Leonardo Tozzi

All Publications

• Neural circuit basis of pathological anxiety. Nature reviews. Neuroscience Akiki, T. J., Jubeir, J., Bertrand, C., Tozzi, L., Williams, L. M. 2024

  Abstract

  Anxiety disorders are the most prevalent mental health conditions worldwide. Unfortunately, the understanding of the precise neurobiological mechanisms that underlie these disorders remains limited. Current diagnostic classifications, based on observable symptoms rather than underlying pathophysiology, do not capture the heterogeneity within and across anxiety disorders. Recent advances in functional neuroimaging have provided new insights into the neural circuits implicated in pathological anxiety, revealing dysfunctions that cut across traditional diagnostic boundaries. In this Review, we synthesize evidence that highlights abnormalities in neurobehavioural systems related to negative valence, positive valence, cognitive systems and social processes. We emphasize that pathological anxiety arises not only from heightened reactivity in acute threat ('fear') circuits but also from alterations in circuits that mediate distant (potential) and sustained threat, reward processing, cognitive control and social processing. We discuss how circuit vulnerabilities can lead to the emergence and maintenance of pathological anxiety. Once established, these neural abnormalities can be exacerbated by maladaptive behaviours that prevent extinction learning and perpetuate anxiety disorders. By delineating the specific neural mechanisms in each neurobiological system, we aim to contribute to a more comprehensive understanding of the neurobiology of anxiety disorders, potentially informing future research directions in this field.

  View details for DOI 10.1038/s41583-024-00880-4

  View details for PubMedID 39604513

  View details for PubMedCentralID 8776563

• Adaptive cognitive control circuit changes associated with problem-solving ability and depression symptom outcomes over 24 months. Science translational medicine Zhang, X., Pines, A., Stetz, P., Goldstein-Piekarski, A. N., Xiao, L., Lv, N., Tozzi, L., Lavori, P. W., Snowden, M. B., Venditti, E. M., Smyth, J. M., Suppes, T., Ajilore, O., Ma, J., Williams, L. M. 2024; 16 (763): eadh3172

  Abstract

  Mechanistically targeted behavioral interventions are a much-needed strategy for improving outcomes in depression, especially for vulnerable populations with comorbidities such as obesity. Such interventions may change behavior and outcome by changing underlying neural circuit function. However, it is unknown how these circuit-level modifications unfold over intervention and how individual differences in early circuit-level modifications may explain the heterogeneity of treatment effects. We addressed this need within a clinical trial of problem-solving therapy for participants with depression symptoms and comorbid obesity, focusing on the cognitive control circuit as a putative neural mechanism of action. Functional magnetic resonance imaging was applied to measure the cognitive control circuit activity at five time points over 24 months. Compared with participants who received usual care, those receiving problem-solving therapy showed that attenuations in cognitive control circuit activity were associated with enhanced problem-solving ability, which suggests that this circuit plays a key role in the mechanisms of problem-solving therapy. Attenuations in circuit activity were also associated with improved depression symptoms. Changes in cognitive control circuit activity at 2 months better predicted changes in problem-solving ability and depression symptoms at 6, 12, and 24 months, with predictive improvements ranging from 17.8 to 104.0%, exceeding baseline demographic and symptom characteristics. Our findings suggest that targeting the circuit mechanism of action could enhance the prediction of treatment outcomes, warranting future model refinement and improvement to pave the way for its clinical application.

  View details for DOI 10.1126/scitranslmed.adh3172

  View details for PubMedID 39231241

• Psychiatric Symptoms, Cognition, and Symptom Severity in Children. JAMA psychiatry Pines, A., Tozzi, L., Bertrand, C., Keller, A. S., Zhang, X., Whitfield-Gabrieli, S., Hastie, T., Larsen, B., Leikauf, J., Williams, L. M. 2024

  Abstract

  Mental illnesses are a leading cause of disability globally, and functional disability is often in part caused by cognitive impairments across psychiatric disorders. However, studies have consistently reported seemingly opposite findings regarding the association between cognition and psychiatric symptoms.To determine if the association between general cognition and mental health symptoms diverges at different symptom severities in children.A total of 5175 children with complete data at 2 time points assessed 2 years apart (aged 9 to 11 years at the first assessment) from the ongoing Adolescent Brain and Cognitive Development (ABCD) study were evaluated for a general cognition factor and mental health symptoms from September 2016 to August 2020 at 21 sites across the US. Polynomial and generalized additive models afforded derivation of continuous associations between cognition and psychiatric symptoms across different ranges of symptom severity. Data were analyzed from December 2022 to April 2024.Aggregate cognitive test scores (general cognition) were primarily evaluated in relation to total and subscale-specific symptoms reported from the Child Behavioral Checklist.The sample included 5175 children (2713 male [52.4%] and 2462 female [47.6%]; mean [SD] age, 10.9 [1.18] years). Previously reported mixed findings regarding the association between general cognition and symptoms may consist of several underlying, opposed associations that depend on the class and severity of symptoms. Linear models recovered differing associations between general cognition and mental health symptoms, depending on the range of symptom severities queried. Nonlinear models confirm that internalizing symptoms were significantly positively associated with cognition at low symptom burdens higher cognition = more symptoms) and significantly negatively associated with cognition at high symptom burdens.The association between mental health symptoms and general cognition in this study was nonlinear. Internalizing symptoms were both positively and negatively associated with general cognition at a significant level, depending on the range of symptom severities queried in the analysis sample. These results appear to reconcile mixed findings in prior studies, which implicitly assume that symptom severity tracks linearly with cognitive ability across the entire spectrum of mental health. As the association between cognition and symptoms may be opposite in low vs high symptom severity samples, these results reveal the necessity of clinical enrichment in studies of cognitive impairment.

  View details for DOI 10.1001/jamapsychiatry.2024.2399

  View details for PubMedID 39196567

• Personalized brain circuit scores identify clinically distinct biotypes in depression and anxiety. Nature medicine Tozzi, L., Zhang, X., Pines, A., Olmsted, A. M., Zhai, E. S., Anene, E. T., Chesnut, M., Holt-Gosselin, B., Chang, S., Stetz, P. C., Ramirez, C. A., Hack, L. M., Korgaonkar, M. S., Wintermark, M., Gotlib, I. H., Ma, J., Williams, L. M. 2024

  Abstract

  There is an urgent need to derive quantitative measures based on coherent neurobiological dysfunctions or 'biotypes' to enable stratification of patients with depression and anxiety. We used task-free and task-evoked data from a standardized functional magnetic resonance imaging protocol conducted across multiple studies in patients with depression and anxiety when treatment free (n = 801) and after randomization to pharmacotherapy or behavioral therapy (n = 250). From these patients, we derived personalized and interpretable scores of brain circuit dysfunction grounded in a theoretical taxonomy. Participants were subdivided into six biotypes defined by distinct profiles of intrinsic task-free functional connectivity within the default mode, salience and frontoparietal attention circuits, and of activation and connectivity within frontal and subcortical regions elicited by emotional and cognitive tasks. The six biotypes showed consistency with our theoretical taxonomy and were distinguished by symptoms, behavioral performance on general and emotional cognitive computerized tests, and response to pharmacotherapy as well as behavioral therapy. Our results provide a new, theory-driven, clinically validated and interpretable quantitative method to parse the biological heterogeneity of depression and anxiety. Thus, they represent a promising approach to advance precision clinical care in psychiatry.

  View details for DOI 10.1038/s41591-024-03057-9

  View details for PubMedID 38886626

  View details for PubMedCentralID 7653736

• Targeting the Cognitive Biotype of Depression With a Selective Alpha 2A Receptor Agonist Using a Stratified Precision Medicine Design Hack, L., Jubeir, J., Hilton, R., Tozzi, L., Schatzberg, A., O'Hara, R., Williams, L. ELSEVIER SCIENCE INC. 2024: S165

  View details for Web of Science ID 001282811900386

• Brain circuit derived biotypes for treatment selection in mood disorders: A critical review and illustration of a functional neuroimaging tool for clinical translation. Biological psychiatry Song, E. J., Tozzi, L., Williams, L. M. 2024

  Abstract

  Although the lifetime burden due to major depressive disorder is increasing, we lack tools for selecting the most effective treatments for each patient. A third to one half of patients with major depressive disorder do not respond to treatment, and we lack strategies for selecting among available treatments or expediting access to new treatment options. This critical review concentrates on functional neuroimaging as a modality of measurement for precision psychiatry. We begin by summarizing the current landscape of how functional neuroimaging-derived circuit predictors can forecast treatment outcomes in depression. We then outline the opportunities and challenges in integrating circuit predictors into clinical practice. We highlight one standardized and reproducible approach for quantifying brain circuit function at an individual level, which could serve as a model for clinical translation. We conclude by evaluating the prospects and practicality of employing neuroimaging tools, like the one we propose, in routine clinical practice.

  View details for DOI 10.1016/j.biopsych.2024.03.016

  View details for PubMedID 38552866

• Specific alterations of resting-state functional connectivity in the triple network related to comorbid anxiety in major depressive disorder. The European journal of neuroscience Beckmann, F. E., Gruber, H., Seidenbecher, S., Schirmer, S. T., Metzger, C. D., Tozzi, L., Frodl, T. 2024

  Abstract

  The brain's default mode network (DMN) and the executive control network (ECN) switch engagement are influenced by the ventral attention network (VAN). Alterations in resting-state functional connectivity (RSFC) within this so-called triple network have been demonstrated in patients with major depressive disorder (MDD) or anxiety disorders (ADs). This study investigated alterations in the RSFC in patients with comorbid MDD and ADs to better understand the pathophysiology of this prevalent group of patients. Sixty-eight participants (52.9% male, mean age 35.3 years), consisting of 25 patients with comorbid MDD and ADs (MDD + AD), 20 patients with MDD only (MDD) and 23 healthy controls (HCs) were investigated clinically and with 3T resting-state fMRI. RSFC utilizing a seed-based approach within the three networks belonging to the triple network was compared between the groups. Compared with HC, MDD + AD showed significantly reduced RSFC between the ECN and the VAN, the DMN and the VAN and within the ECN. No differences could be found for the MDD group compared with both other groups. Furthermore, symptom severity and medication status did not affect RSFC values. The results of this study show a distinct set of alterations of RSFC for patients with comorbid MDD and AD compared with HCs. This set of dysfunctions might be related to less adequate switching between the DMN and the ECN as well as poorer functioning of the ECN. This might contribute to additional difficulties in engaging and utilizing consciously controlled emotional regulation strategies.

  View details for DOI 10.1111/ejn.16249

  View details for PubMedID 38217400

• Canonical correlation analysis in high dimensions with structured regularization. Statistical modelling Tuzhilina, E., Tozzi, L., Hastie, T. 2023; 23 (3): 203-227

  Abstract

  Canonical correlation analysis (CCA) is a technique for measuring the association between two multivariate data matrices. A regularized modification of canonical correlation analysis (RCCA) which imposes an ℓ2 penalty on the CCA coefficients is widely used in applications with high-dimensional data. One limitation of such regularization is that it ignores any data structure, treating all the features equally, which can be ill-suited for some applications. In this article we introduce several approaches to regularizing CCA that take the underlying data structure into account. In particular, the proposed group regularized canonical correlation analysis (GRCCA) is useful when the variables are correlated in groups. We illustrate some computational strategies to avoid excessive computations with regularized CCA in high dimensions. We demonstrate the application of these methods in our motivating application from neuroscience, as well as in a small simulation example.

