Clinical and functional spectrum of RAC2-related immunodeficiency.

ABSTRACT: Mutations in the small Rho-family guanosine triphosphate hydrolase RAC2, critical for actin cytoskeleton remodeling and intracellular signal transduction, are associated with neonatal severe combined immunodeficiency (SCID), infantile neutrophilic disorder resembling leukocyte adhesion deficiency (LAD), and later-onset combined immune deficiency (CID). We investigated 54 patients (23 previously reported) from 37 families yielding 15 novel RAC2 missense mutations, including one present only in homozygosity. Data were collected from referring physicians and literature reports with updated clinical information. Patients were grouped by presentation: neonatal SCID (n = 5), infantile LAD-like disease (n = 5), or CID (n = 44). Disease correlated to RAC2 activity: constitutively active RAS-like mutations caused neonatal SCID, dominant-negative mutations caused LAD-like disease, whereas dominant-activating mutations caused CID. Significant T- and B-lymphopenia with low immunoglobulins were seen in most patients; myeloid abnormalities included neutropenia, altered oxidative burst, impaired neutrophil migration, and visible neutrophil macropinosomes. Among 42 patients with CID with clinical data, upper and lower respiratory infections and viral infections were common. Twenty-three distinct RAC2 mutations, including 15 novel variants, were identified. Using heterologous expression systems, we assessed downstream effector functions including superoxide production, p21-activated kinase 1 binding, AKT activation, and protein stability. Confocal microscopy showed altered actin assembly evidenced by membrane ruffling and macropinosomes. Altered protein localization and aggregation were observed. All tested RAC2 mutant proteins exhibited aberrant function; no single assay was sufficient to determine functional consequence. Most mutants produced elevated superoxide; mutations unable to support superoxide formation were associated with bacterial infections. RAC2 mutations cause a spectrum of immune dysfunction, ranging from early onset SCID to later-onset combined immunodeficiencies depending on RAC2 activity. This trial was registered at www.clinicaltrials.gov as #NCT00001355 and #NCT00001467.

Treatment with Elapegademase Restores Immunity in Infants with Adenosine Deaminase Deficient Severe Combined Immunodeficiency.

PURPOSE: Patients with adenosine deaminase 1 deficient severe combined immunodeficiency (ADA-SCID) are initially treated with enzyme replacement therapy (ERT) with polyethylene glycol-modified (PEGylated) ADA while awaiting definitive treatment with hematopoietic stem cell transplant (HSCT) or gene therapy. Beginning in 1990, ERT was performed with PEGylated bovine intestinal ADA (ADAGEN®). In 2019, a PEGylated recombinant bovine ADA (Revcovi®) replaced ADAGEN following studies in older patients previously treated with ADAGEN for many years. There are limited longitudinal data on ERT-naïve newborns treated with Revcovi. METHODS: We report our clinical experience with Revcovi as initial bridge therapy in three newly diagnosed infants with ADA-SCID, along with comprehensive biochemical and immunologic data. RESULTS: Revcovi was initiated at twice weekly dosing (0.2 mg/kg intramuscularly), and monitored by following plasma ADA activity and the concentration of total deoxyadenosine nucleotides (dAXP) in erythrocytes. All patients rapidly achieved a biochemically effective level of plasma ADA activity, and red cell dAXP were eliminated within 2-3 months. Two patients reconstituted B-cells and NK-cells within the first month of ERT, followed by naive T-cells one month later. The third patient reconstituted all lymphocyte subsets within the first month of ERT. One patient experienced declining lymphocyte counts with improvement following Revcovi dose escalation. Two patients developed early, self-resolving thrombocytosis, but no thromboembolic events occurred. CONCLUSION: Revcovi was safe and effective as initial therapy to restore immune function in these newly diagnosed infants with ADA-SCID, however, time course and degree of reconstitution varied. Revcovi dose may need to be optimized based on immune reconstitution, clinical status, and biochemical data.

Baseline Functional Connectivity in Resting State Networks Associated with Depression and Remission Status after 16 Weeks of Pharmacotherapy: A CAN-BIND Report.

