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Background: The putamen has been implicated in depressive disorders, but how its structure and function increase depression risk is not clearly understood. Here, we examined how putamen volume, neuronal density, and mood-modulated functional activity relate to family history and prospective course of depression., Methods: The study includes 115 second- and third-generation offspring at high or low risk for depression based on the presence or absence of major depressive disorder in the first generation. Offspring were followed longitudinally using semistructured clinical interviews blinded to their familial risk; putamen structure, neuronal integrity, and functional activation were indexed by structural magnetic resonance imaging (MRI), proton magnetic resonance spectroscopy (N-acetylaspartate/creatine ratio), and functional MRI activity modulated by valence and arousal components of a mood induction task, respectively., Results: After adjusting for covariates, the high-risk individuals had lower putamen volume (standardized betas, β- left  = -0.17, β- right  = -0.15, ps = .002), N-acetylaspartate/creatine ratio (β- left = -0.40, β- right = -0.37, ps < .0001), and activation modulated by valence (β- left  = -0.22, β- right  = -0.27, ps < .05) than low-risk individuals. Volume differences were greater at younger ages, and N-acetylaspartate/creatine ratio differences were greater at older ages. Lower putamen volume also predicted major depressive disorder episodes up to 8 years after the scan (β- left  = -0.72, p = .013; β- right  = -0.83, p = .037). Magnetic resonance spectroscopy and task functional MRI measures were modestly correlated (0.27 ≤ r ≤ 0.33)., Conclusions: Findings demonstrate abnormalities in putamen structure and function in individuals at high risk for major depressive disorder. Future studies should focus on this region as a potential biomarker for depressive illness, noting meanwhile that differences attributable to family history may peak at different ages based on which MRI modality is being used to assay them., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Adolescents with a family history (FH+) of substance use disorder (SUD) are at a greater risk for SUD, suggested to be partly due to the transmission of behavioral impulsivity. We used a delay discounting task to compare impulsivity in decision-making and its associated brain functioning among FH+ and FH - minority adolescents. Participants chose between Smaller Sooner (SS) and Larger Later (LL) rewards. The SS was available immediately (Now trials) or in the future (Not-Now trials), allowing for greater differentiation between impulsive decisions. The FH+ group showed greater impatience by responding SS more frequently than the FH - group, only on the Now trials, and even when the relative reward differences (RRD) increased. Surprisingly, there were no differences in brain activity between the groups. Combined, the groups showed greater reward activity during the Now vs. Not-Now trials in medial prefrontal/anterior cingulate, posterior cingulate, precuneus, and inferior frontal gyrus (i.e., an immediacy effect). As the RRD increased activation in the reward network decreased, including the striatum, possibly reflecting easy decision-making. These results indicate that risk for SUD, seen behaviorally among FH+ adolescents, may not yet be associated with discernable brain changes, suggesting that early intervention has the potential to reduce this risk., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Brain gray matter is organized in a manner with interconnected brain regions, resulting in a notable covariance pattern that recapitulates either the functional coactivation or structural connectivity of brain regions, which is believed to underpin psychiatric disorders such as depression. This study aimed to investigate whether and how antidepressants took effect in treating depression and reducing symptoms by altering the gray matter covariance pattern. We combined structural magnetic resonance imaging (MRI) scans acquired in two randomized, double-blind, placebo-controlled trial (RCT) studies of the treatment using serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant medications in patients with persistent depressive disorder (PDD). One was an RCT of 10-week duloxetine medication that consisted of patients who received duloxetine (N = 21) or placebo (N = 21), and the other was an RCT of 12-week desvenlafaxine medication that consisted of 19 and 17 patients respectively who received desvenlafaxine or placebo. We examined treatment effect on gray matter volume (GMV) and topological organization of GMV covariance pattern (i.e., GMV-based network). We found a treatment-by-time effect on GMV in the angular gyrus and cuneus areas, whereas the GMV change rate of the cuneus was inversely correlated with the response rate. We observed a significant increase in the local efficiency of the GMV-based network following medication treatment compared with placebo. Our findings provide preliminary evidence for a GMV-based network-specific reconfiguration caused by antidepressants compared to placebo and the cuneus may be a possible candidate region to predict antidepressant response., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Exposure therapy is the treatment of choice