Bio

Bio


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)

Research & Scholarship

Lab Affiliations


Publications

All Publications


  • 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

  • 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

  • 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

  • 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 11?-hydroxysteroiddehydrogenase type 1 (11?-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 11?-HSD1 mRNA measures. There was a negative association between interleukin 1-? (IL-1?) 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

    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

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