  View details for DOI 10.1177/1471082x211041033

  View details for PubMedID 37334164

  View details for PubMedCentralID PMC10274416

• A Cognitive Biotype of Depression and Symptoms, Behavior Measures, Neural Circuits, and Differential Treatment Outcomes: A Prespecified Secondary Analysis of a Randomized Clinical Trial. JAMA network open Hack, L. M., Tozzi, L., Zenteno, S., Olmsted, A. M., Hilton, R., Jubeir, J., Korgaonkar, M. S., Schatzberg, A. F., Yesavage, J. A., O'Hara, R., Williams, L. M. 2023; 6 (6): e2318411

  Abstract

  Cognitive deficits in depression have been associated with poor functional capacity, frontal neural circuit dysfunction, and worse response to conventional antidepressants. However, it is not known whether these impairments combine together to identify a specific cognitive subgroup (or "biotype") of individuals with major depressive disorder (MDD), and the extent to which these impairments mediate antidepressant outcomes.To undertake a systematic test of the validity of a proposed cognitive biotype of MDD across neural circuit, symptom, social occupational function, and treatment outcome modalities.This secondary analysis of a randomized clinical trial implemented data-driven clustering in findings from the International Study to Predict Optimized Treatment in Depression, a pragmatic biomarker trial in which patients with MDD were randomized in a 1:1:1 ratio to antidepressant treatment with escitalopram, sertraline, or venlafaxine extended-release and assessed at baseline and 8 weeks on multimodal outcomes between December 1, 2008, and September 30, 2013. Eligible patients were medication-free outpatients with nonpsychotic MDD in at least the moderate range, and were recruited from 17 clinical and academic practices; a subset of these patients underwent functional magnetic resonance imaging. This prespecified secondary analysis was performed between June 10, 2022, and April 21, 2023.Pretreatment and posttreatment behavioral measures of cognitive performance across 9 domains, depression symptoms assessed using 2 standard depression scales, and psychosocial function assessed using the Social and Occupational Functioning Assessment Scale and World Health Organization Quality of Life scale were analyzed. Neural circuit function engaged during a cognitive control task was measured using functional magnetic resonance imaging.A total of 1008 patients (571 [56.6%] female; mean [SD] age, 37.8 [12.6] years) participated in the overall trial and 96 patients participated in the imaging substudy (45 [46.7%] female; mean [SD] age, 34.5 [13.5] years). Cluster analysis identified what may be referred to as a cognitive biotype of 27% of depressed patients with prominent behavioral impairment in executive function and response inhibition domains of cognitive control. This biotype was characterized by a specific profile of pretreatment depressive symptoms, worse psychosocial functioning (d = -0.25; 95% CI, -0.39 to -0.11; P < .001), and reduced activation of the cognitive control circuit (right dorsolateral prefrontal cortex: d = -0.78; 95% CI, -1.28 to -0.27; P = .003). Remission was comparatively lower in the cognitive biotype positive subgroup (73 of 188 [38.8%] vs 250 of 524 [47.7%]; P = .04) and cognitive impairments persisted regardless of symptom change (executive function: ηp2 = 0.241; P < .001; response inhibition: ηp2 = 0.750; P < .001). The extent of symptom and functional change was specifically mediated by change in cognition but not the reverse.Our findings suggest the presence of a cognitive biotype of depression with distinct neural correlates, and a functional clinical profile that responds poorly to standard antidepressants and instead may benefit from therapies specifically targeting cognitive dysfunction.ClinicalTrials.gov Identifier: NCT00693849.

  View details for DOI 10.1001/jamanetworkopen.2023.18411

  View details for PubMedID 37318808

• Machine Learning Prediction of Estimated Risk for Bipolar Disorders Using Hippocampal Subfield and Amygdala Nuclei Volumes. Brain sciences Huth, F., Tozzi, L., Marxen, M., Riedel, P., Bröckel, K., Martini, J., Berndt, C., Sauer, C., Vogelbacher, C., Jansen, A., Kircher, T., Falkenberg, I., Thomas-Odenthal, F., Lambert, M., Kraft, V., Leicht, G., Mulert, C., Fallgatter, A. J., Ethofer, T., Rau, A., Leopold, K., Bechdolf, A., Reif, A., Matura, S., Biere, S., Bermpohl, F., Fiebig, J., Stamm, T., Correll, C. U., Juckel, G., Flasbeck, V., Ritter, P., Bauer, M., Pfennig, A., Mikolas, P. 2023; 13 (6)

  Abstract

  The pathophysiology of bipolar disorder (BD) remains mostly unclear. Yet, a valid biomarker is necessary to improve upon the early detection of this serious disorder. Patients with manifest BD display reduced volumes of the hippocampal subfields and amygdala nuclei. In this pre-registered analysis, we used structural MRI (n = 271, 7 sites) to compare volumes of hippocampus, amygdala and their subfields/nuclei between help-seeking subjects divided into risk groups for BD as estimated by BPSS-P, BARS and EPIbipolar. We performed between-group comparisons using linear mixed effects models for all three risk assessment tools. Additionally, we aimed to differentiate the risk groups using a linear support vector machine. We found no significant volume differences between the risk groups for all limbic structures during the main analysis. However, the SVM could still classify subjects at risk according to BPSS-P criteria with a balanced accuracy of 66.90% (95% CI 59.2-74.6) for 10-fold cross-validation and 61.9% (95% CI 52.0-71.9) for leave-one-site-out. Structural alterations of the hippocampus and amygdala may not be as pronounced in young people at risk; nonetheless, machine learning can predict the estimated risk for BD above chance. This suggests that neural changes may not merely be a consequence of BD and may have prognostic clinical value.

  View details for DOI 10.3390/brainsci13060870

  View details for PubMedID 37371350

  View details for PubMedCentralID PMC10296102

• A Cognitive Biotype of Depression Linking Symptoms, Behavior Measures, Neural Circuits, and Treatment Outcomes Hack, L., Tozzi, L., Zenteno, S., Olmsted, A., Hilton, R., Yesavage, J., Schatzberg, A., O'Hara, R., Williams, L. ELSEVIER SCIENCE INC. 2023: S72-S73

  View details for Web of Science ID 000993018500174

• Leveraging Brain Circuit Function Across Multiple Large Datasets to Identify Mood Disorders Subtypes Which Map to Symptoms, Cognition and Treatment Outcomes Tozzi, L. ELSEVIER SCIENCE INC. 2023: S3

  View details for Web of Science ID 000993018500009

• Long-term cortisol stress response in depression and comorbid anxiety is linked with reduced N-acetylaspartate in the anterior cingulate cortex. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry Bonnekoh, L. M., Seidenbecher, S., Knigge, K., Hunecke, A., Metzger, C. D., Tempelmann, C., Kanowski, M., Kaufmann, J., Meyer-Lotz, G., Schlaaff, K., Dobrowolny, H., Tozzi, L., Gescher, D. M., Steiner, J., Kirschbaum, C., Frodl, T. 2022: 1-35

  Abstract

  Objectives Major Depression (MDD) and anxiety disorders are stress-related disorders that share pathophysiological mechanisms. There is evidence for alterations of glutamate-glutamine, N-acetylaspartate (NAA) and GABA in the anterior cingulate cortex (ACC), a stress-sensitive region affected by hypothalamic-pituitary-adrenal axis (HPA). The aim was to investigate metabolic alterations in the ACC and whether hair cortisol, current stress or early life adversity predict them.Methods We investigated 22 patients with MDD and comorbid anxiety disorder and 23 healthy controls. Proton magnetic resonance spectroscopy was performed with voxels placed in pregenual (pg) and dorsal (d) ACC in 3T. Analysis of hair cortisol was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS).Results The N-acetylaspartate/Creatin ratio (NAA/Cr) was reduced in patients in both pgACC (p=0.040) and dACC (p=0.016). A significant interactive effect of diagnosis and cortisol on both pg-NAA/Cr (F=5.00, p=0.033) and d-NAA/Cr (F=7.86, p=0.009) was detected, whereby in controls cortisol was positively correlated with d-NAA/Cr (r=0.61, p=0.004).Conclusions Our results suggest a relationship between NAA metabolism in ACC and HPA axis activity as represented by long-term cortisol output.

  View details for DOI 10.1080/15622975.2022.2058084

  View details for PubMedID 35332851

• C-reactive protein is related to a distinct set of alterations in resting-state functional connectivity contributing to a differential pathophysiology of major depressive disorder. Psychiatry research. Neuroimaging Beckmann, F., Seidenbecher, S., Metzger, C. D., Gescher, D. M., Carballedo, A., Tozzi, L., O'Keane, V., Frodl, T. 2022; 321: 111440

  Abstract

  BACKGROUND: Several studies in major depressive disorder (MDD) have found inflammation, especially C-reactive protein (CRP), to be consistently associated with MDD and network dysfunction. The aim was to investigate whether CRP is linked to a distinct set of resting-state functional connectivity (RSFC) alterations.METHODS: For this reason, we investigated the effects of diagnosis and elevated blood plasma CRP levels on the RSFC in 63 participants (40 females, mean age 31.4 years) of which were 27 patients with a primary diagnosis of MDD and 36 healthy control-subjects (HC), utilizing a seed-based approach within five well-established RSFC networks obtained using fMRI.RESULTS: Of the ten network pairs examined, five showed increased between-network RSFC-values unambiguously connected either to a diagnosis of MDD or elevated CRP levels. For elevated CRP levels, increased RSFC between DMN and AN was found. Patients showed increased RSFC within DMN areas and between the DMN and ECN and VAN, ECN and AN and AN and DAN.CONCLUSIONS: The results of this study show dysregulated neural circuits specifically connected to elevated plasma CRP levels and independent of other alterations of RSFC in MDD. This dysfunction in neural circuits might in turn result in a certain immune-inflammatory subtype of MDD.

  View details for DOI 10.1016/j.pscychresns.2022.111440

  View details for PubMedID 35131572

• Toward Precision Characterization of Dimensions of Threat Response Pathology in Depression and Anxiety: Testing a Theoretical Model That Integrates Circuits, Symptoms and Quality of Life Hagerty, S., Zhang, X., Tozzi, L., Williams, L. SPRINGERNATURE. 2021: 516-517

  View details for Web of Science ID 000725511402137

• Convergence, preliminary findings and future directions across the four human connectome projects investigating mood and anxiety disorders. NeuroImage Tozzi, L., Anene, E. T., Gotlib, I. H., Wintermark, M., Kerr, A. B., Wu, H., Seok, D., Narr, K. L., Sheline, Y. I., Whitfield-Gabrieli, S., Williams, L. M. 2021: 118694

  Abstract

  In this paper we provide an overview of the rationale, methods, and preliminary results of the four Connectome Studies Related to Human Disease investigating mood and anxiety disorders. The first study, "Dimensional connectomics of anxious misery" (HCP-DAM), characterizes brain-symptom relations of a transdiagnostic sample of anxious misery disorders. The second study, "Human connectome Project for disordered emotional states" (HCP-DES), tests a hypothesis-driven model of brain circuit dysfunction in a sample of untreated young adults with symptoms of depression and anxiety. The third study, "Perturbation of the treatment resistant depression connectome by fast-acting therapies" (HCP-MDD), quantifies alterations of the structural and functional connectome as a result of three fast-acting interventions: electroconvulsive therapy, serial ketamine therapy, and total sleep deprivation. Finally, the fourth study, "Connectomes related to anxiety and depression in adolescents" (HCP-ADA), investigates developmental trajectories of subtypes of anxiety and depression in adolescence. The four projects use comparable and standardized Human Connectome Project magnetic resonance imaging (MRI) protocols, including structural MRI, diffusion-weighted MRI, and both task and resting state functional MRI. All four projects also conducted comprehensive and convergent clinical and neuropsychological assessments, including (but not limited to) demographic information, clinical diagnoses, symptoms of mood and anxiety disorders, negative and positive affect, cognitive function, and exposure to early life stress. The first round of analyses conducted in the four projects offered novel methods to investigate relations between functional connectomes and self-reports in large datasets, identified new functional correlates of symptoms of mood and anxiety disorders, characterized the trajectory of connectome-symptom profiles over time, and quantified the impact of novel treatments on aberrant connectivity. Taken together, the data obtained and reported by the four Connectome Studies Related to Human Disease investigating mood and anxiety disorders describe a rich constellation of convergent biological, clinical, and behavioral phenotypes that span the peak ages for the onset of emotional disorders. These data are being prepared for open sharing with the scientific community following screens for quality by the Connectome Coordinating Facility (CCF). The CCF also plans to release data from all projects that have been pre-processed using identical state-of-the-art pipelines. The resultant dataset will give researchers the opportunity to pool complementary data across the four projects to study circuit dysfunctions that may underlie mood and anxiety disorders, to map cohesive relations among circuits and symptoms, and to probe how these relations change as a function of age and acute interventions. This large and combined dataset may also be ideal for using data-driven analytic approaches to inform neurobiological targets for future clinical trials and interventions focused on clinical or behavioral outcomes.