Understanding the neural underpinnings of major depressive disorder (MDD) and its treatment could improve treatment outcomes. So far, findings are variable and large sample replications scarce. We aimed to replicate and extend altered functional connectivity associated with MDD and pharmacotherapy outcomes in a large, multisite sample. Resting-state fMRI data were collected from 129 patients and 99 controls through the Canadian Biomarker Integration Network in Depression. Symptoms were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS). Connectivity was measured as correlations between four seeds (anterior and posterior cingulate cortex, insula and dorsolateral prefrontal cortex) and all other brain voxels. Partial least squares was used to compare connectivity prior to treatment between patients and controls, and between patients reaching remission (MADRS ≤ 10) early (within 8 weeks), late (within 16 weeks), or not at all. We replicated previous findings of altered connectivity in patients. In addition, baseline connectivity of the anterior/posterior cingulate and insula seeds differentiated patients with different treatment outcomes. The stability of these differences was established in the largest single-site subsample. Our replication and extension of altered connectivity highlighted previously reported and new differences between patients and controls, and revealed features that might predict remission prior to pharmacotherapy. Trial registration:ClinicalTrials.gov: NCT01655706.

Frontal EEG asymmetry moderates the relation between borderline personality disorder features and feelings of social rejection in adolescents.

Although associations among borderline personality disorder (BPD), social rejection, and frontal EEG alpha asymmetry scores (FAA, a neural correlate of emotion regulation and approach-withdrawal motivations) have been explored in different studies, relatively little work has examined these relations during adolescence in the same study. We examined whether FAA moderated the relation between BPD features and rejection sensitivity following a validated social exclusion paradigm, Cyberball. A mixed, clinical-community sample of 64 adolescents (females = 62.5%; Mage = 14.45 years; SD = 1.6; range = 11-17 years) completed psychodiagnostic interviews and a self-report measure of BPD (Time 1). Approximately two weeks later (Time 2), participants completed a resting EEG recording followed by Cyberball. FAA moderated the relation between BPD features and overall feelings of rejection following Cyberball: individuals with greater relative left FAA had the highest and lowest feelings of social rejection depending on whether they had high and low BPD feature scores, respectively. Results remained after controlling for age, sex, gender, depression, and BPD diagnosis. These results suggest that FAA may moderate the relation between BPD features and social rejection, and that left frontal brain activity at rest may be differentially associated with those feelings in BPD. Findings are discussed in terms of the link between left frontal brain activity in the regulation and dysregulation of social approach behaviors, characteristic of BPD.

Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group.

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.

Assessing the inhibitory properties of a latent inhibitor in flavor-aversion learning.

In Experiment 1, rats received 16 nonreinforced trials of exposure to a flavor (A) that was subsequently used as the conditioned stimulus in flavor-aversion conditioning. In the critical condition, Flavor A was presented in compound with a different novel flavor on each of the eight daily trials. This treatment produced latent inhibition, in that this preexposure retarded conditioning just as did 16 trials with A alone. Rats in the control conditions, given no preexposure or exposure just to the sequence of novel flavors, learned readily. Experiment 2 examined the effects of these forms of preexposure on performance on a summation test, in which Flavor A was presented in compound with a separately conditioned flavor (X). The preexposure procedure in which A was presented along with novel flavors rendered A effective in inhibiting the response conditioned to X on that test. The conclusion, that this form of training can establish the target stimulus as a conditioned inhibitor, is predicted by the account of latent inhibition put forward by Hall and Rodríguez (2010) which proposes that the latent inhibition effect is a consequence both of a reduction in the associability of the stimulus and of a process of inhibitory associative learning that opposes the initial expectation that a novel event will be followed by some consequence.

Resting state fMRI scanner instabilities revealed by longitudinal phantom scans in a multi-center study.

