bluuebunny/crossref_metadata_2025 huggingface dataset:
Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios
Authors: Zhang Lingli , Huang Chu-Chung , Dai Yuan , Luo Qiang , Ji Yiting , Wang Kai , Deng Shining , Yu Juehua , Xu Mingyu , Du Xiujuan , Tang Yun , Shen Chun , Feng Jianfeng , Sahakian Barbara J , Lin Ching-Po , Li Fei
Published: February 2020

Bumetanide has been reported to alter synaptic excitation–inhibition (E-I) balance by potentiating the action of γ-aminobutyric acid (GABA), thereby attenuating the severity of autism spectrum disorder (ASD) in animal models. However, clinical evidence of its efficacy in young patients with ASD is limited. This was investigated in the present clinical trial of 83 patients, randomised to the bumetanide group (bumetanide treatment, 0.5 mg twice daily) or the control group (no bumetanide treatment). Primary [Children Autism Rating Scale (CARS)], secondary [Clinical Global Impressions (CGI)], and exploratory [inhibitory (γ-aminobutyric acid, GABA) and excitatory (glutamate, Glx) neurotransmitter concentrations measured in the insular cortex (IC) and visual cortex (VC) by magnetic resonance spectroscopy (MRS)] outcome measures were evaluated at baseline and at the 3-month follow-up. Side effects were monitored throughout the treatment course. Compared with the control group, the bumetanide group showed significant reduction in symptom severity, as indicated by both total CARS score and number of items assigned a score ≥ 3. The improvement in clinical symptoms was confirmed by CGI. GABA/Glx ratio in both the IC and VC decreased more rapidly over the 3-month period in the bumetanide group than that in the control group. This decrease in the IC was associated with the symptom improvement in the bumetanide group. Our study confirmed the clinical efficacy of bumetanide on alleviating the core symptoms of ASD in young children and it is the first demonstration that the improvement is associated with reduction in GABA/Glx ratios. This study suggests that the GABA/Glx ratio measured by MRS may provide a neuroimaging biomarker for assessing treatment efficacy for bumetanide.
Pro-neurogenic effect of fluoxetine in the olfactory bulb is concomitant to improvements in social memory and depressive-like behavior of socially isolated mice
Authors: Guarnieri Leonardo O. , Pereira-Caixeta Ana Raquel , Medeiros Daniel C. , Aquino Nayara S. S. , Szawka Raphael E. , Mendes Eduardo M. A. M. , Moraes Márcio F. D. , Pereira Grace S.
Published: February 2020

Although loneliness is a human experience, it can be estimated in laboratory animals deprived from physical contact with conspecifics. Rodents under social isolation (SI) tend to develop emotional distress and cognitive impairment. However, it is still to be determined whether those conditions present a common neural mechanism. Here, we conducted a series of behavioral, morphological, and neurochemical analyses in adult mice that underwent to 1 week of SI. We observed that SI mice display a depressive-like state that can be prevented by enriched environment, and the antidepressants fluoxetine (FLX) and desipramine (DES). Interestingly, chronic administration of FLX, but not DES, was able to counteract the deleterious effect of SI on social memory. We also analyzed cell proliferation, neurogenesis, and astrogenesis after the treatment with antidepressants. Our results showed that the olfactory bulb (OB) was the neurogenic niche with the highest increase in neurogenesis after the treatment with FLX. Considering that after FLX treatment social memory was rescued and depressive-like behavior decreased, we propose neurogenesis in the OB as a possible mechanism to unify the FLX ability to counteract the deleterious effect of SI.
Large epigenome-wide association study of childhood ADHD identifies peripheral DNA methylation associated with disease and polygenic risk burden
Authors: Mooney Michael A. , Ryabinin Peter , Wilmot Beth , Bhatt Priya , Mill Jonathan , Nigg Joel T.
Published: February 2020

Epigenetic variation in peripheral tissues is being widely studied as a molecular biomarker of complex disease and disease-related exposures. To date, few studies have examined differences in DNA methylation associated with attention-deficit hyperactivity disorder (ADHD). In this study, we profiled genetic and methylomic variation across the genome in saliva samples from children (age 7–12 years) with clinically established ADHD (N = 391) and nonpsychiatric controls (N = 213). We tested for differentially methylated positions (DMPs) associated with both ADHD diagnosis and ADHD polygenic risk score, by using linear regression models including smoking, medication effects, and other potential confounders in our statistical models. Our results support previously reported associations between ADHD and DNA methylation levels at sites annotated to VIPR2, and identify several novel disease-associated DMPs (p < 1e–5), although none of them were genome-wide significant. The two top-ranked, ADHD-associated DMPs (cg17478313 annotated to SLC7A8 and cg21609804 annotated to MARK2) are also significantly associated with nearby SNPs (p = 1.2e–46 and p = 2.07e–59), providing evidence that disease-associated DMPs are under genetic control. We also report a genome-wide significant association between ADHD polygenic risk and variable DNA methylation at a site annotated to the promoter of GART and SON (p = 6.71E–8). Finally, we show that ADHD-associated SNPs colocalize with SNPs associated with methylation levels in saliva. This is the first large-scale study of DNA methylation in children with ADHD. Our results represent novel epigenetic biomarkers for ADHD that may be useful for patient stratification, reinforce the importance of genetic effects on DNA methylation, and provide plausible molecular mechanisms for ADHD risk variants.
Emotional remodeling with oxytocin durably rescues trauma-induced behavioral and neuro-morphological changes in rats: a promising treatment for PTSD
Authors: Le Dorze Claire , Borreca Antonella , Pignataro Annabella , Ammassari-Teule Martine , Gisquet-Verrier Pascale
Published: February 2020

