Team Members | Shemesh Lab

Learning and rehabilitation-induced microstructural changes revealed by diffusion-weighted MRI

Neuroplasticity refers to the brain’s potential to reorganize structural and functionally in response to learning and experience. Animal models suggest the existence of a sensitive period (SP) of heightened plasticity immediately after stroke, with obvious similarities with developmental critical periods, and characterised by increased responsiveness to training. Despite the existing behavioural evidence of such effect in rodents performing a motor prehension task, the mechanisms underlying neuroplastic phenomena remain largely unknown. In this project, we aim to implement ultrahigh field magnetic resonance (MR) techniques, namely diffusion-weighted MR, to track in vivo the microstructural changes of mice learning in healthy condition and rehabilitating from stroke, while using quantitative kinematics from video recordings to monitor the underlying behavioural evolution in a motor prehension task. Our ultimate goal is to unravel aspects of neuronal reorganization, fundamental for paving the way towards understanding neuroplastic mechanisms.

Figure Credits: Teresa Serradas Duarte and Rita Alves.

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Functional MRI of the rodent visual pathway

The visual system is highly complex and widespread in the brain. Many methods, such as electrophysiological recordings and EEG, have provided immense insight into the visual pathway’s underpinnings; however, capturing the entire distributed pathway in rodents would represent a major step forward. Functional MRI can non-invasively investigate the underpinnings of the visual system, but most studies in rodents to date relied on presentation of simple flickering stimuli. Therefore, the need arises to develop a system that would enable more complex visual tasks and a sensitive investigation of the entire visual pathway of the mouse using fMRI. However, the long and narrow scanner bores, the high-field strengths of pre-clinical MRI scanners and the susceptibility to radiofrequency interference make it difficult to build a new MR-safe mouse visual stimulation system that can probe a large portion of the visual field. In this project, we aim to design and develop a setup capable of delivering accurate and complex visual stimuli, and that, when coupled to the high-field MRI scanner, enables the high signal-to-noise ratio, spatial resolution and sensitive investigation of different properties in the entire pathway, such as retinotopy or motion, orientation, direction or even shape dependence, of the anesthetized or awake rodent.

Figure Credits: Francisca Fernandes.

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Ultra-fast functional MRI reveals neuroplasticity-driven modulations upon mice dark rearing

Throughout life, several neuroplasticity events at distinct spatial and temporal scales play fundamental roles for example in brain development from birth until adulthood, adaptation to new environments, learning or even injury recovery. Microscopic features of neuroplasticity events at individual time points have been accessed with invasive techniques such as electrophysiology or optical imaging. However, network level changes, which occur during longer timescales and underpin higher order processes such as behaviour and cognition, are much harder to decipher. To tackle the mesoscopic features of neuroplasticity, functional MRI methods can be applied. FMRI studies have mostly detected neuroplasticity events through changes in spatial extent or amplitude modulations of the BOLD responses however, the temporal dimension of neuroplasticity modulations has not yet been investigated possibly due to the temporal resolution constraints of BOLD fMRI. Several studies looking at cortical columns have shown that early BOLD timings acquired with high temporal resolution are more closely related to neural input order along the different cortical layers. In this line, the first goals of this project were to develop an ultra-fast fMRI approach in order to robustly measure early BOLD timings along distributed pathways such as the visual pathway, and correlate these with the already known pathway neural input order. In order to investigate BOLD temporal modulations due to neuroplasticity events, the dark rearing mouse model was chosen. Future steps of this project include: manipulations of the dark rearing and after light exposure regimes and times, as well as electrophysiological recordings, calcium imaging and fluorescence microscopy to dissect the underlying mechanisms behind early BOLD time differences and modulations upon dark rearing.

Figure Credits: Rita Gil.

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Sónia Gonçalves, PhD
Postdoctoral Fellow

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Sónia I. Gonçalves graduated in Physics by Instituto Superior Técnico, Universidade Técnica de Lisboa. She pursued her PhD degree in Biophysics in Faculdade de Ciências, Universidade de Lisboa and VU Medical Centre, Free University of Amsterdam, having obtained her (cum laude) degree in 2002.