Quality assurance (QA) is crucial in longitudinal and/or multi-site studies, which involve the collection of data from a group of subjects over time and/or at different locations. It is important to regularly monitor the performance of the scanners over time and at different locations to detect and control for intrinsic differences (e.g., due to manufacturers) and changes in scanner performance (e.g., due to gradual component aging, software and/or hardware upgrades, etc.). As part of the Ontario Neurodegenerative Disease Research Initiative (ONDRI) and the Canadian Biomarker Integration Network in Depression (CAN-BIND), QA phantom scans were conducted approximately monthly for three to four years at 13 sites across Canada with 3T research MRI scanners. QA parameters were calculated for each scan using the functional Biomarker Imaging Research Network's (fBIRN) QA phantom and pipeline to capture between- and within-scanner variability. We also describe a QA protocol to measure the full-width-at-half-maximum (FWHM) of slice-wise point spread functions (PSF), used in conjunction with the fBIRN QA parameters. Variations in image resolution measured by the FWHM are a primary source of variance over time for many sites, as well as between sites and between manufacturers. We also identify an unexpected range of instabilities affecting individual slices in a number of scanners, which may amount to a substantial contribution of unexplained signal variance to their data. Finally, we identify a preliminary preprocessing approach to reduce this variance and/or alleviate the slice anomalies, and in a small human data set show that this change in preprocessing can have a significant impact on seed-based connectivity measurements for some individual subjects. We expect that other fMRI centres will find this approach to identifying and controlling scanner instabilities useful in similar studies.

Exploring brain connectivity changes in major depressive disorder using functional-structural data fusion: A CAN-BIND-1 study.

There is a growing interest in examining the wealth of data generated by fusing functional and structural imaging information sources. These approaches may have clinical utility in identifying disruptions in the brain networks that underlie major depressive disorder (MDD). We combined an existing software toolbox with a mathematically dense statistical method to produce a novel processing pipeline for the fast and easy implementation of data fusion analysis (FATCAT-awFC). The novel FATCAT-awFC pipeline was then utilized to identify connectivity (conventional functional, conventional structural and anatomically weighted functional connectivy) changes in MDD patients compared to healthy comparison participants (HC). Data were acquired from the Canadian Biomarker Integration Network for Depression (CAN-BIND-1) study. Large-scale resting-state networks were assessed. We found statistically significant anatomically-weighted functional connectivity (awFC) group differences in the default mode network and the ventral attention network, with a modest effect size (d < 0.4). Functional and structural connectivity seemed to overlap in significance between one region-pair within the default mode network. By combining structural and functional data, awFC served to heighten or reduce the magnitude of connectivity differences in various regions distinguishing MDD from HC. This method can help us more fully understand the interconnected nature of structural and functional connectivity as it relates to depression.

Prefrontal cortex VAMP1 gene network moderates the effect of the early environment on cognitive flexibility in children.

During development, genetic and environmental factors interact to modify specific phenotypes. Both in humans and in animal models, early adversities influence cognitive flexibility, an important brain function related to behavioral adaptation to variations in the environment. Abnormalities in cognitive functions are related to changes in synaptic connectivity in the prefrontal cortex (PFC), and altered levels of synaptic proteins. We investigated if individual variations in the expression of a network of genes co-expressed with the synaptic protein VAMP1 in the prefrontal cortex moderate the effect of early environmental quality on the performance of children in cognitive flexibility tasks. Genes overexpressed in early childhood and co-expressed with the VAMP1 gene in the PFC were selected for study. SNPs from these genes (post-clumping) were compiled in an expression-based polygenic score (PFC-ePRS-VAMP1). We evaluated cognitive performance of the 4 years-old children in two cohorts using similar cognitive flexibility tasks. In the first cohort (MAVAN) we utilized two CANTAB tasks: (a) the Intra-/Extra-dimensional Set Shift (IED) task, and (b) the Spatial Working Memory (SWM) task. In the second cohort, GUSTO, we used the Dimensional Change Card Sort (DCCS) task. The results show that in 4 years-old children, the PFC-ePRS-VAMP1 network moderates responsiveness to the effects of early adversities on the performance in attentional flexibility tests. The same result was observed for a spatial working memory task. Compared to attentional flexibility, reversal learning showed opposite effects of the environment, as moderated by the ePRS. A parallel ICA analysis was performed to identify relationships between whole-brain voxel based gray matter density and SNPs that comprise the PFC-ePRS-VAMP1. The early environment predicts differences in gray matter content in regions such as prefrontal and temporal cortices, significantly associated with a genetic component related to Wnt signaling pathways. Our data suggest that a network of genes co-expressed with VAMP1 in the PFC moderates the influence of early environment on cognitive function in children.

