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Background: White matter hyperintensities (WMHs) are associated with higher anxiety or depression (A/D) incidence. We investigated associations of WMHs with A/D, cerebrovascular reactivity (CVR), and functional connectivity (FC) to identify potential pathomechanisms., Methods: Participants with WMH (n = 239) and normal controls (NCs, n = 327) were assessed for A/D using the Hamilton Anxiety Rating Scale (HAMA) and Hamilton Depression Rating Scale (HAMD). The CVR and FC maps were constructed from resting-state functional MRI. Two-way analysis of covariance with fixed factors A/D and WMH was performed to identify regional CVR abnormalities. Seed-based FC analyses were then conducted on regions with WMH × A/D interaction effects on CVR. Logistic regression models were constructed to examine the utility of these measurements for identifying WMH-related A/D., Results: Participants with WMH related A/D exhibited significantly greater CVR in left insula and lower CVR in right superior frontal gyrus (SFG.R), and HAMA scores were negatively correlated with CVR in SFG.R (r = -0.156, P = 0.016). Insula-SFG.R negative FC was significantly weaker in WMH patients with suspected or definite A/D. A model including CVR plus FC changes identified WMH-associated A/D with highest sensitivity and specificity. In contrast, NCs with A/D exhibited greater CVR in prefrontal cortex and stronger FC within the default mode network (DMN) and between the DMN and executive control network., Limitations: This cross-sectional study requires validation by longitudinal and laboratory studies., Conclusions: Impaired CVR in SFG.R and weaker negative FC between prefrontal cortex and insula may contribute to WMH-related A/D, providing potential diagnostic imaging markers and therapeutic targets., Competing Interests: Declaration of competing interest The authors report no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Dimensional models of psychopathology may provide insight into mechanisms underlying comorbid depression and anxiety and improve specificity and sensitivity of neuroanatomical findings. The present study is the first to examine neural structure alterations using the empirically derived Tri-level Model. Depression and anxiety symptoms of 269 young adults were assessed using the Tri-level Model dimensions: General Distress (transdiagnostic depression and anxiety symptoms), Anhedonia-Apprehension (relatively specific depression symptoms), and Fears (specific anxiety symptoms). Using structural MRI, gray matter volumes were extracted for emotion generation (amygdala, nucleus accumbens) and regulation (orbitofrontal, ventrolateral, and dorsolateral prefrontal cortex) regions, often implicated in depression and anxiety. Each Tri-level symptom was regressed onto each region of interest, separately, adjusting for relevant covariates. General Distress was significantly associated with smaller gray matter volumes in bilateral orbitofrontal cortex and ventrolateral prefrontal cortex, independent of Anhedonia-Apprehension and Fears symptom dimensions. These results suggests that prefrontal alterations are associated with transdiagnostic dysphoric mood common across depression and anxiety, rather than unique symptoms of these disorders. Additionally, no regions of interest were associated with Anhedonia-Apprehension or Fears, highlighting the importance of studying transdiagnostic features of depression and anxiety. This has implications for understanding mechanisms of and interventions for depression and anxiety., 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 © 2024 Elsevier B.V. All rights reserved.)

Machine learning is an emerging tool in clinical psychology and neuroscience for the individualized prediction of psychiatric symptoms. However, its application in non-clinical populations is still in its infancy. Given the widespread morphological changes observed in psychiatric disorders, our study applies five supervised machine learning regression algorithms-ridge regression, support vector regression, partial least squares regression, least absolute shrinkage and selection operator regression, and Elastic-Net regression-to predict anxiety and depressive symptom scores. We base these predictions on the whole-brain gray matter volume in a large non-clinical sample (n = 425). Our results demonstrate that machine learning algorithms can effectively predict individual variability in anxiety and depressive symptoms, as measured by the Mood and Anxiety Symptoms Questionnaire. The most discriminative features contributing to the prediction models were primarily located in the prefrontal-parietal, temporal, visual, and sub-cortical regions (e.g. amygdala, hippocampus, and putamen). These regions showed distinct patterns for anxious arousal and high positive affect in three of the five models (partial least squares regression, support vector regression, and ridge regression). Importantly, these predictions were consistent across genders and robust to demographic variability (e.g. age, parental education, etc.). Our findings offer critical insights into the distinct brain morphological patterns underlying specific components of anxiety and depressive symptoms, supporting the existing tripartite theory from a neuroimaging perspective., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Depression and anxiety are associated with grey matter changes in subcortical regions in adults and adolescents. Parent psychopathology is associated with offspring brain structure, but it's unclear whether altered brain structure in children is associated with severity of parental depression and anxiety symptoms. We examined 123 youth (Mean age = 13.64; 62% female) with no clinically significant history of depression or anxiety and one parent diagnosed with current or past depressive or anxiety disorders. Parents completed the Mini International Neuropsychiatric Interview to assess diagnostic status and the Beck Depression Inventory-II, and the Generalized Anxiety Disorder-7 to assess current symptom severity. Youth underwent T1 weighted structural Magnetic Resonance Imaging scans. Bivariate analyses revealed higher parental depressive severity was not significantly associated with offspring grey matter. Parental anxiety severity was significantly associated with less left global surface area. When controlling for offspring age, sex and intracranial volume (ICV), offspring right surface area was negatively associated with parental depressive severity at a trend level. In previously depressed parents, greater parental depressive severity was significantly associated with offspring decreased left and right surface area. There were no significant associations between parental anxiety severity in previously depressed parents and offspring subcortical or cortical brain regions. These results highlight associations between parental depressive symptom severity and offspring brain structure and suggest that even within an already high-risk group of adolescents, there may be altered cortical surface area depending on parent symptom severity. This may help identify youth most at risk for developing a mood disorder and could help further early intervention and identification efforts., Competing Interests: Declaration of competing interest All authors have no financial disclosures or conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The hypothalamus plays a crucial role in regulating sleep-wake cycle and motivated behavior. Sleep disturbance is associated with impairment in cognitive and affective functions. However, how hypothalamic dysfunction may contribute to inter-related sleep, cognitive, and emotional deficits remain unclear., Methods: We curated the Human Connectome Project dataset and investigated how hypothalamic resting state functional connectivities (rsFC) were associated with sleep dysfunction, as evaluated by the Pittsburgh Sleep Quality Index (PSQI), cognitive performance, and subjective mood states in 687 young adults (342 women). Imaging data were processed with published routines and evaluated with a corrected threshold. We examined the inter-relationship amongst hypothalamic rsFC, PSQI score, and clinical measures with mediation analyses., Results: In whole-brain regressions with age and drinking severity as covariates, men showed higher hypothalamic rsFC with the right insula in correlation with PSQI score. No clusters were identified in women at the same threshold. Both hypothalamic-insula rsFC and PSQI score were significantly correlated with anxiety and depression scores in men. Further, mediation analyses showed that PSQI score mediated the relationship between hypothalamic-insula rsFC and anxiety/depression symptom severity bidirectionally in men., Conclusions: Sleep dysfunction is associated with negative emotions and hypothalamic rsFC with the right insula, a core structure of the interoceptive circuits. Notably, anxiety-depression symptom severity and altered hypothalamic-insula rsFC are related bidirectionally by poor sleep quality. These findings are specific to men, suggesting potential sex differences in the neural circuits regulating sleep and emotional states that need to be further investigated., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Persistent and negative stress stimulation is one of the most important factors leading to anxiety and depression in individuals, and it can negatively affect the normal function and structure of brain-related regions. However, the maladaptive changes of brain neural networks in anxiety and depression induced by chronic stress have not been explored in detail. In this study, we analyzed the changes in global information transfer efficiency, stress related blood oxygen level dependent (BOLD)- and diffusion tensor imaging (DTI)- signals and functional connectivity (FC) in rat models based on resting-state functional magnetic resonance imaging (rs-fMRI). The results showed that compared to control group, rats treated with chronic restraint stress (CRS) for 5 weeks had reconstructed the small-world network properties. In addition, CRS group had increased coherence and activity in bilateral Striatum (ST_R & L), but decreased coherence and activity in unilateral (left) Frontal Association Cortex (FrA_L) and unilateral (left) Medial Entorhinal Cortex (MEC_L). DTI analysis and correlation analysis confirmed the disrupted integrity of MEC_L and ST_R & L and their correlation to anxiety- and depressive-liked behaviors. Functional connectivity further showed these regions of interest (ROI) had decreased positive correlations with several brain areas, respectively. Our study comprehensively revealed the adaptive changes of brain neural networks induced by chronic stress and emphasized the abnormal activity and functional connectivity of ST_R & L and MEC_L in the pathological condition., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflict of interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Major depression (MDD) and generalized anxiety disorder (GAD) have become one of the leading global causes of disability and both are characterized by marked interpersonal and social impairments. However, despite high comorbidity and overlapping social-emotional deficits, it remains unclear whether MDD and GAD share a common neural basis during interpersonal processing. In the present study, we combined an emotional face processing paradigm with fMRI and dimensional and categorical analyses in a sample of unmedicated MDD and GAD patients (N = 72) as well as healthy controls (N = 35). No group differences were found in categorical analyses. However, the dimensional analyses revealed that dorsolateral prefrontal cortex (dlPFC) reactivity to sad facial expressions was positively associated with depression symptom load, yet negatively associated with anxiety symptom load in the entire sample. On the network level depression symptom load was positively associated with functional connectivity between the bilateral amygdala and a widespread network including the anterior cingulate and insular cortex. Together, these findings suggest that the dlPFC - engaged in cognitive and emotional processing - exhibits symptom- and emotion-specific alteration during interpersonal processing. Dysregulated communication between the amygdala and core regions of the salience network may represent depression-specific neural dysregulations., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