Recent evidence indicates that reactivated memories are malleable and can integrate new information upon their reactivation. We injected rats with oxytocin to investigate whether the delivery of a drug which dampens anxiety and fear before the reactivation of trauma memory decreases the emotional load of the original representation and durably alleviates PTSD-like symptoms. Rats exposed to the single prolonged stress (SPS) model of PTSD were classified 15 and 17 days later as either resilient or vulnerable to trauma on the basis of their anxiety and arousal scores. Following 2 other weeks, they received an intracerebral infusion of oxytocin (0.1 µg/1 µL) or saline 40 min before their trauma memory was reactivated by exposure to SPS reminders. PTSD-like symptoms and reactivity to PTSD-related cues were examined 3–14 days after oxytocin treatment. Results showed that vulnerable rats treated with saline exhibited a robust PTSD syndrome including increased anxiety and decreased arousal, as well as intense fear reactions to SPS sensory and contextual cues. Exposure to a combination of those cues resulted in c-fos hypo-activation and dendritic arbor retraction in prefrontal cortex and amygdala neurons, relative to resilient rats. Remarkably, 83% of vulnerable rats subjected to oxytocin-based emotional remodeling exhibited a resilient phenotype, and SPS-induced morphological alterations in prelimbic cortex and basolateral amygdala were eliminated. Our findings emphasize the translational potential of the present oxytocin-based emotional remodeling protocol which, when administered even long after the trauma, produces deep re-processing of traumatic memories and durable attenuation of the PTSD symptomatology.
Predicting treatment dropout after antidepressant initiation
Authors: Pradier Melanie F. , McCoy Jr Thomas H. , Hughes Michael , Perlis Roy H. , Doshi-Velez Finale
Published: February 2020

Antidepressants exhibit similar efficacy, but varying tolerability, in randomized controlled trials. Predicting tolerability in real-world clinical populations may facilitate personalization of treatment and maximize adherence. This retrospective longitudinal cohort study aimed to determine the extent to which incorporating patient history from electronic health records improved prediction of unplanned treatment discontinuation at index antidepressant prescription. Clinical data were analyzed from individuals from health networks affiliated with two large academic medical centers between March 1, 2008 and December 31, 2014. In total, the study cohorts included 51,683 patients with at least one International Classification of Diseases diagnostic code for major depressive disorder or depressive disorder not otherwise specified who initiated antidepressant treatment. Among 70,121 total medication changes, 16,665 (23.77%) of them were followed by failure to return; maximum risk was observed with paroxetine (27.71% discontinuation), and minimum with venlafaxine (20.78% discontinuation); Mantel–Haenzel χ2 (8 df) = 126.44, p = 1.54e–23 <1e–6. Models incorporating diagnostic and procedure codes and medication prescriptions improved per-medication Areas Under the Curve (AUCs) to a mean of 0.69 [0.64–0.73] (ranging from 0.62 for paroxetine to 0.80 for escitalopram), with similar performance in the second, replication health system. Machine learning applied to coded electronic health records facilitates identification of individuals at high-risk for treatment dropout following change in antidepressant medication. Such methods may assist primary care physicians and psychiatrists in the clinic to personalize antidepressant treatment on the basis not solely of efficacy, but of tolerability.
Sex differences in the association of body mass index with symptoms and cognitive deficits in Chinese patients with chronic schizophrenia
Authors: Wei Chang Wei , Chen Ying Qi , Ma Mi , Xiu Mei Hong , Zhang Xiang Yang
Published: February 2020

Accumulating studies have revealed gender differences in many aspects of schizophrenia (SZ), including obesity and cognitive function. The relationship between obesity and cognitive impairment in SZ has been studied before; however, the results are inconsistent. This study was designed to examine the sex differences in the relationship between body mass index (BMI) and cognitive deficits in Chinese patients with chronic SZ, which have not been investigated yet. 176 chronic patients with SZ (male/female = 108/68) and 200 controls (male/female = 120/80) were enrolled to compare the sex differences in cognitive functions measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), BMI, and their associations. The clinical symptoms were evaluated using the positive and negative syndrome scales (PANSS). Our results showed that male patients had lower BMI and more negative symptoms but fewer positive symptoms than female patients (all p < 0.05). However, there was no significant sex difference in RBANS scores. In male patients, BMI was correlated with age of onset, PANSS general psychopathology, total score, negative symptom, together with RBANS language, visuospatial/construction, and attention. Further regression analysis showed that in male patients, BMI was significantly associated with RBANS language, PANSS general psychopathology, PANSS total score, and age of onset, with adjusted R2 = 0.22. These findings revealed significant sex differences in BMI, cognitive dysfunctions and their association in SZ. Nonetheless, these results should only be considered as preliminary because of the cross-sectional design, which will deserve further replication in first-episode patients using a prospective longitudinal design.
A clinical staging model for bipolar disorder: longitudinal approach
Authors: de la Fuente-Tomás Lorena , Sierra Pilar , Sanchez-Autet Mónica , Arranz Belén , García-Blanco Ana , Safont Gemma , García-Portilla Maria P.
Published: February 2020