From 2003 to 2008, she worked on using co-registered EEG-fMRI to study spontaneous brain activity, a rather pioneering work at the time (Gonçalves, S. I. et al. 2006. NeuroImage, 30(1), 203-213). For this she was distinguished in 2005 with one of the four Medalhas de Honra L’Óreal Portugal para as Mulheres na Ciência awards. From 2009 to 2011 she worked on the 3T MR unit in the Academic Medical Centre (AMC), University of Amsterdam, where she developed a variation of alternating-TR steady-state free precession sequences for abdominal imaging at 3T (Magn Res Med, 67(3), 595-600, 2012).

In 2010 she moved back to Portugal and went to Coimbra where she was invited assistant professor and research associate at the Medical Faculty, University of Coimbra. She has lectured on MR Physics, Radiological protection and has supervised several MSc theses. At the Institute for Biomedical Engineering and Life Sciences, she worked on the development of MR based techniques for clinical applications (Gurney-Champion et al., Inv Rad, 2016). She has been reviewer for several brain imaging and biomedical engineering journals such as NeuroImage, or IEEE Transactions in Biomedical Engineering and also for organizations such as Fonds Wetenschappelijk Onderzoek Vlaanderen.

Research wise what makes her twinkle is to grab a (basic or clinical) problem, and devise the most simple and direct method to solve it! That may imply going to the basics of MR Physics and design a new MR pulse sequence or rather work at a biosignal processing level to retrieve the desired information. Ultimately, what makes her smile is to see the new methodology working in a clinical setting.

Besides science, she likes hiking, fitness and walking her dog on the beach.

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Email: sonia.goncalves@research.fchampalimaud.org

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Rafael Henriques, PhD
Postdoctoral Fellow

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Rafael Neto Henriques completed his Master in Biomedical Engineering and Biophysics in 2012 at the Faculty of Science, University of Lisbon. During the last year of his master, he developed some main algorithms to process diffusion-weighted MRI data for the large collaborative project Cambridge Centre for Ageing and Neuroscience (cam-can.org). He then worked as an associate researcher at the “Instituto de Biofísica e Engenharia Biomédica” (Lisbon, Portugal) for a year (2012-2013), where he developed algorithms to non-invasively reconstruct crossing white matter pathways of the brain (tractography) based on the non-Gaussian properties of diffusion. He did his PhD at the University of Cambridge (2013-2017), where he studied the microstructural changes beyond healthy brain ageing using advanced diffusion MRI models compatible with human clinical scanners.

He started a Post-Doc position at the Champalimaud Centre for the Unknown in October 2017. His main interest is to identify the benefits and pitfalls of dMRI techniques and illustrate their applicability to study brain plasticity on different healthy and pathological conditions (particularly, brain development, stroke, cancer and Parkinson disease). For this, he is developing and validating different advanced and non-conventional diffusion-weighted techniques in pre-clinical high field MRI scanners.

Since 2015, Rafael Neto Henriques is also an active contributor of the large-scale open-source project diffusion in python (dipy.org) to promote the reproducibility of research based on diffusion MRI techniques.

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Email: rafael.henriques@research.fchampalimaud.org

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Rita Gil
2016 INDP PhD Student

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Rita Gil finished her master degree in Biomedical Engineering in October 2015 and joined the lab in December of that year as a research technician. She is part of the 2016 International Neuroscience Doctoral Programme (INDP) class which started in January 2017 and re-joined the Shemesh lab as a PhD student. In her PhD she has been investigating the BOLD mechanism and its relationship with neural activity. For that she has developed a set-up which allows imaging of acute brain slices and optogenetic stimulation while infusing artificial cerebrospinal fluid to maintain the viability of the brain tissue. She has also been involved in fast imaging acquisitions (up to 50 milliseconds temporal resolution) which allow a more robust BOLD responses quantification, such as measurement of early response timings and the investigation of their relationship with neural events in different brain regions. She is also investigating negative BOLD neural sources in the rat visual pathway.

Since she joined the Shemesh lab, she has attended the 24^th, 25^th, 26^th and 27^th editions of ISMRM conference and received two Magna Cum Laude Merit Awards (24^th and 27^th editions).

In her free time, she enjoys travelling, spending time with her friends and doing all kinds of sports such as going to the gym, rock climbing and surfing.

