The locations of focused ultrasound lesions relative to the GP parcels were also analyzed in 11 patients with PD. RESULTS Radiologically, three distinct parcels were identified within the GP in healthy controls and PD patients: posterior, central, and anterior. The posterior and central parcels comprised the motor subregion and the anterior parcel was classified as a nonmotor subregion based on their tractography connections. The focused ultrasound lesions preferentially overlapped with the motor subregion (posterior more than central). The hotspots for motor improvement were localized in the posterior GP parcel. CONCLUSIONS Using a data-driven approach of ODF-based parcellation, the authors radiologically distinguished GP motor subregions in patients with PD. This method can aid stereotactic targeting in patients with PD undergoing surgical treatments, especially focused ultrasound ablation.

BACKGROUND: Based on findings from adults with Obsessive-Compulsive Disorder (OCD), this study examined alterations in resting-state functional connectivity (rs-fc) between the basolateral amygdala (BLA) and the ventromedial prefrontal cortex (vmPFC) in children and adolescents with OCD. We also assessed whether such BLA-vmPFC connectivity changed with or predicted response to Exposure and Response Prevention (E/RP), the first-line treatment for pediatric OCD, given the involvement of these regions in fear processing, regulation, and extinction learning—a probable mechanism of action of E/RP. METHODS: Resting state functional magnetic resonance imaging scans were acquired from 25 unmedicated, treatment-naïve pediatric patients with OCD (12.8 ± 2.9 years) and 23 age- and sex-matched healthy controls (HCs; 11.0 ± 3.3 years). Patients completed a 12–16-week E/RP intervention for OCD. Participants were rescanned after the 12–16-week period. ANCOVAs tested group differences in baseline rs-fc. Cross-lagged panel models examined relationships between BLA-vmPFC rs-fc and OCD symptoms pre- and post-treatment. All tests were adjusted for participants’ age, sex, and head motion. RESULTS: Right BLA-vmPFC rs-fc was significantly reduced (more negative) in patients with OCD relative to HCs at baseline, and increased following treatment. In patients, more positive (less negative) right BLA-vmPFC rs-fc pre-treatment predicted greater OCD symptoms reduction post-treatment. Changes in BLA-vmPFC rs-fc was unassociated with change in OCD symptoms pre- to post-treatment. CONCLUSIONS: These results provide further evidence of the BLA-vmPFC pathway as a potential target for novel treatments or prevention strategies aimed at facilitating adaptive learning and fear extinction in children with OCD or subclinical OCD symptoms.

Contains fulltext : 235277.pdf (Publisher’s version ) (Closed access) BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. FUNDING: British Heart Foundation and Stroke Association.

Background and Purpose: The causes of recurrent ischemic stroke despite anticoagulation for atrial fibrillation are uncertain but might include small vessel occlusion. We investigated whether magnetic resonance imaging markers of cerebral small vessel disease (SVD) are associated with ischemic stroke risk during follow-up in patients anticoagulated for atrial fibrillation after recent ischemic stroke or transient ischemic attack. Methods: We analyzed data from a prospective multicenter inception cohort study of ischemic stroke or transient ischemic attack anticoagulated for atrial fibrillation (CROMIS-2 [Clinical Relevance of Microbleeds in Stroke Study]). We rated markers of SVD on baseline brain magnetic resonance imaging: basal ganglia perivascular spaces (number ≥11); cerebral microbleeds (number ≥1); lacunes (number ≥1); and white matter hyperintensities (periventricular Fazekas grade 3 or deep white matter Fazekas grade ≥2). We investigated the associations of SVD presence (defined as presence of ≥1 SVD marker) and severity (composite SVD score) with the risk of ischemic stroke during follow-up using a Cox proportional hazards model adjusted for congestive heart failure, hypertension, age >75, diabetes, stroke, vascular disease, age 65–74, female score. Results: We included 1419 patients (mean age: 75.8 years [SD, 10.4]; 42.1% female). The ischemic stroke rate during follow-up in patients with any SVD was 2.20 per 100-patient years (95% CI, 1.60–3.02), compared with 0.98 per 100 patient-years (95% CI, 0.59–1.62) in those without SVD ( P =0.008). After adjusting for congestive heart failure, hypertension, age >75, diabetes, stroke, vascular disease, age 65–74, female score, SVD presence remained significantly associated with ischemic stroke during follow-up (hazard ratio, 1.89 [95% CI, 1.01–3.53]; P =0.046); the risk of recurrent ischemic stroke increased with SVD score (hazard ratio per point increase, 1.33 [95% CI, 1.04–1.70]; P =0.023). Conclusions: In patients anticoagulated for atrial fibrillation after ischemic stroke or transient ischemic attack, magnetic resonance imaging markers of SVD are associated with an increased risk of ischemic stroke during follow-up; improved stroke prevention treatments are required in this population. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02513316.

Background and Objectives: Prenatal exposure to environmental tobacco smoke (ETS) is associated with increased attention problems in children, however, the effects of such exposure on children’s brain structure and function have not been studied. Herein, we probed effects of prenatal ETS on children’s cognitive control circuitry and behavior. Methods: Forty-one children (7–9 years) recruited from a prospective longitudinal birth cohort of non-smoking mothers completed structural and task-functional magnetic resonance imaging to evaluate effects of maternal ETS exposure, measured by maternal prenatal urinary cotinine. Attention problems and externalizing behaviors were measured by parent report on the Child Behavior Checklist. Results: Compared to non-exposed children, exposed children had smaller left and right thalamic and inferior frontal gyrus (IFG) volumes, with large effect sizes (p-FDR

Nonverbal Learning Disability (NVLD) is characterized by deficits in visual-spatial, but not verbal, reasoning. Nevertheless, the functioning of the neural circuits supporting spatial processing have yet to be assessed in children with NVLD. We compared the resting state functional connectivity of a spatial brain network among children with NVLD, children with reading disorder (RD), and typically developing (TD) children. Seventy-five participants (7–15 years old) were included in the study (20 TD, 24 NVLD, and 31 RD). Group differences in global efficiency and functional connectivity among 12 regions comprising a previously defined spatial network were evaluated. Associations with behavior were explored. Global efficiency of the spatial network associated positively with spatial ability and inversely with socioemotional problems. Within the spatial network, associations between left posterior cingulate (PCC) and right retrosplenial cortical activity were reduced in children with NVLD relative to those without spatial deficits (RD and TD). Connectivity between left PCC and right posterior cerebellum (Crus I and II) was reduced in both groups of children with learning disabilities (NVLD and RD) relative to TD children. Functional connectivity of the spatial network was atypically associated with cognitive and socioemotional performance in children with NVLD. Identifying a neurobiological substrate for NVLD provides evidence that it is a discrete clinical entity and suggests targets for treatment.

