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Insomnia is the second most prevalent psychiatric disorder worldwide, but the understanding of the pathophysiology of insomnia remains fragmented. In this study, we calculated the connectome gradient in 50 chronic insomnia disorder (CID) patients and 38 healthy controls (HC) to assess changes due to insomnia and utilized these gradients in a connectome-based predictive modeling (CPM) to predict clinical symptoms associated with insomnia. The results suggested that insomnia led to significant alterations in the functional gradients of some brain areas. Specifically, the gradient scores in the middle frontal gyrus, superior anterior cingulate gyrus, and right nucleus accumbens were significantly higher in the CID patients than in the HC group, whereas the scores in the middle occipital gyrus, right fusiform gyrus, and right postcentral gyrus were significantly lower than in the HC group. Further correlation analysis revealed that the right middle frontal gyrus is positively correlated with the self-rating anxiety scale (r=0.3702). Additionally, the prediction model built with functional gradients could well predict the sleep quality (r=0.5858), anxiety (r=0.6150), and depression (r=0.4022) levels of insomnia patients. This offers an objective depiction of the clinical diagnosis of insomnia, yielding a beneficial impact on the identification of effective biomarkers and the comprehension of insomnia., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Somatic anxiety refers to the tendency to appraise situations as threatening, leading to heightened physiological arousal. Symptoms associated with higher levels of somatic anxiety that reflect autonomic arousal and perceptions of threat include elevated heartbeat perception, difficulty breathing, and palpitation. Somatic anxiety is generally associated with increased stimulus-driven attention; however, it is currently unknown how somatic anxiety modulates neural synchrony, measured by intersubject correlations (ISC), in response to complex audiovisual stimuli. The present study seeks to identify how differing levels of somatic anxiety are associated with neural synchrony during psychological processing of audiovisual stimuli, as measured by ISC and intersubject representational similarity analyses. We hypothesize that individuals with higher levels of somatic anxiety will show heightened ISC in response to an audiovisual stimulus in regions associated with stimulus-driven attention, including the superior parietal lobule, supplementary motor area, and precentral gyrus. Results from this study identified that higher levels of somatic anxiety are associated with widespread heightened ISC across the brain, including in regions associated with perceptual processing and stimulus-driven attention. Taken together, this research suggests that higher levels of somatic anxiety are associated with similar processing in brain regions involved in stimulus-driven attention and top-down processing, whereas lower levels of somatic anxiety are associated with similar processing in brain regions associated with higher level visual processing. These results collectively emphasize that somatic anxiety levels should be measured and controlled for during naturalistic functional magnetic resonance imaging paradigms, as this trait may have an influence on synchronous neurological activity. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Some mental health problems such as depression and anxiety are more common in females, while others such as autism and attention deficit/hyperactivity (AD/H) are more common in males. However, the neurobiological origins of these sex differences are poorly understood. Animal studies have shown substantial sex differences in neuronal and glial cell structure, while human brain imaging studies have shown only small differences, which largely reflect overall body and brain size. Advanced diffusion MRI techniques can be used to examine intracellular, extracellular, and free water signal contributions and provide unique insights into microscopic cellular structure. However, the extent to which sex differences exist in these metrics of subcortical gray matter structures implicated in psychiatric disorders is not known. Here, we show large sex-related differences in microstructure in subcortical regions, including the hippocampus, thalamus, and nucleus accumbens in a large sample of young adults. Unlike conventional T1-weighted structural imaging, large sex differences remained after adjustment for age and brain volume. Further, diffusion metrics in the thalamus and amygdala were associated with depression, anxiety, AD/H, and antisocial personality problems. Diffusion MRI may provide mechanistic insights into the origin of sex differences in behavior and mental health over the life course and help to bridge the gap between findings from experimental, epidemiological, and clinical mental health research., Competing Interests: Competing interests statement:A.M.D. is a Founder of and holds equity in CorTechs Labs, Inc., and serves on its Scientific Advisory Board. He is a member of the Scientific Advisory Board of Human Longevity, Inc., and the Mohn Medical Imaging and Visualization Centre in Bergen, Norway. He receives funding through research agreements with General Electric Healthcare. The terms of these arrangements have been reviewed and approved by UCSD in accordance with its conflict of interest policies. The other authors declare no competing interests.

Background: Irritable bowel syndrome (IBS) interacts with psychopathology in a complex way; however, little is known about the underlying brain, biochemical, and genetic mechanisms., Methods: To clarify the phenotypic and genetic associations between IBS and brain health, we performed a comprehensive retrospective cohort study on a large population. Our study included 171,104 participants from the UK Biobank who underwent a thorough assessment of IBS, with the majority also providing neuroimaging, behavioral, biochemical, and genetic information. Multistage linked analyses were conducted, including phenome-wide association analysis, polygenic risk score calculation, and 2-sample Mendelian randomization analysis., Results: The phenome-wide association analysis showed that IBS was linked to brain health problems, including anxiety and depression, and poor cognitive performance. Significantly lower brain volumes associated with more severe IBS were found in key areas related to emotional regulation and higher-order cognition, including the medial orbitofrontal cortex/ventromedial prefrontal cortex, anterior insula, anterior and mid-cingulate cortices, dorsolateral prefrontal cortex, and hippocampus. Higher triglycerides, lower high-intensity lipoprotein, and lower platelets were also related (p < 1 × 10 -10 ) to more severe IBS. Finally, Mendelian randomization analyses demonstrated potential causal relationships between IBS and brain health and indicated possible mediating effects of dyslipidemia and inflammation., Conclusions: For the first time, this study provides a comprehensive understanding of the relationship between IBS and brain health phenotypes, integrating perspectives from neuroimaging, behavioral performance, biochemical factors, and genetics, which is of great significance for clinical applications to potentially address brain health impairments in patients with IBS., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Engaging in regular physical activity and establishing exercise habits is known to have multifaceted benefits extending beyond physical health to cognitive and mental well-being. This study explores the intricate relationship between exercise habits, brain imaging markers, and mental health outcomes. While extensive evidence supports the positive impact of exercise on cognitive functions and mental health, recent advancements in multimodal imaging techniques provide a new dimension to this exploration. By using a cross-sectional multimodal brain-behavior statistic in participants with different exercise habits, we aim to unveil the intricate mechanisms underlying exercise's influence on cognition and mental health, including the status of depression, anxiety, and quality of life. This integration of exercise science and imaging promises to substantiate cognitive benefits on mental health and uncover functional and structural changes underpinning these effects. This study embarks on a journey to explore the significance of multimodal imaging metrics (i.e., structural and functional metrics) in deciphering the intricate interplay between exercise habits and mental health, enhancing the comprehension of how exercise profoundly shapes psychological well-being. Our analysis of group comparisons uncovered a strong association between regular exercise habits and improved mental well-being, encompassing factors such as depression, anxiety levels, and overall life satisfaction. Additionally, individuals who engaged in exercise displayed enhanced brain metrics across different modalities. These metrics encompassed greater gray matter volume within the left frontal regions and hippocampus, improved white matter integrity in the frontal-occipital fasciculus, as well as more robust functional network configurations in the anterior segments of the default mode network. The interplay between exercise habits, brain adaptations, and mental health outcomes underscores the pivotal role of an active lifestyle in nurturing a resilient and high-functioning brain, thus paving the way for tailored interventions and improved well-being., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Childhood adversity is associated with abnormalities in brain structure, but this association has not been tested for childhood unpredictability, one form of adversity. We studied whether abnormalities in gray matter volume (GMV) could be a mechanism linking childhood unpredictability and psychopathology, over and above the effect of childhood trauma., Methods: Participants were 158 right-handed healthy young adults (aged 17-28 years, M = 22.07, s.d. = 2.08; 66.46% female) who underwent structural magnetic resonance imaging measurements and provided retrospective reports of childhood unpredictability. The anxiety and depression subscales of the self-report Brief Symptom Inventory-53 were used to index psychopathology., Results: Whole-brain voxel-based morphometric analyses showed that after controlling for the effect of childhood trauma, childhood unpredictability was correlated with greater GMV in bilateral frontal pole, bilateral precuneus, bilateral postcentral gyrus, right hemisphere of fusiform, and lingual gyrus, and left hemisphere of ventrolateral prefrontal cortex as well as occipital gyrus. Greater GMV in bilateral frontal pole, bilateral precuneus, and bilateral postcentral gyrus mediated associations between unpredictability and symptoms of depression and anxiety., Conclusions: The findings suggest that childhood unpredictability could exact unique effects on neural development, over and above the effect of childhood trauma. These findings are relevant for understanding the occurrence of psychopathology following childhood unpredictability and have implications for intervention.