Bipolar disorder (BD) has been identified as a life-course illness with different clinical manifestations from an at-risk to a late stage, supporting the assumption that it would benefit from a staging model. In a previous study, we used a clustering approach to stratify 224 patients with a diagnosis of BD into five clusters based on clinical characteristics, functioning, cognition, general health, and health-related quality of life. This study was design to test the construct validity of our previously developed k-means clustering model and to confirm its longitudinal validity over a span of 3 years. Of the 224 patients included at baseline who were used to develop our model, 129 (57.6%) reached the 3-year follow-up. All life domains except mental health-related quality of life (QoL) showed significant worsening in stages (p < 0.001), suggesting construct validity. Furthermore, as patients progressed through stages, functional decline (p < 0.001) and more complex treatment patterns (p = 0.002) were observed. As expected, at 3 years, the majority of patients remained at the same stage (49.6%), or progressed (20.9%) or regressed (23.3%) one stage. Furthermore, 85% of patients who stayed euthymic during that period remained at the same stage or regressed to previous stages, supporting its longitudinal validity. For that reason, this study provides evidence of the construct and longitudinal validity of an empirically developed, comprehensive staging model for patients with BD. Thus, it may help clinicians and researchers to better understand the disorder and, at the same time, to design more accurate and personalized treatment plans.
Genetic associations with clozapine-induced myocarditis in patients with schizophrenia
Authors: Lacaze Paul , Ronaldson Kathlyn J. , Zhang Eunice J. , Alfirevic Ana , Shah Hardik , Newman Leah , Strahl Maya , Smith Melissa , Bousman Chad , Francis Ben , Morris Andrew P. , Wilson Trevor , Rossello Fernando , Powell David , Vasic Vivien , Sebra Robert , McNeil John J. , Pirmohamed Munir
Published: February 2020

Clozapine is the most effective antipsychotic drug for schizophrenia, yet it can cause life-threatening adverse drug reactions, including myocarditis. The aim of this study was to determine whether schizophrenia patients with clozapine-induced myocarditis have a genetic predisposition compared with clozapine-tolerant controls. We measured different types of genetic variation, including genome-wide single-nucleotide polymorphisms (SNPs), coding variants that alter protein expression, and variable forms of human leucocyte antigen (HLA) genes, alongside traditional clinical risk factors in 42 cases and 67 controls. We calculated a polygenic risk score (PRS) based on variation at 96 different genetic sites, to estimate the genetic liability to clozapine-induced myocarditis. Our genome-wide association analysis identified four SNPs suggestive of increased myocarditis risk (P < 1 × 10−6), with odds ratios ranging 5.5–13.7. The SNP with the lowest P value was rs74675399 (chr19p13.3, P = 1.21 × 10−7; OR = 6.36), located in the GNA15 gene, previously associated with heart failure. The HLA-C*07:01 allele was identified as potentially predisposing to clozapine-induced myocarditis (OR = 2.89, 95% CI: 1.11–7.53), consistent with a previous report of association of the same allele with clozapine-induced agranulocytosis. Another seven HLA alleles, including HLA-B*07:02 (OR = 0.25, 95% CI: 0.05–1.2) were found to be putatively protective. Long-read DNA sequencing provided increased resolution of HLA typing and validated the HLA associations. The PRS explained 66% of liability (P value = 9.7 × 10−5). Combining clinical and genetic factors together increased the proportion of variability accounted for (r2 0.73, P = 9.8 × 10−9). However, due to the limited sample size, individual genetic associations were not statistically significant after correction for multiple testing. We report novel candidate genetic associations with clozapine-induced myocarditis, which may have potential clinical utility, but larger cohorts are required for replication.
Expression quantitative trait loci-derived scores and white matter microstructure in UK Biobank: a novel approach to integrating genetics and neuroimaging
Authors: Barbu Miruna C. , Spiliopoulou Athina , Colombo Marco , McKeigue Paul , Clarke Toni-Kim , Howard David M. , Adams Mark J. , Shen Xueyi , Lawrie Stephen M. , McIntosh Andrew M. , Whalley Heather C.
Published: February 2020

Expression quantitative trait loci (eQTL) are genetic variants associated with gene expression. Using genome-wide genotype data, it is now possible to impute gene expression using eQTL mapping efforts. This approach can be used to analyse previously unexplored relationships between gene expression and heritable in vivo measures of human brain structural connectivity. Using large-scale eQTL mapping studies, we computed 6457 gene expression scores (eQTL scores) using genome-wide genotype data in UK Biobank, where each score represents a genetic proxy measure of gene expression. These scores were then tested for associations with two diffusion tensor imaging measures, fractional anisotropy (NFA = 14,518) and mean diffusivity (NMD = 14,485), representing white matter structural integrity. We found FDR-corrected significant associations between 8 eQTL scores and structural connectivity phenotypes, including global and regional measures (βabsolute FA = 0.0339–0.0453; MD = 0.0308–0.0381) and individual tracts (βabsolute FA = 0.0320–0.0561; MD = 0.0295–0.0480). The loci within these eQTL scores have been reported to regulate expression of genes involved in various brain-related processes and disorders, such as neurite outgrowth and Parkinson’s disease (DCAKD, SLC35A4, SEC14L4, SRA1, NMT1, CPNE1, PLEKHM1, UBE3C). Our findings indicate that eQTL scores are associated with measures of in vivo brain connectivity and provide novel information not previously found by conventional genome-wide association studies. Although the role of expression of these genes regarding white matter microstructural integrity is not yet clear, these results suggest it may be possible, in future, to map potential trait- and disease-associated eQTL to in vivo brain connectivity and better understand the mechanisms of psychiatric disorders and brain traits, and their associated imaging findings.
Modelling associations between neurocognition and functional course in young people with emerging mental disorders: a longitudinal cohort study
Authors: Crouse Jacob J. , Chitty Kate M. , Iorfino Frank , Carpenter Joanne S. , White Django , Nichles Alissa , Zmicerevska Natalia , Guastella Adam J. , Scott Elizabeth M. , Lee Rico S. C. , Naismith Sharon L. , Scott Jan , Hermens Daniel F. , Hickie Ian B.
Published: February 2020

