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The dynamic functional connectivity (dFC) in functional magnetic resonance imaging (fMRI) is beneficial for the analysis and diagnosis of neurological brain diseases. The dFCs between regions of interest (ROIs) are generally delineated by a specific template and clustered into multiple different states. However, these models inevitably fell into the model-driven self-contained system which ignored the diversity at spatial level and the dynamics at time level of the data. In this study, we proposed a spatial and time domain feature extraction approach for Alzheimer's disease (AD) and autism spectrum disorder (ASD)-assisted diagnosis which exploited the dynamic connectivity among independent functional sub networks in brain. Briefly, independent sub networks were obtained by applying spatial independent component analysis (SICA) to the preprocessed fMRI data. Then, a sliding window approach was used to segment the time series of the spatial components. After that, the functional connections within the window were obtained sequentially. Finally, a temporal signal-sensitive long short-term memory (LSTM) network was used for classification. The experimental results on Alzheimer's Disease Neuroimaging Initiative (ADNI) and Autism Brain Imaging Data Exchange (ABIDE) datasets showed that the proposed method effectively predicted the disease at the early stage and outperformed the existing algorithms. The dFCs between the different components of the brain could be used as biomarkers for the diagnosis of diseases such as AD and ASD, providing a reliable basis for the study of brain connectomics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Qiao, Wang, Liu, Xu and Wang.)

It has been suggested that intergenerational transmission of risk for substance use disorder (SUD) manifests in the brain anatomy of substance naïve adolescents. While volume and shapes of subcortical structures (SSS) have been shown to be heritable, these structures, especially the pallidum, putamen, nucleus accumbens, and hippocampus, have also been associated with substance use disorders. However, it is not clear if those anatomical differences precede substance use or are the result of that use. Therefore, we examined if volume and SSS of adolescents with a family history (FH+) of SUD differed from adolescents without such a history (FH-). Because risk for SUD is associated with anxiety and impulsivity, we also examined correlations between these psychological characteristics and volume/SSS. Using structural MRI and FSL software, we segmented subcortical structures and obtained indices of SSS and volumes of 64 FH+ and 58 FH- adolescents. We examined group differences in volume and SSS, and the correlations between volume/SSS and trait anxiety and impulsivity. FH+ adolescents had a significant inward deformation in the shape of the right anterior hippocampus compared to FH- adolescents, while the volume of this structure did not differ between groups. Neither shape nor volume of the other subcortical structures differed between groups. In the FH+ adolescents, the left hippocampus shape was positively correlated with both trait anxiety and impulsivity, while in FH- adolescents a negative correlation pattern of SSS was seen in the hippocampus. SSS appears to capture local anatomical features that traditional volumetric analysis does not. The inward shape deformation in the right anterior hippocampus in FH+ adolescents may be related to the known increased risk for behavioral dysregulation leading to SUD in FH+ offspring. Hippocampus shape also exhibits opposite patterns of correlation with anxiety and impulsivity scores across the FH+ and FH- adolescents. These novel findings may reveal neural correlates, not captured by traditional volumetric analysis, of familial transmission of increased vulnerability to SUD., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Obsessive-compulsive disorder (OCD) implicates alterations in cortico-striato-thalamo-cortical and fronto-limbic circuits. Building on prior structural findings, this is the largest study to date examining subcortical surface morphometry in OCD., Methods: Structural magnetic resonance imaging data were collected from 200 participants across development (5-55 years): 28 youth and 75 adults with OCD and 27 psychiatrically healthy youth and 70 adults. General linear models were used to assess group differences and group-by-age interactions on subcortical shape (FSL FIRST)., Results: Compared to healthy participants, those with OCD exhibited surface expansions on the right nucleus accumbens and inward left amygdala deformations, which were associated with greater OCD symptom severity ([Children's] Yale-Brown Obsessive-Compulsive Scale). Group-by-age interactions indicated that accumbens group differences were driven by younger participants and that right pallidum shape was associated inversely with age in healthy participants, but not in participants with OCD. No differences in the shape of other subcortical regions or in volumes (FreeSurfer) were detected in supplementary analyses., Conclusions: This study is the largest to date examining subcortical shape in OCD and the first to do so across the developmental spectrum. NAcc and amygdala shape deformation builds on extant neuroimaging findings and suggests subtle, subregional alterations beyond volumetric findings. Results shed light on morphometric alterations in OCD, informing current pathophysiological models., (© 2022 Wiley Periodicals LLC.)