Despite the significant health consequences of anxiety, the neural basis of regulation for personal anxious events is not well understood. We examined brain activity and functional connectivity during cognitive emotion regulation strategies (reappraisal and acceptance) for personal anxious events. Functional MRI (fMRI) data were obtained while 35 college students were thinking about (the control condition), reappraising, or accepting their own anxiety-provoking situations. Although reappraisal and acceptance decreased anxiety, no statistically significant differences were observed in the brain activation levels between cognitive emotion regulation strategies and the control condition. However, acceptance decreased activation in the posterior cingulate cortex and precuneus more than reappraisal. Moreover, functional connectivity with the amygdala and ventral anterior insula distinguished the emotion regulation strategies for anxiety. Reappraisal showed stronger negative functional connectivity with the amygdala and cognitive control regions than other strategies. In addition, reappraisal had negative functional coupling between the ventral anterior insula and temporal pole compared with acceptance. In contrast, acceptance showed stronger positive functional coupling between the ventral anterior insula and precentral and postcentral gyrus compared with the control condition. Our findings contribute to the understanding of emotion regulation processes by revealing the brain activity and functional connectivity patterns in reappraisal and acceptance for personal anxious events., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Tsujimoto et al.)

Anxiety is a common disease within human psychiatric disorders and has also been described as a frequently neuropsychiatric problem in dogs. Human neuroimaging studies showed abnormal functional brain networks might be involved in anxiety. In this study, we expected similar changes in network topology are also present in dogs. We performed resting-state functional MRI on 25 healthy dogs and 13 patients. The generic Canine Behavioral Assessment & Research Questionnaire was used to evaluate anxiety symptoms. We constructed functional brain networks and used graph theory to compare the differences between two groups. No significant differences in global network topology were found. However, focusing on the anxiety circuit, global efficiency and local efficiency were significantly higher, and characteristic path length was significantly lower in the amygdala in patients. We detected higher connectivity between amygdala-hippocampus, amygdala-mesencephalon, amygdala-thalamus, frontal lobe-hippocampus, frontal lobe-thalamus, and hippocampus-thalamus, all part of the anxiety circuit. Moreover, correlations between network metrics and anxiety symptoms were significant. Altered network measures in the amygdala were correlated with stranger-directed fear and excitability; altered degree in the hippocampus was related to attachment/attention seeking, trainability, and touch sensitivity; abnormal frontal lobe function was related to chasing and familiar dog aggression; attachment/attention seeking was correlated with functional connectivity between amygdala-hippocampus and amygdala-thalamus; familiar dog aggression was related to global network topology change. These findings may shed light on the aberrant topological organization of functional brain networks underlying anxiety in dogs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Xu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Brain-body interactions can be studied by using directed coupling measurements of fMRI oscillations in the low (0.1-0.2 Hz) and high frequency bands (HF; 0.2-0.4 Hz). Recently, a preponderance of oscillations in the information flow between the brainstem and the prefrontal cortex at around 0.15/0.16 Hz was shown. The goal of this study was to investigate the information flow between BOLD-, respiratory-, and heart beat-to-beat interval (RRI) signals in the HF band in healthy subjects with high anxiety during fMRI examinations. A multivariate autoregressive model was concurrently applied to the BOLD signals from the middle frontal gyrus (MFG), precentral gyrus and the brainstem, as well as to respiratory and RRI signals. Causal coupling between all signals was determined using the Directed Transfer Function (DTF). We found a salience of fast respiratory waves with a period of 3.1 s (corresponding to ~ 0.32 Hz) and a highly significant (p < 0.001) top-down information-flow from BOLD oscillations in the MFG to the brainstem. Additionally, there was a significant (p < 0.01) information flow from RRI to respiratory oscillations. We speculate that brain oscillations around 0.32 Hz, triggered by nasal breathing, are projected downwards to the brainstem. Particularly interesting is the driving force of cardiac to respiratory waves with a ratio of 1:1 or 1:2. These results support the binary hierarchy model with preferred respiratory frequencies at 0.32 Hz and 0.16 Hz., (© 2023. The Author(s).)

Depression and anxiety are associated with abnormalities in brain regions that process rewards including the medial orbitofrontal cortex (mOFC), the ventral striatum (VS), and the amygdala. However, there are inconsistencies in these findings. This may be due to past reliance on categorical diagnoses that, while valuable, provide less precision than may be required to understand subtle neural changes associated with symptoms of depression and anxiety. In contrast, the tri-level model defines symptom dimensions that are common (General Distress) or relatively specific (Anhedonia-Apprehension, Fears) to depression and anxiety related disorders, which provide increased precision. In the current study, eligibility was assessed by quasi-orthogonal screening questionnaires measuring reward and threat sensitivity (Behavioral Activation Scale; Eysenck Personality Questionnaire-Neuroticism). These participants were assessed on tri-level symptom severity and completed the Monetary Incentive Delay task during fMRI scanning. VS-mOFC and VS-amygdala connectivity were estimated during reward anticipation and reward outcome. Heightened General Distress was associated with lower VS-mOFC connectivity during reward anticipation (b = -0.064, p = 0.021) and reward outcome (b = -0.102, p = 0.014). Heightened Anhedonia-Apprehension was associated with greater VS-amygdala connectivity during reward anticipation (b = 0.065, p = 0.004). The present work has important implications for understanding the coupling between the mOFC and vS and the amygdala and the vS during reward processing in the pathophysiology of mood and anxiety symptoms and for developing targeted behavioral, pharmacological, and neuromodulatory interventions to help manage these symptoms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Social anxiety is a symptom widely prevalent among young adults, and when present in excess, can lead to maladaptive patterns of social behavior. Recent approaches that incorporate brain functional radiomic features and machine learning have shown potential for predicting certain phenotypes or disorders from functional magnetic resonance images. In this study, we aimed to predict the level of social anxiety in young adult participants by training machine learning models with resting-state brain functional radiomic features including the regional homogeneity, fractional amplitude of low-frequency fluctuation, fractional resting-state physiological fluctuation amplitude, and degree centrality. Among the machine learning models, the XGBoost model achieved the best performance with balanced accuracy of 77.7% and F1 score of 0.815. Analysis of input feature importance demonstrated that the orbitofrontal cortex and the degree centrality were most relevant to predicting the level of social anxiety among the input brain regions and the input type of radiomic features, respectively. These results suggest potential validity for predicting social anxiety with machine learning of the resting-state brain functional radiomic features and provide further understanding of the neural basis of the symptom., (© 2022. The Author(s).)

Depression, anxiety and apathy are 'common neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD). We aimed to find regional gray matter (GM) volume difference of these symptoms, in AD patients compared to AD control, and investigate possible associations of GM atrophy with cognitive covariant. Study subjects were retrieved from the Alzheimer's Disease Neuroimaging Initiative database. Thirty-five participants are AD control, 27 AD patients with anxiety, 19 with depression and 24 with apathy, ages ≥ 55.1 years. Recruited subjects had an assessment of their clinical and structural MRI data. GM differences and clinical data were analyzed using voxel-based morphometry and ANOVA with Scheffe post hoc test, respectively. We found significant GM volumes differences in the left insula, left parahippocampal, posterior cingulate and the bilateral putamen in the anxiety group. The results also revealed that the right parahippocampal, Brodmann area 38 and the middle frontal gyrus were significant in patients with depression. Significant results were with a p < 0.05, corrected with AlphaSim program for multiple comparisons. The left insula had a strong negative association with Clinical Dementia Rate Sum of Boxes and Alzheimer's Disease Assessment Scale-cognitive subscale-13 items in anxiety and apathy groups. The difference in GM density in the left insula and hippocampus plays a crucial role in depression, anxiety and apathy NPS and outline precise approaches to test these symptoms., (© 2020. Belgian Neurological Society.)