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Email: rita.gil@research.fchampalimaud.org

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Cristina Chavarrías, PhD
Postdoctoral Fellow and Scientific Lab Manager

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Dr. Cristina Chavarrías is a postdoc and Scientific Lab Manager of the group. She started to work on medical imaging in 2007 as a pregraduate Telecomm engineering student, on different imaging modalities and both on the experimental and the analytical sides. She specialized on biomedical engineering and obtained her PhD on fMRI research and joined the lab in February 2016 as a Marie Curie fellow to implement advanced fMRI techniques. Her passions range from technology to social interactions, dancing, singing or playing team sports with friends.

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Email: cristina.chavarrias@neuro.fchampalimaud.org

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Andrada Ianuş, PhD
Postdoctoral Fellow

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Andrada Ianuş has a bachelor degree in physics from Jacobs University in Bremen, Germany and a PhD degree in medical and biomedical imaging from University College London, UK. Her research is focused on quantitative MRI techniques for mapping tissue microstructure, in particular advanced acquisition sequences and modelling for diffusion MRI. She has been collaborating with the lab from 2015 and has joined as a full time post-doctoral fellow in 2019.

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Email: andrada.ianus@neuro.fchampalimaud.org

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Joana Carvalho, PhD
Postdoctoral Fellow

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Joana graduated in Biomedical Engineering and Biophysics followed by a PhD in Computational Visual Neuroscience at the university of Groningen. She joined the Shemesh lab as a post doctoral researcher in January 2020. Her project is directed to: 1) unravel the neuronal mechanisms underlying brain plasticity and 2) map the functional organisation of rodent’s brain with a high level of spatial and temporal detail. To do so she will combine ultra-high resolution fMRI with calcium recordings and visual stimulation.

Joana is a brain fanatic particularly interested on understanding how does the brain change following damage or environmental factors. Besides science, she enjoys travelling, outdoor activities, reading, music festivals and hanging out with family and friends.

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Email: joana.carvalho@resarch.fchampalimaud.org

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Carlos Bilreiro, MD
PhD Student

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Carlos is a medical doctor specialized in Radiology. He has previously done clinical research in the fields of abdominal radiology and interventional radiology. He joined the Shemesh lab in May 2019 and is now working with ultra-high field MRI for studying pancreatic cancer and pre-malignant lesions.

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Email: carlos.bilreiro@research.fchampalimaud.org

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Vesna Petojevic
Lab Administrator

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Email: vesna.petojevic@neuro.fchampalimaud.org

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Joana Cabral, PhD
Visiting Scientist

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Joana graduated in Biomedical Engineering followed by a PhD in Computational Neuroscience and a postdoc at the Oxford Psychiatry department. She joined the Shemesh lab as a visiting researcher in March 2019, coming from the University of Minho. Joana is exploring frequency-specific patterns of ultra-fast BOLD signal fluctuations in rats. Joana is curious about fundamental mechanisms of brain function. She enjoys travelling and spending time in the nature with her family.

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Email: joana.cabral@research.fchampalimaud.org

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Ruxanda Lungu
Research Assistant

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Ruxanda graduated in Biology in Lisbon and followed a masters degree of Genetics in Paris. After working in different laboratories in Lisbon, Paris and Durham (USA), she joined the Shemesh lab, in November 2019, in the pursuit of a scientific career developing her PhD research project. Her previous scientific research experience focused on cancer, cellular repair, neurobiology of genetic diseases and neurodevelopment.

At Champalimaud, her research mainly involves fMRI and Optogenetics in animal models and treatment. Her focus is the genetics and imaging of Parkinson’s Disease mouse model and she aims to decipher contributions of different genes into plasticity and/or aberrations of neural networks.

She also joined the Green Team @CCU aiming to give her contribution for a more sustainable scientific research and a better world. She is as well a freelance scientific illustrator and in her free time, she enjoys good music and cinematography.

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Email: ruxanda.lungu@research.fchampalimaud.org

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Francisca Fernandes
Research Technician

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Francisca is a biomedical engineer that joined the lab in February 2017 to develop her Master’s Thesis. In her project, she investigated the mouse visual pathway by combining high-field BOLD fMRI with emerging visual stimulation techniques and anaesthetic protocols that provide stable and recoverable sedation without compromising the neurovascular coupling.