Bulimia nervosa (BN) is associated with functional abnormalities in frontostriatal and frontolimbic circuits. Although structural alterations in the frontal portions of these circuits have been observed, this is the first study of subcortical surface morphometry and the largest study of subcortical volume in BN.Anatomical magnetic resonance scans were acquired from 62 female participants with full and subthreshold BN (mean age ± SD, 18.7 ± 4.0 years) and 65 group-matched healthy control participants (mean age ± SD, 19.3 ± 5.7 years). General linear models were used to compare groups and assess the significance of group-by-age interactions on the shape and total volume of 15 subcortical structures (p.05, familywise error corrected). Associations with illness severity and duration were assessed in the BN group.Subcortical volumes did not differ across groups, but vertexwise analyses revealed inward shape deformations on the anterior surface of the pallidum in BN relative to control participants that were associated with binge-eating frequency and illness duration. Inward deformations on the ventrolateral thalamus and dorsal amygdala were more pronounced with advancing age in the BN group, and inward deformations on the caudate, putamen, and amygdala were associated with self-induced vomiting frequency.Our findings point to localized deformations on the surface of subcortical structures in areas that comprise both reward and cognitive control circuits. These deformations were more pronounced among older BN participants and among those with the most severe symptoms. Such precise localization of alterations in subcortical morphometry may ultimately aid in efforts to identify markers of risk and BN persistence.

The intrauterine environment strongly influences development. Neurodevelopmental effects of in utero exposure to maternal SARS-CoV-2 infection are widely speculated but currently unknown. The COVID-19 Mother Baby Outcomes (COMBO) initiative was established at Columbia University Irving Medical Center (CUIMC) in New York City to prospectively study the health and wellbeing of infants with and without in utero exposure to maternal SARS-CoV-2 infection. We report findings on 6-month neurodevelopmental outcomes using the parental-report Ages & Stages Questionnaire, 3rd Edition (ASQ-3), from 107 in utero exposed and 131 unexposed full-term infants born between March and December, 2020. We compare these infants to a historical cohort comprised of 62 infants born at CUIMC at least two months prior to the onset of the pandemic. In utero exposure to maternal SARS-CoV-2 infection was not associated with differences on any ASQ-3 subdomain regardless of infection timing or severity, however, infants born during the pandemic had significantly lower scores on gross motor, fine motor, and personal-social subdomains when compared to the historical cohort. Infants born to women who were in the first trimester of pregnancy during the peak of the pandemic in NYC had the lowest personal-social scores. Birth during the pandemic, but not maternal SARS-CoV-2 infection, was associated with differences in neurodevelopmental outcomes at 6-months. These early findings suggest significantly higher public health impact for the generation born during the COVID-19 pandemic than previously anticipated.

ObjectiveAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders.MethodsStructural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures).ResultsWe found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed.ConclusionOur findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.

Reading disorder (RD) is characterized by deficient phonological processing, but children with RD also have cognitive control deficits, the neural correlates of which are not fully understood. We used fMRI to assess neural activity during the resolution of cognitive conflict on the Simon Spatial Incompatibility task and patterns of resting-state functional connectivity (RSFC) from task control (TC) regions in 7–12-year-old children with RD compared to their typically developing (TD) peers. Relative to TD children (n = 17), those with RD (n = 16) over-engaged a right superior/medial frontal cluster during the resolution of conflict (p = .05). Relative to TD children (n = 18), those with RD (n = 17) also showed reduced RSFC (voxel-wise p

The DSM provides distinct criteria for obsessive compulsive and various types of anxiety disorders, but phenomenological overlap, high rates of comorbidity, and early onset suggest common underlying mechanisms. This notion is further supported by use of the same treatments – cognitive behavioral therapy (CBT) and serotonin reuptake inhibitor medication – for managing both obsessive compulsive disorder (OCD) and non-OCD anxiety disorders in clinical settings. While early intervention with these gold standard treatments is recommended for pediatric OCD and anxiety disorders, young patients often remain symptomatic even after treatment. To guide the development of novel, mechanistically targeted treatments to better resolve OCD and anxiety symptoms, the identification of neural circuits underlying psychological constructs with relevance across disorders has been recommended. One construct that may be relevant for understanding pediatric OCD and anxiety disorders is cognitive control, given the difficulty that young patients experience in dismissing obsessions, compulsions and worry despite recognition that these symptoms are excessive and unreasonable. In this review, we examine findings from a growing body of literature implicating brain-behavioral markers of cognitive control in pediatric OCD and anxiety disorders, including before and after treatment. We conclude by suggesting that interventions designed to enhance the functioning of the task control circuits underlying cognitive control may facilitate brain maturation to help affected youth overcome symptoms.

Objective Bulimia nervosa (BN) is characterized by excessive attention to self and specifically to body shape and weight, but the ventral attention (VAN) and default mode (DMN) networks that support attentional and self-referential processes are understudied in BN. This study assessed whether altered functional connectivity within and between these networks contributes to such excessive concerns in adolescents with BN early the course of the disorder. Method Resting-state functional magnetic resonance images were acquired from 33 adolescents with BN and 37 healthy control adolescents (12–21 years) group matched by age and body mass index. Region-of-interest analyses were performed to examine group differences in functional connectivity within and between the VAN and DMN. In addition associations of VAN-DMN connectivity with BN symptoms, body shape/weight concerns, and sustained attention were explored using the Continuous Performance Test (CPT). Results Compared with control adolescents, those with BN showed significantly increased positive connectivity between the right ventral supramarginal gyrus and all DMN regions and between the right ventrolateral prefrontal cortex and the left lateral parietal cortex. Within-network connectivity did not differ between groups. VAN-DMN connectivity was associated with BN severity and body shape/weight concerns in the BN group. No significant group-by-CPT interactions on VAN-DMN connectivity were detected. Conclusion Increased positive VAN-DMN connectivity in adolescents with BN could reflect abnormal engagement of VAN-mediated attentional processes at rest, perhaps related to their excessive attention to self-referential thoughts about body shape/weight. Future studies should further investigate these circuits as targets for the development of early interventions aimed at decreasing excessive body shape/weight concerns.