Previous neuroimaging studies have shown that serotonin-norepinephrine reuptake inhibitor antidepressants alter functional activity in large expanses of brain regions. However, it is not clear how these regions are systemically organized on a connectome level with specific topological properties, which may be crucial to revealing neural mechanisms underlying serotonin-norepinephrine reuptake inhibitor treatment of persistent depressive disorder. To investigate the effect of serotonin-norepinephrine reuptake inhibitor antidepressants on brain functional connectome reconfiguration in persistent depressive disorder and whether this reconfiguration promotes the improvement of clinical symptoms, we combined resting-state functional magnetic resonance imaging (fMRI) scans acquired in two randomized, double-blind, placebo-controlled trial studies of serotonin-norepinephrine reuptake inhibitor antidepressant treatment of patients with persistent depressive disorder. One was a randomized, double-blind, placebo-controlled trial of 10-week duloxetine medication treatment, which included 17 patients in duloxetine group and 17 patients in placebo group (ClinicalTrials.gov Identifier: NCT00360724); the other one was a randomized, double-blind, placebo-controlled trial of 12-week desvenlafaxine medication treatment, which included 16 patients in desvenlafaxine group and 15 patients in placebo group (ClinicalTrials.gov Identifier: NCT01537068). The 24-item Hamilton Depression Rating Scale was used to measure clinical symptoms, and graph theory was employed to examine serotonin-norepinephrine reuptake inhibitor antidepressant treatment effects on the topological properties of whole-brain functional connectome of patients with persistent depressive disorder. We adopted a hierarchical strategy to examine the topological property changes caused by serotonin-norepinephrine reuptake inhibitor antidepressant treatment, calculated their small-worldness, global integration, local segregation and nodal clustering coefficient in turn. Linear regression analysis was used to test associations of treatment, graph properties changes and clinical symptom response. Symptom scores were more significantly reduced after antidepressant than placebo administration ( η 2 = 0.18). There was a treatment-by-time effect that optimized the functional connectome in a small-world manner, with increased global integration and increased nodal clustering coefficient in the bilateral thalamus (left thalamus η 2 = 0.21; right thalamus η 2 = 0.23). The nodal clustering coefficient increment of the right thalamus (ratio = 29.86; 95% confidence interval, -4.007 to -0.207) partially mediated the relationship between treatment and symptom improvement, and symptom improvement partially mediated (ratio = 21.21; 95% confidence interval, 0.0243-0.444) the relationship between treatment and nodal clustering coefficient increments of the right thalamus. Our study may indicate a putative mutually reinforcing association between nodal clustering coefficient increment of the right thalamus and symptom improvement from serotonin-norepinephrine reuptake inhibitor antidepressant treatments with duloxetine or desvenlafaxine., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

A family history (FH+) of substance use disorder (SUD) increases an adolescent's risk for substance use initiation and progression. Greater impulsivity and reward seeking behavior is known to be associated with such risk. At the neurological level, dysfunction of cortico-striatal and cortico-limbic pathways have been proposed as contributors to the increased SUD risk in adolescents with FH+. In addition, disadvantaged environments have been associated with atypical brain connectivity and higher SUD risk. However, it remains unclear if this increased risk is manifested in structural and functional brain abnormalities prior to regular drug use. To examine this, we employed complementary imaging of structural and functional connectivity of 60 FH+ and 55 FH- minority adolescents, all from families with low socio-economic status. We acquired diffusion tensor-imaging (DTI) and resting state fMRI data across the whole brain. Structural connectivity was examined by measuring fractional anisotropy (FA) using DTI, to indicate integrity of the white matter tracts. Functional connectivity within and between resting state networks was assessed by the correlation of blood-oxygen-level-dependent (BOLD) signal between intra and inter-network nodes. Psychological measures of impulsivity and reward seeking were also obtained with standardized measures, the BIS-11 and the BIS/BAS, and their association with FA and functional connectivity was evaluated. We found no differences in white matter integrity between the groups. Compared to FH-, FH + adolescents showed significantly greater functional connectivity between posterior regions of the Default Mode Network (DMN) and the Fronto-Parietal Network (FPN). While psychological measures of reward seeking behavior did not differ between the FH+ and FH- groups, impulsivity, assessed by the BIS-11, was significantly higher for FH+. However, we did not find significant differences between the FH+ and FH- groups when comparing associations of BIS-11 scores and white matter integrity or functional connectivity measures. The stronger inter-network functional connectivity between the DMN and FPN in FH + adolescents suggests that transmitted risk for SUD may be related to large-scale brain dynamics. The lack of structural differences support the importance of early prevention efforts for FH + adolescents, before initiation of drug use, allowing for healthy brain development., Competing Interests: Financial disclosures All authors report no biomedical financial interests and no potential conflicts of interest.

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.)

