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Neurobioimaging Lab

Angelo Bifone - PI

Research activity

Our research activity is focused primarily on the development of biomedical imaging techniques, with an emphasis on Magnetic Resonance Imaging (MRI) and its application to the neurosciences. We strive to improve sensitivity, resolution and specificity of MRI, and to push the boundaries of this technique as a diagnostic and research tool to study brain structure and function. A distinctive aspect of our research is the use of imaging agents and advanced image-analysis methods to improve functional MRI, a method to map hemodynamic responses in the brain as a surrogate for changes in the underlying neuronal activity. Typically, fMRI relies on an intrinsic contrast mechanism, the Blood Oxygen Level-Dependent (BOLD) effect, which yields relatively modest MR signal changes, often in the range of just a few percent, at best. The use of exogenous agents can dramatically increase the sensitivity of fMRI, thus improving spatial resolution and making it possible to resolve the brain functional architecture at a finer level. We have extensively applied these methods, dubbed phMRI, in models of human neurological and psychiatric disease, like autism and schizophrenia, with the goal to identify imaging endophenotypes (i.e., biological markers of disease traits) and functional markers of response to treatment. PhMRI has proven particularly impactful in the drug discovery process, providing a powerful translational tool to accelerate progression of novel therapeutic agents towards the clinic. More recently, we have explored the combination of MR Imaging and transgenic technology to study the neurophysiological basis of brain connectivity and its derangements in neurological and psychiatric disease, with a particular focus on drug addiction. Techniques like chemo-genetics can be used to reversible modulate the activity and connectivity of specific brain circuits, thus making it possible to test causal relationships between aberrant connectivity pathways and behavior. In combination with imaging methods, this approach has contributed to elucidating the key role of specific regions and circuits, like the Anterior Insular Cortex and the Salience Network, in the dependence on alcohol, heroin and other addictive substances in murine models (Fig.1). 

 

Figure 1

Figure 1. (A) Anatomical detail of the rat brain, indicating the location of the Anterior Insular Cortex (AIC); (B) expression of artificial receptors in the AIC that focally and reversibly activate or inhibit neuronal activity upon administration of a non-endogenous ligand; (C) functional MRI of the patterns of downstream activation triggered by chemo-genetic stimulation of the Anterior Insula. Behaviorally, stimulation of the AIC resulted in a strong reduction in drug-seeking and -taking behaviors in animal models of Alcohol Use Disorder. Adapted from Haaranen et al., 2020. 

The use of MRI, a translational approach par excellence, has been instrumental to validate preclinical findings in humans, where the same circuits appear to play an homologous role (Fig.2).

The notable implications of this research encompass the identification of new therapeutic targets and methodologies, among them Transcranial Magnetic Stimulation (TMS). On a more foundational level, our focus lies in the exploration of innovative imaging techniques and agents, positioning our group at the forefront of a dynamically evolving field. Presently, we are engaged in research concerning the utilization of nanodiamonds and other nanostructured materials as imaging probes, as well as their application in hyperpolarizing nuclear spins for the production of hyperpolarized agents for in vivo cellular and tissue imaging. Lastly, we recognize the transformative role that Artificial Intelligence is poised to assume in the fields of radiology and bioimaging. With its unparalleled ability to process extensive datasets and discern subtle patterns, AI holds the potential to dramatically enhance the efficacy and efficiency of contrast agents in diagnostic imaging. By way of example, we have recently demonstrated the ability of AI, in combination with Gadolinium-based contrast agents, to increase detectability of small, low-enhancing lesions (Fig. 3), thus improving sensitivity and diagnostic power. We are committed to explore the synergy between AI and contrast agents to revolutionize diagnostic imaging and improve patient outcomes.

Studying the early stages of neurodevelopment presents a considerable challenge. Recently, we have made significant advancements by using MRI in conjunction with activity-sensitive contrast agents to map brain function in chick embryos in ovo. This study has produced the first direct evidence that brain lateralization is influenced by exposure to sensory stimuli already at the embryonic level, a mechanism that could be relevant for all vertebrates, including humans. While these findings are preliminary, they pave the way to tackling numerous unresolved issues in the field of developmental biology. We will leverage these methods to investigate the neurochemical factors underpinning both typical and atypical brain development. Moreover, we will deploy novel molecular imaging techniques to unravel the metabolic pathways involved at different stages of development, as well as the metabolic mechanisms that support rapid changes in brain activity induced by sensory or pharmacological stimuli. Ultimately, we intend to apply these groundbreaking methodologies to explore and validate pharmacological approaches aimed at rescuing aberrant brain connectivity and miswiring, as observed in various neurodevelopmental disorders.