Objective Nonverbal learning disability (NVLD) is a putative neurodevelopmental disorder characterized by spatial processing deficits as well as social deficits similar to those characteristic of autism spectrum disorder (ASD). Nonetheless, NVLD may be a distinct disorder that is differentially associated with the functioning and connectivity of the salience (SN) and default mode (DMN) networks that support social processing. Thus, we sought to assess and compare connectivity across these networks in children with NVLD, ASD, and typically developing children. Method Resting-state fMRI data were examined in 17 children with NVLD, 17 children with ASD selected from the Autism Brain Imaging Data Exchange (ABIDE), and 40 TD children (20 from ABIDE). Average DMN and SN functional connectivity and pairwise region-to-region connectivity were compared across groups. Associations with social impairment and IQ were assessed. Results Children with NVLD showed reduced connectivity between SN regions (anterior insula to anterior cingulate and to rostral prefrontal cortex [rPFC]), whereas children with ASD showed greater connectivity between SN regions (supramarginal gyrus to rPFC) relative to the other groups. Both clinical groups showed higher levels of parent-reported social problems, which related to altered SN connectivity in the NVLD group. No differences were detected in overall average connectivity within or between networks. Conclusions The social deficits common across children with NVLD and ASD may derive from distinct alterations in connectivity within the SN. Such findings represent the first step toward identifying a neurobiological signature of NVLD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Background Frontostriatal and frontoparietal abnormalities likely contribute to deficits in control and attentional processes in individuals with bulimia nervosa and to the persistence of dysregulated eating across development. This study assessed these processes and cortical thickness in a large sample of adolescent girls and women with bulimia nervosa compared with healthy controls. Methods We collected anatomical MRI data from adolescent girls and women (ages 12-38 yr) with full or subthreshold bulimia nervosa and age-matched healthy controls who also completed the Conners Continuous Performance Test-II (CPT-II). Groups were compared on task performance and cortical thickness. Mediation analyses explored associations among cortical thickness, CPT-II variables, bulimia nervosa symptoms and age. Results We included 60 girls and women with bulimia nervosa and 54 controls in the analyses. Compared with healthy participants, those with bulimia nervosa showed increased impulsivity and inattention on the CPT-II, along with reduced thickness of the right pars triangularis, right superior parietal and left dorsal posterior cingulate cortices. In the bulimia nervosa group, exploratory analyses revealed that binge eating frequency correlated inversely with cortical thickness of frontoparietal and insular regions and that reduced frontoparietal thickness mediated the association between age and increased symptom severity and inattention. Binge eating frequency also mediated the association between age and lower prefrontal cortical thickness. Limitations These findings are applicable to only girls and women with bulimia nervosa, and our cross-sectional design precludes understanding of whether cortical thickness alterations precede or result from bulimia nervosa symptoms. Conclusion Structural abnormalities in the frontoparietal and posterior cingulate regions comprising circuits that support control and attentional processes should be investigated as potential contributors to the maintenance of bulimia nervosa and useful targets for novel interventions.

Background Previous cross-sectional findings from adolescents and adults with Bulimia Nervosa (BN) suggest disturbances in fronto-striatal and cingulo-opercular task control circuits that support self-regulatory processes, including the resolution of cognitive conflict. Herein, we used longitudinal data to examine the developmental trajectories of such disturbances and how the functioning of these circuits relates to changes in BN symptoms over adolescence. Methods Thirty-two adolescent females with BN symptoms and 28 healthy control (HC) adolescents participated in the study. Functional magnetic resonance images (fMRI) during performance of a Simon task were acquired at three time points within 2-year intervals over adolescence. From the initial sample, 70% and 30% of the participants completed the second and third time points, respectively. Participants who completed all study time points did not differ from those lost to attrition on baseline demographic characteristics or any outcome measures. Using a region-of-interest approach, growth curve models tested group differences in the trajectory of conflict-related activation in task control circuits over time. Cross-lagged panel models examined transactional relationships between conflict-related activation in the same regions and BN symptoms over time. Results Growth curve models revealed different trajectories of conflict-related activation in right task control regions across BN and HC adolescents, such that HC but not BN adolescents showed activation decreases over time. These group differences were greatest when including only the BN adolescents whose symptoms remitted over time. Cross-lagged panel models revealed that less frequent bulimic episodes at first follow-up predicted later increases in conflict-related activation in bilateral task control regions. Conclusions These longitudinal findings suggest overengagement of task control circuits in BN adolescents, especially those most resilient to persistent illness. Such overengagement may compensate for regulatory disturbances, allowing them to regulate eating behaviors over development. Thus, task control circuits may constitute targets for early interventions that enhance self-regulatory control.

Background It is likely that a proportion of poststroke cognitive impairment is sometimes attributable to unidentified prestroke decline; prestroke cognitive function is also clinically relevant because it is associated with poor functional outcomes, including death. We investigated the radiological and prognostic associations of preexisting cognitive impairment in patients with ischemic stroke or transient ischemic attack associated with atrial fibrillation. Methods and Results We included 1102 patients from the prospective multicenter observational CROMIS ‐2 (Clinical Relevance of Microbleeds in Stroke 2) atrial fibrillation study. Preexisting cognitive impairment was identified using the 16‐item Informant Questionnaire for Cognitive Decline in the Elderly. Functional outcome was measured using the modified Rankin scale. Preexisting cognitive impairment was common (n=271; 24.6%). The presence of lacunes (odds ratio [OR], 1.50; 95% CI , 1.03–1.05; P =0.034), increasing periventricular white matter hyperintensity grade (per grade increase, OR , 1.38; 95% CI , 1.17–1.63; P OR , 1.26; 95% CI , 1.05–1.51; P =0.011), and medial temporal atrophy grade (per grade increase, OR , 1.61; 95% CI , 1.34–1.95; P mRS >2; adjusted OR , 2.43; 95% CI , 1.42–4.20; P =0.001). Conclusions Preexisting cognitive impairment in patients with atrial fibrillation–associated ischemic stroke or transient ischemic attack is common, and associated with imaging markers of cerebral small vessel disease and neurodegeneration, as well as with longer‐term functional outcome. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 02513316.