Background: Major depressive disorder (MDD) is associated with aberrant limbic neural responses to emotional stimuli. We assessed how self-generated emotions modulate trial-by-trial limbic activity and whether this brain-emotion synchrony varies by familial MDD risk (regardless of personal MDD history) and neuroticism., Methods: Participants (n = 74, mean age = 34 years) were later-generation family members of depressed or nondepressed probands as part of a longitudinal cohort study. Using an emotion induction task, we examined participant-specific modulation of anatomically defined limbic neurobiology. Neuroticism, mental health, and familial parenting style were assessed, and MDD assessments were routinely collected throughout the previous longitudinal assessments of the study., Results: Participant-specific emotional arousal modulated amygdala and hippocampal activity. Lasso regression identified attenuated right amygdala arousal modulation as being relatively more associated with neuroticism (even though neuroticism was not associated with arousal ratings). Attenuated amygdala modulation and neuroticism were significantly more likely in offspring of parents with MDD. Parental MDD, but not personal history of MDD, predicted attenuated amygdala modulation., Conclusions: Attenuated right amygdala modulation by emotional arousal was associated with neuroticism, indicating that the amygdala was less synchronous with emotional experiences in individuals higher in neuroticism. This neurophenotype was predicted by participants' parental MDD history but not by their own MDD history; that is, it was observed in unaffected and affected offspring of parents with MDD. These data suggest that weak amygdala-emotion synchrony may be a predisposing risk factor for MDD, rather than a result of the illness, and they suggest pathways by which this risk factor for depression is passed intergenerationally., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The term perceptual closure refers to the neural processes responsible for "filling-in" missing information in the visual image under highly adverse viewing conditions such as fog or camouflage. Here we used a closure task that required the participants to identify barely recognizable fragmented line-drawings of common objects. Patients with schizophrenia have been shown to perform poorly on this task. Following priming, controls and importantly patients can complete the line-drawings at greater levels of fragmentation behaviorally, suggesting an improvement in their ability to perform the task. Closure phenomena have been shown to involve a distributed network of cortical regions, notably the lateral occipital complex (LOC) of the ventral visual stream, dorsal visual stream (DS), hippocampal formation (HIPP) and the prefrontal cortex (PFC). We have previously demonstrated the failure of closure processes in schizophrenia and shown that the dysregulation in the sensory information transmitted to the prefrontal cortex plays a critical role in this failure. Here, using a multimodal imaging approach in patients, combining event related electrophysiological recordings (ERP) and functional magnetic resonance imaging (fMRI), we characterize the spatiotemporal dynamics of priming in perceptual closure. Using directed functional connectivity measures we demonstrate that priming modifies the network-level interactions between the nodes of closure processing in a manner that is functionally advantageous to patients resulting in the mitigation of their deficit in perceptual closure., (Copyright © 2020 Sehatpour, Bassir Nia, Adair, Wang, DeBaun, Silipo, Martinez and Javitt.)

Objectives: To evaluate bladder cancer by integrating multiple imaging features acquired using multimodal 3.0T magnetic resonance imaging (MRI)., Methods: We prospectively enrolled 163 consecutive patients including 142 men (mean age, 65.2 years) and 21 women (mean age, 65.8 years). We evaluated the efficiency and reliability of the multiple imaging modalities including T2-weighted spectral attenuated inversion recovery (SPAIR) imaging, dynamic contrast-enhanced (DCE) imaging and diffusion-weighted (DW) imaging, and the imaging feature, apparent diffusion coefficient (ADC) in the identification of the T staging and grading. We compared our imaging findings with the results of histological examination using McNemar's test. We reported the results under the significance of p < 0.05. Approval for the study was obtained from the local institutional review board., Results: The sensitivity and specificity using T2 SPAIR plus DW imaging (sensitivity: 85.2%; specificity: 93.2%), DCE plus DW imaging (sensitivity: 92.4%; specificity: 96.8%), and all the three imaging modalities combined, i.e., T2 SPAIR plus DCE plus DW imaging (sensitivity: 92.5%; specificity: 97.4%), were significantly greater than using T2 SPAIR imaging alone (sensitivity: 74.1%; specificity: 72.2%). One hundred six (93.0%) lesions showed a thin, pedicle arch-like shape and thus primarily demonstrated to be in Ta stage; by contrast, a large number of lesions (137 [85.6%]) were sessile and were found to be in T1 stage. The differences in the ADC were significant between low-grade (877.57 ± 24.15) and high-grade (699.54 ± 23.82) lesions (P < .01)., Conclusions: T2 SPAIR and DCE plus DW imaging provided useful information for evaluating T staging and grading in bladder cancer. Those imaging features to distinguish Ta stage from T1 stage were presented., (Copyright © 2020 Yuan, Li, Mu, Zhang, Kong, Cheng, Shu, Zhang and Wang.)

Purpose: Our objectives were to assess the abnormalities of subcortical nuclei by combining volume and shape analyses and potential association with cognitive impairment., Patients and Methods: Twenty-nine patients with severe ACS of the unilateral internal carotid artery and 31 controls were enrolled between January 2017 to August 2018. All participants underwent a comprehensive neuropsychological evaluation, blood lipid biochemical measurements, and structural magnetic resonance imaging (MRI) to measure subcortical volumes and sub-regional shape deformations. Basic statistics, correction for multiple comparisons. Seventeen ACS patients underwent carotid endarterectomy (CEA) within one week after baseline measurements, cognitive assessments and MRI scans were repeated 6 months after CEA., Results: The ACS patients had higher apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) ratio and worse performance in all cognitive domains than controls. Moreover, the ACS patients showed more profound thalamic atrophy assessed by shape and volume analysis, especially in the medial dorsal thalamus. No significant differences were found in other subcortical nuclei after multiple comparisons correction. At baseline, thalamic atrophy correlated with cognitive impairment and ApoB/ApoA1 ratio. Furthermore, mediation analysis at baseline showed that the association of carotid intima-media thickness with executive functioning was mediated by thalamic volume. After CEA, cognitive improvement and increase in the bilateral medial dorsal thalamic volume were observed., Conclusion: Our study identified the distinct atrophy of subcortical nuclei and their association with cognition in patients with ACS. Assessments of the thalamus by volumetric and shape analysis may provide an early marker for cerebral ischemia and reperfusion after CEA., Competing Interests: The authors report no potential conflicts of interest in this work., (© 2020 Zhang et al.)