Disrupted brain structures and several life environmental factors have been shown to influence depression and anxiety, but their interactions with anxiety and depression remain elusive. Genome-wide association study datasets of 15 brain structure longitudinal changes (N = 15,640) were obtained from the published study. Genotype and phenotype-related data of depression, anxiety, and life environmental factors (including smoking, alcohol drinking, coffee intake, maternal smoking, physical activity, vitamin D, insomnia, sleep duration, and family satisfaction) were collected from UK Biobank. We calculated the polygenic risk scores (PRS) of 15 brain structure changes and then conducted linear regression analyses to explore the interactions of brain structure changes and life environmental factors on depression and anxiety using 15 brain structure change-related PRS, life environmental factors and interactions of them as instrumental variables, and depression score or anxiety score as outcomes. Sex stratification in all analyses was performed to reveal sex-specific differences in the interactions. We found 14 shared interactions related to both depression and anxiety in total sample, such as alcohol drinking × cerebellum white matter 3 (WM; beta = -.003, p = .018 for depression; beta = -003, p = .008 for anxiety) and maternal smoking × nucleus accumbens 2 (beta = .088, p = .002 for depression; beta = .070, p = .008 for anxiety). We also observed sex-specific differences in the interactions, for instance, alcohol drinking × cerebellum WM 3 was negatively associated with depression and anxiety in males (beta = -.004, p = .020 for depression; beta = -.005, p = .002 for anxiety). Our study results reveal the important interactions between brain structure changes and several life environmental factors on depression and anxiety, which may help to explore the pathogenesis of depression and anxiety., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

A variety of childhood experiences can lead to anxious/depressed (A/D) symptoms. The aim of the present study was to explore the brain morphological (cortical thickness and surface area) correlates of A/D symptoms and the extent to which these phenotypes vary depending on the quality of the parenting context in which children develop. Structural magnetic resonance imaging (MRI) scans were acquired on 45 children with Child Protective Services (CPS) involvement due to risk of not receiving adequate care (high-risk group) and 25 children without CPS involvement (low-risk group) (range age = 8.08-12.14; M age = 10.05) to assess cortical thickness (CT) and cortical surface area (SA). A/D symptoms were measured using the Child Behavioral Checklist. The association between A/D symptoms and CT, but not SA, differed by risk status such that high-risk children showed decreasing CT as A/D scores increased, whereas low-risk children showed increasing CT as A/D scores increased. This interaction was specific to CT in prefrontal, frontal, temporal, and parietal cortical regions. The groups had marginally different A/D scores, in the direction of higher risk being associated with lower A/D scores. Results suggest that CT correlates of A/D symptoms are differentially shaped by the quality of early caregiving experiences and should be distinguished between high- and low-risk children.

Objective: Neuroimaging studies of obsessive-compulsive disorder (OCD) patients have highlighted the important role of deep gray matter structures. Less work has however focused on subcortical shape in OCD patients., Methods: Here we pooled brain MRI scans from 412 OCD patients and 368 controls to perform a meta-analysis utilizing the ENIGMA-Shape protocol. In addition, we investigated modulating effects of medication status, comorbid anxiety or depression, and disease duration on subcortical shape., Results: There was no significant difference in shape thickness or surface area between OCD patients and healthy controls. For the subgroup analyses, OCD patients with comorbid depression or anxiety had lower thickness of the hippocampus and caudate nucleus and higher thickness of the putamen and pallidum compared to controls. OCD patients with comorbid depression had lower shape surface area in the thalamus, caudate nucleus, putamen, hippocampus, and nucleus accumbens and higher shape surface area in the pallidum. OCD patients with comorbid anxiety had lower shape surface area in the putamen and the left caudate nucleus and higher shape surface area in the pallidum and the right caudate nucleus. Further, OCD patients on medication had lower shape thickness of the putamen, thalamus, and hippocampus and higher thickness of the pallidum and caudate nucleus, as well as lower shape surface area in the hippocampus and amygdala and higher surface area in the putamen, pallidum, and caudate nucleus compared to controls. There were no significant differences between OCD patients without co-morbid anxiety and/or depression and healthy controls on shape measures. In addition, there were also no significant differences between OCD patients not using medication and healthy controls., Conclusions: The findings here are partly consistent with prior work on brain volumes in OCD, insofar as they emphasize that alterations in subcortical brain morphology are associated with comorbidity and medication status. Further work is needed to understand the biological processes contributing to subcortical shape., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