Background: The pervasiveness of subclinical anxiety in children, highlights the need to identify its neurobiological underpinnings to better inform interventions. Given the now well-established link between aberrant emotion processing and anxiety disorders and yet limited neurobiologically-informed research in this area, this study examined the neural correlates of emotion recognition (ER) in children with sub-clinical anxiety., Method: Ninety children (aged 9-11 years) with sub-clinical anxiety, completed an emotion recognition task whilst undergoing functional magnetic resonance imaging. The ER task required participants to match shapes and match emotional faces in the context of shape distractors. Participants also completed the Spence Children's Anxiety Scale (SCAS)., Results: Greater blood oxygenation level dependent (BOLD) changes associated with ER were observed in the lateral occipital cortex, middle frontal gyrus, superior middle frontal gyrus, inferior frontal gyrus, superior parietal lobule, inferior parietal lobule, superior temporal gyrus, and middle temporal gyrus symmetrically. The clusters also included posterior cingulate cortex, insula, hippocampus, amygdala and cerebellum during matching emotions than those matching shapes. Females showed greater BOLD changes associated with ER than males in the right middle frontal gyrus. The BOLD changes associated with ER in the right middle frontal gyrus and right insula were greater in children with SCAS subscale (physical injury fear) scores in the normal range than those with elevated scores., Discussion: The findings in this study implicate the right middle frontal gyrus and insula as key regions in the neurobiological underpinnings of sub-clinical anxiety as they relate to attention impairments in anxious children., Conclusion: The results of this study indicate there are gender differences in young participants during emotion processing and provides a neurobiological target for attention impairments in anxious children., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Although about 1-2% of MRI examinations must be aborted due to anxiety, there is little research on how MRI-related anxiety affects BOLD signals in resting states., Methods: We re-analyzed cardiac beat-to beat interval (RRI) and BOLD signals of 23 healthy fMRI participants in four resting states by calculation of phase-coupling in the 0.07-0.13 Hz band and determination of positive time delays (pTDs; RRI leading neural BOLD oscillations) and negative time delays (nTDs; RRI lagging behind vascular BOLD oscillations). State anxiety of each subject was assigned to either a low anxiety (LA) or a high anxiety (HA, with most participants exhibiting moderate anxiety symptoms) category based on the inside scanner assessed anxiety score., Results: Although anxiety strongly differed between HA and LA categories, no significant difference was found for nTDs. In contrast, pTDs indicating neural BOLD oscillations exhibited a significant cumulation in the high anxiety category., Conclusions: Findings may suggest that vascular BOLD oscillations related to slow cerebral blood circulation are of about similar intensity during low/no and elevated anxiety. In contrast, neural BOLD oscillations, which might be associated with a central rhythm generating mechanism (pacemaker-like activity), appear to be significantly intensified during elevated anxiety., Significance: The study provides evidence that fMRI-related anxiety can activate a central rhythm generating mechanism very likely located in the brain stem, associated with slow neural BOLD oscillation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: Functional constipation (FC) is a common gastrointestinal disorder. Anxiety and/or depressive disorders are common in patients with FC (FCAD). Brain dysfunction may play a role in FC, but the contribution of comorbid anxiety and/or depression in patients with FC is poorly understood., Methods: Sixty-five FC patients and 42 healthy controls (HCs) were recruited, and a hierarchical clustering algorithm was used to classify FC patients into FCAD and patients without anxiety/depressive status (FCNAD) based on neuropsychological assessment. Resting-state functional magnetic resonance imaging measures including fractional amplitude of low-frequency fluctuation (fALFF) and functional connectivity were used to investigate brain functional differences., Results: Thirty-seven patients were classified as FCAD, and 28 patients were classified as FCNAD; as compared with HC, both groups showed decreased activity (fALFF) in the perigenual anterior cingulate cortex (pACC), dorsomedial prefrontal cortex (DMPFC), and precuneus; enhanced precentral gyrus-thalamus connectivity and attenuated precuneus-thalamus connectivity in FCAD/FCNAD highlighted the thalamus as a critical connectivity node in the brain network (pFWE < .05). In comparison with FCNAD/HC, the FCAD group also had decreased fALFF in the orbitofrontal cortex (OFC) and thalamus, and increased OFC-hippocampus connectivity. In the FCNAD group, brain activities (pACC/DMPFC) and connection (precuneus-thalamus) had correlations only with symptoms; in the FCAD group, brain activities (OFC, pACC/DMPFC) and connectivities (OFC-hippocampus/precentral gyrus-thalamus) showed correlations with both constipation symptoms and anxiety/depressive status ratings. Mediation analysis indicated that the relationship between abdominal distension and OFC activity was completely mediated by anxiety in FCAD., Conclusions: These findings provide evidence of differences in brain activity and functional connectivity between FCAD and FCNAD, potentially providing important clues for improving treatment strategies., (Copyright © 2021 by the American Psychosomatic Society.)

Geriatric depression and anxiety disorders often manifest as neuropsychiatric symptoms among those with mild cognitive impairment. Both tend to co-occur, and overlap in symptomology and etiology. Such commonalities are likely to be reflected in the brain as common neural correlates. Using connectome-based predictive modeling (CPM), we examined the functional and structural connectomes predicting depression and anxiety symptoms, and subsequently the overlap and cross-syndrome generalization of the connectomes associated with either disorder. Ninety-one older adults completed self-reported measures of depression and anxiety, and underwent diffusion tensor imaging and resting-state functional magnetic resonance imaging. Functional connectivity (FC) and structural connectivity (SC) matrices were derived from these scans and, in various combinations, entered into CPM models to predict either type of symptoms. Leave-one-out cross-validation was performed. Predictive accuracy was assessed via the correlation between predicted and observed scores (ρ predicted-observed ). While FC or SC features alone significantly predicted either type of symptoms, these symptoms were best predicted by models that consisted of both FC and SC features (depression: ρ predicted-observed  = 0.497; anxiety: ρ predicted-observed  = 0.455). The features common to depression and anxiety were identified and entered into another model which was similarly accurate in predicting either type of symptoms. Moreover, cross-syndrome generalization was observed- the depression-associated features significantly predicted anxiety symptoms (ρ predicted-observed  = 0.403) and vice-versa (ρ predicted-observed  = 0.378). These FC and SC features are complementary biomarkers of geriatric depression and anxiety symptoms. Both types of symptoms are largely underpinned by common patterns of altered FC and SC, alluding to the transdiagnostic neurobiological susceptibility in both disorders., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Quantitative analysis of the high-resolution T1-weighted images provides useful markers to measure anatomical changes during brain degeneration related to major depressive disorder (MDD). However, there are controversial findings regarding these volume alterations in MDD indicating even to increased volumes in some specific regions in MDD patients., Methods: This study is a case-controlled study including 23 depression patients and 15 healthy subject person and 20-38 years of age, who have been treated at the Neurology and Psychiatry Department here. We compared specific anatomic regions between drug-free MDD patients and control group through MRI-Cloud, which is a novel brain imaging method that enables to analyze multiple brain regions simultaneously., Results: We have found that frontal, temporal, and parietal hemispheric volumes and middle frontal gyrus, inferior frontal gyrus, superior parietal gyrus, cingulum-hippocampus, lateral fronto-orbital gyrus, superior temporal gyrus, superior temporal white matter, middle temporal gyrus subanatomic regions were significantly reduced bilaterally in MDD patients compared to the control group, while striatum, amygdala, putamen, and nucleus accumbens bilaterally increased in MDD group compared to the control group suggesting that besides the heterogeneity among studies, also comorbid factors such as anxiety and different personal traits could be responsible for these discrepant results., Conclusion: Our study gives a strong message that depression is associated with altered structural brain volumes, especially, in drug-free and first-episode MDD patients who present with similar duration and severity of depression while the role of demographic and comorbid risk factors should not be neglected., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Excessive response to unexpected or "deviant" stimuli during infancy and early childhood represents an early risk marker for anxiety disorders. However, research has yet to delineate the specific brain regions underlying the neonatal response to deviant stimuli near birth and the relation to risk for anxiety disorders. The authors used task-based functional MRI (fMRI) to delineate the neonatal response to deviant stimuli and its relationship to maternal trait anxiety., Methods: The authors used fMRI to measure brain activity evoked by deviant auditory stimuli in 45 sleeping neonates (mean age, 27.8 days; 60% female; 64% African American). In 41 of the infants, neural response to deviant stimuli was examined in relation to maternal trait anxiety on the State-Trait Anxiety Inventory, a familial risk factor for offspring anxiety., Results: Neonates manifested a robust and widespread neural response to deviant stimuli that resembles patterns found previously in adults. Higher maternal trait anxiety was related to higher responses within multiple brain regions, including the left and right anterior insula, the ventrolateral prefrontal cortex, and multiple areas within the anterior cingulate cortex. These areas overlap with brain regions previously linked to anxiety disorders and other psychiatric illnesses in adults., Conclusions: The neural architecture sensitive to deviant stimuli robustly functions in newborns. Excessive responsiveness of some circuitry components at birth may signal risk for anxiety and other psychiatric disorders.