Neurocognitive impairment is commonly associated with functional disability in established depressive, bipolar and psychotic disorders. However, little is known about the longer-term functional implications of these impairments in early phase transdiagnostic cohorts. We aimed to examine associations between neurocognition and functioning at baseline and over time. We used mixed effects models to investigate associations between neurocognitive test scores and longitudinal social and occupational functioning (“Social and Occupational Functioning Assessment Scale”) at 1–7 timepoints over five-years in 767 individuals accessing youth mental health services. Analyses were adjusted for age, sex, premorbid IQ, and symptom severity. Lower baseline functioning was associated with male sex (coefficient −3.78, 95% CI −5.22 to −2.34 p < 0.001), poorer verbal memory (coefficient 0.90, 95% CI 0.42 to 1.38, p < 0.001), more severe depressive (coefficient −0.28, 95% CI −0.41 to −0.15, p < 0.001), negative (coefficient −0.49, 95% CI −0.74 to −0.25, p < 0.001), and positive symptoms (coefficient −0.25, 95% CI −0.41 to −0.09, p = 0.002) and lower premorbid IQ (coefficient 0.13, 95% CI 0.07 to 0.19, p < 0.001). The rate of change in functioning over time varied among patients depending on their sex (male; coefficient 0.73, 95% CI 0.49 to 0.98, p < 0.001) and baseline level of cognitive flexibility (coefficient 0.14, 95% CI 0.06 to 0.22, p < 0.001), such that patients with the lowest scores had the least improvement in functioning. Impaired cognitive flexibility is common and may represent a meaningful and transdiagnostic target for cognitive remediation in youth mental health settings. Future studies should pilot cognitive remediation targeting cognitive flexibility while monitoring changes in functioning.
Effects of COMT rs4680 and BDNF rs6265 polymorphisms on brain degree centrality in Han Chinese adults who lost their only child
Authors: Qi Rongfeng , Luo Yifeng , Zhang Li , Weng Yifei , Surento Wesley , Li Lingjiang , Cao Zhihong , Lu Guang Ming
Published: February 2020

Losing one’s only child is a major traumatic life event that may lead to posttraumatic stress disorder (PTSD); however, not all parents who experience this trauma develop PTSD. Genetic variants are associated with the risk of developing PTSD. Catechol-O-methyltransferase (COMT) rs4680 and brain-derived neurotrophic factor (BDNF) rs6265 are two most well-described single-nucleotide polymorphisms that relate to stress response; however, the neural mechanism underlying their effects on adults who lost an only child remains poorly understood. Two hundred and ten Han Chinese adults who had lost their only child (55 with PTSD and 155 without PTSD) were included in this imaging genetics study. Participants were divided into subgroups according to their COMT rs4680 and BDNF rs6265 genotypes. Degree Centrality (DC)—a resting-state fMRI index reflecting the brain network communication—was compared with a three-way (PTSD diagnosis, COMT, and BDNF polymorphisms) analysis of covariance. Diagnosis state had a significant effect on DC in bilateral inferior parietal lobules and right middle frontal gyrus (MFG), where PTSD adults showed weaker DC. BDNF × diagnosis interaction effect was found in the right MFG and hippocampus, and these two regions were reversely modulated. Also, there was a significant COMT × BDNF interaction effect in left cuneus, middle temporal gyrus, right inferior occipital gyrus, and bilateral putamen, independent of PTSD diagnosis. These findings suggest that the modulatory effect of BDNF polymorphism on the MFG and hippocampus may contribute to PTSD development in bereaved adults. Interactions of COMT × BDNF polymorphisms modulate some cortices and basal ganglia, irrespective of PTSD development.
High/low cortisol reactivity and food intake in people with obesity and healthy weight
Authors: Herhaus Benedict , Ullmann Enrico , Chrousos George , Petrowski Katja
Published: February 2020