  • POC NODES 2023 – Spoke 2 Green and sustainable technologies: ROSEWATER (Reduction of contrast agents in wastewater), Principal Investigator (starting December 2023). 

  • EC Horizon 2020: GA 8581492, FET-OPEN AlternativesToGd (Alternatives to Gadolinium) 1/10/2019 - 30/9/2023, Principal Investigator. 

  • EC Horizon 2020: GA 76642, ITN- ZULF (Zero and Ultra-Low Field MRI), 1/1/2018 - 30/6/2022, Principal Investigator. 

  • CRT Foundation: RF 2019.0610. Alcohol dependence and brain connectivity, 1/1/2020 - 30/6/2022, Principal Investigator. 

  • EC Horizon 2020: GA 668863, SyBill-AA “Systems Biology of Alcohol Addiction: Modeling and validating disease state networks in human and animal brains for understanding pathophysiology, predicting outcomes and improving therapy”, 1/1/2016 - 31/12/2019, Principal Investigator 

  •  “Manganese Enhanced Magnetic Resonance Imaging reveals light-induced brain asymmetry in embryo” E. Lorenzi, S. Tambalo, G. Vallortigara, and A. Bifone eLife 12, e86116 (2023) https://doi.org/10.7554/eLife.86116 

  • “Amplifying the effects of Contrast Agents on Magnetic Resonance Images using a Deep Learning method trained on synthetic data”A. Fringuello Mingo et al., Investigative Radiology (2023) DOI: 10.1097/RLI.0000000000000998

  •  “Increased network centrality of the anterior insula in early abstinence from alcohol”C. Bordier, G. Weil, P. Bach, G. Scuppa, C. Nicolini, G. Forcellini, U. Pérez-Ramirez, D. Moratal, S. Canals, S. Hofmann, D. Hermann, S. Vollstädt-Klein, F. Kiefer, P. Kirsch, W.H. Sommer, and A. Bifone Addiction Biology e13096, doi. org/10.1111/adb.13096, 27(1) e13096 (2022) (featured on the cover) https://doi.org/10.1111/adb.13096 

  •  “Anterior insula stimulation suppresses appetitive behavior while inducing forebrain activation in alcohol-preferring rats” M. Haaranen et al., Translational Psychiatry 10:150, 1-11 (2020) https://doi.org/10.1038/s41398-020-0833-7

  • “Aberrant insular cortex connectivity in abstinent alcohol-dependent rats is reversed by dopamine D3 receptor blockade” G. Scuppa, S. Tambalo, S. Pfarr, W.H. Sommer, and A. Bifone Addiction Biology 25(3), e12744 (2020) https://doi.org/10.1111/adb.12744 

  • “Fast and sensitive detection of paramagnetic species using coupled charge and spin dynamics in strongly fluorescent nanodiamonds” F. Gorrini, R. Giri, C.E. Avalos, S. Tambalo, P. Marzola, A. Miotello, and A. Bifone ACS Applied Materials and Interfaces 11:27, 24412-24422 (2019) https://doi.org/10.1021/acsami.9b05779 

  • “phMRI, neurochemical and behavioral responses to psychostimulants distinguishing genetically selected alcohol-preferring from genetically heterogeneous rats” A. Bifone, A. Gozzi, A. Cippitelli, A. Matzeu, E. Domi, H. Li, G. Scuppa, N. Cannella, M. Ubaldi, F. Weiss, R. Ciccocioppo Addiction Biology 24(5):981- 993 (2019) https://doi.org/10.1111/adb.12671 

  • "Disrupted modular organization of primary sensory brain areas in schizophrenia” C. Bordier, C. Nicolini, G. Forcellini and A. Bifone NeuroImage: Clinical 18, 682- 693 (2018) doi.org/10.1016/j.nicl.2018.02.035 

  •  “Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior” Y. Zhan et al., Nature Neuroscience 17(3), 400- 4006 (2014) https://doi.org/10.1038/nn.3641 

  • "Distributed BOLD and CBV-weighted resting-state networks in the mouse brain" F Sforazzini, AJ Schwarz, A Galbusera, A Bifone, A Gozzi Neuroimage 87, 403-415 (2014) https://doi.org/10.1016/j.neuroimage.2013.09.05

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