Anxiety-related illnesses are highly prevalent in human society. Being able to identify neurobiological markers signaling high trait anxiety could aid the assessment of individuals with high risk for mental illness. Here, we applied connectome-based predictive modeling (CPM) to whole-brain resting-state functional connectivity (rsFC) data to predict the degree of trait anxiety in 76 healthy participants. Using a computational "lesion" approach in CPM, we then examined the weights of the identified main brain areas as well as their connectivity. Results showed that the CPM successfully predicted individual anxiety based on whole-brain rsFC, especially the rsFC between limbic areas and prefrontal cortex. The prediction power of the model significantly decreased from simulated lesions of limbic areas, lesions of the connectivity within limbic areas, and lesions of the connectivity between limbic areas and prefrontal cortex. Importantly, this neural model generalized to an independent large sample (n = 501). These findings highlight important roles of the limbic system and prefrontal cortex in anxiety prediction. Our work provides evidence for the usefulness of connectome-based modeling in predicting individual personality differences and indicates its potential for identifying personality factors at risk for psychopathology., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

In this study, fifty-four male Wistar rats were randomly divided into four groups according to the static magnetic field (SMF) intensity, namely, control, low-intensity, moderate-intensity, and high-intensity groups. The rats' whole body was exposed to a superconducting magnet exposure source. The exposure SMF intensity for the low-intensity, moderate-intensity, and high-intensity groups was 50 m T, 100 m T, and 200 m T, respectively, and the exposure time was 1 h/day for consecutive 15 days. After different exposure times, glucose metabolism in rats' brain was evaluated by micro-positron emission tomography (micro-PET), and the expression of hexokinase 1(HK1) and 6-phosphate fructokinase-1(PFK1) was detected by western blot. The exploration and locomotion abilities of the rats were evaluated by conducting open field test (OFT). Furthermore, pathological changes of rats' brain were observed under a microscope by using hematoxylin-eosin staining. PET results showed that moderate-intensity SMFs could cause fluctuant changes in glucose metabolism in rats' brain and the abnormalities were SMF intensity dependent. The expression of the two rate-limiting enzymes HK1 and PFK1 in glucose metabolism in brain significantly decreased after SMF exposure. The OFT showed that the total distance, surrounding distance, activity time, and climbing and standing times significantly decreased after SMF exposure. The main pathological changes in the brain were pyknosis, edema of neurons, and slight widening of the perivascular space, which occurred after 15 times of exposure. This study indicated that SMF exposure could lead to abnormal glucose metabolism in the brain and might result in anxiety-like behaviors., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Bereavement, the experience of losing a loved one, is one of the most catastrophic but inevitable events in life. It causes grief and intense depression-like sadness. Recent studies have revealed the effectiveness and proficiency of mindfulness-based cognitive therapy (MBCT) in emotional regulation among bereavement populations. MBCT improves the well-being of the bereaved by enhancing cognitive performances. Regarding the neural correlates of bereavement grief, previous studies focused on the alleviation of emotion-cognition interferences at specific brain regions. Here, we hypothesized that the bereavement grief fundamentally triggers global alterations in the resting-state brain networks and part of the internetwork connectivity could be reformed after MBCT intervention. We recruited 19 bereaved individuals who participated the 8-week MBCT program. We evaluated (a) the large-scale changes in brain connectivity affected by the MBCT program; as well as (b) the association between connectivity changes and self-rated questionnaire. First, after MBCT, the bereaved individuals showed the reduction of the internetwork connectivity in the salience, default-mode and fronto-parietal networks in the resting state but not under emotional arousal, implying the alleviated attention to spontaneous mind wandering after MBCT. Second, the alterations of functional connectivity between subcortical (e.g., caudate) and cortical networks (e.g., cingulo-opercular/sensorimotor) were associated with the changes of the mindfulness scale, the anxiety and the emotion regulation ability. In summary, MBCT could enhance spontaneous emotion regulation among the bereaved individuals through the internetwork reorganizations in the resting state., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Vasoactive intestinal polypeptide (VIP) is a neuroendocrine peptide distributed throughout the human body, including the CNS, where it is particularly abundant in brain regions associated with anxiety and depression. Based on earlier studies indicating that peripheral VIP may cross through the blood-brain barrier, we hypothesized plasma VIP levels to be associated with symptoms of anxiety and depression, as well as brain volume and resting-state functional connectivity in the amygdala, hippocampus, parahippocampus, and orbitofrontal cortex. Plasma VIP concentrations and anxiety/depression symptoms were measured in 37 healthy females. Functional and structural magnetic resonance imaging were used to evaluate functional connectivity and brain volume respectively, and their associations with VIP concentrations within brain regions associated with anxiety and depression. Negative correlations were found between VIP levels and symptoms of anxiety (r = - 0.44, p = 0.002) and depression (r = - 0.50, p = 0.001). Functional connectivity demonstrated significant VIP-dependent positive associations between the amygdala seed region with both the right parahippocampus (t (33)  = 3.1, p FDR  = 0.02) and right lateral orbitofrontal cortex (OFC; t (33)  = 2.9, p FDR  = 0.02). Moreover, VIP concentrations were significantly, positively correlated with brain volume in the left amygdala (r = 0.28, p = 0.007) and left lateral OFC (r = 0.29, p = 0.004). The present findings highlight a potential role for VIP in the neurobiology of affective symptoms.

To minimize motion-related distortion of reconstructed images, conventional positron emission tomography (PET) measurements of the brain inevitably require a firm and tight head restraint. While such a restraint is now a routine procedure in brain imaging, the physiological and psychological consequences resulting from the restraint have not been elucidated. To address this problem, we developed a restraint-free brain PET system and conducted PET scans under both restrained and non-restrained conditions. We examined whether head restraint during PET scans could alter brain activities such as regional cerebral blood flow (rCBF) and dopamine release along with psychological stress related to head restraint. Under both conditions, 20 healthy male participants underwent [ 15 O]H 2 O and [ 11 C]Raclopride PET scans during working memory tasks with the same PET system. Before, during, and after each PET scan, we measured physiological and psychological stress responses, including the State-Trait Anxiety Inventory (STAI) scores. Analysis of the [ 15 O]H 2 O-PET data revealed higher rCBF in regions such as the parahippocampus in the restrained condition. We found the binding potential (BP ND ) of [ 11 C]Raclopride in the putamen was significantly reduced in the restrained condition, which reflects an increase in dopamine release. Moreover, the restraint-induced change in BP ND was correlated with a shift in the state anxiety score of the STAI, indicating that less anxiety accompanied smaller dopamine release. These results suggest that the stress from head restraint could cause unsolicited responses in brain physiology and emotional states. The restraint-free imaging system may thus be a key enabling technology for the natural depiction of the mind., Competing Interests: Declaration of Competing Interest T.I., M.I., M.F., K.S., S.I., T.S., A.K., H.O., and E.Y. are research employees of Hamamatsu Photonics K.K. The company had no control over the interpretation, writing, or publication of this work., (Copyright © 2020. Published by Elsevier Inc.)