Increased food intake, termed “comfort eating”, is a pathologic coping mechanism in chronic stress. Cortisol reactivity under stress is a potent predictor of stress-induced eating behavior affecting the body mass index (BMI). However, cortisol reactivity and food intake under stress in people with obesity has not been evaluated. The aim of this study was to investigate the effect of high/low cortisol reactivity on food intake in people with obesity and healthy weight test controls, following standardized stress induction and a resting condition. Thirty-six men and women with obesity (BMI: 33.00 ± 3.23 kg/m²), as well as 36 age- and gender-matched healthy weight controls (BMI: 21.98 ± 1.81 kg/m²) were categorized into high cortisol reactors (HCR) and low cortisol reactors (LCR) in the Trier Social Stress Test (TSST). Following the TSST and a resting condition, the food intake of all participants was recorded in a standardized laboratory meal. Obese HCR demonstrated a significantly higher food intake than LCR (t (34) = −2.046, p ≤ 0.05). However, there were no significant differences between HCR and LCR in the healthy weight controls (p = 0.26). In addition, HCR of the people with obesity showed lower values in the emotion coping strategy of cognitive reappraisal than obese LCR (t (32) = 2.087, p ≤ 0.05). In conclusion, the magnitude of the cortisol reactivity to stress predicts stress-induced food intake in people with obesity, but not in the healthy weight controls. Limited use of cognitive reappraisal in emotion regulation in the obese HCR may be a marker of vulnerability to stress-induced eating.
Stress genomics revisited: gene co-expression analysis identifies molecular signatures associated with childhood adversity
Authors: Dieckmann Linda , Cole Steve , Kumsta Robert
Published: February 2020

Childhood adversity is related to an increased risk for psychopathology in adulthood. Altered regulation of stress response systems, as well as the changes in stress-immune interplay have been suggested as potential mechanisms underlying these long-term effects. We have previously shown altered transcriptional responses to acute psychosocial stress in adults reporting the experience of childhood adversity. Here, we extend these analyses using a network approach. We performed a co-expression network analysis of genome-wide mRNA data derived from isolated monocytes, sampled 3 h after stress exposure from healthy adults, who experienced childhood adversity and a matched control group without adverse childhood experiences. Thirteen co-expression modules were identified, of which four modules were enriched for genes related to immune system function. Gene set enrichment analysis showed differential module activity between the early adversity and control group. In line with previous findings reporting a pro-inflammatory bias following childhood adversity, one module included genes associated with pro-inflammatory function (hub genes: IL6, TM4SF1, ADAMTS4, CYR61, CCDC3), more strongly expressed in the early adversity group. Another module downregulated in the early adversity group was related to platelet activation and wound healing (hub genes: GP9, CMTM5, TUBB1, GNG11, PF4), and resembled a co-expression module previously found over-expressed in post-traumatic stress disorder resilient soldiers. These discovery analysis results provide a system wide and more holistic understanding of gene expression programs associated with childhood adversity. Furthermore, identified hub genes can be used in directed hypothesis testing in future studies.
A polygenic predictor of treatment-resistant depression using whole exome sequencing and genome-wide genotyping
Authors: Fabbri Chiara , Kasper Siegfried , Kautzky Alexander , Zohar Joseph , Souery Daniel , Montgomery Stuart , Albani Diego , Forloni Gianluigi , Ferentinos Panagiotis , Rujescu Dan , Mendlewicz Julien , Uher Rudolf , Lewis Cathryn M. , Serretti Alessandro
Published: February 2020

Treatment-resistant depression (TRD) occurs in ~30% of patients with major depressive disorder (MDD) but the genetics of TRD was previously poorly investigated. Whole exome sequencing and genome-wide genotyping were available in 1209 MDD patients after quality control. Antidepressant response was compared to non-response to one treatment and non-response to two or more treatments (TRD). Differences in the risk of carrying damaging variants were tested. A score expressing the burden of variants in genes and pathways was calculated weighting each variant for its functional (Eigen) score and frequency. Gene-based and pathway-based scores were used to develop predictive models of TRD and non-response using gradient boosting in 70% of the sample (training) which were tested in the remaining 30% (testing), evaluating also the addition of clinical predictors. Independent replication was tested in STAR*D and GENDEP using exome array-based data. TRD and non-responders did not show higher risk to carry damaging variants compared to responders. Genes/pathways associated with TRD included those modulating cell survival and proliferation, neurodegeneration, and immune response. Genetic models showed significant prediction of TRD vs. response and they were improved by the addition of clinical predictors, but they were not significantly better than clinical predictors alone. Replication results were driven by clinical factors, except for a model developed in subjects treated with serotonergic antidepressants, which showed a clear improvement in prediction at the extremes of the genetic score distribution in STAR*D. These results suggested relevant biological mechanisms implicated in TRD and a new methodological approach to the prediction of TRD.
Threat-induced anxiety during goal pursuit disrupts amygdala–prefrontal cortex connectivity in posttraumatic stress disorder
Authors: Sun Delin , Gold Andrea L. , Swanson Chelsea A. , Haswell Courtney C. , Brown Vanessa M. , Stjepanovic Daniel ,   VA Mid-Atlantic MIRECC Workgroup, Beckham Jean C. , Brancu Mira , Calhoun Patrick S. , Dedert Eric , Elbogen Eric B. , Green Kimberly T. , Kimbrel Nathan , Kirby Angela , McCarthy Gregory , Moore Scott D. , Runnals Jennifer J. , Swinkels Cindy , Tupler Larry A. , Van Voorhees Elizabeth E. , Weiner Richard D. , LaBar Kevin S. , Morey Rajendra A.
Published: February 2020