  View details for DOI 10.1016/j.neuroimage.2021.118694

  View details for PubMedID 34732328

• Canonical correlation analysis in high dimensions with structured regularization STATISTICAL MODELLING Tuzhilina, E., Tozzi, L., Hastie, T. 2021

  View details for DOI 10.1177/1471082X211041033

  View details for Web of Science ID 000705084300001

• Coping Strategies, Neural Structure, and Depression and Anxiety During the COVID-19 Pandemic: A Longitudinal Study in a Naturalistic Sample Spanning Clinical Diagnoses and Subclinical Symptoms. Biological psychiatry global open science Holt-Gosselin, B., Tozzi, L., Ramirez, C. A., Gotlib, I. H., Williams, L. M. 2021

  Abstract

  Background: Although the COVID-19 pandemic has been shown to worsen anxiety and depression symptoms, we do not understand which behavioral and neural factors may mitigate this impact. To address this gap, we assessed whether adaptive and maladaptive coping strategies affect symptom trajectory during the pandemic. We also examined whether pre-pandemic integrity of brain regions implicated in depression and anxiety affect pandemic symptoms.Methods: In a naturalistic sample of 169 adults (66.9% female; age 19-74 years) spanning psychiatric diagnoses and subclinical symptoms, we assessed anhedonia, tension, and anxious arousal symptoms using validated components (21-item Depression, Anxiety, and Stress Scale), coping strategies (Brief-Coping Orientation to Problems Experienced), and gray matter volume (amygdala) and cortical thickness (hippocampus, insula, anterior cingulate cortex) from magnetic resonance imaging T1-weighted scans. We conducted general linear mixed-effects models to test preregistered hypotheses that 1) maladaptive coping pre-pandemic and 2) lower structural integrity pre-pandemic would predict more severe pandemic symptoms; and 3) coping would interact with neural structure to predict pandemic symptoms.Results: Greater use of maladaptive coping strategies was associated with more severe anxious arousal symptoms during the pandemic (p= .011, false discovery rate-corrected p [p FDR]= .035), specifically less self-distraction (p= .014, p FDR= .042) and greater self-blame (p= .002, p FDR= .012). Reduced insula thickness pre-pandemic predicted more severe anxious arousal symptoms (p= .001, p FDR= .027). Self-distraction interacted with amygdala volume to predict anhedonia symptoms (p= .005, p FDR= .020).Conclusions: Maladaptive coping strategies and structural variation in brain regions may influence clinical symptoms during a prolonged stressful event (e.g., COVID-19 pandemic). Future studies that identify behavioral and neural factors implicated in responses to global health crises are warranted for fostering resilience.

  View details for DOI 10.1016/j.bpsgos.2021.06.007

  View details for PubMedID 34604834

• Relating whole-brain functional connectivity to self-reported negative emotion in a large sample of young adults using group regularized canonical correlation analysis. NeuroImage Tozzi, L., Tuzhilina, E., Glasser, M. F., Hastie, T. J., Williams, L. M. 2021: 118137

  Abstract

  The goal of our study was to use functional connectivity to map brain function to self-reports of negative emotion. In a large dataset of healthy individuals derived from the Human Connectome Project (N=652), first we quantified functional connectivity during a negative face-matching task to isolate patterns induced by emotional stimuli. Then, we did the same in a complementary task-free resting state condition. To identify the relationship between functional connectivity in these two conditions and self-reports of negative emotion, we introduce group regularized canonical correlation analysis (GRCCA), a novel algorithm extending canonical correlations analysis to model the shared common properties of functional connectivity within established brain networks. To minimize overfitting, we optimized the regularization parameters of GRCCA using cross-validation and tested the significance of our results in a held-out portion of the data set using permutations. GRCCA consistently outperformed plain regularized canonical correlation analysis. The only canonical correlation that generalized to the held-out test set was based on resting state data (r=0.175, permutation test p=0.021). This canonical correlation loaded primarily on Anger-aggression. It showed high loadings in the cingulate, orbitofrontal, superior parietal, auditory and visual cortices, as well as in the insula. Subcortically, we observed high loadings in the globus pallidus. Regarding brain networks, it loaded primarily on the primary visual, orbito-affective and ventral multimodal networks. Here, we present the first neuroimaging application of GRCCA, a novel algorithm for regularized canonical correlation analyses that takes into account grouping of the variables during the regularization scheme. Using GRCCA, we demonstrate that functional connections involving the visual, orbito-affective and multimodal networks are promising targets for investigating functional correlates of subjective anger and aggression. Crucially, our approach and findings also highlight the need of cross-validation, regularization and testing on held out data for correlational neuroimaging studies to avoid inflated effects.

  View details for DOI 10.1016/j.neuroimage.2021.118137

  View details for PubMedID 33951512

• Reduced functional connectivity of default mode network subsystems in depression: Meta-analytic evidence and relationship with trait rumination. NeuroImage. Clinical Tozzi, L. n., Zhang, X. n., Chesnut, M. n., Holt-Gosselin, B. n., Ramirez, C. A., Williams, L. M. 2021; 30: 102570

  Abstract

  Resting-state functional connectivity changes in the default mode network (DMN) of patients with major depressive disorder (MDD) have been linked to rumination. The DMN is divided into three subsystems: a midline Core, a dorsal medial prefrontal cortex (DMPFC) subsystem, and a medial temporal lobe (MTL) subsystem. We examined resting-state functional connectivity within and between DMN subsystems in MDD and its association with rumination. First, we conducted a meta-analysis on a large multi-site dataset of 618 MDD and 683 controls to quantify the differences in DMN subsystem functional connectivity between MDD and controls. Second, we tested the association of DMN subsystem functional connectivity and rumination in a sample of 115 unmedicated participants with symptoms of anxiety/depression and 48 controls. In our meta-analysis, only functional connectivity in the DMN Core was significantly reduced in MDD compared to controls (g = -0.246, CI = [-0.417; -0.074], pFDR = 0.048). Functional connectivity in the DMPFC subsystem and between the Core and DMPFC subsystems was slightly reduced but not significantly (g = -0.162, CI = [-0.310; -0.013], pFDR = 0.096; g = -0.249, CI = [-0.464; -0.034], pFDR = 0.084). Results were heterogeneous across sites for connectivity in the Core and between Core and DMPFC (I2 = 0.348 and I2 = 0.576 respectively). Prediction intervals consistently encompassed 0. In the independent sample we collected, functional connectivity within the DMN Core, DMPFC and between Core and DMPFC was not reduced in MDD compared to controls (all pFDR > 0.05). Trait rumination did not predict connectivity within and between DMN subsystems (all pFDR > 0.05). We conclude that MDD as a diagnostic category shows slightly reduced functional connectivity within the DMN Core, independent of illness duration, treatment, symptoms and trait rumination. However, this effect is small, highly variable and heterogeneous across samples, so that we could only detect it at the meta-analytic level, with a sample size of several hundreds. Our results indicate that reduced Core DMN connectivity has significant limitations as a potential clinical or prognostic marker for the diagnosis of MDD and might be more relevant to consider as a characteristic distinguishing a subgroup of individuals within this diagnostic category.

  View details for DOI 10.1016/j.nicl.2021.102570

  View details for PubMedID 33540370

• Aerobic exercise increases hippocampal subfield volumes in younger adults and prevents volume decline in the elderly BRAIN IMAGING AND BEHAVIOR Frodl, T., Strehl, K., Carballedo, A., Tozzi, L., Doyle, M., Amico, F., Gormley, J., Lavelle, G., O'Keane, V. 2020; 14 (5): 1577–87

  View details for DOI 10.1007/s11682-019-00088-6

  View details for Web of Science ID 000579512100026

• Test-retest reliability of the human functional connectome over consecutive days: identifying highly reliable portions and assessing the impact of methodological choices NETWORK NEUROSCIENCE Tozzi, L., Fleming, S. L., Taylor, Z. D., Raterink, C. D., Williams, L. M. 2020; 4 (3): 925–45

  View details for DOI 10.1162/netn_a_00148

  View details for Web of Science ID 000569091800007

• Test-retest reliability of the human functional connectome over consecutive days: identifying highly reliable portions and assessing the impact of methodological choices. Network neuroscience (Cambridge, Mass.) Tozzi, S. L., Fleming, S. L., Taylor, Z. D., Raterink, C. D., Williams, L. M. 2020; 4 (3): 925-945

  Abstract

  Countless studies have advanced our understanding of the human brain and its organization by using functional magnetic resonance imaging (fMRI) to derive network representations of human brain function. However, we do not know to what extent these "functional connectomes" are reliable over time. In a large public sample of healthy participants (N = 833) scanned on two consecutive days, we assessed the test-retest reliability of fMRI functional connectivity and the consequences on reliability of three common sources of variation in analysis workflows: atlas choice, global signal regression, and thresholding. By adopting the intraclass correlation coefficient as a metric, we demonstrate that only a small portion of the functional connectome is characterized by good (6-8%) to excellent (0.08-0.14%) reliability. Connectivity between prefrontal, parietal, and temporal areas is especially reliable, but also average connectivity within known networks has good reliability. In general, while unreliable edges are weak, reliable edges are not necessarily strong. Methodologically, reliability of edges varies between atlases, global signal regression decreases reliability for networks and most edges (but increases it for some), and thresholding based on connection strength reduces reliability. Focusing on the reliable portion of the connectome could help quantify brain trait-like features and investigate individual differences using functional neuroimaging.

  View details for DOI 10.1162/netn_a_00148

  View details for PubMedID 33615097

  View details for PubMedCentralID PMC7888485

• Variability in the analysis of a single neuroimaging dataset by many teams. Nature Botvinik-Nezer, R., Holzmeister, F., Camerer, C. F., Dreber, A., Huber, J., Johannesson, M., Kirchler, M., Iwanir, R., Mumford, J. A., Adcock, R. A., Avesani, P., Baczkowski, B. M., Bajracharya, A., Bakst, L., Ball, S., Barilari, M., Bault, N., Beaton, D., Beitner, J., Benoit, R. G., Berkers, R. M., Bhanji, J. P., Biswal, B. B., Bobadilla-Suarez, S., Bortolini, T., Bottenhorn, K. L., Bowring, A., Braem, S., Brooks, H. R., Brudner, E. G., Calderon, C. B., Camilleri, J. A., Castrellon, J. J., Cecchetti, L., Cieslik, E. C., Cole, Z. J., Collignon, O., Cox, R. W., Cunningham, W. A., Czoschke, S., Dadi, K., Davis, C. P., Luca, A. D., Delgado, M. R., Demetriou, L., Dennison, J. B., Di, X., Dickie, E. W., Dobryakova, E., Donnat, C. L., Dukart, J., Duncan, N. W., Durnez, J., Eed, A., Eickhoff, S. B., Erhart, A., Fontanesi, L., Fricke, G. M., Fu, S., Galván, A., Gau, R., Genon, S., Glatard, T., Glerean, E., Goeman, J. J., Golowin, S. A., González-García, C., Gorgolewski, K. J., Grady, C. L., Green, M. A., Guassi Moreira, J. F., Guest, O., Hakimi, S., Hamilton, J. P., Hancock, R., Handjaras, G., Harry, B. B., Hawco, C., Herholz, P., Herman, G., Heunis, S., Hoffstaedter, F., Hogeveen, J., Holmes, S., Hu, C. P., Huettel, S. A., Hughes, M. E., Iacovella, V., Iordan, A. D., Isager, P. M., Isik, A. I., Jahn, A., Johnson, M. R., Johnstone, T., Joseph, M. J., Juliano, A. C., Kable, J. W., Kassinopoulos, M., Koba, C., Kong, X. Z., Koscik, T. R., Kucukboyaci, N. E., Kuhl, B. A., Kupek, S., Laird, A. R., Lamm, C., Langner, R., Lauharatanahirun, N., Lee, H., Lee, S., Leemans, A., Leo, A., Lesage, E., Li, F., Li, M. Y., Lim, P. C., Lintz, E. N., Liphardt, S. W., Losecaat Vermeer, A. B., Love, B. C., Mack, M. L., Malpica, N., Marins, T., Maumet, C., McDonald, K., McGuire, J. T., Melero, H., Méndez Leal, A. S., Meyer, B., Meyer, K. N., Mihai, G., Mitsis, G. D., Moll, J., Nielson, D. M., Nilsonne, G., Notter, M. P., Olivetti, E., Onicas, A. I., Papale, P., Patil, K. R., Peelle, J. E., Pérez, A., Pischedda, D., Poline, J. B., Prystauka, Y., Ray, S., Reuter-Lorenz, P. A., Reynolds, R. C., Ricciardi, E., Rieck, J. R., Rodriguez-Thompson, A. M., Romyn, A., Salo, T., Samanez-Larkin, G. R., Sanz-Morales, E., Schlichting, M. L., Schultz, D. H., Shen, Q., Sheridan, M. A., Silvers, J. A., Skagerlund, K., Smith, A., Smith, D. V., Sokol-Hessner, P., Steinkamp, S. R., Tashjian, S. M., Thirion, B., Thorp, J. N., Tinghög, G., Tisdall, L., Tompson, S. H., Toro-Serey, C., Torre Tresols, J. J., Tozzi, L., Truong, V., Turella, L., van 't Veer, A. E., Verguts, T., Vettel, J. M., Vijayarajah, S., Vo, K., Wall, M. B., Weeda, W. D., Weis, S., White, D. J., Wisniewski, D., Xifra-Porxas, A., Yearling, E. A., Yoon, S., Yuan, R., Yuen, K. S., Zhang, L., Zhang, X., Zosky, J. E., Nichols, T. E., Poldrack, R. A., Schonberg, T. 2020; 582 (7810): 84-88

  Abstract

  Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses1. The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset2-5. Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed.