Evaluating Adherence to Return to School and Activity Protocols in Children After Concussion.

OBJECTIVE: The need to have a pediatric-specific concussion management protocol on Return to School (RTS) and Return to Activity (RTA) after concussion has been recognized internationally. The first step to evaluate the protocol effectiveness is to establish whether children and youth are adhering to these recommendations. The objective of this study was to explore the prevalence and predictors of adherence to RTS and RTA concussion management protocols for children/youth. DESIGN: A prospective cohort of children/youth with concussion. SETTING: Childhood Disability Research Centre. PARTICIPANTS: One hundred thirty-nine children/youth aged 5 to 18 years, diagnosed with concussion and symptomatic upon enrollment, were followed for up to 6 months. Primary recruitment occurred from a Children's Hospital Emergency Department. INTERVENTION: Provision of RTS/RTA guidelines. MAIN OUTCOME MEASURES: Measurement of adherence came from multiple sources, including the child's and parent's knowledge of protocols, research personnel evaluations, and self-reported stages of RTS/RTA and Post-Concussion Symptom Scale (PCSS) scores. RESULTS: Spearman correlations and logistic regression were used, investigating the relationship between PCSS and progression of protocols and determining predictors of adherence. Significant negative associations between total PCSS score and stage of RTS/RTA protocols were found. Fifty-three percent and 56% of the participants adhered to the RTS and RTA protocols, respectively. CONCLUSIONS: Children's knowledge of protocols and total PCSS scores significantly predicted adherence to RTS/RTA and may be the most important factors in predicting adherence during recovery from concussion.

Reliability of a functional magnetic resonance imaging task of emotional conflict in healthy participants.

Task-based functional neuroimaging methods are increasingly being used to identify biomarkers of treatment response in psychiatric disorders. To facilitate meaningful interpretation of neural correlates of tasks and their potential changes with treatment over time, understanding the reliability of the blood-oxygen-level dependent (BOLD) signal of such tasks is essential. We assessed test-retest reliability of an emotional conflict task in healthy participants collected as part of the Canadian Biomarker Integration Network in Depression. Data for 36 participants, scanned at three time points (weeks 0, 2, and 8) were analyzed, and intra-class correlation coefficients (ICC) were used to quantify reliability. We observed moderate reliability (median ICC values between 0.5 and 0.6), within occipital, parietal, and temporal regions, specifically for conditions of lower cognitive complexity, that is, face, congruent or incongruent trials. For these conditions, activation was also observed within frontal and sub-cortical regions, however, their reliability was poor (median ICC < 0.2). Clinically relevant prognostic markers based on task-based fMRI require high predictive accuracy at an individual level. For this to be achieved, reliability of BOLD responses needs to be high. We have shown that reliability of the BOLD response to an emotional conflict task in healthy individuals is moderate. Implications of these findings to further inform studies of treatment effects and biomarker discovery are discussed.

DCC gene network in the prefrontal cortex is associated with total brain volume in childhood.

BACKGROUND: Genetic variation in the guidance cue DCC gene is linked to psychopathologies involving dysfunction in the prefrontal cortex. We created an expression-based polygenic risk score (ePRS) based on the DCC coexpression gene network in the prefrontal cortex, hypothesizing that it would be associated with individual differences in total brain volume. METHODS: We filtered single nucleotide polymorphisms (SNPs) from genes coexpressed with DCC in the prefrontal cortex obtained from an adult postmortem donors database (BrainEAC) for genes enriched in children 1.5 to 11 years old (BrainSpan). The SNPs were weighted by their effect size in predicting gene expression in the prefrontal cortex, multiplied by their allele number based on an individual's genotype data, and then summarized into an ePRS. We evaluated associations between the DCC ePRS and total brain volume in children in 2 community-based cohorts: the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) and University of California, Irvine (UCI) projects. For comparison, we calculated a conventional PRS based on a genome-wide association study of total brain volume. RESULTS: Higher ePRS was associated with higher total brain volume in children 8 to 10 years old (ß = 0.212, p = 0.043; n = 88). The conventional PRS at several different thresholds did not predict total brain volume in this cohort. A replication analysis in an independent cohort of newborns from the UCI study showed an association between the ePRS and newborn total brain volume (ß = 0.101, p = 0.048; n = 80). The genes included in the ePRS demonstrated high levels of coexpression throughout the lifespan and are primarily involved in regulating cellular function. LIMITATIONS: The relatively small sample size and age differences between the main and replication cohorts were limitations. CONCLUSION: Our findings suggest that the DCC coexpression network in the prefrontal cortex is critically involved in whole brain development during the first decade of life. Genes comprising the ePRS are involved in gene translation control and cell adhesion, and their expression in the prefrontal cortex at different stages of life provides a snapshot of their dynamic recruitment.