Background: Early pubertal maturation has been posited to be a biopsychosocial risk factor for the onset of internalizing psychopathology in adolescence; further, early-maturing youths exhibit heightened reactivity to stressful events. School closures and enforced social distancing, as well as health and financial uncertainties, during the COVID-19 pandemic are expected to adversely affect mental health in youths, particularly adolescents who are already at risk for experiencing emotional difficulties. The executive control network (ECN) supports cognitive processes required to successfully navigate novel challenges and regulate emotions in stressful contexts., Methods: We examined whether functional coherence of the ECN, measured using resting-state functional magnetic resonance imaging 5 years before the pandemic (T1), is a neurobiological marker of resilience to increases in the severity of internalizing symptoms during COVID-19 in adolescents who were in more advanced stages of puberty at T1 relative to their same-age peers (N = 85, 49 female)., Results: On average, participants reported an increase in symptoms from the 3 months before pandemic to the 2 most recent weeks during the pandemic. We found that early-maturing youths exhibited greater increases in internalizing symptoms during the pandemic if their ECN coherence was low; in contrast, relative pubertal stage was not associated with changes in internalizing symptoms in adolescents with higher ECN coherence at T1., Conclusions: These findings highlight the role of the functional architecture of the brain that supports executive functioning in protecting against risk factors that may exacerbate symptoms of internalizing psychopathology during periods of stress and uncertainty., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Maternal depression during pregnancy is associated with elevated risk of anxiety and depression in offspring, but the mechanisms are incompletely understood. Here we conducted a neuroimaging follow-up of a prenatal birth cohort from the European Longitudinal Study of Pregnancy and Childhood (n = 131; 53% women, age 23-24) to test whether deviations from age-normative structural brain development in young adulthood may partially underlie this link. Structural brain age was calculated based on previously published neuroanatomical age prediction models using cortical thickness maps from healthy controls aged 6-89. Brain age gap was computed as the difference between chronological and structural brain age. Participants also completed self-report measures of anxiety and mood dysregulation. Further, mothers of a subset of participants (n = 103, 54% women) answered a self-report questionnaire in 1990-1992 about depressive symptoms during pregnancy. Higher exposure to maternal depressive symptoms in utero showed a linear relationship with elevated brain age gap, which showed a quadratic relationship with anxiety and mood dysregulation in the young adult offspring. Our findings suggest that exposure to maternal depressive symptoms in utero may be associated with accelerated brain maturation and that deviations from age-normative structural brain development in either direction predict more anxiety and dysregulated mood in young adulthood., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Brain age prediction based on imaging data and machine learning (ML) methods has great potential to provide insights into the development of cognition and mental disorders. Though different ML models have been proposed, a systematic comparison of ML models in combination with imaging features derived from different modalities is still needed. In this study, we evaluate the prediction performance of 36 combinations of imaging features and ML models including deep learning. We utilize single and multimodal brain imaging data including MRI, DTI, and rs-fMRI from a large data set with 839 subjects. Our study is a follow-up to the initial work (Liang et al., 2019. Human Brain Mapping) to investigate different analytic strategies to combine data from MRI, DTI, and rs-fMRI with the goal to improve brain age prediction accuracy. Additionally, the traditional approach to predicting the brain age gap has been shown to have a systematic bias. The potential nonlinear relationship between the brain age gap and chronological age has not been thoroughly tested. Here we propose a new method to correct the systematic bias of brain age gap by taking gender, chronological age, and their interactions into consideration. As the true brain age is unknown and may deviate from chronological age, we further examine whether various levels of behavioral performance across subjects predict their brain age estimated from neuroimaging data. This is an important step to quantify the practical implication of brain age prediction. Our findings are helpful to advance the practice of optimizing different analytic methodologies in brain age prediction., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Suicidal ideation increases in adolescence, especially for anxious youth, and is a frequent precursor to suicide. This study examined whether neural processing of social rejection interacted with negative social experiences to predict suicidal ideation. Thus, to our knowledge this is the first study to examine how brain function may interact with the environment to contribute to suicidal ideation in youth, consistent with a developmental psychopathology perspective. Thirty-six anxious youth (ages 11 to 16) completed diagnostic interviews and questionnaires, an ecological momentary assessment (EMA) protocol, and a functional magnetic resonance imaging paradigm. Results showed that youth experienced greater severity of suicidal ideation when they exhibited heightened activation to social rejection in the right anterior insula and also experienced high levels of peer victimization or EMA-measured daily negative social experiences. Findings provide preliminary evidence that alterations in neural processing of social rejection interacts with exposure to negative social experiences to contribute to suicidal ideation.

Transcendental Meditation (TM) is defined as a mental process of transcending using a silent mantra. Previous work showed that relatively brief period of TM practice leads to decreases in stress and anxiety. However, whether these changes are subserved by specific morpho-functional brain modifications (as observed in other meditation techniques) is still unclear. Using a longitudinal design, we combined psychometric questionnaires, structural and resting-state functional magnetic resonance imaging (RS-fMRI) to investigate the potential brain modifications underlying the psychological effects of TM. The final sample included 19 naïve subjects instructed to complete two daily 20-min TM sessions, and 15 volunteers in the control group. Both groups were evaluated at recruitment (T0) and after 3 months (T1). At T1, only meditators showed a decrease in perceived anxiety and stress (t (18) = 2.53, p = 0.02), which correlated negatively with T1-T0 changes in functional connectivity among posterior cingulate cortex (PCC), precuneus and left superior parietal lobule. Additionally, TM practice was associated with increased connectivity between PCC and right insula, likely reflecting changes in interoceptive awareness. No structural changes were observed in meditators or control subjects. These preliminary findings indicate that beneficial effects of TM may be mediated by functional brain changes that take place after a short practice period of 3 months., Competing Interests: Declaration of Competing Interest M M.F.F. is a member of the David Lynch Foundation and has received a teacher honorarium for the initial training of subjects in the meditation group. M.F.F. was not involved in data collection and analysis. The other authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Internalizing disorders (i.e., depression and anxiety) are common comorbidities in people with epilepsy. In adults with epilepsy, comorbid depression or anxiety is associated with worse seizure control and reduced quality of life, and may be linked to specific neural biomarkers. Less is known about brain correlates of internalizing symptoms in pediatric populations. In the current study, we performed a retrospective analysis of 45 youth between the ages of 6 and 18 years old with intractable epilepsy. Individuals were evaluated for internalizing symptoms on the Child Behavior Checklist (CBCL) and underwent magnetic resonance (MR) and fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging as part of the clinical evaluation for surgical treatment of epilepsy. Forty-two percent of patients experienced clinically significant internalizing symptoms based on parent report. Compared with individuals who scored in the normal range, youth with clinical levels of internalizing problems showed overall reductions in cortex volume, as well as widespread reductions in cortical thickness and functional activation in the bilateral occipital/parietal lobe, left temporal regions, and left inferior frontal cortex on MR and PET scans. There were no group differences in amygdala or hippocampus volumes, nor other patient- or illness-related variables such as age, sex, or the type, lateralization, or duration of epilepsy. Results suggest that high rates of internalizing disorders are present in youth with refractory epilepsy. Multifocal reductions in cortical thickness and function may be nonspecific risk factors for clinically meaningful internalizing symptoms in youth with chronic epilepsy. As such, the presence of broad cortical thinning and reduced glucose uptake upon radiological examination may warrant more focused clinical evaluation of psychological symptoms., Competing Interests: Declaration of competing interest None., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We present a Human Connectome Project study tailored toward adolescent anxiety and depression. This study is one of the first studies of the Connectomes Related to Human Diseases initiative and is collecting structural, functional, and diffusion-weighted brain imaging data from up to 225 adolescents (ages 14-17 years), 150 of whom are expected to have a current diagnosis of an anxiety and/or depressive disorder. Comprehensive clinical and neuropsychological evaluations and longitudinal clinical data are also being collected. This article provides an overview of task functional magnetic resonance imaging (fMRI) protocols and preliminary findings (N = 140), as well as clinical and neuropsychological characterization of adolescents. Data collection is ongoing for an additional 85 adolescents, most of whom are expected to have a diagnosis of an anxiety and/or depressive disorder. Data from the first 140 adolescents are projected for public release through the National Institutes of Health Data Archive (NDA) with the timing of this manuscript. All other data will be made publicly-available through the NDA at regularly scheduled intervals. This article is intended to serve as an introduction to this project as well as a reference for those seeking to clinical, neurocognitive, and task fMRI data from this public resource., (Copyright © 2020. Published by Elsevier Inc.)