  View details for DOI 10.1038/s41586-020-2314-9

  View details for PubMedID 32483374

• Variability in the analysis of a single neuroimaging dataset by many teams NATURE Botvinik-Nezer, R., Holzmeister, F., Camerer, C. F., Dreber, A., Huber, J., Johannesson, M., Kirchler, M., Iwanir, R., Mumford, J. A., Adcock, R., Avesani, P., Baczkowski, B. M., Bajracharya, A., Bakst, L., Ball, S., Barilari, M., Bault, N., Beaton, D., Beitner, J., Benoit, R. G., Berkers, R. J., Bhanji, J. P., Biswal, B. B., Bobadilla-Suarez, S., Bortolini, T., Bottenhorn, K. L., Bowring, A., Braem, S., Brooks, H. R., Brudner, E. G., Calderon, C. B., Camilleri, J. A., Castrellon, J. J., Cecchetti, L., Cieslik, E. C., Cole, Z. J., Collignon, O., Cox, R. W., Cunningham, W. A., Czoschke, S., Dadi, K., Davis, C. P., Luca, A., Delgado, M. R., Demetriou, L., Dennison, J. B., Di, X., Dickie, E. W., Dobryakova, E., Donnat, C. L., Dukart, J., Duncan, N. W., Durnez, J., Eed, A., Eickhoff, S. B., Erhart, A., Fontanesi, L., Fricke, G., Fu, S., Galvan, A., Gau, R., Genon, S., Glatard, T., Glerean, E., Goeman, J. J., Golowin, S. E., Gonzalez-Garcia, C., Gorgolewski, K. J., Grady, C. L., Green, M. A., Guassi Moreira, J. F., Guest, O., Hakimi, S., Hamilton, J., Hancock, R., Handjaras, G., Harry, B. B., Hawco, C., Herholz, P., Herman, G., Heunis, S., Hoffstaedter, F., Hogeveen, J., Holmes, S., Hu, C., Huettel, S. A., Hughes, M. E., Iacovella, V., Iordan, A. D., Isager, P. M., Isik, A. I., Jahn, A., Johnson, M. R., Johnstone, T., Joseph, M. E., Juliano, A. C., Kable, J. W., Kassinopoulos, M., Koba, C., Kong, X., Koscik, T. R., Kucukboyaci, N., Kuhl, B. A., Kupek, S., Laird, A. R., Lamm, C., Langner, R., Lauharatanahirun, N., Lee, H., Lee, S., Leemans, A., Leo, A., Lesage, E., Li, F., Li, M. C., Lim, P., Lintz, E. N., Liphardt, S. W., Losecaat Vermeer, A. B., Love, B. C., Mack, M. L., Malpica, N., Marins, T., Maumet, C., McDonald, K., McGuire, J. T., Melero, H., Mendez Leal, A. S., Meyer, B., Meyer, K. N., Mihai, G., Mitsis, G. D., Moll, J., Nielson, D. M., Nilsonne, G., Notter, M. P., Olivetti, E., Onicas, A. I., Papale, P., Patil, K. R., Peelle, J. E., Perez, A., Pischedda, D., Poline, J., Prystauka, Y., Ray, S., Reuter-Lorenz, P. A., Reynolds, R. C., Ricciardi, E., Rieck, J. R., Rodriguez-Thompson, A. M., Romyn, A., Salo, T., Samanez-Larkin, G. R., Sanz-Morales, E., Schlichting, M. L., Schultz, D. H., Shen, Q., Sheridan, M. A., Silvers, J. A., Skagerlund, K., Smith, A., Smith, D. V., Sokol-Hessner, P., Steinkamp, S. R., Tashjian, S. M., Thirion, B., Thorp, J. N., Tinghog, G., Tisdall, L., Tompson, S. H., Toro-Serey, C., Torre Tresols, J., Tozzi, L., Truong, V., Turella, L., van 't Veer, A. E., Verguts, T., Vettel, J. M., Vijayarajah, S., Vo, K., Wall, M. B., Weeda, W. D., Weis, S., White, D. J., Wisniewski, D., Xifra-Porxas, A., Yearling, E. A., Yoon, S., Yuan, R., Yuen, K. L., Zhang, L., Zhang, X., Zosky, J. E., Nichols, T. E., Poldrack, R. A., Schonberg, T. 2020

  View details for DOI 10.1038/s41586-020-2314-9

  View details for Web of Science ID 000535225300001

• Clustering of Disordered Emotional States Across Research Domain Criteria Units of Analysis Tozzi, L., Holt-Gosselin, B., Chestnut, M., Whicker, C., Hartley, J., Williams, L. ELSEVIER SCIENCE INC. 2020: S373

  View details for Web of Science ID 000535308201156

• Interactive impact of childhood maltreatment, depression, and age on cortical brain structure: mega-analytic findings from a large multi-site cohort PSYCHOLOGICAL MEDICINE Tozzi, L., Garczarek, L., Janowitz, D., Stein, D. J., Wittfeld, K., Dobrowolny, H., Lagopoulos, J., Hatton, S. N., Hickie, I. B., Carballedo, A., Brooks, S. J., Vuletic, D., Uhlmann, A., Veer, I. M., Walter, H., Buelow, R., Voelzke, H., Klinger-Koenig, J., Schnell, K., Schoepf, D., Grotegerd, D., Opel, N., Dannlowski, U., Kugel, H., Schramm, E., Konrad, C., Kircher, T., Jueksel, D., Nenadic, I., Krug, A., Hahn, T., Steinstraeter, O., Redlich, R., Zaremba, D., Zurowski, B., Fu, C. Y., Dima, D., Cole, J., Grabe, H. J., Connolly, C. G., Yang, T. T., Ho, T. C., Lewinn, K. Z., Li, M., Groenewold, N. A., Salminen, L. E., Walter, M., Simmons, A. N., van Erp, T. M., Jahanshad, N., Baune, B. T., van der Wee, N. A., van Tol, M., Penninx, B. H., Hibar, D. P., Thompson, P. M., Veltman, D. J., Schmaal, L., Frodl, T., ENIGMA-MDD Consortium 2020; 50 (6): 1020–31

  View details for DOI 10.1017/S003329171900093X

  View details for Web of Science ID 000529554900014

• ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries. Translational psychiatry Thompson, P. M., Jahanshad, N., Ching, C. R., Salminen, L. E., Thomopoulos, S. I., Bright, J., Baune, B. T., Bertolin, S., Bralten, J., Bruin, W. B., Bulow, R., Chen, J., Chye, Y., Dannlowski, U., de Kovel, C. G., Donohoe, G., Eyler, L. T., Faraone, S. V., Favre, P., Filippi, C. A., Frodl, T., Garijo, D., Gil, Y., Grabe, H. J., Grasby, K. L., Hajek, T., Han, L. K., Hatton, S. N., Hilbert, K., Ho, T. C., Holleran, L., Homuth, G., Hosten, N., Houenou, J., Ivanov, I., Jia, T., Kelly, S., Klein, M., Kwon, J. S., Laansma, M. A., Leerssen, J., Lueken, U., Nunes, A., Neill, J. O., Opel, N., Piras, F., Piras, F., Postema, M. C., Pozzi, E., Shatokhina, N., Soriano-Mas, C., Spalletta, G., Sun, D., Teumer, A., Tilot, A. K., Tozzi, L., van der Merwe, C., Van Someren, E. J., van Wingen, G. A., Volzke, H., Walton, E., Wang, L., Winkler, A. M., Wittfeld, K., Wright, M. J., Yun, J., Zhang, G., Zhang-James, Y., Adhikari, B. M., Agartz, I., Aghajani, M., Aleman, A., Althoff, R. R., Altmann, A., Andreassen, O. A., Baron, D. A., Bartnik-Olson, B. L., Marie Bas-Hoogendam, J., Baskin-Sommers, A. R., Bearden, C. E., Berner, L. A., Boedhoe, P. S., Brouwer, R. M., Buitelaar, J. K., Caeyenberghs, K., Cecil, C. A., Cohen, R. A., Cole, J. H., Conrod, P. J., De Brito, S. A., de Zwarte, S. M., Dennis, E. L., Desrivieres, S., Dima, D., Ehrlich, S., Esopenko, C., Fairchild, G., Fisher, S. E., Fouche, J., Francks, C., Frangou, S., Franke, B., Garavan, H. P., Glahn, D. C., Groenewold, N. A., Gurholt, T. P., Gutman, B. A., Hahn, T., Harding, I. H., Hernaus, D., Hibar, D. P., Hillary, F. G., Hoogman, M., Hulshoff Pol, H. E., Jalbrzikowski, M., Karkashadze, G. A., Klapwijk, E. T., Knickmeyer, R. C., Kochunov, P., Koerte, I. K., Kong, X., Liew, S., Lin, A. P., Logue, M. W., Luders, E., Macciardi, F., Mackey, S., Mayer, A. R., McDonald, C. R., McMahon, A. B., Medland, S. E., Modinos, G., Morey, R. A., Mueller, S. C., Mukherjee, P., Namazova-Baranova, L., Nir, T. M., Olsen, A., Paschou, P., Pine, D. S., Pizzagalli, F., Renteria, M. E., Rohrer, J. D., Samann, P. G., Schmaal, L., Schumann, G., Shiroishi, M. S., Sisodiya, S. M., Smit, D. J., Sonderby, I. E., Stein, D. J., Stein, J. L., Tahmasian, M., Tate, D. F., Turner, J. A., van den Heuvel, O. A., van der Wee, N. J., van der Werf, Y. D., van Erp, T. G., van Haren, N. E., van Rooij, D., van Velzen, L. S., Veer, I. M., Veltman, D. J., Villalon-Reina, J. E., Walter, H., Whelan, C. D., Wilde, E. A., Zarei, M., Zelman, V., ENIGMA Consortium 2020; 10 (1): 100

  Abstract

  This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.

  View details for DOI 10.1038/s41398-020-0705-1

  View details for PubMedID 32198361

• The human connectome project for disordered emotional states: Protocol and rationale for a research domain criteria study of brain connectivity in young adult anxiety and depression. NeuroImage Tozzi, L., Staveland, B., Holt-Gosselin, B., Chesnut, M., Chang, S. E., Choi, D., Shiner, M. L., Wu, H., Lerma-Usabiaga, G., Sporns, O., Barch, D., Gotlib, I. H., Hastie, T. J., Kerr, A. B., Poldrack, R. A., Wandell, B. A., Wintermark, M., Williams, L. M. 2020: 116715

  Abstract

  Through the Human Connectome Project (HCP) our understanding of the functional connectome of the healthy brain has been dramatically accelerated. Given the pressing public health need, we must increase our understanding of how connectome dysfunctions give rise to disordered mental states. Mental disorders arising from high levels of negative emotion or from the loss of positive emotional experience affect over 400 million people globally. Such states of disordered emotion cut across multiple diagnostic categories of mood and anxiety disorders and are compounded by accompanying disruptions in cognitive function. Not surprisingly, these forms of psychopathology are the leading cause of disability worldwide. The Research Domain Criteria (RDoC) initiative spearheaded by NIMH offers a framework for characterizing the relations among connectome dysfunctions, anchored in neural circuits and phenotypic profiles of behavior and self-reported symptoms. Here, we report on our Connectomes Related to Human Disease protocol for integrating an RDoC framework with HCP protocols to characterize connectome dysfunctions in disordered emotional states, and present quality control data from a representative sample of participants. We focus on three RDoC domains and constructs most relevant to depression and anxiety: 1) loss and acute threat within the Negative Valence System (NVS) domain; 2) reward valuation and responsiveness within the Positive Valence System (PVS) domain; and 3) working memory and cognitive control within the Cognitive System (CS) domain. For 29 healthy controls, we present preliminary imaging data: functional magnetic resonance imaging collected in the resting state and in tasks matching our constructs of interest ("Emotion", "Gambling" and "Continuous Performance" tasks), as well as diffusion-weighted imaging. All functional scans demonstrated good signal-to-noise ratio. Established neural networks were robustly identified in the resting state condition by independent component analysis. Processing of negative emotional faces significantly activated the bilateral dorsolateral prefrontal and occipital cortices, fusiform gyrus and amygdalae. Reward elicited a response in the bilateral dorsolateral prefrontal, parietal and occipital cortices, and in the striatum. Working memory was associated with activation in the dorsolateral prefrontal, parietal, motor, temporal and insular cortices, in the striatum and cerebellum. Diffusion tractography showed consistent profiles of fractional anisotropy along known white matter tracts. We also show that results are comparable to those in a matched sample from the HCP Healthy Young Adult data release. These preliminary data provide the foundation for acquisition of 250 subjects who are experiencing disordered emotional states. When complete, these data will be used to develop a neurobiological model that maps connectome dysfunctions to specific behaviors and symptoms.