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.)

Premature ejaculation (PE) is the most common male sexual dysfunction. The brain disturbances that cause this disorder remain poorly understood. This study aimed to investigate how the morphology of cortical and subcortical brain structures differed in PE, how these morphologic differences were associated with severity measures of PE, such as intravaginal ejaculatory latency time (IELT), and how these cortical and subcortical structures were causally connected through mediation analysis. Anatomical MRI scans were acquired from 39 male participants, 23 with PE (28.78 ± 4.32 years), and 16 without PE (27.88 ± 3.65 years). We used a subcortical analysis package within FSL to perform subcortical shape segmentation and statistical analysis. The PE group was compared with the normal control (NC) group in the shapes of 15 subcortical structures with general linear models [ p < 0.05, family-wise error (FWE)-corrected]. We analyzed the cortical complexity revealed by the gyrification index using the Computational Anatomy Toolbox (CAT12). Vertex-wise shape analyses revealed outward shape deformations (expansions) in the left hippocampus and bilateral thalamus. Gyrification index analyses revealed that the right orbital frontal cortex and the right nucleus accumbens had greater complexity in PE patients. The shape deformations were positively correlated with the IELTs in the NC group, while this relationship was interrupted in the PE group. PE is associated with outward deformations of the subcortical surfaces and more complexity of the cortical structures. These morphological differences may be the basis of the brain functional alterations underlying PE., (Copyright © 2020 Lu, Yuan, Jin, Yang, Zhang, Li, Zhang, Wang, Wu, Chen, Qing, Dai, Zhang and Wang.)

Objective: The purpose of this study was to examine the neural substrates and mechanisms that generate memory deficits, seizures and neuropsychiatric abnormalities in encephalitis with LGI1 antibodies using a data-driven, multimodal magnetic resonance imaging (MRI) approach. Methods: Functional MRI data were acquired from 14 anti-LGI1 encephalitis patients and 14 age and gender matched normal controls. Independent component analysis with hierarchical partner matching (HPM-ICA) was used to assess the whole-brain intrinsic functional connectivity. Granger causality (GC) was applied to investigate the effective connectivity among the brain regions that identified by HPM-ICA. Diffusion tensor imaging (DTI) was utilized to investigate white matter microstructural changes of the patients. Results: Participants with LGI1 antibodies encephalitis presented reduced functional connectivity in the brain areas associated with memory, cognition and motion circuits, while increased functional connectivity in putamen and caudate in comparison to the normal controls. Moreover, the effective connectivity in patients was decreased from the frontal cortex to supplementary motor area. Finally, patients had significant reductions in fractional anisotropy (FA) for the corpus callosum, internal capsule, corona radiata and superior longitudinal fasciculus, accompanied by increases in mean diffusivity (MD) for these regions as compared to controls. Conclusion: Our findings suggest that the neural disorder and behavioral deficits of anti-LGI1 encephalitis may be associated with extensive changes in brain connectivity and microstructure. These pathological alterations affect the basal ganglia and limbic system besides the temporal and frontal lobe., (Copyright © 2020 Qiao, Zhao, Wang, Li, Wang, Cao and Wang.)