for anxiety disorders but requires people to confront feared situations and can be distressing. We tested the hypothesis that exposure without conscious awareness would reduce fear in participants with specific phobia by harnessing the neural circuitry supporting the automatic extinction of fear., Methods: In this single-centre, randomised controlled experiment, we recruited women aged 18-29 years from an ethnically diverse, community-based population in northeastern USA, between Sept 1, 2013, and Aug 1, 2016. Eligible participants classified as having phobia met the DSM-5 criteria for specific phobia but not for any other disorder, had scores in the top 10% of respondents to the Fear of Spiders Questionnaire, and exhibited impairing avoidance of a live tarantula. Eligible controls met no criteria for any disorder, were in the bottom 30% of questionnaire respondents, and displayed no avoidance of the tarantula. The randomisation schedule was generated with the open source Research Randomizer Tool. A research assistant randomly assigned participants to the active intervention of very brief exposure (VBE)-the repeated presentation of masked phobic stimuli (ie, spiders)-or the control intervention which used masked flowers (VBF). VBE and VBF were given code numbers to prevent staff from knowing which intervention they were administering. During a 10 min functional MRI (fMRI) task, each participant was exposed to 16 blocks of ten masked target stimuli (spiders or flowers), alternating with 16 blocks of ten masked neutral stimuli. A few minutes after fMRI, participants with spider phobia approached the tarantula again so we could measure changes in phobic behaviour. The primary outcome was real-time changes in brain activity measured by fMRI. All analyses were done by intention to treat., Results: We recruited 82 women, of whom 42 had spider phobia and 40 were controls. VBE generated stronger neural activity in participants with spider phobia than in controls, particularly in regions supporting emotion, emotion regulation, and attention systems, such as the inferior frontal cortex (Cohen's d 0·95, 95% CI 0·93-0·98, Bayesian posterior probability 99·5%) and the caudate nucleus (1·16, 1·14-1·18, 100·0%). In participants with phobia, VBE also generated stronger activity in these regions than did VBF (eg, dorsal anterior cingulate cortex Cohen's d 0·80, 95% CI 0·78-0·80, Bayesian posterior probability 98·5%; caudate nucleus 1·0, 0·98-1·02, 99·5%). VBE reduced avoidance of the live tarantula in participants with phobia. Regions supporting fear extinction (including ventral medial prefrontal cortex) and emotional salience processing mediated this effect. No adverse events occurred., Interpretation: VBE reduced fear non-consciously in participants with spider phobia by recruiting brain regions supporting automatic fear extinction, emotion regulation, and top-down attentional processing. Future studies should explore the use of VBE in other fear-based disorders., Funding: National Institutes of Mental Health and Brain & Behavior Research Foundation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Drs. Cyr, Wang, Tau, Friedl, Marsh, Mr. Zhao, Ms. Stefan, and Ms. Terranova report no biomedical financial interests or potential conflicts of interest., (Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Recently, lysine-specific demethylase 1 (LSD1) was identified as the first histone demethylase. LSD1 interacted with androgen receptor (AR) and promoted androgen-dependent transcription of target genes, such as PSA, by ligand-induced demethylation of mono- and dimethylated histone H3 at Lys 9 (H3K9). Meanwhile, the phenomenon of epithelial-mesenchymal transition (EMT) had received considerable attention in tumor recurrence and metastasis. This study examined the effect of Pargyline (an inhibitor of LSD1) on the process of EMT in vitro and in vivo. SCID mice were injected subcutaneously with LNCap cells. Pargyline was given intraperitoneally or not after castration (implemented with Bilateral orchidectomy), then PSA levels in serum and tumor were determined to assess time to androgen-independent progression. The results showed that LSD1 expression was up-regulated when PCa progressed to Castration Resistant Prostate Cancer (CRPC). Pargyline reduced LNCap cells migration and invasion ability, and inhibited the process of EMT by up-regulating expression of E-cadherin, and down-regulating expressions of N-cadherin and Vimentin in vitro and in vivo. Although, Pargyline did not change the level of AR, it reduced PSA expression both in vitro and in vivo. Furthermore, Pargyline delayed prostate cancer transition from androgen-dependent to androgen-independent state (CRPC). These findings indicated that inhibition of LSD1 might be a promise adjunctive therapy with androgen deprivation therapy (ADT) for locally advanced or metastatic prostate cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The aim of this study was to examine the functioning of fronto-striatal brain circuits that support self-regulatory capacities including conflict resolution and sequential processing in unmedicated adults with obsessive-compulsive disorder (OCD)., Methods: We compared functional magnetic resonance imaging blood oxygen level-dependent response in 22 adults with OCD with 22 healthy, age-matched control subjects during performance of