Most psychopathological disorders develop in adolescence. The biological basis for this development is poorly understood. To enhance diagnostic characterization and develop improved targeted interventions, it is critical to identify behavioural symptom groups that share neural substrates. We ran analyses to find relationships between behavioural symptoms and neuroimaging measures of brain structure and function in adolescence. We found two symptom groups, consisting of anxiety/depression and executive dysfunction symptoms, respectively, that correlated with distinct sets of brain regions and inter-regional connections, measured by structural and functional neuroimaging modalities. We found that the neural correlates of these symptom groups were present before behavioural symptoms had developed. These neural correlates showed case-control differences in corresponding psychiatric disorders, depression and attention deficit hyperactivity disorder in independent clinical samples. By characterizing behavioural symptom groups based on shared neural mechanisms, our results provide a framework for developing a classification system for psychiatric illness that is based on quantitative neurobehavioural measures.

The aims of this work were to evaluate whether the treatment of patients with fibromyalgia with memantine is associated with significant changes in metabolite concentrations in the brain, and to explore any changes in clinical outcome measures. Magnetic resonance spectroscopy was performed of the right anterior and posterior insula, both hippocampi and the posterior cingulate cortex. Questionnaires on pain, anxiety, depression, global function, quality of life and cognitive impairment were used. Ten patients were studied at baseline and after three months of treatment with memantine. Significant increases were observed in the following areas: N-acetylaspartate (4.47 at baseline vs. 4.71 at three months, p  = 0.02) and N-acetylaspartate+N-acetylaspartate glutamate in the left hippocampus (5.89 vs. 5.98; p  = 0.007); N-acetylaspartate+N-acetylaspartate glutamate in the right hippocampus (5.31 vs 5.79; p  = 0.01) and the anterior insula (7.56 vs. 7.70; p  = 0.033); glutamate+glutamine/creatine ratio in the anterior insula (2.03 vs. 2.17; p  = 0.022) and the posterior insula (1.77 vs. 2.00; p  = 0.004); choline/creatine ratio in the posterior cingulate (0.18 vs. 0.19; p  = 0.023); and creatine in the right hippocampus (3.60 vs. 3.85; p  = 0.007). At the three-month follow-up, memantine improved cognitive function assessed by the Cognition Mini-Exam (31.50, SD  = 2.95 vs. 34.40, SD  = 0.6; p  = 0.005), depression measured by the Hamilton Depression Scale (7.70, SD = 0.81 vs. 7.56, SD  = 0.68; p  = 0.042) and severity of illness measured by the Clinical Global Impression severity scale (5.79, SD  = 0.96 vs. 5.31, SD  = 1.12; p  = 0.007). Depression, clinical global impression and cognitive function showed improvement with memantine. Magnetic resonance spectroscopy could be useful in monitoring response to the pharmacological treatment of fibromyalgia.

Respiratory sensations such as breathlessness are prevalent in many diseases and are amplified by increased levels of anxiety. Cortical activation in response to inspiratory occlusions in high- and low-anxious individuals was found different in previous studies using the respiratory-related evoked potential method. However, specific brain areas showed different activation patterns remained unknown in these studies. Therefore, the purpose of this study was to compare cortical and subcortical neural substrates of respiratory sensation in response to inspiratory mechanical occlusion stimuli between high- and low-anxious individuals using functional magnetic resonance imaging (fMRI). In addition, associations between brain activation patterns and levels of anxiety, and breathlessness were examined. Thirty-four (17 high- and 17 low-anxious) healthy non-smoking adults with normal lung function completed questionnaires on anxiety (State Trait Anxiety Inventory - State), and participated in a transient inspiratory occlusion fMRI experiment. The participants breathed with a customized face-mask while respiration was repeatedly interrupted by a transient inspiratory occlusion of 150-msec, delivered every 2 to 4 breaths. Breathlessness was assessed by self-report. At least 32 occluded breaths were collected for data analysis. The results showed that compared to the low-anxious group, the high-anxious individuals demonstrated significantly greater neural activations in the hippocampus, insula, and middle cingulate gyrus in response to inspiratory occlusions. Moreover, a significant relationship was found between anxiety levels and activations of the right inferior parietal gyrus, and the right precuneus. Additionally, breathlessness levels were significantly associated with activations of the bilateral thalamus, bilateral insula and bilateral cingulate gyrus. The above evidences support stronger recruitment of emotion-related cortical and subcortical brain areas in higher anxious individuals, and thus these areas play an important role in respiratory mechanosensation mediated by anxiety.

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder with childhood onset, and is characterized by intrusive thoughts and fears (obsessions) that lead to repetitive behaviors (compulsions). Previously, we identified insulin signaling being associated with OCD and here, we aim to further investigate this link in vivo. We studied TALLYHO/JngJ (TH) mice, a model of type 2 diabetes mellitus, to (1) assess compulsive and anxious behaviors, (2) determine neuro-metabolite levels by 1 H magnetic resonance spectroscopy (MRS) and brain structural connectivity by diffusion tensor imaging (DTI), and (3) investigate plasma and brain protein levels for molecules previously associated with OCD (insulin, Igf1, Kcnq1, and Bdnf) in these subjects. TH mice showed increased compulsivity-like behavior (reduced spontaneous alternation in the Y-maze) and more anxiety (less time spent in the open arms of the elevated plus maze). In parallel, their brains differed in the white matter microstructure measures fractional anisotropy (FA) and mean diffusivity (MD) in the midline corpus callosum (increased FA and decreased MD), in myelinated fibers of the dorsomedial striatum (decreased FA and MD), and superior cerebellar peduncles (decreased FA and MD). MRS revealed increased glucose levels in the dorsomedial striatum and increased glutathione levels in the anterior cingulate cortex in the TH mice relative to their controls. Igf1 expression was reduced in the cerebellum of TH mice but increased in the plasma. In conclusion, our data indicates a role of (abnormal) insulin signaling in compulsivity-like behavior.

Background and Objective:  Progressive impairment of cognitive function is a common feature seen in patients with normal pressure hydrocephalus (NPH). Along with cognitive decline, many of the other classic symptoms of NPH are chronic and rarely present with overwhelming anxiety. We report the case of a 63-year-old man who presented with recent primary psychiatric manifestation of severe disabling anxiety and otherwise a minimal change in gait and no urinary disturbance., Clinical Presentation:  The patient's work-up consisted of magnetic resonance imaging that showed moderate ventriculomegaly but no findings concerning for acute obstructive hydrocephalus. A single-photon emission computed tomography scan was markedly abnormal with severe hypoperfusion consistent with hydrocephalus. Initially shunting was not advised but was eventually performed after a dramatic response to a large-volume lumbar puncture. After considerable discussion, he underwent elective ventriculoperitoneal shunt placement and had dramatic and sustained improvement in his anxiety., Conclusion:  We believe this case report is a unique description of NPH symptomology and might guide future research or clinical decision making., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