Background: Interstitial lung disease requires frequent re-examination, which directly causes excessive cumulative radiation exposure. To date, AI has not been applied to CT for enhancing clinical care; thus, we hypothesize AI may empower CT with intelligence to realize automatic and accurate pulmonary scanning, thus dramatically decrease medical radiation exposure without compromising patient care., Methods: Facial boundary detection was realized by recognizing adjacent jaw position through training and testing a region proposal network (RPN) on 76,882 human faces using a preinstalled 2-dimensional camera; the lung-fields was then segmented by V-Net on another training set with 314 subjects and calculated the moving distance of the scanning couch based on a pre-generated calibration table. A multi-cohort study, including 1,186 patients was used for validation and radiation dose quantification under three clinical scenarios., Findings: A U-HAPPY (United imaging Human Automatic Planbox for PulmonarY) scanning CT was designed. Error distance of RPN was 4·46±0·02 pixels with a success rate of 98·7% in training set and 2·23±0·10 pixels with 100% success rate in testing set. Average Dice's coefficient was 0·99 in training set and 0·96 in testing set. A calibration table with 1,344,000 matches was generated to support the linkage between camera and scanner. This real-time automation makes an accurate plan-box to cover exact location and area needed to scan, thus reducing amounts of radiation exposures significantly (all, P<0·001)., Interpretation: U-HAPPY CT designed for pulmonary imaging acquisition standardization is promising for reducing patient risk and optimizing public health expenditures., Funding: The National Natural Science Foundation of China., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Bulimia nervosa (BN) is associated with functional abnormalities in frontostriatal and frontolimbic circuits. Although structural alterations in the frontal portions of these circuits have been observed, this is the first study of subcortical surface morphometry and the largest study of subcortical volume in BN., Methods: Anatomical magnetic resonance scans were acquired from 62 female participants with full and subthreshold BN (mean age ± SD, 18.7 ± 4.0 years) and 65 group-matched healthy control participants (mean age ± SD, 19.3 ± 5.7 years). General linear models were used to compare groups and assess the significance of group-by-age interactions on the shape and total volume of 15 subcortical structures (p < .05, familywise error corrected). Associations with illness severity and duration were assessed in the BN group., Results: Subcortical volumes did not differ across groups, but vertexwise analyses revealed inward shape deformations on the anterior surface of the pallidum in BN relative to control participants that were associated with binge-eating frequency and illness duration. Inward deformations on the ventrolateral thalamus and dorsal amygdala were more pronounced with advancing age in the BN group, and inward deformations on the caudate, putamen, and amygdala were associated with self-induced vomiting frequency., Conclusions: Our findings point to localized deformations on the surface of subcortical structures in areas that comprise both reward and cognitive control circuits. These deformations were more pronounced among older BN participants and among those with the most severe symptoms. Such precise localization of alterations in subcortical morphometry may ultimately aid in efforts to identify markers of risk and BN persistence., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Patient expectancy of therapeutic improvement is a primary mediator of placebo effects in antidepressant clinical trials, but its mechanisms are poorly understood. This study employed a novel antidepressant trial design, with integrated functional magnetic resonance imaging (fMRI), to manipulate patient outcome expectancy and examine its neural mediators., Method: Twenty-three depressed outpatients, in a randomized controlled trial were assigned to either Open (high outcome expectancy) or Placebo-controlled (low outcome expectancy) treatment with citalopram for eight weeks. fMRI scans were acquired before and after the expectancy manipulation (before medication treatment), while participants performed a masked emotional face task. Focusing on an amygdala region-of-interest (ROI), we tested a model where reduction in amygdala activation mediated outcome expectancy effects on the slope of change in depressive symptoms., Results: Following the manipulation, significant differences between conditions were found in neural activation changes in the amygdala, as well as in superior temporal gyrus, insula, and thalamus. Findings support the proposed mediation model according to which activation in the left amygdala ROI decreased significantly in the Open as opposed to the Placebo-controlled group following randomization (p = 0.009) for sad vs. neutral face contrast. The reduced left amygdala activation, in turn, was a significant predictor of decreased depressive symptoms during the trial (p = 0.007), and the mediation model was significant., Conclusions: Results from this study, the first designed to identify the neural mechanisms of expectancy augmentation in an antidepressant randomized control trial, suggest that therapeutic modulation of amygdala activity may be an important pathway by which patient outcome expectancy influences depressive symptoms. CLINICALTRIALS., Gov Identifier: NCT01919216; Trial name: Placebo Effects in the Treatment of Depression: Cognitive and Neural Mechanisms, URL: https://clinicaltrials.gov/ct2/show/NCT01919216., (Copyright © 2019 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.)

Objectives: This study aims to determine the effects of ozone therapy on restoring impaired Nrf2 activation to ameliorate chronic tubulointerstitial injury in rats with adenine-induced CKD., Materials and Methods: Sprague-Dawley rats were fed with 0.75% adenine-containing diet to induce CKD and chronic tubulointerstitial injury. Ozone therapy was administered by rectal insufflation. After 4 weeks, serum and kidney samples were collected and analyzed. Renal function and systemic electrolyte level were detected. Pathological changes in kidney were assessed by hematoxylin-eosin staining and Masson trichrome staining. Nrf2 activation was detected by immunohistochemistry and Western blot analyses. The levels of SOD, CAT, GSH, PCO, and MDA were detected in the kidney. Immunohistochemistry, Western blot, and real-time PCR analyses were performed to evaluate the activation of the nuclear factor kappa B (NF-κB) P65 pathway and inflammation infiltration in the tubulointerstitium of the rats., Results: Ozone therapy improved severe renal insufficiency and tubulointerstitial morphology injury as well as restored Nrf2 activation and inhibited the NF-κB pathway in rats with adenine-induced CKD. Ozone therapy also up-regulated anti-oxidation enzymes (SOD, CAT, and GSH) and down-regulated oxidation products (PCO and MDA), as well as inflammatory cytokines (IL-1β, IL-6, TNF-α, and ICAM-1) in the kidney., Conclusion: These findings indicated that ozone therapy could attenuate tubulointerstitial injury in rats with adenine-induced CKD by mediating Nrf2 and NF-κB.