a Simon Spatial Incompatibility task. We used general linear modeling to compare groups in their patterns of brain activation during correct responses to conflict-laden stimuli and explore the effects of trial sequence on group differences., Results: Behavioral performance on the Simon task did not differ between groups. In response to conflict-laden stimuli, OCD participants activated fronto-striatal regions significantly more than control subjects, specifically a right hemisphere cluster encompassing the putamen, insula, and inferior frontal gyrus. Their activation of this cluster was driven not by conflict on a current trial but by their response to the alternation of stimulus congruence (incongruent or congruent) across trial sequences (i.e., current and preceding trials) and was most accentuated in participants with more severe symptoms in the doubt/checking dimension. Functional connectivity from the putamen to other fronto-striatal regions was also greater in the OCD compared with control participants., Conclusions: When engaging the self-regulatory control necessary to resolve conflict and process alternating stimuli, OCD participants displayed excessive activation in a fronto-striatal circuit that differs from the orbitofrontal cortex-anterior cingulate cortex-caudate circuit typically implicated in OCD. Dysfunction in this circuit was associated with processing changes in the stimulus context. We speculate that this dysfunction might be related to the cognitive inflexibility typical of persons with OCD., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Emotional reactivity is one of the most disabling symptoms associated with attention-deficit/hyperactivity disorder (ADHD). We aimed to identify neural substrates associated with emotional reactivity and to assess the effects of stimulants on those substrates., Method: We used functional magnetic resonance imaging (fMRI) to assess neural activity in adolescents with (n = 15) and without (n = 15) ADHD while they performed a task involving the subliminal presentation of fearful faces. Using dynamic causal modeling, we also examined the effective connectivity of two regions associated with emotional reactivity, i.e., the amygdala and the lateral prefrontal cortex (LPFC). The participants with ADHD underwent scanning both on and off stimulant medication in a counterbalanced fashion., Results: During the task, we found that activity in the right amygdala was greater in adolescents with ADHD than in control subjects. In addition, in adolescents with ADHD, greater connectivity was detected between the amygdala and LPFC. Stimulants had a normalizing effect on both the activity in the right amygdala and the connectivity between the amygdala and LPFC., Conclusions: Our findings demonstrate that in adolescents with ADHD, a neural substrate of fear processing is atypical, as is the connectivity between the amygdala and LPFC. These findings suggest possible neural substrates for the emotional reactivity that is often present in youths with ADHD, and provide putative neural targets for the development of novel therapeutic interventions for this condition., (Copyright © 2011 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Signal variation in diffusion-weighted images (DWIs) is influenced both by thermal noise and by spatially and temporally varying artifacts, such as rigid-body motion and cardiac pulsation. Motion artifacts are particularly prevalent when scanning difficult patient populations, such as human infants. Although some motion during data acquisition can be corrected using image coregistration procedures, frequently individual DWIs are corrupted beyond repair by sudden, large amplitude motion either within or outside of the imaging plane. We propose a novel approach to identify and reject outlier images automatically using local binary patterns (LBP) and 2D partial least square (2D-PLS) to estimate diffusion tensors robustly. This method uses an enhanced LBP algorithm to extract texture features from a local texture feature of the image matrix from the DWI data. Because the images have been transformed to local texture matrices, we are able to extract discriminating information that identifies outliers in the data set by extending a traditional one-dimensional PLS algorithm to a two-dimension operator. The class-membership matrix in this 2D-PLS algorithm is adapted to process samples that are image matrix, and the membership matrix thus represents varying degrees of importance of local information within the images. We also derive the analytic form of the generalized inverse of the class-membership matrix. We show that this method can effectively extract local features from brain images obtained from a large sample of human infants to identify images that are outliers in their textural features, permitting their exclusion from further processing when estimating tensors using the DWIs. This technique is shown to be superior in performance when compared with visual inspection and other common methods to address motion-related artifacts in DWI data. This technique is applicable to correct motion artifact in other magnetic resonance imaging (MRI) techniques (e.g., the bootstrapping estimation) that use univariate or multivariate regression methods to fit MRI data to a pre-specified model., (Copyright © 2011 Elsevier Inc. All rights reserved.)