Functional connectivity and quality of life in young adults with cerebral palsy: a feasibility study.

BACKGROUND: Cerebral Palsy (CP) is a group of disorders that affect the development of movement and posture. CP results from injuries to the immature brain during the prenatal, perinatal, or postnatal stage of development. Neuroimaging research in CP has focused on the structural changes of the brain during early development, but little is known about brain's structural and functional changes during late adolescence and early adulthood, a period in time when individuals experience major changes as they transition into adulthood. The work reported here served as a feasibility study within a larger program of research (MyStory Study). We aimed to determine whether it would be feasible to scan and obtain good quality data without the use of sedation during a resting state condition for functional connectivity (FC) analyses in young adults with CP. Second, we aimed to identify the FC pattern(s) that are associated with depressive mood ratings, indices of pain and fatigue, and quality of life in this group. METHODS: Resting state functional images were collected from 9 young people with CP (18-29 years). We applied a stringent head motion correction and quality control methods following preprocessing. RESULTS: We were able to scan and obtain good quality data without the use of sedation from this group of young individuals with CP who demonstrated a range of gross motor ability. The functional connectivity networks of interest were identified in the data using standard seed regions. Our analyses further revealed that higher well-being scores were associated with higher levels of FC between the Medial Pre-Frontal Cortex and the right Lateral Parietal regions, which are implicated in prosocial and emotion regulations skills. The implications of this association are discussed. CONCLUSION: The findings of the present study demonstrate that it is feasible to conduct resting state functional connectivity in young adults with CP with different gross motor abilities without the use of sedation. Our results also highlight a neural circuitry that is associated with the self-report of quality of life and emotion regulation. These findings identify these regions/circuitries as important seeds for further investigations into mental health and wellbeing in CP.

Post-concussive depression: evaluating depressive symptoms following concussion in adolescents and its effects on executive function.

Background: Post-concussive depression describes an elevation of depressive symptoms following concussion that occurs in conjunction with other symptoms of concussion. Children with concussion are more likely to diagnosed with depression. The overlapping symptoms between clinical depression and concussion make the diagnosis of depression difficult. The purpose of this study is to explore how post-concussive depression relates to post-concussion symptoms and cognition by investigating symptom-reporting in youth with post-concussive depression and executive function.Methods: Adolescents (age 10-17 years) diagnosed with concussion were divided into two groups based on depression scores on the Children's Depression Inventory (post-concussion depression; non-depression groups). Symptom reporting on the Post-Concussion Symptom Inventory and performance on Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) were compared.Results: Participants with post-concussive depression had heightened emotionality, irritability, and nervousness. Sadness and fatigue were reported by both groups. ImPACT was unable to distinguish between groups but the group overall demonstrated severe neurocognitive deficits.Conclusion: Reports of greater emotionality, irritability, and nervousness on concussion symptom scales may be indicators of post-concussion depression. It is important for clinicians to take note when an adolescent with concussion scores high on these three emotional symptoms as they may be indicative of greater emotional distress.

Testing a deep convolutional neural network for automated hippocampus segmentation in a longitudinal sample of healthy participants.