High rates of comorbidity between depression and anxiety are frequently observed. However, few studies have investigated the relationship between depression and social interaction anxiety using a dimensional approach. The current study aimed to explore the associations between depression and social interaction anxiety with a multivariate approach in a comparably large dataset (n = 194, 95 males). All participants completed a structural and a resting-state functional magnetic resonance imaging (fMRI) scan and self-report measures of depression via Beck's Depression Inventory II and social interaction anxiety by social interaction anxiety scale. Voxel-based morphometry (VBM) results first identified grey matter volumes of insula were positively correlated with depression dimension scores. Next, whole brain seed-to-voxel analyses were conducted using a VBM-identified insula as a seed region to examine associations between depression/social anxiety and functional connectivity. The results suggested that a significant positive effect of depression/social anxiety was found on the connectivity between insula and dorsal lateral prefrontal cortex (dlPFC). Moreover, variations in depression meditated the association between insula-dlPFC connectivity and social interaction anxiety. Overall, the results indicate that individual differences in depression relate more to insula-dlPFC coupling compared to social interaction anxiety., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: We have previously reported activation in reward, salience and executive control regions during functional MRI (fMRI) using an approach-avoidance conflict (AAC) decision-making task with healthy adults. Further investigations into how anxiety and depressive disorders relate to differences in neural responses during AAC can inform their understanding and treatment. We tested the hypothesis that people with anxiety or depression have altered neural activation during AAC., Methods: We compared 118 treatment-seeking adults with anxiety or depression and 58 healthy adults using linear mixed-effects models to examine group-level differences in neural activation (fMRI) during AAC decision-making. Correlational analyses examined relationships between behavioural and neural measures., Results: Adults with anxiety or depression had greater striatal engagement when reacting to affective stimuli ( p = 0.008, d = 0.31) regardless of valence, and weaker striatal engagement during reward feedback ( p = 0.046, d = -0.27) regardless of the presence of monetary reward. They also had blunted amygdala activity during decision-making ( p = 0.023, d = -0.32) regardless of the presence of conflict. Across groups, approach behaviour during conflict decision-making was inversely correlated with striatal activation during affective stimuli ( p < 0.001, r = -0.28) and positively related to striatal activation during reward feedback ( p < 0.001, r = 0.27)., Limitations: Our transdiagnostic approach did not allow for comparisons between specific anxiety disorders, and our cross-sectional approach did not allow for causal inference., Conclusion: Anxiety and depression were associated with altered neural responses to AAC. Findings were consistent with the role of the striatum in action selection and reward responsivity, and they point toward striatal reactivity as a future treatment target. Blunting of amygdala activity in anxiety or depression may indicate a compensatory response to inhibit affective salience and maintain approach., Competing Interests: Competing interests: M. Paulus is an advisor to Spring Care, Inc., a behavioural health startup; has received royalties for an article about methamphetamine in UpToDate; and serves on the board of directors of the Anxiety and Depression Association of America. R. Aupperle has received payment for invited lectures at Harvard Medical School and the University of Michigan, and has participated in a data safety monitoring board at New York University Langone Health. No other competing interests declared., (© 2022 CMA Impact Inc. or its licensors.)

Objective: Long coronavirus disease (Long-COVID) syndrome is a hitherto poorly understood phenomenon with a broad spectrum of symptoms, including depression and anxiety. Depressive symptoms have been associated with brainstem raphe (BR) alterations in transcranial sonography (TCS) that might reflect dysfunction of the serotonergic system. The primary aim was to investigate the connection of BR alterations with depressive and anxiety symptoms in patients with Long-COVID syndrome., Methods: In a cross-sectional study design, we included outpatients fulfilling the criteria of Long-COVID syndrome. All patients were examined by TCS in the axial plane with focus on BR signal alterations. The Hospital Anxiety and Depression Scale (HADS) was used to test for symptoms of anxiety and depression., Results: We included n = 70 patients with Long-COVID syndrome, of which 28.6% (n = 20) exhibited a reduced echogenicity of BR in the TCS examination. Patients with hypoechogenic BR had higher subscores for anxiety and depression compared to normoechogenic patients (HADS depression: median 8 versus 5.5, p = 0.006; HADS anxiety: median 9 versus 6.5, p = 0.006). After adjustment for reasonable confounders, only the odds ratio (OR) for relevant depressive symptoms was higher among Long-COVID patients with hypoechogenic raphe (adjusted OR 3.884, 95% CI 1.244-12.123)., Discussion: Hypoechogenic BR alterations are independently associated with depressive symptoms in Long-COVID patients but are not highly frequent. Future studies should investigate whether the hypoechogenicity of the BR is a direct consequence or whether it reflects a priori a higher susceptibility to depressive symptoms after COVID-19, thus enabling to identify COVID-19 patients at higher risk of developing Long-COVID depressive symptoms., (© 2022. The Author(s).)

The different depressive disorders that exist can take root at adolescence. For instance, some functional and structural changes in several brain regions have been observed from adolescence in subjects that display either high vulnerability to depressive symptoms or subthreshold depression. For instance, adolescents with depressive disorder have been shown to exhibit hyperactivity in hippocampus, amygdala and prefrontal cortex as well as volume reductions in hippocampus and amygdala (prefrontal cortex showing more variable results). However, no animal model of adolescent subthreshold depression has been developed so far. Our objective was to design an animal model of adolescent subthreshold depression and to characterize the neural changes associated to this phenotype. For this purpose, we used adolescent Swiss mice that were evaluated on 4 tests assessing cognitive abilities (Morris water maze), anhedonia (sucrose preference), anxiety (open-field) and stress-coping strategies (forced swim test) at postnatal day (PND) 28-35. In order to identify neural alterations associated to behavioral profiles, we assessed brain resting state metabolic activity in vivo using 18 F-FDG PET imaging at PND 37. We selected three profiles of mice distinguished in a composite Z-score computed from performances in the behavioral tests: High, Intermediate and Low Depressive Risk (HDR, IDR and LDR). Compared to both IDR and LDR, HDR mice were characterized by passive stress-coping behaviors, low cognition and high anhedonia and anxiety and were associated with significant changes of 18 F-FDG uptakes in several cortical and subcortical areas including prelimbic cortex, infralimbic cortex, nucleus accumbens, amygdala, periaqueductal gray and superior colliculus, all displaying higher metabolic activity, while only the thalamus was associated with lower metabolic activity (compared to IDR). LDR displayed an opposing behavioral phenotype and were associated with significant changes of 18 F-FDG uptakes in the dorsal striatum and thalamus that both exhibited markedly lower metabolic activity in LDR. In conclusion, our study revealed changes in metabolic activities that can represent neural signatures for behavioral profiles predicting subthreshold depression at adolescence in a mouse model., (© 2022. The Author(s).)