Anxiety reduction through mere expectation of anxiolytic treatment effects (placebo anxiolysis) has enormous clinical importance. Recent behavioral and electrophysiological data suggest that placebo anxiolysis involves reduced vigilance and enhanced internalization of attention; however, the underlying neurobiological mechanisms are not yet clear. Given the fundamental function of intrinsic connectivity networks (ICNs) in basic cognitive processes, we investigated ICN activity patterns associated with externally and internally directed mental states under the influence of an anxiolytic placebo medication. Based on recent findings, we specifically analyzed the functional role of the rostral anterior cingulate cortex (rACC) in coordinating placebo-dependent cue-related (phasic) and cue-unrelated (sustained) network activity. Under placebo, we observed a down-regulation of the entire salience network (SN), particularly in response to threatening cues. The rACC exhibited enhanced cue-unrelated functional connectivity (FC) with the SN, which correlated with reductions in tonic arousal and anxiety. Hence, apart from the frequently reported modulation of aversive cue responses, the rACC appears to be crucially involved in exerting a tonically dampening control over salience-responsive structures. In line with a more internally directed mental state, we also found enhanced FC within the default mode network (DMN), again predicting reductions in anxiety under placebo., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Trait anxiety, the disposition to experience anxiety, is known to facilitate perception of threats. Trait anxious individuals seem to identify threatening stimuli such as fearful facial expressions more accurately, especially when presented under temporal constraints. In past studies on anxiety and emotion face recognition, only self-report or explicit measures of anxiety have been administered. Implicit measures represent indirect tests allowing to circumvent problems associated with self-report. In our study, we made use of implicit in addition to explicit measures to investigate the relationships of trait anxiety with recognition of and brain response to emotional faces. 75 healthy young volunteers had to identify briefly presented (67 ms) fearful, angry, happy, and neutral facial expressions masked by neutral faces while undergoing functional magnetic resonance imaging. The Implicit Association Test, the State-Trait Anxiety Inventory and the Beck Anxiety Inventory were applied as implicit and explicit measures of trait anxiety. After corrections for multiple testing, neither implicitly nor explicitly measured anxiety correlated with recognition of emotional facial expressions. Moreover, implicitly and explicitly assessed anxiety was not linked to brain response to emotional faces. Our data suggest links between discrimination accuracy and brain response to facial emotions. Activation of the caudate nucleus seems be of particular importance for recognizing fear and happiness from facial expressions. Processes of somatosensory resonance appear to be involved in identifying fear from facial expressions. The present data indicate that, regardless of assessment method, trait anxiety does not affect the recognition of fear or other emotions as has been proposed previously., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Only a minority of individuals experiencing trauma subsequently develop post-traumatic stress disorder (PTSD). However, whether differences in vulnerability to PTSD result from a predisposition or trauma exposure remains unclear. A major challenge in differentiating these possibilities is that clinical studies focus on individuals already exposed to trauma without pre-trauma conditions. Here, using the predator scent model of PTSD in rats and a longitudinal design, we measure pre-trauma brain-wide neural circuit functional connectivity, behavioral and corticosterone responses to trauma exposure, and post-trauma anxiety. Freezing during predator scent exposure correlates with functional connectivity in a set of neural circuits, indicating pre-existing circuit function can predispose animals to differential fearful responses to threats. Counterintuitively, rats with lower freezing show more avoidance of the predator scent, a prolonged corticosterone response, and higher anxiety long after exposure. This study provides a framework of pre-existing circuit function that determines threat responses, which might directly relate to PTSD-like behaviors.

Introduction: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a prodromal stage of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Depressive and anxiety symptoms are frequent features of PD, DLB and iRBD, and some studies suggest that depressive symptoms are a marker for neurodegeneration in iRBD. However, the pathophysiology of depressive and anxiety symptoms in iRBD is still unclear. This study aimed to investigate cortical and subcortical gray matter (GM) volume substrates of depressive and anxiety symptoms in iRBD patients., Methods: Forty-six polysomnography-confirmed iRBD patients and 31 healthy controls (HC) without cognitive or mood impairment were recruited. All participants underwent 3-T magnetic resonance imaging and completed the Beck Depression Inventory Second Edition (BDI-II) and Beck Anxiety Inventory (BAI) questionnaires. Voxel-based morphometry analysis was performed to assess GM volume in cortical and subcortical structures. Between-group comparisons and regressions were performed., Results: iRBD patients with depressive symptoms (BDI-II score > 13 or the use of antidepressants to treat depression) showed reduced GM volume in the caudate nucleus compared to HC and iRBD patients without depressive symptoms. Moreover, iRBD patients with anxiety symptoms (BAI score > 9 or the use of anxiolytics to treat anxiety) showed reduced GM volume in the left amygdala extending to the hippocampus compared to HC and iRBD patients without anxiety symptoms. In iRBD patients, higher BDI-II and BAI total scores were associated with lower GM volumes in these regions respectively., Conclusion: Depressive and anxiety symptoms in iRBD patients are related to patterns of cortical and subcortical GM volume loss., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Interoception involves the processing of a variety of different types of information ascending from the body. Accumulating evidence has indicated that interoception plays a fundamental role in cognitive and emotional processes, such as anxiety, but how different functional connectivity patterns contribute to emotions and visceral feelings during an interoceptive attention state is still unclear. In the present study, an interoceptive attention task was performed during functional magnetic resonance imaging of healthy subjects, and the participants' subjective ratings of the intensity of interoception and feelings of anxiety were recorded. Several network nodes were selected, based on previous studies, to construct task-dependent functional connectivity patterns, which were processed by support vector regression to predict the corresponding feeling scores. The results showed that for interoception, the cingulo-opercular task control network provided the greatest contribution, whereas the most important feature for anxiety was the connections between the sensorimotor area (SSM) and the salience network (SN). There existed four overlapping connections between the two predictions: two negative connections between the default mode network (DMN) and the SSM, one negative connection between the DMN and the SN, and one positive connection between the ventral attention network and the SN; this overlap might suggest common bodily attention processing that is involved in both interoception and anxiety. This study remediates the lack of network-level biomarkers of interoception and provides a reference at the level of the brain for further understanding anxiety from an interoceptive perspective., (© 2018 Wiley Periodicals, Inc.)

Objective: To investigate the whole-brain resting-state functional connectivity in patients with chronic migraine (CM) using a data-driven method., Methods: We prospectively recruited patients with either episodic migraine (EM) or CM aged 18-60 years who visited the headache clinic of the Samsung Medical Center from July 2016 to December 2017. All patients underwent 3 T MRI using an identical scanner. Patients were considered interictal if they did not have a migraine headache at the day and ± 1 days of functional MRI acquisition. Using the group-independent component analysis (ICA), connectivity analysis with a weighted and undirected network model was performed. The between-group differences in degree centrality (DC) values were assessed using 5000 permutation tests corrected with false discovery rate (FDR)., Results: A total of 62 patients (44 EM and 18 CM) were enrolled in this study. Among the seven functionally interpretable spatially independent components (ICs) identified, only one IC, interpreted as the pain matrix, showed a significant between-group difference in DC (CM > EM, p = 0.046). This association remained significant after adjustment for age, sex, migraine with aura (MWA), allodynia, depression, and anxiety (p = 0.038). The pain matrix was functionally correlated with the hypothalamus (p = 0.040, EM > CM) and dorsal raphe nucleus (p = 0.039, CM > EM) with different levels of strength in EM and CM., Conclusion: CM patients have a stronger connectivity in the pain matrix than do EM patients. Functional alteration of the pain network might play a role in migraine chronification.

Understanding the critical features of the human brain at multiple time scales is vital for both normal development and disease research. A recently proposed method, the vertex-wise Index of Functional Criticality (vIFC) based on fMRI, has been testified as a sensitive neuroimaging marker to characterize critical transitions of human brain dynamics during Alzheimer's disease progression. However, it remains unclear whether vIFC in healthy brains is associated with neuropsychological and neurophysiological measurements. Using the Nathan Kline Institute/Rockland lifespan cross-sectional datasets and openfMRI single participant longitudinal datasets, we found consistent spatial patterns of vIFC across the entire cortical mantle: the inferior parietal and the precuneus exhibited high vIFC. On a time scale of years, we observed that vIFC increased with age in the left ventral posterior cingulate gyrus. On a time scale of days and weeks, vIFC demonstrated the capacity to identify a link between anxiety and pulse. These results showed that vIFC can serve as a useful neuroimaging marker for detecting physiological, behavioral, and neurodevelopmental transitions. Based on the criticality theory in nonlinear dynamics, the current vIFC study sheds new light on human brain studies from a nonlinear perspective and opens potential new avenues for normal and abnormal human brain studies., Competing Interests: The authors have declared that no competing interests exist.