Research into the pathophysiology of major depressive disorder (MDD) has focused largely on individuals already affected by MDD. Studies have thus been limited in their ability to disentangle effects that arise as a result of MDD from precursors of the disorder. By studying individuals at high familial risk for MDD, we aimed to identify potential biomarkers indexing risk for developing MDD, a critical step toward advancing prevention and early intervention. Using resting-state functional connectivity MRI (rs-fcMRI) and diffusion MRI (tractography), we examined connectivity within the default mode network (DMN) and between the DMN and the central executive network (CEN) in 111 individuals, aged 11-60 years, at high and low familial risk for depression. Study participants were part of a three-generation longitudinal, cohort study of familial depression. Based on rs-fcMRI, individuals at high vs low familial risk for depression showed increased DMN connectivity, as well as decreased DMN-CEN-negative connectivity. These findings remained significant after excluding individuals with a current or lifetime history of depression. Diffusion MRI measures based on tractography supported the findings of decreased DMN-CEN-negative connectivity. Path analyses indicated that decreased DMN-CEN-negative connectivity mediated a relationship between familial risk and a neuropsychological measure of impulsivity. Our findings suggest that DMN and DMN-CEN connectivity differ in those at high vs low risk for depression and thus suggest potential biomarkers for identifying individuals at risk for developing MDD.

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.)

Individuals with autism spectrum disorders (ASD) often have difficulty recognizing and interpreting facial expressions of emotion, which may impair their ability to navigate and communicate successfully in their social, interpersonal environments. Characterizing specific differences between individuals with ASD and their typically developing (TD) counterparts in the neural activity subserving their experience of emotional faces may provide distinct targets for ASD interventions. Thus we used functional magnetic resonance imaging (fMRI) and a parametric experimental design to identify brain regions in which neural activity correlated with ratings of arousal and valence for a broad range of emotional faces. Participants (51 ASD, 84 TD) were group-matched by age, sex, IQ, race, and socioeconomic status. Using task-related change in blood-oxygen-level-dependent (BOLD) fMRI signal as a measure, and covarying for age, sex, FSIQ, and ADOS scores, we detected significant differences across diagnostic groups in the neural activity subserving the dimension of arousal but not valence. BOLD-signal in TD participants correlated inversely with ratings of arousal in regions associated primarily with attentional functions, whereas BOLD-signal in ASD participants correlated positively with arousal ratings in regions commonly associated with impulse control and default-mode activity. Only minor differences were detected between groups in the BOLD signal correlates of valence ratings. Our findings provide unique insight into the emotional experiences of individuals with ASD. Although behavioral responses to face-stimuli were comparable across diagnostic groups, the corresponding neural activity for our ASD and TD groups differed dramatically. The near absence of group differences for valence correlates and the presence of strong group differences for arousal correlates suggest that individuals with ASD are not atypical in all aspects of emotion-processing. Studying these similarities and differences may help us to understand the origins of divergent interpersonal emotional experience in persons with ASD. Hum Brain Mapp 37:443-461, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Importance: The neural systems that confer risk or vulnerability for developing familial depression, and those that protect against or confer resilience to becoming ill, can be disentangled from the effects of prior illness by comparing brain imaging measures in previously ill and never ill persons who have either a high or low familial risk for depression., Objective: To distinguish risk and resilience endophenotypes for major depression from the effects of prior lifetime illness., Design, Setting, and Participants: We used functional magnetic resonance imaging to measure and compare brain function during performance of an attentional, self-regulatory task across a large sample of multigenerational families ascertained specifically to be at either high or low risk for developing major depression. Study procedures were performed in a university setting. A total of 143 community participants were followed up prospectively for more than 20 years in a university setting. The sample was enriched with persons who were at higher or lower familial risk for developing depression based on being biological offspring of either a clinical sample of persons with major depression or a community control sample of persons with no discernible lifetime illness., Main Outcomes and Measures: Task-related change in blood oxygen level-dependent functional magnetic resonance imaging signal., Results: A risk endophenotype included greater activation of cortical attention circuits. A resilience endophenotype included greater activation of the dorsal anterior cingulate cortex. The effects of prior lifetime illness were common to both risk groups and included greater deactivation of default-mode circuits., Conclusions and Relevance: These findings identify neural systems that increase risk for depression, those that protect from illness, and those that endure following illness onset, and they suggest circuits to target for developing novel preventive and therapeutic interventions.

Importance: The default mode network (DMN) is a collection of brain regions that reliably deactivate during goal-directed behaviors and is more active during a baseline, or so-called resting, condition. Coherence of neural activity, or functional connectivity, within the brain's DMN is increased in major depressive disorder relative to healthy control (HC) subjects; however, whether similar abnormalities are present in persons with dysthymic disorder (DD) is unknown. Moreover, the effect of antidepressant medications on DMN connectivity in patients with DD is also unknown., Objective: To use resting-state functional-connectivity magnetic resonance imaging (MRI) to study (1) the functional connectivity of the DMN in subjects with DD vs HC participants and (2) the effects of antidepressant therapy on DMN connectivity., Design: After collecting baseline MRI scans from subjects with DD and HC participants, we enrolled the participants with DD into a 10-week prospective, double-blind, placebo-controlled trial of duloxetine and collected MRI scans again at the conclusion of the study. Enrollment occurred between 2007 and 2011., Setting: University research institute., Participants: Volunteer sample of 41 subjects with DD and 25 HC participants aged 18 to 53 years. Control subjects were group matched to patients with DD by age and sex., Main Outcome Measures: We used resting-state functional-connectivity MRI to measure the functional connectivity of the brain's DMN in persons with DD compared with HC subjects, and we examined the effects of treatment with duloxetine vs placebo on DMN connectivity., Results: Of the 41 subjects with DD, 32 completed the clinical trial and MRI scans, along with the 25 HC participants. At baseline, we found that the coherence of neural activity within the brain's DMN was greater in persons with DD compared with HC subjects. Following a 10-week clinical trial, we found that treatment with duloxetine, but not placebo, normalized DMN connectivity., Conclusions and Relevance: The baseline imaging findings are consistent with those found in patients with major depressive disorder and suggest that increased connectivity within the DMN may be important in the pathophysiology of both acute and chronic manifestations of depressive illness. The normalization of DMN connectivity following antidepressant treatment suggests an important causal pathway through which antidepressants may reduce depression.