  View details for DOI 10.1016/j.neuroimage.2020.116715

  View details for PubMedID 32147367

• ENIGMA MDD: seven years of global neuroimaging studies of major depression through worldwide data sharing. Translational psychiatry Schmaal, L. n., Pozzi, E. n., C Ho, T. n., van Velzen, L. S., Veer, I. M., Opel, N. n., Van Someren, E. J., Han, L. K., Aftanas, L. n., Aleman, A. n., Baune, B. T., Berger, K. n., Blanken, T. F., Capitão, L. n., Couvy-Duchesne, B. n., R Cullen, K. n., Dannlowski, U. n., Davey, C. n., Erwin-Grabner, T. n., Evans, J. n., Frodl, T. n., Fu, C. H., Godlewska, B. n., Gotlib, I. H., Goya-Maldonado, R. n., Grabe, H. J., Groenewold, N. A., Grotegerd, D. n., Gruber, O. n., Gutman, B. A., Hall, G. B., Harrison, B. J., Hatton, S. N., Hermesdorf, M. n., Hickie, I. B., Hilland, E. n., Irungu, B. n., Jonassen, R. n., Kelly, S. n., Kircher, T. n., Klimes-Dougan, B. n., Krug, A. n., Landrø, N. I., Lagopoulos, J. n., Leerssen, J. n., Li, M. n., Linden, D. E., MacMaster, F. P., M McIntosh, A. n., Mehler, D. M., Nenadić, I. n., Penninx, B. W., Portella, M. J., Reneman, L. n., Rentería, M. E., Sacchet, M. D., G Sämann, P. n., Schrantee, A. n., Sim, K. n., Soares, J. C., Stein, D. J., Tozzi, L. n., van Der Wee, N. J., van Tol, M. J., Vermeiren, R. n., Vives-Gilabert, Y. n., Walter, H. n., Walter, M. n., Whalley, H. C., Wittfeld, K. n., Whittle, S. n., Wright, M. J., Yang, T. T., Zarate, C. n., Thomopoulos, S. I., Jahanshad, N. n., Thompson, P. M., Veltman, D. J. 2020; 10 (1): 172

  Abstract

  A key objective in the field of translational psychiatry over the past few decades has been to identify the brain correlates of major depressive disorder (MDD). Identifying measurable indicators of brain processes associated with MDD could facilitate the detection of individuals at risk, and the development of novel treatments, the monitoring of treatment effects, and predicting who might benefit most from treatments that target specific brain mechanisms. However, despite intensive neuroimaging research towards this effort, underpowered studies and a lack of reproducible findings have hindered progress. Here, we discuss the work of the ENIGMA Major Depressive Disorder (MDD) Consortium, which was established to address issues of poor replication, unreliable results, and overestimation of effect sizes in previous studies. The ENIGMA MDD Consortium currently includes data from 45 MDD study cohorts from 14 countries across six continents. The primary aim of ENIGMA MDD is to identify structural and functional brain alterations associated with MDD that can be reliably detected and replicated across cohorts worldwide. A secondary goal is to investigate how demographic, genetic, clinical, psychological, and environmental factors affect these associations. In this review, we summarize findings of the ENIGMA MDD disease working group to date and discuss future directions. We also highlight the challenges and benefits of large-scale data sharing for mental health research.

  View details for DOI 10.1038/s41398-020-0842-6

  View details for PubMedID 32472038

• The Impact of Childhood Trauma on Developing Bipolar Disorder: Current Understanding and Ensuring Continued Progress. Neuropsychiatric disease and treatment Quide, Y., Tozzi, L., Corcoran, M., Cannon, D. M., Dauvermann, M. R. 2020; 16: 3095–3115

  Abstract

  Childhood trauma (CT) has been repeatedly linked to earlier onset and greater severity of bipolar disorder (BD) in adulthood. However, such knowledge is mostly based on retrospective and cross-sectional studies in adults with BD. The first objective of this selective review is to characterize the short-term effects of CT in the development of BD by focusing on studies in young people. The second objective is to describe the longer-term consequences of CT by considering studies with adult participants. This review first outlines the most prominent hypotheses linking CT exposure and the onset of BD. Then, it summarizes the psychological and biological risk factors implicated in the development of BD, followed by a discussion of original studies that investigated the role of CT in young people with early-onset BD, youths at increased risk of developing BD, or young people with BD with a focus on subclinical and clinical outcome measures. The review considers additional biological and psychological factors associated with a negative impact of CT on the long-term course of BD in later adulthood. Finally, we discuss how the integration of information of CT can improve ongoing early identification of BD and mitigate severe clinical expression in later adulthood.

  View details for DOI 10.2147/NDT.S285540

  View details for PubMedID 33364762

• Using Human Connectome Imaging Within an RDoC Framework to Characterize Disordered Emotional States Tozzi, L. NATURE PUBLISHING GROUP. 2019: 43

  View details for Web of Science ID 000509665600092

• Effects of early life adversity and FKBP5 genotype on hippocampal subfields volume in major depression JOURNAL OF AFFECTIVE DISORDERS Mikolas, P., Tozzi, L., Doolin, K., Farrell, C., O'Keane, V., Frodl, T. 2019; 252: 152–59

  View details for DOI 10.1016/j.jad.2019.04.054

  View details for Web of Science ID 000467801200021

• Longitudinal diffusion weighted imaging of limbic regions in patients with major depressive disorder after 6 years and partial to full remission PSYCHIATRY RESEARCH-NEUROIMAGING Doolin, K., Andrews, S., Carballedo, A., McCarthy, H., O'Hanlon, E., Tozzi, L., Frodl, T. 2019; 287: 75–86

  View details for DOI 10.1016/j.pscychresns.2019.04.004

  View details for Web of Science ID 000465073700011

• Interactive impact of childhood maltreatment, depression, and age on cortical brain structure: mega-analytic findings from a large multi-site cohort. Psychological medicine Tozzi, L., Garczarek, L., Janowitz, D., Stein, D. J., Wittfeld, K., Dobrowolny, H., Lagopoulos, J., Hatton, S. N., Hickie, I. B., Carballedo, A., Brooks, S. J., Vuletic, D., Uhlmann, A., Veer, I. M., Walter, H., Bulow, R., Volzke, H., Klinger-Konig, J., Schnell, K., Schoepf, D., Grotegerd, D., Opel, N., Dannlowski, U., Kugel, H., Schramm, E., Konrad, C., Kircher, T., Juksel, D., Nenadic, I., Krug, A., Hahn, T., Steinstrater, O., Redlich, R., Zaremba, D., Zurowski, B., Fu, C. H., Dima, D., Cole, J., Grabe, H. J., Connolly, C. G., Yang, T. T., Ho, T. C., LeWinn, K. Z., Li, M., Groenewold, N. A., Salminen, L. E., Walter, M., Simmons, A. N., van Erp, T. G., Jahanshad, N., Baune, B. T., van der Wee, N. J., van Tol, M., Penninx, B. W., Hibar, D. P., Thompson, P. M., Veltman, D. J., Schmaal, L., Frodl, T., for the ENIGMA-MDD Consortium 2019: 1–12

  Abstract

  BACKGROUND: Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age.METHODS: Within the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer.RESULTS: CM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions.CONCLUSIONS: Severity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.

  View details for PubMedID 31084657

• Neurobiological correlates of violence perception in martial artists BRAIN AND BEHAVIOR Schoene, M., Seidenbecher, S., Tozzi, L., Kaufmann, J., Griep, H., Fenker, D., Frodl, T., Bogerts, B., Schiltz, K. 2019; 9 (5)

  View details for DOI 10.1002/brb3.1276

  View details for Web of Science ID 000471349100013

• Longitudinal diffusion weighted imaging of limbic regions in patients with major depressive disorder after 6 years and partial to full remission. Psychiatry research. Neuroimaging Doolin, K., Andrews, S., Carballedo, A., McCarthy, H., O'Hanlon, E., Tozzi, L., Frodl, T. 2019; 287: 75–86

  Abstract

  The objective of this study was to determine the effect of major depressive disorder (MDD) on white matter microstructures after a 6-year period compared to healthy controls (HC). This study included a small sample size of 26 participants, including 14 patients with MDD clinically diagnosed at baseline, and 12 HCs. MRI brain scans were conducted at baseline and follow-up, 75.32 (±2.25) months after the initial scan. Tractography of 7 regions including the fornix, cingulum, superior longitudinal fasciculus, inferior fronto-occipital fasciculus and uncinate fasciculus were conducted using ExploreDTI software. Both groups showed significant reduction in tract integrity between time points. MDD diagnosis was shown to have an effect on longitudinal FA of the left dorsal cingulum and the left parahippocampal cingulum. A significant inverse relationship was found between DeltaFA [baseline FA - follow-up FA] of the right uncinate fasciculus and the left rostral cingulum with DeltaHAM-D [baseline HAM-D - follow-up HAM-D] within the MDD group. These preliminary findings support the hypothesis that limbic structures including the cingulum are involved in MDD pathophysiology and may be affected even after remission. Moreover, they indicate that recovery from depression symptoms may slow the rate of WM degradation associated with aging in these regions of interest.

  View details for PubMedID 31004996

• Effects of early life adversity and FKBP5 genotype on hippocampal subfields volume in major depression. Journal of affective disorders Mikolas, P., Tozzi, L., Doolin, K., Farrell, C., O'Keane, V., Frodl, T. 2019; 252: 152–59

  Abstract

  BACKGROUND: Smaller hippocampus volume represents a consistent finding in major depression (MDD). Hippocampal neuroplasticity due to chronic stress might have differential effect on hippocampal subfields. We investigated the effects of the rs1360780 polymorphism of the hypothalamic-pituitary-axis related gene FKBP5 in combination with early life stress (ELA) on the structure of hippocampal subfields in MDD.METHODS: We assessed the hippocampal subfields volumes in 85/67 MDD/healthy controls. We investigated the effects of diagnosis, FKBP5 allelic status and their interaction as predictors of hippocampal subfield volumes as well as the effect of ELA and its interaction with FKBP5.RESULTS: MDD patients had smaller hippocampal volumes, in particular within the cornu ammonis (CA) and dentate gyrus (DG) regions. Patients exposed to ELA had larger hippocampi, in particular within the CA and DG. Among the patients exposed to ELA, the T allele carriers displayed lower volumes within the hippocampus-amygdala-transition-area (HATA) as those subjects homozygous for the C allele.LIMITATIONS: We pooled the subjects from 2 centers in order to increase the sample size. We did not include the cumulative lifetime exposure to medication.CONCLUSIONS: Hippocampal volume reductions in MDD were present particularly in the CA and DG. MDD with ELA display differential volume changes compared to MDD without ELA. The significant interaction between ELA and the rs1360780 polymorphism in HATA suggests a role of FKBP5 in the pathophysiology of structural alterations in depression.