To investigate how unpredictable threat during goal pursuit impacts fronto-limbic activity and functional connectivity in posttraumatic stress disorder (PTSD), we compared military veterans with PTSD (n = 25) vs. trauma-exposed control (n = 25). Participants underwent functional magnetic resonance imaging (fMRI) while engaged in a computerized chase-and-capture game task that involved optimizing monetary rewards obtained from capturing virtual prey while simultaneously avoiding capture by virtual predators. The game was played under two alternating contexts—one involving exposure to unpredictable task-irrelevant threat from randomly occurring electrical shocks, and a nonthreat control condition. Activation in and functional connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC) was tested across threat and nonthreat task contexts with generalized psychophysiological interaction (gPPI) analyses. PTSD patients reported higher anxiety than controls across contexts. Better task performance represented by successfully avoiding capture by predators under threat compared with nonthreat contexts was associated with stronger left amygdala–vmPFC functional connectivity in controls and greater vmPFC activation in PTSD patients. PTSD symptom severity was negatively correlated with vmPFC activation in trauma-exposed controls and with right amygdala–vmPFC functional connectivity across all participants in the threat relative to nonthreat contexts. The findings showed that veterans with PTSD have disrupted amygdala–vmPFC functional connectivity and greater localized vmPFC processing under threat modulation of goal-directed behavior, specifically related to successfully avoiding loss of monetary rewards. In contrast, trauma survivors without PTSD relied on stronger threat-modulated left amygdala–vmPFC functional connectivity during goal-directed behavior, which may represent a resilience-related functional adaptation.
Shared and distinct resting functional connectivity in children and adults with attention-deficit/hyperactivity disorder
Authors: Guo Xiaojie , Yao Dongren , Cao Qingjiu , Liu Lu , Zhao Qihua , Li Hui , Huang Fang , Wang Yanfei , Qian Qiujin , Wang Yufeng , Calhoun Vince D. , Johnstone Stuart J. , Sui Jing , Sun Li
Published: February 2020

Attention-deficit/hyperactivity disorder (ADHD) often persists into adulthood, with a shift of symptoms including less hyperactivity/impulsivity and more co-morbidity of affective disorders in ADHDadult. Many studies have questioned the stability in diagnosing of ADHD from childhood to adulthood, and the shared and distinct aberrant functional connectivities (FCs) between ADHDchild and ADHDadult remain unidentified. We aim to explore shared and distinct FC patterns in ADHDchild and ADHDadult, and further investigated the cross-cohort predictability using the identified FCs. After investigating the ADHD-discriminative FCs from healthy controls (HCs) in both child (34 ADHDchild, 28 HCs) and adult (112 ADHDadult,77 HCs) cohorts, we identified both shared and distinct aberrant FC patterns between cohorts and their association with clinical symptoms. Moreover, the cross-cohort predictability using the identified FCs were tested. The ADHD-HC classification accuracies were 84.4% and 81.0% for children and male adults, respectively. The ADHD-discriminative FCs shared in children and adults lie in the intra-network within default mode network (DMN) and the inter-network between DMN and ventral attention network, positively correlated with total scores of ADHD symptoms. Particularly, inter-network FC between somatomotor network and dorsal attention network was uniquely impaired in ADHDchild, positively correlated with hyperactivity index; whereas the aberrant inter-network FC between DMN and limbic network exhibited more adult-specific ADHD dysfunction. And their cross-cohort predictions were 70.4% and 75.6% between each other. This work provided imaging evidence for symptomatic changes and pathophysiological continuity in ADHD from childhood to adulthood, suggesting that FCs may serve as potential biomarkers for ADHD diagnosis.
Dietary creatine intake and depression risk among U.S. adults
Authors: Bakian Amanda V. , Huber Rebekah S. , Scholl Lindsay , Renshaw Perry F. , Kondo Douglas
Published: February 2020

Creatine monohydrate is actively being researched for its antidepressant effects, yet little is known about the link between dietary creatine and depression risk. This study examines the association between dietary creatine and depression in U.S. adults, using data from the 2005 to 2012 National Health and Nutrition Examination Survey (NHANES). Patient health questionnaire, dietary creatine intake and covariates were obtained on 22,692 NHANES participants ≥20 years of age. Depression prevalence was calculated within quartiles of dietary creatine intake. Adjusted logistic regression models were formulated to determine the relationship between dietary creatine intake and depression risk. Additional covariates included income to poverty ratio, race/ethnicity, sex, age, education level, body mass index, healthcare access, smoking status, physical activity, and antidepressant/anxiolytic medication use. Models were further stratified by sex, age group, and antidepressant/anxiolytic medication use. Depression prevalence was 10.23/100 persons (95% CI: 8.64–11.83) among NHANES participants in the lowest quartile of dietary creatine intake compared with 5.98/100 persons (95% CI: 4.97–6.98) among participants in the highest quartile (p < 0.001). An inverse association was measured between dietary creatine and depression (adjusted odds ratio (AOR) = 0.68, 95% CI: 0.52–0.88). Dietary creatine’s negative association with depression was strongest in females (AOR = 0.62, 95% CI: 0.40–0.98), participants aged 20–39 years (AOR = 0.52, 95% CI: 0.34–0.79) and participants not taking antidepressant/anxiolytic medication (AOR = 0.58, 95% CI: 0.43–0.77). Study results indicate a significant negative relationship between dietary creatine and depression in a nationally representative adult cohort. Further research is warranted to investigate the role creatine plays in depression, particularly among women and across the lifespan.
Behavior and interaction imaging at 9 months of age predict autism/intellectual disability in high-risk infants with West syndrome
Authors: Ouss Lisa , Palestra Giuseppe , Saint-Georges Catherine , Leitgel Gille Marluce , Afshar Mohamed , Pellerin Hugues , Bailly Kevin , Chetouani Mohamed , Robel Laurence , Golse Bernard , Nabbout Rima , Desguerre Isabelle , Guergova-Kuras Mariana , Cohen David
Published: February 2020