Background: Childhood maltreatment is significantly associated with greater occurrence of mental disorders in adulthood such as depression and anxiety. As a key node of the limbic system, the amygdala is engaged in emotional processing and regulation and is dysfunctional in many psychiatric disorders. The present study aimed at exploring the association between childhood maltreatment and amygdala-based functional networks and their potential contributions to depression and anxiety., Methods: Totally 90 Chinese healthy volunteers participated in a resting-state fMRI experiment. Levels of childhood maltreatment experience were assessed using the Childhood Trauma Questionnaire (CTQ-SF) as well as levels of depression and anxiety. Associations between CTQ-SF scores and bilateral amygdala gray matter volume and resting-state functional connectivity (RSFC) of the amygdala and selected regions of interest were analyzed using multiple regression analyses with sex and age as covariates. A subsequent moderation analysis was performed to identify whether associations were predictive of depression and anxiety levels., Results: Childhood maltreatment was significantly negatively associated with RSFC between left amygdala and anterior insula. Further sub-region analyses revealed that this negative association only occurred for the left centromedial amygdala subregion, which subsequently moderated the relationship between levels of childhood emotional abuse and depression / anxiety., Limitations: No psychiatric patients were involved and specific neural associations with different childhood maltreatment subtypes need to be examined in future studies., Conclusion: The present findings provide evidence for altered RSFC of centromedial amygdala and the anterior insula associated with childhood maltreatment and which moderate levels of depression and anxiety in adulthood., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Psychogenic nonepileptic seizures (PNES) are characterized by multifocal and global abnormalities in brain function and connectivity. Only a few studies have examined neuroanatomic correlates of PNES. Traumatic brain injury (TBI) is reported in 83% of patients with PNES and may be a key component of PNES pathophysiology. In this study, we included patients with TBI preceding the onset of PNES (TBI-PNES) and TBI without PNES (TBI-only) to identify neuromorphometric abnormalities associated with PNES., Methods: Adults diagnosed with TBI-PNES (n = 62) or TBI-only (n = 59) completed psychological questionnaires and underwent 3-T magnetic resonance imaging. Imaging data were analyzed by voxel- and surface-based morphometry. Voxelwise general linear models computed group differences in gray matter volume, cortical thickness, sulcal depth, fractal dimension (FDf), and gyrification. Statistical models were assessed with permutation-based testing at 5000 iterations with the Threshold-Free Cluster Enhancement toolbox. Logarithmically scaled p-values corrected for multiple comparisons using familywise error were considered significant at p < .05. Post hoc analyses determined the association between structural and psychological measures (p < .05)., Results: TBI-PNES participants demonstrated atrophy of the left inferior frontal gyrus and the right cerebellum VIII. Relative to TBI-only, TBI-PNES participants had decreased FDf in the right superior parietal gyrus and decreased sulcal depth in the left insular cortex. Significant clusters were positively correlated with global assessment of functioning scores, and demonstrated varying negative associations with measures of anxiety, depression, somatization, and global severity of symptoms., Significance: The diagnosis of PNES was associated with brain atrophy and reduced cortical folding in regions implicated in emotion processing, regulation, and response inhibition. Cortical folds primarily develop during the third trimester of pregnancy and remain relatively constant throughout the remainder of one's life. Thus, the observed aberrations in FDf and sulcal depth could originate early in development. The convergence of environmental, developmental, and neurobiological factors may coalesce to reflect the neuropathophysiological substrate of PNES., (© 2021 International League Against Epilepsy.)

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.)

Rumination and worry are transdiagnostic perseverative cognitions that have overlapping and distinct characteristics. While the mechanisms of perseverative cognitions remain incomplete, limited data indicate anterior cingulate cortex (ACC) as it relates to top-down functions contributes to perseverative cognitions in internalizing conditions. The current study extends this work in patients with major depression (n = 39) or social anxiety (n = 42). During fMRI, participants viewed images comprising letter strings superimposed on task-irrelevant threatening or neutral faces. To moderate task difficulty, there was a low perceptual load condition where the target letter was in a string of identical letters and high load condition with the target letter in a mixed letter string increasing task difficulty. Regions of interest (ROI) comprised dorsal ACC and rostral ACC. Bilateral amygdala was also examined. Results showed diagnostic groups had similar levels of rumination and worry. Exploratory hierarchical regression analysis comprising clinical measures, task performance, and the 4 ROIs revealed significantly less dorsal ACC engagement during low (vs. high) load to task-irrelevant faces corresponded with more rumination, but not worry, regardless of diagnostic status. However, the ACC finding did not survive Bonferroni correction. Preliminary results suggest dorsal ACC response during attentional control may serve as a transdiagnostic mechanism of rumination., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To investigate subjective cognitive decline (SCD) in relation to β-amyloid pathology and to test for associations with anxiety, depression, objective cognition and family history of dementia in the Insight 46 study., Methods: Cognitively unimpaired ~70-year-old participants, all born in the same week in 1946 (n=460, 49% female, 18% amyloid-positive), underwent assessments including the SCD-Questionnaire (MyCog). MyCog scores were evaluated with respect to 18 F-Florbetapir-PET amyloid status (positive/negative). Associations with anxiety, depression, objective cognition (measured by the Preclinical Alzheimer Cognitive Composite, PACC) and family history of dementia were also investigated. The informant's perspective on SCD was evaluated in relation to MyCog score., Results: Anxiety (mean (SD) trait anxiety score: 4.4 (3.9)) was associated with higher MyCog scores, especially in women. MyCog scores were higher in amyloid-positive compared with amyloid-negative individuals (adjusted means (95% CIs): 5.3 (4.4 to 6.1) vs 4.3 (3.9 to 4.7), p=0.044), after accounting for differences in anxiety. PACC (mean (SD) -0.05 (0.68)) and family history of dementia (prevalence: 23.9%) were not independently associated with MyCog scores. The informant's perception of SCD was generally in accordance with that of the participant., Conclusions: This cross-sectional study demonstrates that symptoms of SCD are associated with both β-amyloid pathology, and more consistently, trait anxiety in a population-based cohort of older adults, at an age when those who are destined to develop dementia are still likely to be some years away from symptoms. This highlights the necessity of considering anxiety symptoms when assessing Alzheimer's disease pathology and SCD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Pandemics such as the Covid-19 pandemic have shown to impact our physical and mental well-being, with particular challenges for children and families. We describe data from 43 adults (31♀, ages = 22-51; 21 mothers) and 26 children (10♀, ages = 7-17 years) including pre-pandemic brain function and seven assessment points during the first months of the pandemic. We investigated (1) changes in child and adult well-being, (2) mother-child associations of mental well-being, and (3) associations between pre-pandemic brain activation during mentalizing and later fears or burden. In adults the prevalence of clinically significant anxiety-levels was 34.88% and subthreshold depression 32.56%. Caregiver burden in parents was moderately elevated. Overall, scores of depression, anxiety, and caregiver burden decreased across the 11 weeks after Covid-19-onset. Children's behavioral and emotional problems during Covid-19 did not significantly differ from pre-pandemic levels and decreased during restrictions. Mothers' subjective burden of care was associated with children's emotional and behavioral problems, while depression levels in mothers were related to children's mood. Furthermore, meeting friends was a significant predictor of children's mood during early restrictions. Pre-pandemic neural correlates of mentalizing in prefrontal regions preceded later development of fear of illnesses and viruses in all participants, while temporoparietal activation preceded higher subjective burden in mothers., (© 2021. The Author(s).)