  View details for PubMedID 30986730

• Aerobic exercise increases hippocampal subfield volumes in younger adults and prevents volume decline in the elderly. Brain imaging and behavior Frodl, T., Strehl, K., Carballedo, A., Tozzi, L., Doyle, M., Amico, F., Gormley, J., Lavelle, G., O'Keane, V. 2019

  Abstract

  Exercise improves both physical and mental health and increases neurogenesis in the dendate gyrus (DG) of the hippocampus. The aim of this study was to examine whether exercising, as compared to no change in regular physical activity, would impact on hippocampal volume, and in particular the core hippocampal structures, DG and cornu ammonis (CA) subfields, and whether any changes would be moderated by age. Thirty nine previously sedentary healthy participants were randomized to either a standardized progressive aerobic exercise program or to "no change" for 16weeks. Mental health including profile of mood states (POMS), was assessed before and every 4weeks during the program. Magnetic resonance imaging to examine hippocampal subfields was carried out before and after the program. Aerobic exercise resulted in a significant improvement of the POMS item 'vigour' compared to those in the control group. Overall left hippocampal and left CA4-DG volumes increased significantly in the exercise group while no significant changes were seen in the control group. Older adults in the control group demonstrated significant reductions in CA4-DG subfields over the study, whereas older adults in the exercise group did not show volume decline. These findings reinforce the literature that exercise has a beneficial effect on mental health and can prevent age-related volume decline. Exercise to Improve Resilience, https://register.clinicaltrials.gov/prs/app/action/LoginUser?ts=1&cx=-jg9qo4 , NCT02541136, Rec Ref 2011/45/13.

  View details for PubMedID 30927200

• Neurobiological correlates of violence perception in martial artists. Brain and behavior Schone, M., Seidenbecher, S., Tozzi, L., Kaufmann, J., Griep, H., Fenker, D., Frodl, T., Bogerts, B., Schiltz, K. 2019: e01276

  Abstract

  OBJECTIVES: The direct exertion as well as the visual perception of violence can have a hedonistic effect and elicit positive arousal in predisposed individuals. This appetitive aspect of aggression in healthy subjects has been neglected in psychiatric research so far.METHODS: Using functional magnetic resonance imaging, we tested whether subjects trained in sports with a violent component (martial arts) show altered brain responses in reward-associated brain areas when compared to controls. Sixteen martial artists (e.g., boxing, mixed martial arts) and 24 controls watched violent versus neutral pictures while performing a cognitive cover task. Subjects' aggressiveness was assessed by the aggressiveness factors questionnaire (FAF).RESULTS: While watching violent pictures, martial artists had a stronger activation in the left amygdala than controls. Within the martial artist group however, there was an inverse correlation between activation in the left amygdala and degree of aggressiveness.CONCLUSIONS: Higher amygdala activation while watching violent pictures might reflect that perception of violence conveys increased salience to martial artists as compared to controls. The inverse correlation between amygdala activation and aggressiveness within the martial artist group might be explained by the assumption that the more aggressive martial artists may be more accustomed to violent situations leading to a down-modulation of amygdala activation. Appetitive aggression should be taken into account as a factor contributing to violence.

  View details for PubMedID 30907076

• The Hippocampus in Depression: More Than the Sum of Its Parts? Advanced Hippocampal Substructure Segmentation in Depression BIOLOGICAL PSYCHIATRY Roddy, D. W., Farrell, C., Doolin, K., Roman, E., Tozzi, L., Frodl, T., O'Keane, V., O'Hanlon, E. 2019; 85 (6): 487-497

  View details for DOI 10.1016/j.biopsych.2018.08.021

  View details for Web of Science ID 000458733600010

• Connectivity of the Cognitive Control Network During Response Inhibition as a Predictive and Response Biomarker in Major Depression: Evidence From a Randomized Clinical Trial. Biological psychiatry Tozzi, L. n., Goldstein-Piekarski, A. N., Korgaonkar, M. S., Williams, L. M. 2019

  Abstract

  In treating major depressive disorder, we lack tests anchored in neurobiology that predict antidepressant efficacy. Cognitive impairments are a particularly disabling feature of major depressive disorder. We tested whether functional connectivity during a response-inhibition task can predict response to antidepressants and whether its changes over time are correlated to symptom changes.We analyzed data from outpatients with major depressive disorder (n = 124) randomized to receive escitalopram, sertraline, or venlafaxine (8 weeks) and healthy control subjects (n = 59; age 18-65 years). Before and after treatment, participants were interviewed and scanned using functional magnetic resonance imaging, and functional connectivity was measured using generalized psychophysiological interaction during response inhibition (Go-NoGo task). We investigated the interaction between treatment type and response (≥50% reduction on self-reported symptoms), coupling differences between responders and nonresponders at baseline, their correlation with symptom improvement, and their changes in time.During response inhibition, connectivity between the dorsolateral prefrontal cortex/supramarginal gyrus and supramarginal gyrus/middle temporal gyrus was associated with response to sertraline and venlafaxine, but not escitalopram. Sertraline responders had higher functional connectivity between these regions compared with nonresponders, whereas venlafaxine responders had lower functional connectivity. For sertraline, attenuation of connectivity in the precentral and superior temporal gyri correlated with posttreatment symptom improvement. For venlafaxine, enhancement of connectivity between the orbitofrontal cortex and subcortical regions correlated with symptom improvement.Connectivity of the cognitive control circuit during response inhibition selectively and differentially predicts antidepressant treatment response and correlates with symptom improvement. These quantitative markers tied to the neurobiology of cognitive features of depression could be used translationally to predict and evaluate treatment response.

  View details for DOI 10.1016/j.biopsych.2019.08.005

  View details for PubMedID 31601424

• White matter disturbances in major depressive disorder: a coordinated analysis across 20 international cohorts in the ENIGMA MDD working group. Molecular psychiatry van Velzen, L. S., Kelly, S. n., Isaev, D. n., Aleman, A. n., Aftanas, L. I., Bauer, J. n., Baune, B. T., Brak, I. V., Carballedo, A. n., Connolly, C. G., Couvy-Duchesne, B. n., Cullen, K. R., Danilenko, K. V., Dannlowski, U. n., Enneking, V. n., Filimonova, E. n., Förster, K. n., Frodl, T. n., Gotlib, I. H., Groenewold, N. A., Grotegerd, D. n., Harris, M. A., Hatton, S. N., Hawkins, E. L., Hickie, I. B., Ho, T. C., Jansen, A. n., Kircher, T. n., Klimes-Dougan, B. n., Kochunov, P. n., Krug, A. n., Lagopoulos, J. n., Lee, R. n., Lett, T. A., Li, M. n., MacMaster, F. P., Martin, N. G., McIntosh, A. M., McLellan, Q. n., Meinert, S. n., Nenadić, I. n., Osipov, E. n., Penninx, B. W., Portella, M. J., Repple, J. n., Roos, A. n., Sacchet, M. D., Sämann, P. G., Schnell, K. n., Shen, X. n., Sim, K. n., Stein, D. J., van Tol, M. J., Tomyshev, A. S., Tozzi, L. n., Veer, I. M., Vermeiren, R. n., Vives-Gilabert, Y. n., Walter, H. n., Walter, M. n., van der Wee, N. J., van der Werff, S. J., Schreiner, M. W., Whalley, H. C., Wright, M. J., Yang, T. T., Zhu, A. n., Veltman, D. J., Thompson, P. M., Jahanshad, N. n., Schmaal, L. n. 2019

  Abstract

  Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12-88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen's d between 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen's d between 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD.

  View details for DOI 10.1038/s41380-019-0477-2

  View details for PubMedID 31471575

• Functional Impacts of Acute Stress on Negative Affective Circuit Function in Anxiety and Depression Goldstein-Piekarski, A., Tozzi, L., Sudheimer, K., Schatzberg, A., Williams, L. NATURE PUBLISHING GROUP. 2018: S232

  View details for Web of Science ID 000509546600437

• The Hippocampus in Depression: More Than the Sum of Its Parts? Advanced Hippocampal Substructure Segmentation in Depression. Biological psychiatry Roddy, D. W., Farrell, C., Doolin, K., Roman, E., Tozzi, L., Frodl, T., O'Keane, V., O'Hanlon, E. 2018

  Abstract

  BACKGROUND: Hippocampal volume reduction is the most replicated finding in neuroimaging studies of major depressive disorder (MDD). Varying hippocampal volume definition is a well-established problem in this field. Given that hippocampal function can be mapped onto anatomically defined substructures and that detailed examination of substructure volumes is now possible, we examined different hippocampal composite measures in MDD to look for hippocampal markers of MDD.METHODS: Magnetic resonance imaging brain scans were compared between 80 patients with a range of MDD duration and 83 healthy control subjects. High-resolution T1-weighted and T2-weighted-fluid-attenuated inversion recovery magnetic resonance images were examined using the automated hippocampal substructure module in FreeSurfer 6.0. Between-group volumetric assessments were performed at substructure and composite substructures levels.RESULTS: Patients with MDD showed a bilateral pattern of volume reduction in principal hippocampal substructures: the cornu ammonis (CA1-CA4), dentate gyrus, and subiculum. Changes were more pronounced on the left of these structures and in recurrent depression. CA2 to CA4 were the only substructures reduced in first-presentation depression. Overall changes were most marked in the left CA1, and CA1 volume was a predictor of illness duration.CONCLUSIONS: Hippocampal involvement in MDD is confined to principal substructures only. Differences between patients with MDD and healthy control subjects increased with progressively restricted hippocampal definitions, with the left CA1 emerging as a potential marker of MDD. Changes were more extensive in patients with recurrent, as opposed to first-presentation, MDD, suggesting a hippocampal disease process. These findings identify core hippocampal regions in the pathology of MDD, suggesting a potential marker of disease progression in MDD.

  View details for PubMedID 30528746

• Altered tryptophan catabolite concentrations in major depressive disorder and associated changes in hippocampal subfield volumes PSYCHONEUROENDOCRINOLOGY Doolin, K., Allers, K. A., Pleiner, S., Liesener, A., Farrell, C., Tozzi, L., O'Hanlon, E., Roddy, D., Frodl, T., Harkin, A., O'Keane, V. 2018; 95: 8-17

  View details for DOI 10.1016/j.psyneuen.2018.05.019

  View details for Web of Science ID 000445713400002

• DNA methylation differences at the glucocorticoid receptor gene in depression are related to functional alterations in hypothalamic-pituitary-adrenal axis activity and to early life emotional abuse. Psychiatry research Farrell, C., Doolin, K., O' Leary, N., Jairaj, C., Roddy, D., Tozzi, L., Morris, D., Harkin, A., Frodl, T., Nemoda, Z., Szyf, M., Booij, L., O'Keane, V. 2018; 265: 341–48

  Abstract

  Depression is associated with alterations in hypothalamic-pituitary-adrenal (HPA) axis activity. A proposed mechanism to explain these alterations are changes in DNA methylation levels, secondary to early life adversity (ELA), at stress-related genes. Two gene regions that have been implicated in the literature, the glucocorticoid receptor gene (NR3C1) exon 1F and the FKBP5 gene intron 7 were examined in 67 individuals (33 depressed patients and 34 controls). We investigated whether cortisol concentrations, evaluated in 25 depressed patients and 20 controls, and measures of ELA were associated with the degree of methylation at these candidate gene regions. Mean NR3C1 exon 1F DNA methylation levels were significantly increased in the depressed cohort and the degree of methylation was found to be positively associated with morning cortisol concentrations. DNA methylation levels at specific CG sites within the NR3C1 exon 1F were related to childhood emotional abuse severity. DNA methylation at CG38 was related to both HPA axis and childhood emotional abuse measures in the depressed group. No FKBP5 differences were revealed. Our findings suggest that hypermethylation at the NR3C1 exon 1F may occur in depression. This locus-specific epigenetic change is associated with higher basal HPA axis activity, possibly reflecting acquired glucocorticoid receptor resistance.