Automated behavior analysis are promising tools to overcome current assessment limitations in psychiatry. At 9 months of age, we recorded 32 infants with West syndrome (WS) and 19 typically developing (TD) controls during a standardized mother–infant interaction. We computed infant hand movements (HM), speech turn taking of both partners (vocalization, pause, silences, overlap) and motherese. Then, we assessed whether multimodal social signals and interactional synchrony at 9 months could predict outcomes (autism spectrum disorder (ASD) and intellectual disability (ID)) of infants with WS at 4 years. At follow-up, 10 infants developed ASD/ID (WS+). The best machine learning reached 76.47% accuracy classifying WS vs. TD and 81.25% accuracy classifying WS+ vs. WS−. The 10 best features to distinguish WS+ and WS− included a combination of infant vocalizations and HM features combined with synchrony vocalization features. These data indicate that behavioral and interaction imaging was able to predict ASD/ID in high-risk children with WS.
Neuregulin 3 rs10748842 polymorphism contributes to the effect of body mass index on cognitive impairment in patients with schizophrenia
Authors: Zhou Yongjie , Li Yuhuan , Meng Yujie , Wang Jiesi , Wu Fengchun , Ning Yuping , Li Yi , Cassidy Ryan M. , Li Zezhi , Zhang Xiang Yang
Published: February 2020

There is evidence that obesity or higher body mass index is correlated with cognitive impairment in schizophrenia. Recent studies have demonstrated that genetic risk factors, such as the NRG3, are correlated with both elevated BMI and reduced cognitive function. In present study, we aimed to determine whether possession of the NRG3 rs10748842 influences the correlation between elevated BMI and reduced cognitive ability in schizophrenia. To our knowledge, this has never been examined before. A total of 625 inpatients with schizophrenia and 400 controls were recruited. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was performed to assess cognitive function. We used multiple analysis of covariance (MANCOVA), analyses of covariance (ANCOVA), Pearson correlations, partial correlations, and multivariate regression analysis to test the influence of NRG3 rs10748842 on the aforementioned variables. All RBANS five sub-scores and total score were lower in patients than those in controls (all p < 0.001). Patients carrying NRG3 rs10748842 TC + CC heterozygous genotype had lower attention score compared to TT homozygous genotype (adjusted F = 4.77, p = 0.029). BMI was positively associated with language score in patients (β = 0.387, t = 2.59, p = 0.01). Interestingly, we further found positive association between BMI and language score in TT carriers (partial correlations: r = 0.13, adjusted p = 0.004; multivariate regression: β = 0.42, t = 2.66, p = 0.008), but not in CT + CC carrier (p > 0.05). Our study demonstrated that NRG3 rs10748842 was associated with cognitive impairments, especially attention performance in schizophrenia. Moreover, NRG3 rs10748842 altered the effect of BMI on cognitive impairments as measured by the RBANS language score in chronic patients with schizophrenia.
Correction: Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios
Authors: Zhang Lingli , Huang Chu-Chung , Dai Yuan , Luo Qiang , Ji Yiting , Wang Kai , Deng Shining , Yu Juehua , Xu Mingyu , Du Xiujuan , Tang Yun , Shen Chun , Feng Jianfeng , Sahakian Barbara J , Lin Ching-Po , Li Fei
Published: February 2020

An important detail was omitted in the Method of the original Article, I.E, The CARS and other evaluations were conducted ‘blind' to condition (Bumetanide or no treatment) by experienced clinicians. This has now been updated in the HTML and PDF versions of this Article.
The role of H1 antihistamines in contralateral breast cancer: a Danish nationwide cohort study
Authors: Bens Annet , Dehlendorff Christian , Friis Søren , Cronin-Fenton Deirdre , Jensen Maj-Britt , Ejlertsen Bent , Lash Timothy L. , Kroman Niels , Mellemkjær Lene
Published: February 2020

Background

Preclinical studies have shown both pro- and antineoplastic effects of antihistamines. Here, we evaluated the effect of H1 antihistamines on contralateral breast cancer (CBC) risk, and whether cationic amphiphilic (CAD) antihistamines could increase the sensitivity to chemotherapy.

Methods

From the Danish Breast Cancer Group clinical database, we identified all women aged ≥20 years with a first-time diagnosis of breast cancer during 1996–2012. Information on drug use, CBC and potential confounding factors was retrieved from nationwide registries. Using Cox proportional hazard regression models, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for CBC associated with H1-antihistamine use.

Results

We identified 52,723 patients with breast cancer with a total of 310,583 person-years of follow-up. Among them, 1444 patients developed a new primary tumour in the contralateral breast. Post-diagnosis use of H1 antihistamines (≥2 prescriptions) was not strongly associated with CBC risk (HR 1.08, 95% CI: 0.90–1.31) compared with non-use (<2 prescriptions). Use of CAD antihistamines among patients receiving chemotherapy was not associated with a decrease in CBC risk.