Behavioral interference elicited by competing response tendencies adapts to contextual changes. Recent nonhuman primate research suggests a key mnemonic role of distinct prefrontal cells in supporting such context-driven behavioral adjustments by maintaining conflict information across trials, but corresponding prefrontal functions have yet to be probed in humans. Using event-related functional magnetic resonance imaging, we investigated the human neural substrates of contextual adaptations to conflict. We found that a neural system comprising the rostral dorsomedial prefrontal cortex and portions of the dorsolateral prefrontal cortex specifically encodes the history of previously experienced conflict and influences subsequent adaptation to conflict on a trial-by-trial basis. This neural system became active in anticipation of stimulus onsets during preparatory periods and interacted with a second neural system engaged during the processing of conflict. Our findings suggest that a dynamic interaction between a system that represents conflict history and a system that resolves conflict underlies the contextual adaptation to conflict.

The circumplex model of affect construes all emotions as linear combinations of 2 independent neurophysiological dimensions, valence and arousal. We used functional magnetic resonance imaging to identify the neural networks subserving valence and arousal, and we assessed, in 10 participants, the associations of the BOLD (blood oxygen level-dependent) response, an indirect index of neural activity, with ratings of valence and arousal during the emotional experiences induced by the presentation of evocative sentences. Unpleasant emotional experience was associated with increased BOLD signal intensities in the supplementary motor, anterior midcingulate, right dorsolateral prefrontal, occipito-temporal, inferior parietal, and cerebellar cortices. Highly arousing emotions were associated with increased BOLD signal intensities in the left thalamus, globus pallidus, caudate, parahippocampal gyrus, amygdala, premotor cortex, and cerebellar vermis. Separate analyses using a finite impulse response model confirmed these results and revealed that pleasant emotions engaged an additional network that included the midbrain, ventral striatum, and caudate nucleus, all portions of a reward circuit. These findings suggest the existence of distinct networks subserving the valence and arousal dimensions of emotions, with midline and medial temporal lobe structures mediating arousal and dorsal cortical areas and mesolimbic pathways mediating valence.

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

Context: Disturbances in neural systems that mediate voluntary self-regulatory processes may contribute to bulimia nervosa (BN) by releasing feeding behaviors from regulatory control., Objective: To study the functional activity in neural circuits that subserve self-regulatory control in women with BN., Design: We compared functional magnetic resonance imaging blood oxygenation level-dependent responses in patients with BN with healthy controls during performance of the Simon Spatial Incompatibility task., Setting: University research institute., Participants: Forty women: 20 patients with BN and 20 healthy control participants. Main Outcome Measure We used general linear modeling of Simon Spatial Incompatibility task-related activations to compare groups on their patterns of brain activation associated with the successful or unsuccessful engagement of self-regulatory control., Results: Patients with BN responded more impulsively and made more errors on the task than did healthy controls; patients with the most severe symptoms made the most errors. During correct responding on incongruent trials, patients failed to activate frontostriatal circuits to the same degree as healthy controls in the left inferolateral prefrontal cortex (Brodmann area [BA] 45), bilateral inferior frontal gyrus (BA 44), lenticular and caudate nuclei, and anterior cingulate cortex (BA 24/32). Patients activated the dorsal anterior cingulate cortex (BA 32) more when making errors than when responding correctly. In contrast, healthy participants activated the anterior cingulate cortex more during correct than incorrect responses, and they activated the striatum more when responding incorrectly, likely reflecting an automatic response tendency that, in the absence of concomitant anterior cingulate cortex activity, produced incorrect responses., Conclusions: Self-regulatory processes are impaired in women with BN, likely because of their failure to engage frontostriatal circuits appropriately. These findings enhance our understanding of the pathogenesis of BN by pointing to functional abnormalities within a neural system that subserves self-regulatory control, which may contribute to binge eating and other impulsive behaviors in women with BN.