  View details for PubMedID 29793048

• DNA methylation differences at the glucocorticoid receptor gene in depression are related to functional alterations in hypothalamic-pituitary-adrenal axis activity and to early life emotional abuse PSYCHIATRY RESEARCH Farrell, C., Doolin, K., O'Leary, N., Jairaj, C., Roddy, D., Tozzi, L., Morris, D., Harkin, A., Frodl, T., Nemoda, Z., Szyf, M., Booij, L., O'Keane, V. 2018; 265: 341-348

  View details for DOI 10.1016/j.psychres.2018.04.064

  View details for Web of Science ID 000435428300051

• Altered tryptophan catabolite concentrations in major depressive disorder and associated changes in hippocampal subfield volumes. Psychoneuroendocrinology Doolin, K., Allers, K. A., Pleiner, S., Liesener, A., Farrell, C., Tozzi, L., O'Hanlon, E., Roddy, D., Frodl, T., Harkin, A., O'Keane, V. 2018; 95: 8–17

  Abstract

  BACKGROUND: Tryptophan depletion is a well-replicated biological finding in Major Depressive Disorder (MDD). The kynurenine pathway (KP) and its rate-limiting tryptophan degrading enzyme, indolamine 2,3 dioxygenase (IDO), have been implicated in the pathogenesis of depression. IDO expression is driven by inflammatory cytokines, providing a putative link between inflammation and neuropathology. This study examined circulating concentrations of C-reactive protein (CRP), plasma tryptophan, kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QUIN) and whole blood mRNA expression of IDO in patients with major depressive disorder (MDD) compared with healthy controls (HC).METHODS: A diagnosis of major depression was made according to DSM-IV. Depression severity was assessed using the Hamilton depression (HAM-D) rating scale. 74 MDD patients, 39 with a first presentation of MDD (fpMDD) and 35 with chronic or recurrent episodes (rMDD), and 37 HC were recruited to the study. Whole blood and plasma samples were collected. Expression of markers in whole blood were measured by PCR, circulating CRP by ELISA and KP metabolites by LC-MS/MS. Hippocampal cornu ammonis (CA) and subiculum volumes were determined by MRI and calculated using FreeSurfer.RESULTS: Tryptophan concentrations were significantly reduced in MDD compared to HC. There was a positive correlation between QUIN and both CRP concentrations and whole blood IDO1 in MDD. KYNA concentrations were reduced in MDD patients presenting with a first episode (fpMDD) compared to those presenting with recurrent depression (rMDD) and HC. By contrast QUIN concentrations were elevated in rMDD compared to fpMDD and HC. KYNA/QUIN was reduced in MDD and rMDD but not fpMDD compared to HC. Hippocampal subfield volumes were smaller in MDD patients than HC for CA1 (left only), CA2/3 (left and right) and CA4 (right only). CRP and CA1 volumes were negatively correlated bilaterally in MDD patients. KYNA and subiculum volume were positively correlated bilaterally.DISCUSSION: This study found evidence of KP metabolism imbalance in MDD patients in addition to tryptophan reduction and mild immune activation. Relationships between CRP and KYNA with some hippocampal subfield volumes in MDD patients suggest that this inflammatory signature may be associated with reduced hippocampal subfield volumes in depression.

  View details for PubMedID 29787958

• Awakening Neuropsychiatric Research Into the Stria Medullaris: Development of a Diffusion-Weighted Imaging Tractography Protocol of This Key Limbic Structure FRONTIERS IN NEUROANATOMY Roddy, D. W., Roman, E., Rooney, S., Andrews, S., Farrell, C., Doolin, K., Levins, K. J., Tozzi, L., Tierney, P., Barry, D., Frodl, T., O'Keane, V., O'Hanlon, E. 2018; 12: 39

  Abstract

  The Stria medullaris (SM) Thalami is a discrete white matter tract that directly connects frontolimbic areas to the habenula, allowing the forebrain to influence midbrain monoaminergic output. Habenular dysfunction has been shown in various neuropsychiatric conditions. However, there exists a paucity of research into the habenula's principal afferent tract, the SM. Diffusion-weighted tractography may provide insights into the properties of the SM in vivo, opening up investigation of this tract in conditions of monoamine dysregulation such as depression, schizophrenia, addiction and pain. We present a reliable method for reconstructing the SM using diffusion-weighted imaging, and examine the effects of age and gender on tract diffusion metrics. We also investigate reproducibility of the method through inter-rater comparisons. In consultation with neuroanatomists, a Boolean logic gate protocol was developed for use in ExploreDTI to extract the SM from constrained spherical deconvolution based whole brain tractography. Particular emphasis was placed on the reproducibility of the tract, attention to crossing white matter tract proximity and anatomical consistency of anterior and posterior boundaries. The anterior commissure, pineal gland and mid point of the thalamus were defined as anatomical fixed points used for reconstruction. Fifty subjects were scanned using High Angular Resolution Diffusion Imaging (HARDI; 61 directions, b-value 1500 mm3). Following constrained spherical deconvolution whole brain tractography, two independent raters isolated the SM. Each output was checked, examined and cleaned for extraneous streamlines inconsistent with known anatomy of the tract by the rater and a neuroanatomist. A second neuroanatomist assessed tracts for face validity. The SM was reconstructed with excellent inter-rater reliability for dimensions and diffusion metrics. Gender had no effect on the dimensions or diffusion metrics, however radial diffusivity (RD) showed a positive correlation with age. Reliable identification and quantification of diffusion metrics of the SM invites further exploration of this key habenula linked structure in neuropsychiatric disorders such as depression, anxiety, chronic pain and addiction. The accurate anatomical localization of the SM may also aid preoperative stereotactic localization of the tract for deep brain stimulation (DBS) treatment.

  View details for PubMedID 29867378

• Epigenetic Changes of FKBP5 as a Link Connecting Genetic and Environmental Risk Factors with Structural and Functional Brain Changes in Major Depression. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Tozzi, L., Farrell, C., Booij, L., Doolin, K., Nemoda, Z., Szyf, M., Pomares, F. B., Chiarella, J., O'Keane, V., Frodl, T. 2017

  Abstract

  The gene for the glucocorticoid receptor regulator FK506 binding protein 5 (FKBP5) plays a role for risk, response to treatment, and changes in brain areas in major depressive disorder (MDD). Chronic stress is associated with lower methylation of FKBP5. Our aim was to investigate whether methylation of FKBP5 reflected exposure to childhood adversity in MDD and controls and whether it was associated with structure and function of emotional processing regions. FKBP5 intron 7 GR response element region methylation and rs1360780 allelic status were assessed from whole blood in 56 MDD adults and 50 controls. Using magnetic resonance imaging, we assessed gray matter concentration of selected areas and their function during valence recognition of emotional images. Childhood adversity was investigated using the Childhood Trauma Questionnaire. In MDD patients carrying the high-risk T allele of rs1360780, lower methylation of FKBP5 was predicted by childhood adversity (F=4.95, p=0.04). In all participants, lower FKBP5 intron methylation levels were associated with reduced gray matter concentration in the inferior frontal orbital gyrus bilaterally (Wald chi-square=11.93, pFDR<0.01) and, in MDD, with its bilaterally higher activation during valence recognition (Wald chi-square=5.58, p=0.02). Activation of this region, regardless of side, was found to be lower in MDD compared to controls (Wald chi-square=3.88, p=0.049) and to be inversely correlated with depression severity (Wald chi-square=4.65, p=0.03). Our findings support the hypothesis that, in genetically predisposed individuals carrying a high-risk variant of the gene, childhood maltreatment might induce demethylation of FKBP5. This is in turn associated with structural and functional changes in the inferior frontal orbital gyrus, a relevant area for the clinical symptoms of MDD.Neuropsychopharmacology advance online publication, 20 December 2017; doi:10.1038/npp.2017.290.

  View details for DOI 10.1038/npp.2017.290

  View details for PubMedID 29182159

• Diurnal Hypothalamic-Pituitary-Adrenal Axis Measures and Inflammatory Marker Correlates in Major Depressive Disorder. International journal of molecular sciences Doolin, K., Farrell, C., Tozzi, L., Harkin, A., Frodl, T., O'Keane, V. 2017; 18 (10)

  Abstract

  Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory systems is a consistent finding in patients with Major Depressive Disorder (MDD). Cortisol is often assessed by measurement of the cortisol awakening response (CAR) and/or diurnal cortisol levels. Some methods of cortisol measurement overestimate cortisol concentration due to detection of other glucocorticoids including the relatively inert cortisone, therefore this study aimed to assess the presence of both cortisol and cortisone, and the cortisol-cortisone catalyzing enzyme 11β-hydroxysteroiddehydrogenase type 1 (11β-HSD1), in depressed patients and controls. Because the HPA axis is known to regulate the body's immune system, relationships between measures of cytokines and cortisol were also assessed. Saliva samples were collected from 57 MDD patients and 40 healthy controls at five post-wakening time points (0, +30, +60, +720 and +750 min). Glucocorticoid concentrations were measured by liquid chromatography mass spectrometry. Whole blood mRNA expression of several inflammatory markers was measured by quantitative polymerase chain reaction. This study replicated the common finding of elevated morning cortisol and reduced CAR reactivity in MDD and found no differences in cortisone or 11β-HSD1 mRNA measures. There was a negative association between interleukin 1-β (IL-1β) mRNA and morning cortisol reactivity within the depressed group, indicating that dysregulation of the HPA axis and immune system may be interconnected.

  View details for DOI 10.3390/ijms18102226

  View details for PubMedID 29064428

  View details for PubMedCentralID PMC5666905

• Recent Advances in Translational Magnetic Resonance Imaging in Animal Models of Stress and Depression. Frontiers in cellular neuroscience McIntosh, A. L., Gormley, S., Tozzi, L., Frodl, T., Harkin, A. 2017; 11: 150

  Abstract

  Magnetic resonance imaging (MRI) is a valuable translational tool that can be used to investigate alterations in brain structure and function in both patients and animal models of disease. Regional changes in brain structure, functional connectivity, and metabolite concentrations have been reported in depressed patients, giving insight into the networks and brain regions involved, however preclinical models are less well characterized. The development of more effective treatments depends upon animal models that best translate to the human condition and animal models may be exploited to assess the molecular and cellular alterations that accompany neuroimaging changes. Recent advances in preclinical imaging have facilitated significant developments within the field, particularly relating to high resolution structural imaging and resting-state functional imaging which are emerging techniques in clinical research. This review aims to bring together the current literature on preclinical neuroimaging in animal models of stress and depression, highlighting promising avenues of research toward understanding the pathological basis of this hugely prevalent disorder.

  View details for DOI 10.3389/fncel.2017.00150

  View details for PubMedID 28596724

  View details for PubMedCentralID PMC5442179

• Childhood adversity impacts on brain subcortical structures relevant to depression JOURNAL OF PSYCHIATRIC RESEARCH Frodl, T., Janowitz, D., Schmaal, L., Tozzi, L., Dobrowolny, H., Stein, D. J., Veltman, D. J., Wittfeld, K., van Erp, T. G., Jahanshad, N., Block, A., Hegenscheid, K., Voelzke, H., Lagopoulos, J., Hatton, S. N., Hickie, I. B., Frey, E. M., Carballedo, A., Brooks, S. J., Vuletic, D., Uhlmann, A., Veer, I. M., Walter, H., Schnell, K., Grotegerd, D., Arolt, V., Kugel, H., Schramm, E., Konrad, C., Zurowski, B., Baune, B. T., van der Wee, N. J., van Tol, M., Penninx, B. W., Thompson, P. M., Hibar, D. P., Dannlowski, U., Grabe, H. J. 2017; 86: 58-65

  Abstract

  Childhood adversity plays an important role for development of major depressive disorder (MDD). There are differences in subcortical brain structures between patients with MDD and healthy controls, but the specific impact of childhood adversity on such structures in MDD remains unclear. Thus, aim of the present study was to investigate whether childhood adversity is associated with subcortical volumes and how it interacts with a diagnosis of MDD and sex. Within the ENIGMA-MDD network, nine university partner sites, which assessed childhood adversity and magnetic resonance imaging in patients with MDD and controls, took part in the current joint mega-analysis. In this largest effort world-wide to identify subcortical brain structure differences related to childhood adversity, 3036 participants were analyzed for subcortical brain volumes using FreeSurfer. A significant interaction was evident between childhood adversity, MDD diagnosis, sex, and region. Increased exposure to childhood adversity was associated with smaller caudate volumes in females independent of MDD. All subcategories of childhood adversity were negatively associated with caudate volumes in females - in particular emotional neglect and physical neglect (independently from age, ICV, imaging site and MDD diagnosis). There was no interaction effect between childhood adversity and MDD diagnosis on subcortical brain volumes. Childhood adversity is one of the contributors to brain structural abnormalities. It is associated with subcortical brain abnormalities that are relevant to psychiatric disorders such as depression.