Contains fulltext : 208975.pdf (Publisher’s version ) (Open Access) BACKGROUND: Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke. METHODS: We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602. FINDINGS: Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1.34 years [IQR 0.19-2.44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1.35 (95% CI 1.20-1.50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2.45 (1.82-3.29) for intracranial haemorrhage and 1.23 (1.08-1.40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4.55 [95% CI 3.08-6.72] for intracranial haemorrhage vs 1.47 [1.19-1.80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5.52 [3.36-9.05] vs 1.43 [1.07-1.91]; and for >/=20 cerebral microbleeds, aHR 8.61 [4.69-15.81] vs 1.86 [1.23-1.82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48-84] per 1000 patient-years vs 27 intracranial haemorrhages [17-41] per 1000 patient-years; and for >/=20 cerebral microbleeds, 73 ischaemic strokes [46-108] per 1000 patient-years vs 39 intracranial haemorrhages [21-67] per 1000 patient-years). INTERPRETATION: In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden. FUNDING: British Heart Foundation and UK Stroke Association.

Objective: structural brain imaging studies in obsessive compulsive disorder (OCD) have produced inconsistent findings. This may be partially due to limited statistical power from relatively small samples and clinical heterogeneity related to variation in illness profile and developmental stage. To address these limitations, the authors conducted meta and mega-analyses of data from OCD sites worldwide. Method: T-1 images from 1,830 OCD patients and 1,759 control subjects were analyzed, using coordinated and standardized processing, to identify subcortical brain volumes that differ between OCD patients and healthy subjects. The authors performed a meta analysis on the mean of the left and right hemisphere measures of each subcortical structure, and they performed a mega-analysis by pooling these volumetric measurements from each site. The authors additionally examined potential modulating effects of clinical characteristics on morphological differences in OCD patients. Results: the meta-analysis indicated that adult patients had significantly smaller hippocampal volumes (Cohen's d=-0.13; % difference=-2.80) and larger pallidum volumes (d=0.16; % difference=3.16) compared with adult controls. Both effects were stronger in medicated patients compared with controls (d=-0.29, % difference=-4.18, and d=0.29, % difference=4.38, respectively). Unmedicated pediatric patients had significantly larger thalamic volumes (d=0.38, % difference=3.08) compared with pediatric controls. None of these findings were mediated by sample characteristics, such as mean age or scanning field strength. The mega-analysis yielded similar results. Conclusions: the results indicate different patterns of sub cortical abnormalities in pediatric and adult OCD patients. The patlidum and hippocampus seem to be of importance in adult OCD, whereas the thalamus seems to be key in pediatric OCD. These findings highlight the potential importance of neurodevelopmental alterations in OCD and suggest that further research on neuroplasticity in OCD may be useful.

Aims This study aims to determine the rate of prenatal detection of tracheoesophageal fistula and oesophageal atresia (TOF/OA), by identifying a small or absent stomach bubble with or without polyhydramnios, on the prenatal ultrasound scans (USS). Methods A retrospective study of prenatal ultrasound findings of babies with a prenatal and postnatal diagnosis of TOF/OA born between 1st January 2004 and 31st December 2013 was undertaken. Results A total of 58 babies were born with TOF/OA. 40% of mothers had their prenatal investigations performed within our tertiary centre, and the remaining 60% had their antenatal care at their local district general hospital (DGH). The overall sensitivity for prenatal USS was 26%, with a specificity of 99% and a positive predictive value (PPV) of 35%. However, the sensitivity of the prenatal USS within the tertiary centre was significantly higher at 57%, while only 2 cases were detected prenatally in the DGHs. Polyhydramnios was seen in 67% of mothers that had a prenatal diagnosis of TOF/OA and its presence did significantly increase the positive predictive value of prenatal USS (from 35% to 63%). Of those that were postnatally diagnosed, 21% had prenatal polyhydramnios. There was no significant difference in postnatal outcomes between those that were prenatally diagnosed and those that were postnatally diagnosed. Conclusion Prenatal diagnosis of TOF/OA remains challenging. However within a specialist centre the accuracy of successful prenatal detection can be significantly improved. This is beneficial both for prenatal counselling of families and for planning appropriate perinatal and postnatal care for the baby.

Objective Children of parents with depression are two to three times more likely to develop major depressive disorder than children without parental history; however, subcortical brain volume abnormalities characterizing major depressive disorder risk remain unclear. The Adolescent Brain and Cognitive Development (ABCD) Study provides an opportunity to identify subcortical differences associated with parental depressive history. Method Structural magnetic resonance data were acquired from 9- and 10-year-old children (N = 11,876; release 1.1, n = 4,521; release 2.0.1, n = 7,355). Approximately one-third of the children had a parental depressive history, providing sufficient power to test differences in subcortical brain volume between low- and high-risk youths. Children from release 1.1 were examined as a discovery sample, and we sought to replicate effects in release 2.0.1. Secondary analyses tested group differences in the prevalence of depressive disorders and clarified whether subcortical brain differences were present in youths with a lifetime depressive disorder history. Results Parental depressive history was related to smaller right putamen volume in the discovery (release 1.1; d = −0.10) and replication (release 2.0.1; d = −0.10) samples. However, in release 1.1, this effect was driven by maternal depressive history (d = −0.14), whereas in release 2.0.1, paternal depressive history showed a stronger relationship with putamen volume (d = −0.09). Furthermore, high-risk children exhibited a near twofold greater occurrence of depressive disorders relative to low-risk youths (maternal history odds ratio =1.99; paternal history odds ratio = 1.45), but youths with a lifetime depressive history did not exhibit significant subcortical abnormalities. Conclusion A parental depressive history was associated with smaller putamen volume, which may affect reward learning processes that confer increased risk for major depressive disorder.

