Dr. Leonardo Tozzi graduated as a Medical Doctor from Pisa University and Sant'Anna School of Advanced Studies in 2013. Immediately thereafter, his interest in the investigation of mood disorders using Magnetic Resonance Imaging led him to join the R'Birth Consortium, a Marie Curie Initial Training Network spanning across 7 European countries. In 2017, he was awarded his Ph.D. from Trinity College Dublin for his research on the interaction between genetic risk factors, epigenetic modifications and environmental stressors as predictors of structural and functional brain changes related to Major Depression.
Dr. Tozzi joined Williams PANLab at Stanford University at the start of 2018 as a post-doctoral fellow within the framework of the Human Connectome Project. His goal is to use functional and structural connectivity analyses to develop precision psychiatry metrics related to the biology underpinning anxiety and depression. By combining connectomics and predictive algorithms, he also aims to assess the potential of these measures for clinical applications such as guiding treatment selection and estimating therapy response.

Honors & Awards

  • Full Scholarship, Sant'Anna School of Advanced Studies (2008-2013)

Professional Education

  • Diploma, Higher Schl Univ & Adv Stu Sant' Anna (2014)
  • Doctor of Medicine, Universita Degli Studi Di Pisa (2013)
  • Doctor of Philosophy, University Of Dublin, Trinity College (2017)

Lab Affiliations

All Publications

  • 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


    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
  • 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
  • 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
  • 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
  • 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
  • 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


    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


    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


    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


    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

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


    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

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


    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


    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


    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


    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, , 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


    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

  • 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


    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

  • 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


    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

  • 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


    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

  • 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


    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

  • 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


    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


    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

  • 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


    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


    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

  • 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. n., Farrell, C. n., Booij, L. n., Doolin, K. n., Nemoda, Z. n., Szyf, M. n., Pomares, F. B., Chiarella, J. n., O'Keane, V. n., Frodl, T. n. 2017


    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

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


    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

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


    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

  • 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


    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


    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


    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


    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


    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-?


    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