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: Depressive symptoms are known to affect memory efficiency in various populations. More specifically, several studies conducted in patients suffering from schizophrenia have indicated that memory efficiency is affected by depressed mood in female patients and by anxiety in male patients. We investigated, using neuroimaging techniques, whether similar gender-specific associations with subclinical depression and anxiety could be observed in a non-clinical sample., Method: Forty-five healthy Spanish-speaking individuals (23 females) were administered a verbal memory task. Lists of high- and low-frequency words were presented. Immediate free recall was requested after the learning of each list, and a yes/no recognition task was completed during the acquisition of the fMRI data., Results: Regression analyses revealed that higher depression scores in women, and higher anxiety scores in men, were associated with poorer recall. In women, higher depression scores were further associated with decreased cerebral activity in the right temporoparietal junction, left inferior occipitotemporal gyrus, bilateral thalamus, and left anterior cingulate during correct recognition of target words. In men, anxiety scores were not associated with any cerebral activity., Conclusions: Subclinical depression in women appears to affect memory efficiency by impacting cerebral regions specifically recruited for the cognitive demands of the task, as well as cerebral regions more generally involved in arousal, decision-making, and emotional regulation. Anxiety in men might impact the encoding memory processes. The results, although preliminary, suggest that gender differences may need to be taken into account when developing strategies for the cognitive and pharmacological remediation of memory impairment., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Anxiety and depression are the most common withdrawal symptoms of methamphetamine (METH) abuse, which further exacerbate relapse of METH abuse. To date, no effective pharmacotherapy exists for METH abuse and its withdrawal symptoms. Therefore, understanding the neuromechanism underlying METH abuse and its withdrawal symptoms is essential for developing clinical strategies and improving patient care. The aims of this study were to investigate brain network abnormalities in METH abusers (MAs) and their associations with affective symptoms. Forty-eight male abstinent MAs and 48 age-gender matched healthy controls were recruited and underwent resting state functional magnetic resonance imaging (fMRI). The severity of patient anxiety and depressive symptoms were measured by Hamilton anxiety and depression rating scales, which decreased across the duration of abstinence. Independent component analysis was used to investigate the brain network functional connectivity (FC) properties. Compared with healthy controls, MAs demonstrated hypo-intra-network FC in the cerebellar network and hyper-intra-network FC in the posterior salience network. A whole-brain regression analysis revealed that FC strength of clusters located in the right rostral anterior cingulate cortex (rACC) within the ventromedial network (VMN) was associated with affective symptoms in the patients. Importantly, the intra-network FC strength of the rACC in VMN mediated the association between abstinence duration and the severity level of affective symptoms. Our results demonstrate alterations in brain functional networks underlying METH abuse, and that the FC of rACC within VMN serve as a neural substrate in the association between abstinence length and affective symptom severity in the MAs., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: While prior research shows that mental illness is associated with lower utilization of screening imaging, little is known about how mental illness impacts use of diagnostic imaging, other than for screening. This study explores the association between a history of anxiety or depression in the prior year and utilization of diagnostic imaging., Methods: Commercial and Medicare Advantage health plan claims from 2017 and 2018 from patients with plans from one national organization were extracted. Exclusions were made for patients without continuous plan enrollment. History of anxiety or depression was determined using 2017 claims, and downstream diagnostic imaging was determined using 2018 claims. Univariate associations were assessed with Chi-square tests. A matched sample was created using Coarsened Exact Matching, with history of mental illness serving as the treatment variable. Logistic regressions were used to calculate adjusted odds ratios, before and after matching, controlling for age, sex, urbanicity, local income, comorbidities, claims history, region, and health plan characteristics. Associations between mental illness and chest imaging, neuroimaging, and emergency department imaging were also evaluated., Results: The sample included 2,381,851 patients before matching. Imaging was significantly more likely for patients with a history of anxiety (71.1% vs. 55.7%, P < .001) and depression (73.2% vs. 55.3%, P < .001). The adjusted odds of any imaging were 1.24 (95% confidence interval [CI]: 1.22-1.26) for patients with a history of anxiety, and 1.43 (CI: 1.41-1.45) for patients with a history of depression before matching, and 1.18 (CI: 1.16-1.20) for a history of anxiety and 1.33 (CI: 1.32-1.35) for a history of depression after matching. Adjusted analyses found significant, positive associations between mental illness and chest imaging, neuroimaging, and emergency department imaging both before and after matching., Discussion: In contrast to prior findings on screening, anxiety and depression were associated with greater likelihood of diagnostic imaging within the population studied., Competing Interests: The authors have read the journal’s policy, and the authors of the study have the following competing interests to declare: AP and DF report an employment or consulting relationship with HealthHelp/WNS at the time the study was written. JWL and KJS report employment by Humana Inc. GC reports he is the sole owner of Schooner Strategies and serves as the President & CEO of RadSite, an accreditation organization that accredits imaging systems. AP additionally reports employment by Payer+Provider Syndicate, and stock ownership of Berkshire Hathaway, HCA Healthcare, Payer+Provider Syndicate, and Tenet Healthcare Corp. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Functional magnetic resonance imaging (fMRI) studies consistently demonstrate altered neural activation in youth experiencing anxiety and depression in a way that is distinct from adult-onset disorders. However, there is a paucity of research systematically reviewing this, and no meta-analyses have been conducted using Activation Likelihood Estimation (ALE). The present study conducted a systematic literature search to identify fMRI studies in youth (age 4-18) with depression or anxiety disorders. 48 studies with over 2000 participants were identified that met the inclusion criteria. Significant foci were extracted. Five ALE meta-analyses were conducted: a) activation for both anxiety disorders and depression; b) activation for anxiety disorders only; c) activation for depression only; d) deactivation for both anxiety disorders and depression; e) deactivation for depression. Results indicated significant clusters of increased activation in the bilateral amygdala for youth with internalising disorders, and specifically for those with anxiety disorders. Significant increased activation extended into the dorsal anterior cingulate, entorhinal cortex, the putamen, and the medial and lateral globus pallidus in youth with anxiety disorders. These findings help to detail the nature of anxiety being an amygdala hyperactivity disorder, whilst also defining the distinction between neural activation patterns in anxiety and depression., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