Conclusions

Taken together, our findings do not suggest any association of H1-antihistamine use with CBC development.
TG01/GM-CSF and adjuvant gemcitabine in patients with resected RAS-mutant adenocarcinoma of the pancreas (CT TG01-01): a single-arm, phase 1/2 trial
Authors: Palmer Daniel H. , Valle Juan W. , Ma Yuk Ting , Faluyi Olusola , Neoptolemos John P. , Jensen Gjertsen Trine , Iversen Berit , Amund Eriksen Jon , Møller Anne-Sophie , Aksnes Anne-Kirsti , Miller Robert , Dueland Svein
Published: February 2020

Background

TG01 is the first cancer immunotherapy targeting KRAS oncogenic mutations. This study assessed the safety and efficacy of TG01/GM-CSF in patients with resected pancreatic adenocarcinoma.

Methods

Patients with stage I or II pancreatic adenocarcinoma who had undergone surgical resection (R0 or R1) received adjuvant gemcitabine with TG01/GM-CSF using two schedules of vaccination. Immune response was defined as a positive delayed-type hypersensitivity (DTH) response and/or positive T-cell proliferation assay.

Results

Thirty-two patients were enrolled between February 2013 and May 2016. Nineteen were treated with the high antigen burden, with four serious adverse reactions considered possibly related to TG01 treatment, including three allergic reactions. On this basis, a further 13 patients received a modified vaccination schedule with reduced antigen burden, with no serious adverse events related to TG01. Ninety-five percent patients in the main cohort and 92% in the modified cohort had a positive immune response. Median overall survival (OS) was 33.1 months, and median disease-free survival (DFS) was 13.9 months for the main cohort. For the modified cohort, the median OS was 34.3 months and median DFS was 19.5 months.

Conclusions

TG01/GM-CSF with gemcitabine was well tolerated, with high levels of immune activation. OS and DFS compare favourably with published data for adjuvant gemcitabine.

Clinical trial registration

This clinical trial was registered at ClinicalTrials.gov (NCT02261714).
BORIS/CTCFL promotes a switch from a proliferative towards an invasive phenotype in melanoma cells
Authors: Janssen Sanne Marlijn , Moscona Roy , Elchebly Mounib , Papadakis Andreas Ioannis , Redpath Margaret , Wang Hangjun , Rubin Eitan , van Kempen Léon Cornelis , Spatz Alan
Published: February 2020

Melanoma is among the most aggressive cancers due to its tendency to metastasize early. Phenotype switching between a proliferative and an invasive state has been suggested as a critical process for metastasis, though the mechanisms that regulate state transitions are complex and remain poorly understood. Brother of Regulator of Imprinted Sites (BORIS), also known as CCCTC binding factor-Like (CTCFL), is a transcriptional modulator that becomes aberrantly expressed in melanoma. Yet, the role of BORIS in melanoma remains elusive. Here, we show that BORIS is involved in melanoma phenotype switching. Genetic modification of BORIS expression in melanoma cells combined with whole-transcriptome analysis indicated that BORIS expression contributes to an invasion-associated transcriptome. In line with these findings, inducible BORIS overexpression in melanoma cells reduced proliferation and increased migration and invasion, demonstrating that the transcriptional switch is accompanied by a phenotypic switch. Mechanistically, we reveal that BORIS binds near the promoter of transforming growth factor-beta 1 (TFGB1), a well-recognized factor involved in the transition towards an invasive state, which coincided with increased expression of TGFB1. Overall, our study indicates a pro-invasive role for BORIS in melanoma via transcriptional reprogramming.
NF90 stabilizes cyclin E1 mRNA through phosphorylation of NF90-Ser382 by CDK2
Authors: Ding Donglin , Huang Huixing , Li Quanfu , Yu Wenbo , Wang Chenji , Ma Haijie , Wu Jiaxue , Dang Yongjun , Yu Long , Jiang Wei
Published: February 2020

Nuclear factor 90 (NF90), an RNA-binding protein, has been implicated in regulating interleukin-2 (IL-2) and the immune response. It was recently reported that NF90 is upregulated in hepatocellular carcinoma (HCC) tissues and promotes HCC proliferation through upregulating cyclin E1 at the posttranscription level. However, the regulation of NF90 in HCC remains unclear. We demonstrate here that cyclin-dependent kinase (CDK) 2 interacts with NF90 and phosphorylated it at serine382. Mechanistically, phosphorylation of NF90-Ser382 determines the nuclear export of NF90 and stabilization of cyclin E1 mRNA. We also demonstrate that the phosphorylation deficient mutant NF90-S382A inhibits cell growth and induces cell cycle arrest at the G1 phase in HCC cells. Moreover, an NF90-S382A xenograft tumor had a decreased size and weight compared with the wildtype NF90. The NF90-S382A xenograft contained a significantly lower level of the proliferation marker Ki-67. Additionally, in HCC patients, NF90-Ser382 phosphorylation was stronger in tumor than in non-tumor tissues. Clinically, phosphorylation of NF90-Ser382 is significantly associated with larger tumor sizes, higher AFP levels, and shorter overall survival rates. These results suggest NF90-Ser382 phosphorylation serves as a potential diagnosis and prognostic marker and a promising pharmacological target for HCC.