Subtle changes in hippocampal volumes may occur during both physiological and pathophysiological processes in the human brain. Assessing hippocampal volumes manually is a time-consuming procedure, however, creating a need for automated segmentation methods that are both fast and reliable over time. Segmentation algorithms that employ deep convolutional neural networks (CNN) have emerged as a promising solution for large longitudinal neuroimaging studies. However, for these novel algorithms to be useful in clinical studies, the accuracy and reproducibility should be established on independent datasets. Here, we evaluate the performance of a CNN-based hippocampal segmentation algorithm that was developed by Thyreau and colleagues - Hippodeep. We compared its segmentation outputs to manual segmentation and FreeSurfer 6.0 in a sample of 200 healthy participants scanned repeatedly at seven sites across Canada, as part of the Canadian Biomarker Integration Network in Depression consortium. The algorithm demonstrated high levels of stability and reproducibility of volumetric measures across all time points compared to the other two techniques. Although more rigorous testing in clinical populations is necessary, this approach holds promise as a viable option for tracking volumetric changes in longitudinal neuroimaging studies.

The Canadian Biomarker Integration Network in Depression (CAN-BIND): magnetic resonance imaging protocols

Studies of clinical populations that combine MRI data generated at multiple sites are increasingly common. The Canadian Biomarker Integration Network in Depression (CAN-BIND; www.canbind.ca) is a national depression research program that includes multimodal neuroimaging collected at several sites across Canada. The purpose of the current paper is to provide detailed information on the imaging protocols used in a number of CAN-BIND studies. The CAN-BIND program implemented a series of platform-specific MRI protocols, including a suite of prescribed structural and functional MRI sequences supported by real-time monitoring for adherence and quality control. The imaging data are retained in an established informatics and databasing platform. Approximately 1300 participants are being recruited, including almost 1000 with depression. These include participants treated with antidepressant medications, transcranial magnetic stimulation, cognitive behavioural therapy and cognitive remediation therapy. Our ability to analyze the large number of imaging variables available may be limited by the sample size of the substudies. The CAN-BIND program includes a multimodal imaging database supported by extensive clinical, demographic, neuropsychological and biological data from people with major depression. It is a resource for Canadian investigators who are interested in understanding whether aspects of neuroimaging ­ alone or in combination with other variables ­ can predict the outcomes of various treatment modalities.

Impact of maternal adverse childhood experiences on child socioemotional function in rural Kenya: Mediating role of maternal mental health.

Mothers in low- and middle-income countries (LMIC) suffer heightened vulnerability for adverse childhood experiences (ACEs), which is exacerbated by the multitude of risk factors associated with poverty and may lead to increased risk of psychiatric disorder. The constellation of complex, co-occurring biological, environmental, social, economic and psychological risk factors are in turn transmitted to her child, conferring vulnerability for adverse development. This study examines the association between maternal intra- and extra-familial ACEs, maternal education and the mental health of her child, mediated by maternal mental health. Mother-child dyads (n = 121) in Machakos, Kenya were examined cross-sectionally using self-report measures of ACEs, maternal mental health and child internalizing and externalizing mental health problems. The four models proposed to examine the relationship between intra- and extra-familial maternal ACEs and child internalizing and externalizing problems demonstrated indirect pathways through maternal mental health. These effects were found to be conditional on levels of maternal education, which served as a protective factor at lower levels of maternal ACEs. These models demonstrate how the impact of ACEs persists across the lifespan resulting in a negative impact on maternal mental health and conferring further risk to subsequent generations. Elucidating the association between ACEs and subsequent intergenerational sequelae, especially in LMIC where risk is heightened, may improve targeted caregiver mental health programs for prevention and intervention.

Cortical thickness correlates of cognitive performance in cognitively-matched individuals with and without schizophrenia.