Background: Individuals with anxiety/depression may impulsively use cannabis to acutely induce positive affect and attenuate aversive mood states. However, few studies have attempted to parse impulsivity displayed by anxious/depressed cannabis users. This investigation examined what aspects of impulsivity characterize those individuals using self-report and functional MRI (fMRI) measures., Methods: Individuals with any lifetime anxiety/depression diagnoses and problematic cannabis use ("Anx/Dep+CB"; n=42) were compared to a propensity score-matched group with very low cannabis use ("Anx/Dep-lowCB"; n=42), and a healthy control group (n=37). Impulsivity was measured using the UPPS-P Impulsivity Questionnaire and the Stop Signal Task (SST) during fMRI. For UPPS-P, regression models estimated group-by-impulsivity subscale interactions with post-hoc pairwise tests. For the SST, similar regression models were estimated with four a-priori regions of interest (ROIs; right opercularis, orbitalis, dorsal and ventral anterior insula) during stop-success and stop-failure processing. Null SST findings were followed up using Bayes factor analysis to quantify the evidence in support of the null hypothesis., Results: For the UPPS-P, a significant group-by-subscale interaction indicated that the Anx/Dep+CB group exhibited higher levels of impulsivity on the negative- and positive-urgency subscales relative to both comparison groups. Higher negative-urgency correlated with heavier lifetime cannabis use across groups. For the SST, there were no ROI task activation differences. Bayes factor analysis determined the null findings were at least three times more likely than the alternative hypothesis for all ROIs., Conclusions: Impulsivity under periods of heightened affect, but not motor response inhibitions, characterized anxious/depressed individuals who use cannabis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Prenatal alcohol exposure (PAE) is associated with a variety of structural abnormalities in the brain, including several within the para-limbic system. Children with PAE have higher rates of internalizing disorders, including depression and anxiety, which may be related to underlying limbic system anomalies., Methods: Children aged 8 to 16 with PAE (n = 41) or without PAE (n = 36) underwent an magnetic resonance imaging of the brain and parents completed behavioral questionnaires about their children. Semi-automated procedures (FreeSurfer) were used to derive para-limbic volumes from T1-weighted anatomical images., Results: There were significant group differences (PAE vs. nonexposed controls) in the caudate, hippocampus, and the putamen; children with PAE had smaller volumes in these regions even after controlling for total intracranial volume. A trend-level association was seen between caudate volume and internalizing symptoms in children with PAE; smaller caudate volumes (presumably reflecting less optimal neurodevelopment) were associated with higher levels of anxiety and depression symptoms in these children., Conclusions: Caudate structure may be disproportionately affected by PAE and may be associated with the later development of internalizing symptoms in those affected by PAE., (© 2020 Research Society on Alcoholism.)

Gambling disorder (GD) is a psychiatric disease that has been recently classified as a behavioural addiction. So far, a very few studies have investigated the alteration of functional connectivity in GD patients, thus the concrete interplay between relevant function-dependent circuitries in such disease has not been comprehensively assessed. The aim of this research was to investigate resting-state functional connectivity in GD patients, searching for a correlation with GD symptoms severity. GD patients were assessed for gambling behaviour, impulsivity, cognitive distortions, anxiety and depression, in comparison with healthy controls (HC). Afterwards, they were assessed for resting-state functional magnetic resonance imaging; functional connectivity was assessed through a data-driven approach, by using independent component analysis. The correlation between gambling severity and the strength of specific resting-state networks was also investigated. Our results show that GD patients displayed higher emotional and behavioural impairment than HC, together with an increased resting state functional connectivity in the network including anterior cingulate cortex, the caudate nucleus and nucleus accumbens, and within the cerebellum, in comparison with the control group. Moreover, a significant correlation between behavioural parameters and the strength of the resting-state cerebellar network was found. Overall, the functional alterations in brain connectivity involving the cerebellum observed in this study underpin the emotional and behavioural impairment recorded in GD patients. This evidence suggests the employment of novel neuromodulatory therapeutic approaches involving specific and salient targets such as the cerebellum in addictive disorders., (Copyright © 2020 Elsevier B.V. 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.)

Cytochrome P450 C19 (CYP2C19) metabolizes exogenous and endogenous compounds. Although CYP2C19 is highly expressed in the liver, it is also expressed in the brain during early life. Previous human and animal studies have linked CYP2C19 genotype-predicted enzyme activity to hippocampal volumes, depressive symptoms, and anxiety-like behaviors. We examined these promising associations in a general community sample comprising 386 Caucasian adults with no history of psychiatric or neurological illnesses. Contrary to previous findings, CYP2C19 genotype-predicted enzyme activity was not associated with hippocampal volumes, nor depressive and anxiety symptoms. Interstudy differences in CYP2C19 frequencies and/or study methodology may explain this discrepancy., Competing Interests: Declaration of Competing Interests 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 © 2020 Elsevier B.V. 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.)

The Connectomes Related to Human Diseases (CRHD) initiative was developed with the Human Connectome Project (HCP) to provide high-resolution, open-access, multi-modal MRI data to better understand the neural correlates of human disease. Here, we present an introduction to a CRHD project, the Boston Adolescent Neuroimaging of Depression and Anxiety (BANDA) study, which is collecting multimodal neuroimaging, clinical, and neuropsychological data from 225 adolescents (ages 14-17), 150 of whom are expected to have a diagnosis of depression and/or anxiety. Our transdiagnostic recruitment approach samples the full spectrum of depressed/anxious symptoms and their comorbidity, consistent with NIMH Research Domain Criteria (RDoC). We focused on an age range that is critical for brain development and for the onset of mental illness. This project sought to harmonize imaging sequences, hardware, and functional tasks with other HCP studies, although some changes were made to canonical HCP methods to accommodate our study population and questions. We present a thorough overview of our imaging sequences, hardware, and scanning protocol. We detail similarities and differences between this study and other HCP studies. We evaluate structural-, diffusion-, and functional-image-quality measures that may be influenced by clinical factors (e.g., disorder, symptomatology). Signal-to-noise and motion estimates from the first 140 adolescents suggest minimal influence of clinical factors on image quality. We anticipate enrollment of an additional 85 participants, most of whom are expected to have a diagnosis of anxiety and/or depression. Clinical and neuropsychological data from the first 140 participants are currently freely available through the National Institute of Mental Health Data Archive (NDA)., (Copyright © 2020 The Authors. Published by 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.)

Previous structural and functional neuroimaging studies have implicated distributed brain regions and networks in depression. However, there are no robust imaging biomarkers that are specific to depression, which may be due to clinical heterogeneity and neurobiological complexity. A dimensional approach and fusion of imaging modalities may yield a more coherent view of the neuronal correlates of depression. We used linked independent component analysis to fuse cortical macrostructure (thickness, area, gray matter density), white matter diffusion properties and resting-state functional magnetic resonance imaging default mode network amplitude in patients with a history of depression (n = 170) and controls (n = 71). We used univariate and machine learning approaches to assess the relationship between age, sex, case-control status, and symptom loads for depression and anxiety with the resulting brain components. Univariate analyses revealed strong associations between age and sex with mainly global but also regional specific brain components, with varying degrees of multimodal involvement. In contrast, there were no significant associations with case-control status, nor symptom loads for depression and anxiety with the brain components, nor any interaction effects with age and sex. Machine learning revealed low model performance for classifying patients from controls and predicting symptom loads for depression and anxiety, but high age prediction accuracy. Multimodal fusion of brain imaging data alone may not be sufficient for dissecting the clinical and neurobiological heterogeneity of depression. Precise clinical stratification and methods for brain phenotyping at the individual level based on large training samples may be needed to parse the neuroanatomy of depression., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, 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.