Previous data suggest structural and functional deficits in frontal control circuits in adolescents and adults with bulimia nervosa (BN), but less is known about the microstructure of white matter in these circuits early in the course of the disorder. Diffusion tensor imaging (DTI) data were acquired from 28 female adolescents and adults with BN and 28 age- and BMI-matched healthy female participants. Tract-based spatial statistics (TBSS) was used to detect group differences in white matter microstructure and explore the differential effects of age on white matter microstructure across groups. Significant reductions in fractional anisotropy (FA) were detected in the BN compared with healthy control group in multiple tracts including forceps minor and major, superior longitudinal, inferior fronto-occipital, and uncinate fasciculi, anterior thalamic radiation, cingulum, and corticospinal tract. FA reductions in forceps and frontotemporal tracts correlated inversely with symptom severity and Stroop interference in the BN group. These findings suggest that white matter microstructure is abnormal in BN in tracts extending through frontal and temporoparietal cortices, especially in those with the most severe symptoms. Age-related differences in both FA and RD in these tracts in BN compared with healthy individuals may represent an abnormal trajectory of white matter development that contributes to the persistence of functional impairments in self-regulation in BN.

Human brain imaging can help improve our understanding of mechanisms underlying brain function and how they drive behavior in health and disease. Such knowledge may eventually help us to devise better treatments for psychiatric disorders. However, the brain imaging literature in psychiatry and especially eating disorders has been inconsistent, and studies are often difficult to replicate. The extent or severity of extremes of eating and state of illness, which are often associated with differences in, for instance hormonal status, comorbidity, and medication use, commonly differ between studies and likely add to variation across study results. Those effects are in addition to the well-described problems arising from differences in task designs, data quality control procedures, image data preprocessing and analysis or statistical thresholds applied across studies. Which of those factors are most relevant to improve reproducibility is still a question for debate and further research. Here we propose guidelines for brain imaging research in eating disorders to acquire valid results that are more reliable and clinically useful.

This study aimed to determine whether functional disturbances in fronto-striatal control circuits characterize adolescents with Bulimia Nervosa (BN) spectrum eating disorders regardless of clinical severity. FMRI was used to assess conflict-related brain activations during performance of a Simon task in two samples of adolescents with BN symptoms compared with healthy adolescents. The BN samples differed in the severity of their clinical presentation, illness duration and age. Multi-voxel pattern analyses (MVPAs) based on machine learning were used to determine whether patterns of fronto-striatal activation characterized adolescents with BN spectrum disorders regardless of clinical severity, and whether accurate classification of less symptomatic adolescents (subthreshold BN; SBN) could be achieved based on patterns of activation in adolescents who met DSM5 criteria for BN. MVPA classification analyses revealed that both BN and SBN adolescents could be accurately discriminated from healthy adolescents based on fronto-striatal activation. Notably, the patterns detected in more severely ill BN compared with healthy adolescents accurately discriminated less symptomatic SBN from healthy adolescents. Deficient activation of fronto-striatal circuits can characterize BN early in its course, when clinical presentations are less severe, perhaps pointing to circuit-based disturbances as useful biomarker or risk factor for the disorder, and a tool for understanding its developmental trajectory, as well as the development of early interventions.

Pediatric reading disorder (RD) is associated with an increased risk of anxiety symptoms, yet understudied are the neurobiological factors that might underlie anxiety in children with RD. Given the role of the amygdala in anxiety, we assessed resting state functional connectivity of amygdalar subregions in children with RD to identify functional correlates of anxiety and reading impairment. We collected resting state functional MRI data from 22 children with RD and 21 typically developing (TD) children, ages 7 to 13 years. We assessed group differences in resting state functional connectivity (RSFC) from amygdalar subregions. Associations of amygdalar RSFC and volume with reading impairment, reading fluency scores, and anxiety symptoms were explored. Relative to TD children, those with RD showed increased RSFC from amygdalar nuclei to medial prefrontal cortex. Across all subjects, RSFC from right centromedial amygdala to left medial prefrontal cortex positively predicted both reading impairment and self-reported anxiety, and anxiety mediated the relationship between RSFC and reading impairment. These findings are consistent with amygdalar functional abnormalities in pediatric anxiety disorders, suggesting a common neurobiological mechanism underlying anxiety and reading impairment in children. Thus, aberrant patterns of RSFC from amygdalar subregions may serve as potential targets for the treatment of anxiety symptoms that typically co-occur with RD. Our dimensional approach to studying anxiety in RD revealed how amygdalar connectivity underlies anxiety and reading impairment across a continuum from normal to abnormal.

Rationale aims and objectives. This study sought to evaluate potential reductions in risk associated with midazolam injection, a sedating medication, following a United Kingdom National Patient Safety Alert. This alert, ‘Reducing risk of overdose with midazolam injection in adults’, was sent to all National Health Service organisations as a Rapid Response Report detailing actions services should take to minimise risks. Method. To evaluate any potential changes arising from this alert, a number of data sources were explored including reported incidents to a national reporting system for health care error, clinician survey and audit data, pharmaceutical purchasing patterns and feedback from NHS managers. Results. Prior to the Rapid Response Report, 498 incidents were received by the National Patient Safety Agency including 3 deaths. Post implementation of the Rapid Response Report (June 2009), no incidents resulting in death or severe harm had been received. All organisations reported having completed the Rapid Response Report actions. Purchase and use of risk-prone, high-strength sedating midazolam by health care organisations decreased significantly as did the increased use of safer, lower strength doses (as recommended in the Rapid Response Report). Conclusions. Organisations can achieve safer medication practices, better knowledge, awareness and implementation of national safer practice recommendations. Risks from inadvertent overdose of midazolam injection was reduced post implementation of national recommendations. Ongoing monitoring of this particular adverse event will be required with a sustained patient safety message to health services to maintain awareness of the issue and reduction in the number of midazolam related errors.