The time delay estimation (TDE) is an important issue in modern signal processing and it has found extensive applications in the spatial propagation feature extraction of biomedical signals as well. Due to the extreme complexity and variability of the underlying systems, biomedical signals are usually nonstationary, unstable and even chaotic. Furthermore, due to the limitations of the measurement environments, biomedical signals are often noise-contaminated. Therefore, the TDE of biomedical signals is a challenging issue. A new TDE algorithm based on the least absolute deviation neural network (LADNN) and its application experiments are presented in this paper. The LADNN is the neural implementation of the least absolute deviation (LAD) optimization model, also called unconstrained minimum L1-norm model, with a theoretically proven global convergence. In the proposed LADNN-based TDE algorithm, a given signal is modeled using the moving average (MA) model. The MA parameters are estimated by using the LADNN and the time delay corresponds to the time index at which the MA coefficients have a peak. Due to the excellent features of L1-norm model superior to Lp-norm (p > 1) models in non-Gaussian noise environments or even in chaos, especially for signals that contain sharp transitions (such as biomedical signals with spiky series or motion artifacts) or chaotic dynamic processes, the LADNN-based TDE is more robust than the existing TDE algorithms based on wavelet-domain correlation and those based on higher-order spectra (HOS). Unlike these conventional methods, especially the current state-of-the-art HOS-based TDE, the LADNN-based method is free of the assumption that the signal is non-Gaussian and the noises are Gaussian and, thus, it is more applicable in real situations. Simulation experiments under three different noise environments, Gaussian, non-Gaussian and chaotic, are conducted to compare the proposed TDE method with the existing HOS-based method. Real application experiment is conducted to extract time delay information between every two adjacent channels of gastric myoelectrical activity (GMA) to assess the spatial propagation characteristics of GMA during different phases of the migrating myoelectrical complex (MMC).

Nonlinear feedback induces oscillation, whereas dynamic equilibrium between positive and negative nonlinear feedback generates rhythm. Physiological rhythms are central to life. No absolutely stable or periodic rhythm exists in living tissues. It has been extensively reported that many rhythms in human and animal organs, such as the heart and brain, are, in fact chaotic. The aim of this paper is to investigate whether the migrating myoelectrical complex (MMC) of the stomach was chaotic. The study was performed in eight healthy female hound dogs (15-22 kg), implanted with four pairs of bipolar electrodes on the serosa of the stomach along the greater curvature. After the dogs were completely recovered from the surgery, one complete cycle of gastric MMC was recorded from the serosal electrodes. Using Takens' embedding theorem, two parameters reflecting chaotic behavior, the attractor and the Lyapunov exponent of the myoelectrical recording, were reconstructed and computed, respectively. Statistical analysis was performed to investigate the difference in the Lyapunov exponents among different phases of the MMC. The results show that the MMC of the stomach is chaotic. Different phases of the MMC are characterized with different shapes of the attractors and different values of Lyapunov exponents. The characteristic chaotic behavior of the gastric MMC may be utilized for the identification of different phases.

The aim of this study was to investigate the correlation of gastric emptying with gastric myoelectrical activity recorded from internal serosal electrodes and with gastric motility measured from strain gauges. The study was performed in eight healthy dogs chronically implanted with four pairs of electrodes and two strain gauges on the gastric serosa and equipped with a duodenal fistula for the assessment of gastric emptying. Each dog was fed four liquid test meals on four separate days with identical calories (320 kcal) and volume (473 ml). A correlation was found between gastric emptying and the energy of contraction in the frequency band of 3.75-7.50 cycles/min during the first 30 min after the meal (r = 0.46, P < 0.05). While none of the parameters of gastric myoelectrical activity was correlated with gastric emptying, two major parameters, percentage of regular gastric slow waves and percentage of slow-wave coupling, were found to be associated with delayed gastric emptying. A significant correlation was found between the frequency of gastric slow waves and that of the contractions in both fasting (r = 0.83, P < 0.001) and fed state (r = 0.70, P < 0.001 at 30 min, r = 0.86, P < 0.001 at 60 min). It was concluded that gastric emptying is correlated with the strength of gastric contractions in a frequency range identical to that of the gastric slow waves, and there is no one-to-one correlation between gastric emptying of liquids and any parameters of gastric myoelectrical activity. However, major parameters of gastric myoelectrical activity are associated with gastric emptying.

Gastroparesis is a disorder with a lack of treatment options and this study investigated the effect of electroacupuncture on gastric emptying and involved mechanisms. Dogs implanted with a duodenal cannula and serosal electrodes were fed with Ensure mixed with phenol red, and the gastric effluent was collected. Electroacupuncture was performed from 30 min before until 45 min after the meal. Gastric myoelectrical activity and electrocardiogram were recorded. Gastric emptying was significantly improved with electroacupuncture. Vagal activity assessed from the spectral analysis of heart rate variability was markedly increased with electroacupuncture. Electroacupuncture increased the regularity of gastric slow waves in both the proximal and distal stomach. It also increased the number of spike bursts in the distal but not proximal stomach. Electroacupuncture accelerates gastric emptying of liquid in dogs and its potential for treating gastroparesis may be explored. The effect may be attributed to improvement in gastric slow-wave rhythmicity and antral contractile (spike) activity and may possibly involve the vagal pathway.