Background: Early-life adversity (ELA) is a risk factor for internalizing psychopathology (IP). ELA is also linked to alterations in neural phenotypes of emotion processing and maladaptive emotion regulatory strategies, such as ruminative brooding, in adulthood. We therefore expected that ELA would predict cortical brain activation to emotional faces in transdiagnostic IP and in turn, mediate the extent of rumination amongst patients with IPs and ELA (IP + ELA)., Method: One hundred and thirty-two individuals, including 102 treatment-seeking adults with heterogeneous IPs and 30 healthy controls (HCs) performed an Emotional Face-Matching Task during functional magnetic resonance imaging. Whole-brain analyses compared HC (n = 30), IP (n = 52), and IP + ELA (n = 50) neural responses to emotional (angry, fearful, happy, and sad) faces v. shapes, controlling for depression and anxiety symptoms. Parameter estimates of activation were extracted for significant between-group differences and tested as a mediator of ruminative brooding in IP + ELA., Results: IP + ELA demonstrated increased activation in the superior frontal gyrus and anterior cingulate cortex (fear), superior parietal lobule, precuneus, posterior cingulate, and inferior temporal gyrus (fear only), and cuneus (fear and angry). These regions were preferentially correlated with ruminative brooding in IP + ELA, many of which mediated the link between IP + ELA and ruminative brooding., Conclusions: Results provide evidence that ELA history amongst IP patients augments engagement of brain regions involved in emotion processing, above and beyond what is accounted for by current symptoms. Though longitudinal designs are needed, alterations in the neural correlates of maladaptive processing of socio-emotional information may be a common pathway by which ELA poses risk for psychopathology.

Objectives: To study the development of cognitive and emotional symptoms between 3 and 12 months after a minor stroke., Material and Methods: We included patients from stroke units at hospitals in the Central Norway Health Authority and from Haukeland University Hospital. We administered a selection of cognitive tests, and the patients completed a questionnaire 3 and 12 months post-stroke. Cognitive impairment was defined as impairment of ≥2 cognitive tests., Results: A total of 324 patients completed the 3-month testing, whereas 37 patients were lost to follow-up at 12 months. The results showed significant improvement of cognitive function defined as impairment of ≥2 cognitive tests (P = .03) from months 3 to 12. However, most patients still showed cognitive impairment at 12 months with a prevalence of 35.4%. There is significant association between several of the cognitive tests and hypertension and smoking (P = .002 and .05). The prevalence of depression, but not anxiety, increased from 3 to 12 months (P = .04). The prevalence of fatigue did not change and was thus still high with 29.5% after 12 months., Conclusions: This study shows that an improvement of cognitive function still occurs between 3 and 12 months. Despite this, the prevalence of mostly minor cognitive impairment still remains high 12 months after the stroke. The increasing prevalence of depressive symptoms highlights the importance of being vigilant of depressive symptoms throughout the rehabilitation period. Furthermore, high prevalence of fatigue persisted., (© 2019 The Authors. Acta Neurologica Scandinavica Published by John Wiley & Sons Ltd.)

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.)

In addition to motor symptoms, behavioural complications are commonly found in patients with Parkinson's disease (PD). Behavioural complications, including depression, anxiety, apathy, impulse control disorder and psychosis, together have a large impact on PD patient's quality of life. Many neuroimaging studies using PET, SPECT and MRI techniques have been conducted to study the underlying neural mechanisms of PD pathogenesis and pathophysiology in relation to its behavioural complications. This review will survey these PET, SPECT and MRI studies to describe the current understanding of the neuro-chemical, functional and structural changes associated with behavioural complications in PD patients.

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.)

Treatment with interferon (IFN) has been associated with depressive side effects. Previous neuroimaging studies have provided information about changes in brain activation patterns in patients under treatment with IFN-alpha, but the effect of other IFNs, or the role of the underlying disease, has yet to be clarified. In the present fMRI study, we looked at brain changes after 8 days of IFN-beta treatment in N = =17 healthy volunteers, thus avoiding the possible confound of the effects of underlying pathology in studies of IFN-treated patients with neurological or other medical disorders. We followed a symptom dimensional approach by simultaneously investigating two distinct symptom domains of depressiveness: negative affect (amygdala) and appetitive motivation (ventral striatum). In these early phases of IFN treatment we detected a selective change in neural substrates of appetitive motivation, consistent with the predominant symptomatic change recorded in psychopathology ratings. In contrast, the fMRI phenotype of negative affect, which is known to characterize disorders of affect involving anxiety and depressiveness as well as individual vulnerability to depression, was unchanged after treatment. These findings suggest that IFN may induce an affective syndrome through a mechanism involving down-regulation of appetitive motivation., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Worries preoccupy the working memory capacity in anxious individuals, thereby affecting their performance during tasks that require efficient attention regulation. According to the attentional control theory (ACT), trait anxiety affects the processing efficiency, i.e. the effort required for task performance, more than the accuracy of task performance. We investigated the relation between trait anxiety and neural response for a reasoning task in healthy subjects. Functional magnetic resonance imaging (fMRI) was carried out on 22 healthy participants and blood oxygenation level dependent (BOLD) contrast estimates were extracted from a priori regions of interest (ROIs) that were earlier implicated in reasoning (i.e., bilaterally caudate head, globus pallidus, thalamus, prefrontal cortex [[ostral, dorsal and ventral regions]] inferior parietal lobule and middle occipital gyrus). Controlling for the effects of age, gender, state anxiety and depressive symptoms, for equivalent levels of task performance, trait anxiety of the participants was found to be associated with an increase in task related BOLD activation in right globus pallidus, left thalamus and left middle occipital gyrus. Our results suggest a reduced processing efficiency for reasoning in high trait anxiety subjects and provides important brain-behaviour relationships with respect to sub-clinical anxiety.

Preclinical research has been indispensable in the exploration of the neurological basis of major depressive disorder (MDD). The present study aimed to examine effects on regional brain activity of two frequently used depression models, the chronic unpredictable mild stress (CUMS)- and the chronic corticosterone (CORT) depression model. The CUMS and CORT depression model were induced by exposing male Long-Evans rats to a 4-week procedure of unpredictable mild stressors or a 3-week procedure of chronic corticosterone, respectively. Positron emission tomography with [ 18 F]FDG was performed to determine alterations in regional brain activity. In addition, depressive- and anxiety-like behaviour was assessed via the forced swim test and the open field test, respectively. The chronic CORT administration, but not the CUMS model, significantly induced depressive-like behaviour and elevated plasma corticosterone levels. Compared to control, induction of the CORT depression model resulted in a significantly reduced glucose consumption in the insular cortex and the striatum, and a significantly elevated consumption in the cerebellum and the midbrain. Induction of the CUMS model replicated the findings with respect to the activity in the striatum region, and cerebellum, but missed significance in the insular cortex and the midbrain. Based on the alterations in behaviour and regional [ 18 F]FDG uptake, a superior face validity and construct validity can be observed after induction of depression via chronic CORT injections, compared to the used CUMS paradigm.