Objective Cross-sectional data suggest functional and anatomical disturbances in inferior and orbital frontal regions in bulimia nervosa (BN). Using longitudinal data, we investigated whether reduced cortical thickness (CT) in these regions arises early and persists over adolescence in BN, independent of symptom remission, and whether CT reductions are markers of BN symptoms. Method A total of 33 adolescent females with BN symptoms (BN or other specified feeding or eating disorder) and 28 healthy adolescents participated in this study. Anatomical magnetic resonance imaging and clinical data were acquired at 3 time points within 2-year intervals over adolescence, with 31% average attrition between assessments. Using a region-of-interest approach, we assessed group differences in CT at baseline and over time, and tested whether between- and within-subject variations in CT were associated with the frequency of BN symptoms. Results Reduced CT in the right inferior frontal gyrus persisted over adolescence in BN compared to healthy adolescents, even in those who achieved full or partial remission. Within the BN group, between-subject variations in CT in the inferior and orbital frontal regions were inversely associated with specific BN symptoms, suggesting, on average over time, greater CT reductions in individuals with more frequent BN symptoms. Conclusion Reduced CT in inferior frontal regions may contribute to illness persistence into adulthood. Reductions in the thickness of the inferior and orbital frontal regions may be markers of specific BN symptoms. Because our sample size precluded correcting for multiple comparisons, these findings should be replicated in a larger sample. Future study of functional changes in associated fronto-striatal circuits could identify potential circuit-based intervention targets.

Objective To assess the functioning of mesolimbic and fronto-striatal areas involved in reward-based spatial learning in teenaged girls with bulimia nervosa (BN) that might be involved in the development and maintenance of maladaptive behaviors characteristic of the disorder. Method We compared functional magnetic resonance imaging blood oxygen level−dependent response in 27 adolescent girls with BN to that of 27 healthy, age-matched control participants during a reward-based learning task that required learning to use extra-maze cues to navigate a virtual 8-arm radial maze to find hidden rewards. We compared groups in their patterns of brain activation associated with reward-based spatial learning versus a control condition in which rewards were unexpected because they were allotted pseudo-randomly to experimentally prevent learning. Results Both groups learned to navigate the maze to find hidden rewards, but group differences in brain activity associated with maze navigation and reward processing were detected in the fronto-striatal regions and right anterior hippocampus. Unlike healthy adolescents, those with BN did not engage the right inferior frontal gyrus during maze navigation, activated the right anterior hippocampus during the receipt of unexpected rewards (control condition), and deactivated the left superior frontal gyrus and right anterior hippocampus during expected reward receipt (learning condition). These patterns of hippocampal activation in the control condition were significantly associated with the frequency of binge-eating episodes. Conclusion Adolescents with BN displayed abnormal functioning of the anterior hippocampus and fronto-striatal regions during reward-based spatial learning. These findings suggest that an imbalance in control and reward circuits may arise early in the course of BN. Clinical trial registration information —An fMRI Study of Self-Regulation in Adolescents With Bulimia Nervosa; https://clinicaltrials.gov/; NCT00345943.

Verbal-spatial discrepancies are common in healthy individuals and in those with neurodevelopmental disorders associated with cognitive control deficits including: Autism Spectrum Disorder, Non-Verbal Learning Disability, Fragile X, 22q11 deletion, and Turner Syndrome. Previous data from healthy individuals suggest that the magnitude of the difference between verbal IQ (VIQ) and performance IQ (PIQ) scores (the VIQ>PIQ discrepancy) is associated with reduced thickness in frontal and parietal cortices (inferior frontal, anterior cingulate, inferior parietal lobule, and supramarginal gyrus) that support cognitive control. Unknown is whether the VIQ>PIQ discrepancy is associated with functional deficits in these areas in healthy or ill children and adolescents. We assessed the effects of the VIQ>PIQ discrepancy on fMRI BOLD response during the resolution of cognitive conflict in 55 healthy children and adolescents during performance of a Simon Spatial Incompatibility task. As the magnitude of the VIQ>PIQ discrepancy increased, activation of fronto-striatal, limbic, and temporal regions decreased during conflict resolution (p < 0.05, corrected). In exploratory analyses, the VIQ>PIQ discrepancy was associated with reduced functional connectivity from right inferior frontal gyrus to right thalamus and increased functional connectivity to right supramarginal gyrus (ps < 0.03, uncorrected). The VIQ>PIQ discrepancy may be an important aspect of an individual’s cognitive profile and likely contributes to, or is associated with, deficient cognitive control processes characteristic of many childhood disorders.

The construct of impulsivity is an important determinant of personality differences, psychiatric disorders, and associated risk-taking behaviors. Most existing knowledge about impulsivity comes from clinical samples. To date, no study has estimated the prevalence of impulsivity and examined its correlates in the general population.We analyzed data from a large national sample of the United States population. Face-to-face surveys of 34 653 adults aged 18 years and older residing in households were conducted during the 2004-2005 period. Diagnoses of mood, anxiety, and drug disorders as well as personality disorders were based on the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV Version.Impulsivity was common (17% of the sample), particularly among males and younger individuals, and associated with a broad range of axis I and II disorders, particularly drug dependence, cluster B, dependent and schizotypal personality disorders, bipolar disorder and ADHD. It was associated with behavioral disinhibition, attention deficits, and lack of planning. Individuals with impulsivity were more likely to engage in behaviors that could be dangerous to themselves or others, including driving recklessly, starting fights, shoplifting, perpetrating domestic violence and trying to hurt or kill themselves. They were exposed to higher risk of lifetime trauma and to substantial physical and psychosocial impairment.Given the association of impulsivity with psychiatric disorders and multiple adverse events, there is a need to target impulsivity in prevention and treatment efforts.