  View details for DOI 10.1016/j.jpsychires.2016.11.010

  View details for Web of Science ID 000394072700009

  View details for PubMedID 27918926

  View details for PubMedCentralID PMC5564511

• Functional magnetic resonance imaging correlates of emotion recognition and voluntary attentional regulation in depression: A generalized psycho-physiological interaction study. Journal of affective disorders Tozzi, L., Doolin, K., Farrel, C., Joseph, S., O'Keane, V., Frodl, T. 2017; 208: 535-544

  Abstract

  Major depression is characterized by an impaired ability to evaluate and modify emotional responses as well as attention deficits, however the neural origins of these features are unresolved. The aim of the study was to investigate activation and functional connectivity changes during recognition and voluntary attentional regulation of emotion in 34 patients with major depressive disorder (MDD) compared to 35 controls.We employed an fMRI task in which participants assessed the valence or the shape of emotional stimuli. Then we analysed BOLD responses and functional connectivity using psycho-physiological interaction during the two conditions.Patients showed more incorrect responses across both trial types. Recognition trials recruited areas belonging to the ventral system, which is involved in the generation and automatic processing of emotion. Shift of attention away from the emotional content activated areas belonging to the dorsal emotion regulation system. Patients showed hyper-connectivity between and within the default mode and task positive networks. While shifting attention away from emotion, patients had a reduced response of the anterior insula and increased connectivity across areas involved in emotion generation and regulation. Connectivity between the amygdala and visual areas was also altered in patients compared to controls during evaluation of negative and positive pictures, which might be related to biased valence processing. Finally, during regulation of negative trials and recognition of positive trials patients showed decreased coupling in areas involved in attention allocation and emotional regulation.Most of the patients were medicated, although potential effects of treatment were investigated.Overall, our findings are compatible with abnormal functional coupling in MDD of regions involved in perception, recognition and attention allocation, especially during regulation of negative images and valence evaluation of positive images.

  View details for DOI 10.1016/j.jad.2016.10.029

  View details for PubMedID 27814960

• Longitudinal functional connectivity changes correlate with mood improvement after regular exercise in a dose-dependent fashion EUROPEAN JOURNAL OF NEUROSCIENCE Tozzi, L., Carballedo, A., Lavelle, G., Doolin, K., Doyle, M., Amico, F., McCarthy, H., Gormley, J., Lord, A., O'Keane, V., Frodl, T. 2016; 43 (8): 1089-1096

  Abstract

  Exercise increases wellbeing and improves mood. It is however unclear how these mood changes relate to brain function. We conducted a randomized controlled trial investigating resting-state modifications in healthy adults after an extended period of aerobic physical exercise and their relationship with mood improvements. We aimed to identify novel functional networks whose activity could provide a physiological counterpart to the mood-related benefits of exercise. Thirty-eight healthy sedentary volunteers were randomised to either the aerobic exercise group of the study or a control group. Participants in the exercise group attended aerobic sessions with a physiotherapist twice a week for 16 weeks. Resting-state modifications using magnetic resonance imaging were assessed before and after the programme and related to mood changes. An unbiased approach using graph metrics and network-based statistics was adopted. Exercise reduced mood disturbance and improved emotional wellbeing. It also induced a decrease in local efficiency in the parahippocampal lobe through strengthening of the functional connections from this structure to the supramarginal gyrus, precentral area, superior temporal gyrus and temporal pole. Changes in mood disturbance following exercise were correlated with those in connectivity between parahippocampal gyrus and superior temporal gyrus as well as with the amount of training. No changes were detected in the control group. In conclusion, connectivity from the parahippocampal gyrus to motor, sensory integration and mood regulation areas was strengthened through exercise. These functional changes might be related to the benefits of regular physical activity on mood.

  View details for DOI 10.1111/ejn.13222

  View details for Web of Science ID 000374645700010

  View details for PubMedID 26929085

• Beyond emotions: A meta-analysis of neural response within face processing system in social anxiety EXPERIMENTAL BIOLOGY AND MEDICINE Gentili, C., Cristea, I. A., Angstadt, M., Klumpp, H., Tozzi, L., Phan, K. L., Pietrini, P. 2016; 241 (3): 225-237

  Abstract

  Patients with social anxiety disorder (SAD) experience anxiety and avoidance in face-to-face interactions. We performed a meta-analysis of functional magnetic resonance imaging (fMRI) studies in SAD to provide a comprehensive understanding of the neural underpinnings of face perception in this disorder. To this purpose, we adopted an innovative approach, asking authors for unpublished data. This is a common procedure for behavioral meta-analyses, which, however has never been used in neuroimaging studies. We searched Pubmed with the key words "Social Anxiety AND faces" and "Social Phobia AND faces." Then, we selected those fMRI studies for which we were able to obtain data for the comparison between SAD and healthy controls (HC) in a face perception task, either from the published papers or from the authors themselves. In this way, we obtained 23 studies (totaling 449 SAD and 424 HC individuals). We identified significant clusters in which faces evoked a higher response in SAD in bilateral amygdala, globus pallidus, superior temporal sulcus, visual cortex, and prefrontal cortex. We also found a higher activity for HC in the lingual gyrus and in the posterior cingulate. Our findings show that altered neural response to face in SAD is not limited to emotional structures but involves a complex network. These results may have implications for the understanding of SAD pathophysiology, as they suggest that a dysfunctional face perception process may bias patient person-to-person interactions.

  View details for DOI 10.1177/1535370215603514

  View details for Web of Science ID 000368826100001

  View details for PubMedID 26341469

  View details for PubMedCentralID PMC4935439

• Single-Nucleotide Polymorphism of the FKBP5 Gene and Childhood Maltreatment as Predictors of Structural Changes in Brain Areas Involved in Emotional Processing in Depression NEUROPSYCHOPHARMACOLOGY Tozzi, L., Carballedo, A., Wetterling, F., McCarthy, H., O'Keane, V., Gill, M., Morris, D., Fahey, C., Meaney, J., Frodl, T. 2016; 41 (2): 487-497

  Abstract

  The gene expressing the FK506 binding protein 51 (FKBP5) is involved in the regulation of glucocorticoid receptor sensitivity. The rs1360780 SNP in this gene (T allele vs C homozygous) has been found to be associated with major depressive disorder (MDD). The aim of our study was to investigate whether this polymorphism might be associated with altered brain structure and function in a cohort of 40 patients with MDD and 43 healthy controls. A functional magnetic resonance imaging (fMRI) emotional attention task was employed. Diffusion tensor imaging (DTI) was also conducted, extracting mean diffusivity (MD) and fractional anisotropy (FA) from brain areas that showed functional differences between patients expressing the two alleles of the rs1360780 SNP. Finally, the effect of the interaction of childhood adversity as measured by the Childhood trauma Questionnaire (CTQ) and rs1360780 allele status was analyzed in relation to DTI measures using a general linear model. All results presented are family-wise error (FWE) corrected. Functional interactions were found between genotype and diagnosis (p<0.01). Patients carrying the high-risk allele, compared with patients not carrying it, showed reduced activity in the rolandic operculum, Heschl gyrus, insula, parahippocampal gyrus, posterior cingulate cortex, inferior frontal gyrus (p<0.05 for all measures); and increased MD and reduced FA measures in many of these regions (p<0.05). An interaction between CTQ scores and allele status was associated with DTI changes in the insula, rolandic operculum, and inferior frontal gyrus. Here, the presence of both the high-risk allele and higher CTQ scores was associated with higher MD and lower FA values (p<0.05). In conclusion, MDD patients expressing the T allele of rs1360780, compared with C homozygous patients, exhibit functional and structural differences in areas involved in emotional perception and inhibition. The interaction between the T allele and childhood maltreatment explained our structural findings in these regions, suggesting that their altered maturation and function might be influenced by early chronic stress in the presence of this genetic trait.

  View details for DOI 10.1038/npp.2015.170

  View details for Web of Science ID 000366599400011

  View details for PubMedID 26076833

  View details for PubMedCentralID PMC5130124

• Impaired reward processing in the human prefrontal cortex distinguishes between persistent and remittent attention deficit hyperactivity disorder HUMAN BRAIN MAPPING Wetterling, F., McCarthy, H., Tozzi, L., Skokauskas, N., O'Doherty, J. P., Mulligan, A., Meaney, J., Fagan, A. J., Gill, M., Frodl, T. 2015; 36 (11): 4648-4663

  Abstract

  Symptoms of attention deficit hyperactivity disorder (ADHD) in children often persist into adulthood and can lead to severe antisocial behavior. However, to-date it remains unclear whether neuro-functional abnormalities cause ADHD, which in turn can then provide a marker of persistent ADHD. Using event-related functional magnetic resonance imaging (fMRI), we measured blood oxygenation level dependent (BOLD) signal changes in subjects during a reversal learning task in which choice of the correct stimulus led to a probabilistically determined 'monetary' reward or punishment. Participants were diagnosed with ADHD during their childhood (N=32) and were paired with age, gender, and education matched healthy controls (N=32). Reassessment of the ADHD group as adults resulted in a split between either persistent (persisters, N=17) or remitted ADHDs (remitters, N=15). All three groups showed significantly decreased activation in the medial prefrontal cortex (PFC) and the left striatum during punished correct responses, however only remitters and controls presented significant psycho-physiological interaction between these fronto-striatal reward and outcome valence networks. Comparing persisters to remitters and controls showed significantly inverted responses to punishment (P<0.05, family-wise error corrected) in left PFC region. Interestingly, the decreased activation shown after punishment was located in different areas of the PFC for remitters compared with controls, suggesting that remitters might have learned compensation strategies to overcome their ADHD symptoms. Thus, fMRI helps understanding the neuro-functional basis of ADHD related behavior differences and differentiates between persistent and remittent ADHD.

  View details for DOI 10.1002/hbm.22944

  View details for Web of Science ID 000364219500030

  View details for PubMedID 26287509

• Modality Dependent Cross-Modal Functional Reorganization Following Congenital Visual Deprivation within Occipital Areas: A Meta-Analysis of Tactile and Auditory Studies MULTISENSORY RESEARCH Ricciardi, E., Tozzi, L., Leo, A., Pietrini, P. 2014; 27 (3-4): 247-262

  Abstract

  Cross-modal responses in occipital areas appear to be essential for sensory processing in visually deprived subjects. However, it is yet unclear whether this functional recruitment might be dependent on the sensory channel conveying the information. In order to characterize brain areas showing task-independent, but sensory specific, cross-modal responses in blind individuals, we pooled together distinct brain functional studies in a single based meta-analysis according only to the modality conveying experimental stimuli (auditory or tactile). Our approach revealed a specific functional cortical segregation according to the sensory modality conveying the non-visual information, irrespectively from the cognitive features of the tasks. In particular, dorsal and posterior subregions of occipital and superior parietal cortex showed a higher cross-modal recruitment across tactile tasks in blind as compared to sighted individuals. On the other hand, auditory stimuli activated more medial and ventral clusters within early visual areas, the lingual and inferior temporal cortex. These findings suggest a modality-specific functional modification of cross-modal responses within different portions of the occipital cortex of blind individuals. Cross-modal recruitment can thus be specifically influenced by the intrinsic features of sensory information.

  View details for DOI 10.1163/22134808-00002454

  View details for Web of Science ID 000343078200005

  View details for PubMedID 25577905

• Gambling among youths in Switzerland and its association with other addictive behaviours. A population-based study. Swiss medical weekly Tozzi, L., Akre, C., Fleury-Schubert, A., Suris, J. 2013; 143: w13768-?

  Abstract

  To assess the prevalence of problem gambling in a population of youths in Switzerland and to determine its association with other potentially addictive behaviours.Cross-sectional survey including 1,102 participants in the first and second year of post-compulsory education, reporting gambling, socio-demographics, internet use and substance use. For three categories of gambling (nongambler; nonproblem gambler and at-risk/problem gambler). socio-demographic and addiction data were compared using a bivariate analysis. All significant variables were included in a multinominal logistic regression using nongamblers as the reference category.The prevalence of gamblers was 37.48% (n = 413), with nonproblem gamblers being 31.94% (n = 352) and at-risk/problem gamblers 5.54% (n = 61). At the bivariate level, severity of gambling increased among adults (over 18 years) and among males, vocational students, participants not living with both parents and youths having a low socio-economic status. Gambling was also associated to the four addictive behaviours studied. At the multivariate level, risk of nonproblem gambling was increased in males, older youths, vocational students, participants of Swiss origin and alcohol misusers. Risk of at-risk/problem gambling was higher for males, older youths, alcohol misusers, participants not living with both parents and problem internet users.One-third of youths in our sample had gambled in the previous year and gambling is associated with other addictive behaviours. Clinicians should screen their adolescent patients for gambling habits, especially if other addictive behaviours are present. Additionally, gambling should be included in prevention campaigns together with other addictive behaviours.

  View details for DOI 10.4414/smw.2013.13768

  View details for PubMedID 23572422