Schizophrenia is characterized by psychosis and, in most cases, cognitive impairment. It is unclear, however, whether these elements of the disorder represent distinct or related disease processes. Accordingly, this study investigated 3-way interactions between group, cognition and cortical thickness in cognitively-matched patients with schizophrenia and healthy control groups. Patients and healthy controls were group-matched on demographics and a broadly-based index of cognitive performance. T1-weighted images were processed using Freesurfer. Variable selection techniques were applied to determine which regions best predicted 3-way interaction effects. Independent variables included age, sex, IQ, and 87 regional cortical thickness values strongly associated with group or cognition. Antipsychotic treatment effects were also investigated. Twenty regions were selected by the best fitting model. The top 6 regions included the left pre- and post-central, left superior frontal and temporal and right rostral and caudal middle frontal cortices. No antipsychotic treatment effects were seen. Cortical thinning in schizophrenia exists even in the absence of cognitive impairment. Our findings support the separation of psychosis and cognitive impairment as independent disease processes, with distinct relations with cortical thickness in prefrontal cortical areas. Parsing out these two disease processes will increase understanding of heterogeneity in schizophrenia and may modify treatment targets.

Facilitation and retardation of flavor preference conditioning following prior exposure to the flavor conditioned stimulus.

In two experiments, rats received pairings of an almond flavor (Experiments 1 and 2B) or a vanilla flavor (Experiment 2A) with sucrose. In each experiment, half of the rats received prior exposure to the flavor and half were exposed to water. Conditioned preference was then assessed through two-bottle, flavor versus water, choice tests. Latent inhibition (indicated by a weaker preference in pre-exposed subjects) was observed in the experiment using the vanilla flavor. However, facilitation (a stronger preference in pre-exposed subjects) instead of latent inhibition was evident with the almond flavor, both across acquisition trials and in the final choice test. These results indicate that, unlike most other paradigms of Pavlovian conditioning, conditioned stimulus pre-exposure in flavor preference learning may either facilitate or retard the acquisition (or the expression) of a conditioned flavor preference. We explore the proposal that the critical difference between the flavors lies in their hedonic values, with facilitation being more likely in a flavor that is initially disliked.

Probiotic Bifidobacterium longum NCC3001 Reduces Depression Scores and Alters Brain Activity: A Pilot Study in Patients With Irritable Bowel Syndrome.

BACKGROUND & AIMS: Probiotics can reduce symptoms of irritable bowel syndrome (IBS), but little is known about their effects on psychiatric comorbidities. We performed a prospective study to evaluate the effects of Bifidobacterium longum NCC3001 (BL) on anxiety and depression in patients with IBS. METHODS: We performed a randomized, double-blind, placebo-controlled study of 44 adults with IBS and diarrhea or a mixed-stool pattern (based on Rome III criteria) and mild to moderate anxiety and/or depression (based on the Hospital Anxiety and Depression scale) at McMaster University in Canada, from March 2011 to May 2014. At the screening visit, clinical history and symptoms were assessed and blood samples were collected. Patients were then randomly assigned to groups and given daily BL (n = 22) or placebo (n = 22) for 6 weeks. At weeks 0, 6, and 10, we determined patients' levels of anxiety and depression, IBS symptoms, quality of life, and somatization using validated questionnaires. At weeks 0 and 6, stool, urine and blood samples were collected, and functional magnetic resonance imaging (fMRI) test was performed. We assessed brain activation patterns, fecal microbiota, urine metabolome profiles, serum markers of inflammation, neurotransmitters, and neurotrophin levels. RESULTS: At week 6, 14 of 22 patients in the BL group had reduction in depression scores of 2 points or more on the Hospital Anxiety and Depression scale, vs 7 of 22 patients in the placebo group (P = .04). BL had no significant effect on anxiety or IBS symptoms. Patients in the BL group had a mean increase in quality of life score compared with the placebo group. The fMRI analysis showed that BL reduced responses to negative emotional stimuli in multiple brain areas, including amygdala and fronto-limbic regions, compared with placebo. The groups had similar fecal microbiota profiles, serum markers of inflammation, and levels of neurotrophins and neurotransmitters, but the BL group had reduced urine levels of methylamines and aromatic amino acids metabolites. At week 10, depression scores were reduced in patients given BL vs placebo. CONCLUSION: In a placebo-controlled trial, we found that the probiotic BL reduces depression but not anxiety scores and increases quality of life in patients with IBS. These improvements were associated with changes in brain activation patterns that indicate that this probiotic reduces limbic reactivity. ClinicalTrials.gov no. NCT01276626.