The purpose of this study was to examine neural activity and connectivity within cortico-striato-thalamo-cortical circuits and to reveal circuit-based neural mechanisms that govern tic generation in Tourette's syndrome.Functional magnetic resonance imaging data were acquired from 13 individuals with Tourette's syndrome and 21 healthy comparison subjects during spontaneous or simulated tics. Independent component analysis with hierarchical partner matching was used to isolate neural activity within functionally distinct regions of cortico-striato-thalamo-cortical circuits. Granger causality was used to investigate causal interactions among these regions.The Tourette's syndrome group exhibited stronger neural activity and interregional causality than healthy comparison subjects throughout all portions of the motor pathway, including the sensorimotor cortex, putamen, pallidum, and substantia nigra. Activity in these areas correlated positively with the severity of tic symptoms. Activity within the Tourette's syndrome group was stronger during spontaneous tics than during voluntary tics in the somatosensory and posterior parietal cortices, putamen, and amygdala/hippocampus complex, suggesting that activity in these regions may represent features of the premonitory urges that generate spontaneous tic behaviors. In contrast, activity was weaker in the Tourette's syndrome group than in the healthy comparison group within portions of cortico-striato-thalamo-cortical circuits that exert top-down control over motor pathways (the caudate and anterior cingulate cortex), and progressively less activity in these regions accompanied more severe tic symptoms, suggesting that faulty activity in these circuits may result in their failure to control tic behaviors or the premonitory urges that generate them.Our findings, taken together, suggest that tics are caused by the combined effects of excessive activity in motor pathways and reduced activation in control portions of cortico-striato-thalamo-cortical circuits.

The authors examined functional activity in the frontostriatal systems that mediate self-regulatory capacities and conflict resolution in adolescents with bulimia nervosa.Functional magnetic resonance imaging was used to compare blood-oxygen-level-dependent response in 18 female adolescents with bulimia nervosa and 18 healthy female age-matched subjects during performance on a Simon spatial incompatibility task. Bayesian analyses were used to compare the two groups on patterns of brain activation during correct responses to conflict stimuli and to explore the effects of antecedent stimulus context on group differences in self-regulation and conflict resolution.Adolescents with and without bulimia nervosa performed similarly on the task. During correct responses in conflict trials, frontostriatal circuits-including the right inferolateral and dorsolateral prefrontal cortices and putamen-failed to activate to the same degree in adolescents with bulimia nervosa as in healthy comparison subjects. Instead, deactivation was seen in the left inferior frontal gyrus as well as a neural system encompassing the posterior cingulate cortex and superior frontal gyrus. Group differences in cortical and striatal regions were driven by the differential responses to stimuli preceded by conflict and nonconflict stimuli, respectively.When engaging the self-regulatory control processes necessary to resolve conflict, adolescents with bulimia nervosa displayed abnormal patterns of activation in frontostriatal and default-mode systems. Their abnormal processing of the antecedent stimulus context conditioned their brain response to conflict differently from that of healthy comparison subjects, specifically in frontal regions. It is suspected that functional disturbances in frontal portions of frontostriatal systems may release feeding behaviors from regulatory control, thereby perpetuating the conflicting desires to consume fattening foods and avoid weight gain that characterize bulimia nervosa.

Neuroimaging studies of healthy individuals inform us about the normative maturation of the frontostriatal circuits that subserve self-regulatory control processes. Findings from these studies can be used as a reference frame against which to compare the aberrant development of these processes in individuals across a wide range of childhood psychopathologies.The authors reviewed extensive neuroimaging evidence for the presence of abnormalities in frontostriatal circuits in children and adults with Tourette's syndrome and obsessive-compulsive disorder (OCD) as well as a more limited number of imaging studies of adolescents and adults with anorexia nervosa or bulimia nervosa that, together, implicate dysregulation of frontostriatal control systems in the pathogenesis of these eating disorders.The presence of an impaired capacity for self-regulatory control that derives from abnormal development of frontostriatal circuits likely interacts in similar ways with normally occurring somatic sensations and motor urges, intrusive thoughts, sensations of hunger, and preoccupation with body shape and weight to contribute, respectively, to the development of the tics of Tourette's syndrome, the obsessions of OCD, the binge eating behaviors of bulimia, and the self-starvation of anorexia.Analogous brain mechanisms in parallel frontostriatal circuits, or even in differing portions of the same frontostriatal circuit, may underlie the differing behavioral disturbances in these multiple disorders, although further research is needed to confirm this hypothesis.

Background Dysfunction in frontostriatal circuits likely contributes to impaired regulatory control in Bulimia Nervosa (BN), resulting in binge-eating and purging behaviors that resemble maladaptive habits. Less is known about the implicit learning processes of these circuits, which may contribute to habit formation. Methods We compared 52 adolescent and adult females with BN to 55 healthy matched-controls during performance of a probabilistic classification learning task, one form of implicit learning. Groups were compared in accuracy and response times, using mixed-models with block, age, and diagnosis as predictors, corrected for multiple comparisons with confounds covaried. Results BN participants showed differences in performance on a probabilistic classification learning task that varied by age. Adolescents with BN initially performed as accurately as healthy adolescents, but showed poorer perseverance over time. Adults with BN initially performed less accurately than healthy adults, but improved to perform equivalently. Symptom severity was associated with poorer accuracy in both adults and adolescents with BN. Conclusions Frontostriatal dysfunction may underlie abnormalities in regulatory control and probabilistic classification learning in BN, likely contributing to the dysregulation of implicitly learned, maladaptive binge-eating and purging behaviors. Such dysfunction in BN may progress with increasing age, first manifesting in poor regulatory control over behaviors and then expanding to implicit learning processes that may underlie habitual behaviors.