The unique neuroanatomical underpinnings of internalizing symptoms and impulsivity during childhood are not well understood. In this study, we examined associations of brain structure with anxiety, depression, and impulsivity in children and adolescents. Participants were 7- to 21-year-olds ( N  = 328) from the Pediatric Imaging, Neurocognition, and Genetics (PING) study who completed high-resolution, 3-Tesla, T1-weighted MRI and self-report measures of anxiety, depression, and/or impulsivity. Cortical thickness and surface area were examined across cortical regions-of-interest (ROIs), and exploratory whole-brain analyses were also conducted. Gray matter volume (GMV) was examined in subcortical ROIs. When considered separately, higher depressive symptoms and impulsivity were each significantly associated with reduced cortical thickness in ventromedial PFC/medial OFC, but when considered simultaneously, only depressive symptoms remained significant. Higher impulsivity, but not depressive symptoms, was associated with reduced cortical thickness in the frontal pole, rostral middle frontal gyrus, and pars orbitalis. No differences were found for regional surface area. Higher depressive symptoms, but not impulsivity, were significantly associated with smaller hippocampal GMV and larger pallidal GMV. There were no significant associations between anxiety symptoms and brain structure. Depressive symptoms and impulsivity may be linked with cortical thinning in overlapping and distinct regions during childhood and adolescence.

Background: Neuropsychiatric symptoms and reduced health-related quality of life (HRQoL) are frequent in multiple sclerosis, where are associated with structural brain changes, but have been less studied in clinically isolated syndrome (CIS)., Objective: To characterize HRQoL, neuropsychiatric symptoms (depressive symptoms, anxiety, apathy and fatigue), their interrelations and associations with structural brain changes in CIS., Methods: Patients with CIS (n = 67) and demographically matched healthy controls (n = 46) underwent neurological and psychological examinations including assessment of HRQoL, neuropsychiatric symptoms and cognitive functioning, and MRI brain scan with global, regional and lesion load volume measurement., Results: The CIS group had more, mostly mild, depressive symptoms and anxiety, and lower HRQoL physical and social subscores (p≤0.037). Neuropsychiatric symptoms were associated with most HRQoL subscores (β≤-0.34, p≤0.005). Cognitive functioning unlike clinical disability was associated with depressive symptoms and lower HRQoL emotional subscores (β≤-0.29, p≤0.019). Depressive symptoms and apathy were associated with right temporal, left insular and right occipital lesion load (ß≥0.29, p≤0.032). Anxiety was associated with lower white matter volume (ß = -0.25, p = 0.045)., Conclusion: Mild depressive symptoms and anxiety with decreased HRQoL are present in patients with CIS. Neuropsychiatric symptoms contributing to decreased HRQoL are the result of structural brain changes and require complex therapeutic approach in patients with CIS., Competing Interests: The authors have declared that no competing interests exist.

Accumulating data suggest attentional control capability varies across psychiatric diagnostic boundaries. The Attentional Control Scale (ACS) assesses self-reported trait attentional control (TAC) and tracks the anterior attention system. Greater TAC is associated with less negative affect, however, its mechanisms in anxiety and depression are poorly understood. Therefore, we examined whether individual differences in TAC modulated top-down mechanisms in a clinical sample. During fMRI, 104 patients with social anxiety, generalized anxiety, and/or major depression and 34 healthy participants completed a validated attentional control paradigm comprising strings of letters superimposed on threatening and neutral face distractors. In the low perceptual load condition, a target letter was in a string of identical letters. In the high load condition, a target letter was in a mixed letter string. Whole-brain regression results for low load revealed more activation to threat (vs. neutral) distractors in the pregenual anterior cingulate cortex was predicted by better TAC (i.e., higher ACS scores). For high load, regression results showed less activation to threat (vs. neutral) distractors in the inferior frontal gyrus was predicted by better TAC. An exploratory whole-brain ANOVA revealed a main effect of group in the superior temporal gyrus and a main effect of perceptual load in parietal, frontal, and limbic regions. No other effects were detected and activation derived from significant ANOVA results did not correlate with ACS scores. In conclusion, regression findings suggest individual differences in brain-behavioral ACS-related activity in frontal structures may be useful in identifying phenotypes in internalizing conditions., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Single ventricle heart disease (SVHD) adolescents show cognitive impairments and anxiety and depressive symptoms, indicating the possibility of brain injury in regions that control these functions. However, brain tissue integrity in cognition, anxiety, and depression regulatory sites in SVHD remains unclear. We examined brain tissue changes in SVHD compared to controls using T2-relaxometry procedures, which measure free water content and show tissue injury., Methods: Proton-density and T2-weighted images, using a 3.0-Tesla MRI, as well as anxiety (Beck anxiety inventory [BAI]), depressive symptoms (patient health questionnaire-9 [PHQ-9]), and cognition (wide range assessment of memory and learning 2 [WRAML2] and Montreal cognitive assessment [MoCA]) data were collected from 20 SVHD (age: 15.8 ± 1.1 years, male/female: 11/9) and 36 controls (age: 16.0 ± 1.1 years, male/female: 19/17). Whole-brain T2-relaxation maps were calculated, normalized to a common space, smoothed, and compared between groups and sexes (analysis of covariance; covariates: age, sex; p < 0.001)., Results: SVHD subjects showed significantly increased BAI and PHQ-9 and reduced MoCA and WRAML2 scores over controls. Several brain regions in SVHD showed increased T2-relaxation values (chronic injury), including the cingulate, and insula, hippocampus/para-hippocampal gyrus, thalamus, hypothalamus, amygdala, frontal white matter, corpus callosum, brainstem, and cerebellar areas. Decreased T2-relaxation values (acute injury) emerged in a few regions, including the prefrontal and cerebellar cortices in SVHD over controls. In addition, male SVHD showed more brain changes over female SVHD., Conclusions: Adolescents with SVHD showed significant brain injury with variable male-female differences in areas that control cognition, anxiety, and depression, which may contribute to functional deficits found in the condition., (© 2018 Wiley Periodicals, Inc.)

Major depression disorder (MDD) and anxiety disorder are both prevalent and debilitating. High rates of comorbidity between MDD and social anxiety disorder (SAD) suggest common pathological pathways, including aberrant neural processing of interpersonal signals. In patient populations, the determination of common and distinct neurofunctional markers of MDD and SAD is often hampered by confounding factors, such as generally elevated anxiety levels and disorder-specific brain structural alterations. This study employed a dimensional disorder approach to map neurofunctional markers associated with levels of depression and social anxiety symptoms in a cohort of 91 healthy subjects using an emotional face processing paradigm. Examining linear associations between levels of depression and social anxiety, while controlling for trait anxiety revealed that both were associated with exaggerated dorsal striatal reactivity to fearful and sad expression faces respectively. Exploratory analysis revealed that depression scores were positively correlated with dorsal striatal functional connectivity during processing of fearful faces, whereas those of social anxiety showed a negative association during processing of sad faces. No linear relationships between levels of depression and social anxiety were observed during a facial-identity matching task or with brain structure. Together, the present findings indicate that dorsal striatal neurofunctional alterations might underlie aberrant interpersonal processing associated with both increased levels of depression and social anxiety., (© 2017 Wiley Periodicals, Inc.)