Objective: Patients with temporal lobe epilepsy (TLE) are similar in their epileptology regardless of whether they have a lesion evident on MRI; this study aims to prospectively clarify whether they are also similar in their neuropsychological profiles., Methods: Participants comprised 152 adults: 79 patients with TLE and 73 healthy controls. Patients and controls did not differ in age, sex, or education ( p > 0.05). Sixty-two percent of patients had an MRI-resolvable lesion (39% with presumed hippocampal sclerosis [HS-TLE], 61% with a lesion other than HS [MRI-positive TLE]); the remaining 38% of patients were lesion-negative. Psychometric measures well established in epilepsy were used., Results: Relative to controls, all 3 patient subgroups showed significantly impaired autobiographical, verbal, and visual memory ( p < 0.05-0.001) and significantly more depression and anxiety ( p < 0.05-0.01). Yet, contrary to expectations, the 3 TLE subgroups did not differ in their severity of memory or mood impairment ( p > 0.05). Lower Full-Scale IQ predicted memory impairments across all TLE subtypes, with early age at seizure onset a predictor unique to MRI-negative TLE., Conclusions: MRI-negative TLE is associated with memory and mood dysfunction equivalent to that seen in patients with hippocampal sclerosis and other MRI-resolvable pathologies. As such, neuropsychological impairments in TLE are not contingent on a macroscopic lesion and might be an intrinsic property of the underlying network disease., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Fear of pain demonstrates significant prognostic value regarding the development of persistent musculoskeletal pain and disability. Its assessment often relies on self-report measures of pain-related fear by a variety of questionnaires. However, based either on "fear of movement/(re)injury/kinesiophobia," "fear avoidance beliefs," or "pain anxiety," pain-related fear constructs plausibly differ while it is unclear how specific the questionnaires are in assessing these different constructs. Furthermore, the relationship of pain-related fear to other anxiety measures such as state or trait anxiety remains ambiguous. Advances in neuroimaging such as machine learning on brain activity patterns recorded by functional magnetic resonance imaging might help to dissect commonalities or differences across pain-related fear constructs. We applied a pattern regression approach in 20 human patients with nonspecific chronic low back pain to reveal predictive relationships between fear-related neural pattern information and different pain-related fear questionnaires. More specifically, the applied multiple kernel learning approach allowed the generation of models to predict the questionnaire scores based on a hierarchical ranking of fear-related neural patterns induced by viewing videos of activities potentially harmful for the back. We sought to find evidence for or against overlapping pain-related fear constructs by comparing the questionnaire prediction models according to their predictive abilities and associated neural contributors. By demonstrating evidence of nonoverlapping neural predictors within fear-processing regions, the results underpin the diversity of pain-related fear constructs. This neuroscientific approach might ultimately help to further understand and dissect psychological pain-related fear constructs.

Background: It is becoming increasingly clear that pathophysiological processes underlying psychiatric disorders categories are heterogeneous on many levels, including symptoms, disease course, comorbidity and biological underpinnings. This heterogeneity poses challenges for identifying biological markers associated with dimensions of symptoms and behaviour that could provide targets to guide treatment choice and novel treatment. In response, the research domain criteria (RDoC) (Insel et al., 2010) was developed to advocate a dimensional approach which omits any disease definitions, disorder thresholds, or cut-points for various levels of psychopathology to understanding the pathophysiological processes underlying psychiatry disorders. In the present study we aimed to apply pattern regression analysis to identify brain signatures during dynamic emotional face processing that are predictive of anxiety and depression symptoms in a continuum that ranges from normal to pathological levels, cutting across categorically-defined diagnoses., Methods: The sample was composed of one-hundred and fifty-four young adults (mean age=21.6 and s.d.=2.0, 103 females) consisting of eighty-two young adults seeking treatment for psychological distress that cut across categorically-defined diagnoses and 72 matched healthy young adults. Participants performed a dynamic face task involving fearful, angry and happy faces (and geometric shapes) while undergoing functional Magnetic Resonance Imaging (fMRI). Pattern regression analyses consisted of Gaussian Process Regression (GPR) implemented in the Pattern Recognition for Neuroimaging toolbox (PRoNTo). Predicted and actual clinical scores were compared using Pearson's correlation coefficient (r) and normalized mean squared error (MSE) to evaluate the models' performance. Permutation test was applied to estimate significance levels., Results: GPR identified patterns of neural activity to dynamic emotional face processing predictive of self-report anxiety in the whole sample, which covered a continuum that ranged from healthy to different levels of distress, including subthreshold to fully-syndromal psychiatric diagnoses. Results were significant using two different cross validation strategies (two-fold: r=0.28 (p-value=0.001), MSE=4.47 (p-value=0.001) and five fold r=0.28 (p-value=0.002), MSE=4.62 (p-value=0.003). The contributions of individual regions to the predictive model were very small, demonstrating that predictions were based on the overall pattern rather than on a small combination of regions., Conclusions: These findings represent early evidence that neuroimaging techniques may inform clinical assessment of young adults irrespective of diagnoses by allowing accurate and objective quantitative estimation of psychopathology., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Anxiety and anxiety disorders are associated with specific alterations to functional brain networks, including intra-networks and inter-networks. Given the heterogeneity within anxiety disorders and inconsistencies in functional network differences across studies, identifying common patterns of altered brain networks in anxiety is imperative. Here, we conducted an activation likelihood estimation meta-analysis of resting-state functional connectivity studies in anxiety and anxiety disorders (including 835 individuals with different levels of anxiety or anxiety disorders and 508 controls). Results show that anxiety can be characterized by hypo-connectivity of the affective network with executive control network (ECN) and default mode network (DMN), as well as decoupling of the ECN with the DMN. The connectivity within the salience network and its connectivity with sensorimotor network are also attenuated. These results reveal consistent dysregulations of affective and cognitive control related networks over networks related to emotion processing in anxiety and anxiety disorders. The current findings provide an empirical foundation for an integrated model of brain network alterations that are common across anxiety and anxiety disorders., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Childhood adversity is associated with a wide range of negative behavioral and neurodevelopmental consequences. However, individuals vary substantially in their sensitivity to such adversity. Here, we examined how individual variability in structural features of the corticolimbic circuit, which plays a key role in emotional reactivity, moderates the association between childhood adversity and later trait anxiety in 798 young adult university students. Consistent with prior research, higher self-reported childhood adversity was significantly associated with higher self-reported trait anxiety. However, this association was attenuated in participants with higher microstructural integrity of the uncinate fasciculus and greater thickness of the orbitofrontal cortex. These structural properties of the corticolimbic circuit may capture a neural profile of relative resiliency to early life stress, especially against the negative effects of childhood adversity on later trait anxiety., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cognitive and emotional functions are supported by the coordinated activity of a distributed network of brain regions. This coordinated activity may be disrupted by psychosocial stress, resulting in the dysfunction of cognitive and emotional processes. Graph theory is a mathematical approach to assess coordinated brain activity that can estimate the efficiency of information flow and determine the centrality of brain regions within a larger distributed neural network. However, limited research has applied graph-theory techniques to the study of stress. Advancing our understanding of the impact stress has on global brain networks may provide new insight into factors that influence individual differences in stress susceptibility. Therefore, the present study examined the brain connectivity of participants that completed the Montreal Imaging Stress Task (Goodman et al., 2016; Wheelock et al., 2016). Salivary cortisol, heart rate, skin conductance response, and self-reported stress served as indices of stress, and trait anxiety served as an index of participant's disposition toward negative affectivity. Psychosocial stress was associated with a decrease in the efficiency of the flow of information within the brain. Further, the centrality of brain regions that mediate emotion regulation processes (i.e., hippocampus, ventral prefrontal cortex, and cingulate cortex) decreased during stress exposure. Interestingly, individual differences in cortisol reactivity were negatively correlated with the efficiency of information flow within this network, whereas cortisol reactivity was positively correlated with the centrality of the amygdala within the network. These findings suggest that stress reduces the efficiency of information transfer and leaves the function of brain regions that regulate the stress response vulnerable to disruption. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Understanding the neural mechanisms underlying psychological therapy could aid understanding of recovery processes and help target treatments. The dual-process model hypothesises that psychological therapy is associated with increased emotional-regulation in prefrontal brain regions and decreased implicit emotional-reactivity in limbic regions; however, research has yielded inconsistent findings. Meta-analyses of brain activity changes accompanying psychological therapy (22 studies, n = 352) and neural predictors of symptomatic improvement (11 studies, n = 293) in depression and anxiety were conducted using seed-based d mapping. Both resting-state and task-based studies were included, and analysed together and separately. The most robust findings were significant decreases in anterior cingulate/paracingulate gyrus, inferior frontal gyrus and insula activation after therapy. Cuneus activation was predictive of subsequent symptom change. The results are in agreement with neural models of improved emotional-reactivity following therapy as evidenced by decreased activity within the anterior cingulate and insula. We propose compensatory as well as corrective neural mechanisms of action underlie therapeutic efficacy, and suggest the dual-process model may be too simplistic to account fully for treatment mechanisms. More research on predictors of psychotherapeutic response is required to provide reliable predictors of response., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)