Clinical evidence suggests that initial attempts to regulate weight gain quickly become habit-like in individuals with eating disorders. These behaviors are controlled excessively in patients with Anorexia Nervosa (AN) and are controlled more intermittently, with periods of lost control, in patients with Bulimia Nervosa (BN). We suspect that abnormalities in frontostriatal systems that subserve self-regulatory control and habit learning may contribute to the development and perpetuation of AN and BN. We summarize previous findings and present a pathophysiological model that provides a framework for understanding the shared and non-shared clinical phenotypes of AN and BN. Whereas dysregulated control systems produce heightened self-regulatory control, permitting individuals with AN to sustain excessive dietary restriction, dysregulated control systems likely result in impaired self-regulatory control in patients with BN, releasing feelings of hunger and urges to binge, thereby resulting in overeating. Interactions with cultural ideals of thinness and impaired habit learning systems may then allow the dieting behaviors of individuals with restricting-type AN to spiral into the habitual and restrictive eating behaviors that typify the disorder. Although these cultural factors likely contribute to the compensatory purging behaviors in BN, interactions with normal habit learning systems may explain the higher recovery rate of BN relative to AN, in which habit learning may be impaired. We describe neuroimaging methods that we are using to test these hypotheses and emphasize the potential utility of studying AN and BN early in the course of illness, to disentangle their causes from epiphenomena or compensatory responses. We believe that this innovative approach to studying eating disorders will lend explanation to the perplexing fact that although many young people diet and overeat at some point in time, only some go on to develop eating disorders.

Bulimia nervosa (BN) is characterized by both recurrent episodes of binge eating that are, in part, defined by a sense of loss of control and compensatory behaviors to avoid weight gain. Impulsive behaviors are also common in individuals with BN, indicating more pervasive difficulties in behavioral self-regulation. Findings from functional and anatomical neuroimaging studies of individuals with BN suggest dysfunction in the dorsal frontostriatal circuits that support self-regulatory capacities and habit learning and in overlapping ventral circuits that support reward processing and reward-based learning. In this review, we describe the normal development of frontostriatal circuits and then present behavioral and neuroimaging data from adolescents and adults with BN. These data suggest that the abnormal maturation of frontostriatal circuits may contribute to the habitual binge-eating and purging behaviors of BN. Future longitudinal imaging studies will improve understanding of how these circuits contribute to the developmental trajectory of BN and will inform novel interventions that could target or prevent the impulsive and habit-like features of this disorder.

The processing of cognitive interference is a self-regulatory capacity that is impaired in persons with internalizing disorders. This investigation was to assess sex differences in the neural correlates of cognitive interference in individuals with and without an illness history of an internalizing disorder. We compared functional magnetic resonance imaging blood-oxygenation-level-dependent responses in both males (n=63) and females (n=80) with and without this illness history during performance of the Simon task. Females deactivated superior frontal gyrus, inferior parietal lobe, and posterior cingulate cortex to a greater extent than males. Females with a prior history of internalizing disorder also deactivated these regions more compared to males with that history, and they additionally demonstrated greater activation of right inferior frontal gyrus. These group differences were represented in a significant sex-by-illness interaction in these regions. These deactivated regions compose a task-negative or default mode network, whereas the inferior frontal gyrus usually activates when performing an attention-demanding task and is a key component of a task-positive network. Our findings suggest that a prior history of internalizing disorders disproportionately influences functioning of the default mode network and is associated with an accompanying activation of the task-positive network in females during the resolution of cognitive interference.

Background The aim of this study was to examine morphometric features of the cerebral surface in adolescent and adult female subjects with bulimia nervosa (BN). Methods Anatomical magnetic resonance images were acquired from 34 adolescent and adult female subjects with BN and 34 healthy age-matched control subjects. We compared the groups in the morphological characteristics of their cerebral surfaces while controlling for age and illness duration. Results Significant reductions of local volumes on the brain surface were detected in frontal and temporoparietal areas in the BN compared with control participants. Reductions in inferior frontal regions correlated inversely with symptom severity, age, and Stroop interference scores in the BN group. Conclusions These findings suggest that local volumes of inferior frontal regions are smaller in individuals with BN compared with healthy individuals. These reductions along the cerebral surface might contribute to functional deficits in self-regulation and to the persistence of these deficits over development in BN.

Dysfunctional learning systems are thought to be central to the pathogenesis of and impair recovery from addictions. The functioning of the brain circuits for episodic memory or learning that support goal-directed behavior has not been studied previously in persons with cocaine dependence (CD). Thirteen abstinent CD and 13 healthy participants underwent MRI scanning while performing a task that requires the use of spatial cues to navigate a virtual-reality environment and find monetary rewards, allowing the functional assessment of the brain systems for spatial learning, a form of episodic memory. Whereas both groups performed similarly on the reward-based spatial learning task, we identified disturbances in brain regions involved in learning and reward in CD participants. In particular, CD was associated with impaired functioning of medial temporal lobe (MTL), a brain region that is crucial for spatial learning (and episodic memory) with concomitant recruitment of striatum (which normally participates in stimulus-response, or habit, learning), and prefrontal cortex. CD was also associated with enhanced sensitivity of the ventral striatum to unexpected rewards but not to expected rewards earned during spatial learning. We provide evidence that spatial learning in CD is characterized by disturbances in functioning of an MTL-based system for episodic memory and a striatum-based system for stimulus-response learning and reward. We have found additional abnormalities in distributed cortical regions. Consistent with findings from animal studies, we provide the first evidence in humans describing the disruptive effects of cocaine on the coordinated functioning of multiple neural systems for learning and memory.

The authors sought to study activity in neural circuits that subserve the inhibition of a semi-involuntary motor behavior, eye blinking, in children and adults with Tourette syndrome and in healthy comparison subjects.Functional magnetic resonance imaging was used to scan 120 participants (51 with Tourette syndrome and 69 comparison subjects) as they either blinked normally or successfully inhibited eye blinking. The authors compared the blood-oxygen-level dependent signal during these two conditions across the Tourette and comparison groups.Relative to comparison subjects, patients with Tourette syndrome activated more strongly the frontal cortex and striatum during eye blink inhibition. Activation increased more with age in the dorsolateral and inferolateral prefrontal cortex and caudate nucleus in the Tourette group relative to comparison subjects. In addition, the Tourette group more strongly activated the middle frontal gyrus, dorsal anterior cingulate, and temporal cortices. The severity of tic symptoms in the Tourette group correlated inversely with activation in the putamen and inferolateral prefrontal cortex.Frontostriatal activity is increased in persons with Tourette syndrome during the inhibition of eye blinks. Activation of frontostriatal circuits in this population may help to maintain regulatory control over semi-involuntary behaviors, whether these are tics or eye blinks.