After graduating, she became a technician in the lab. Her main interests are the development of processing tools for fMRI data and experimental setups for rodent MRI. Since last year, she has also been involved in a few projects on mouse abdominal (liver and pancreas) MRI.

In her free time, she enjoys travelling, cooking and having step classes with her workmates.

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Email: francisca.fernandes@neuro.fchampalimaud.org

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Beatriz Cardoso
Research Technician

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Beatriz has graduated in Biology and due to her curiosity about the human brain, she enrolled on a MsC. in Neuroscience. Throughout her academic career Beatriz has had the opportunity to learn about microbiology, cellular and molecular biology and microscopy. She has joined Shemesh Lab in November 2019 as a technician. Her assistance is focused on processes such as cell culturing and implantation in animal models of cancer, histology and microscopy for validation of MR imaging results.

In the outside world she has danced since she was 6 years old. Nowadays, she is focused the most on dance styles as ballet, contemporary and lyrical jazz. Additionally, she is a big fan of cinema, world gastronomy, different cultures, and obviously hanging out with friends as much as possible.

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Email: beatriz.cardoso@research.fchampalimaud.org

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Rita Alves
Masters Student

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Rita graduated in Biomedical Sciences in 2018 and has been pursuing a master’s degree in Biomedical and Biophysics Engineering since then. She is a part of the lab since September 2019 and is currently working on her master’s thesis project, where she is focusing her research on mapping brain microstructural dynamics in early stages post stroke with diffusion MRI advanced sequences. Understanding different occurring mechanisms by observing the diffusivity and kurtosis alterations is a building block of her main interests. She is also fond of reading, tunes, the seventh art and tennis.

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Email: rita.alves@research.fchampalimaud.org

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Frederico Severo
2017 INDP PhD Student

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Email: frederico.severo@neuro.fchampalimaud.org

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Noam Shemesh, PhD
Principal Investigator

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Noam received his BSc in Chemistry (2006) and his PhD on micro-architectural MRI (2011), from Tel Aviv University, Israel. During his PhD, Noam won the International Society for Magnetic Resonance in Medicine (ISMRM) Young Investigator Award for his studies on Double Diffusion Encoding MR and was subsequently elected Junior Fellow of the ISMRM. His post-doc in the Weizmann Institute of Science, Israel (2011-2013) focused mostly on ultrahigh field MR spectroscopy in animal models of disease. In 2014, Noam started his own Lab in the Champalimaud Centre for the Unknown in Lisbon, Portugal. The Shemesh Lab focuses on ultrahigh field MRI of microstructure and function in rodents and on characterization of cancer in animal models and from a translational perspective. In 2019, Noam was promoted to Associate Investigator level, and named Director of the Champalimaud preclinical MRI Centre. During his career, Noam has published >55 peer-reviewed papers, 3 book chapters and >100 peer-reviewed conference abstracts that achieved ~1720 citations (h-index: 24). His Lab is funded by an ERC Starting Grant (2016), Portuguese FCT (2016), Marie Sklodowska Curie Individual Fellowship (2015), and four Marie Curie Fellowships awarded to post-docs in the Shemesh Lab. Noam currently supervises 7 post-doctoral fellows, 4 PhD students, 2 research technicians and one master’s student. Two of his former students are now Assistant Level Professors.

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Email: noam.shemesh@neuro.fchampalimaud.org

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Tal Shemesh, PhD
Postdoctoral Fellow

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Email: tal.shemesh@research.fchampalimaud.org

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Rui Simões, PhD
Postdoctoral Fellow

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Email: rui.simoes@research.fchampalimaud.org

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Characterization of lymph nodes in rectal cancer in preclinical and clinical environments

This project spans both the preclinical and clinical environments. It consists of a new application in magnetic resonance imaging for the distinction between benign and malignant mesorectal lymph nodes in rectal cancer. We first studied individual lymph nodes ex vivo, from the surgical specimens of patients, at 16.4T; and then applied the same methodology in vivo, at 1.5T, upon clinical staging.

Figure Credits: Inês Santiago and Andrada Ianuş.

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Development of advanced MR imaging methods

Modern state-of-the-art MR scanners make it possible to generate high-resolution images of the brain and body, which allows us to retrieve information about the structure and function of these biological systems. In this project, we are interested in developing advanced MR imaging methods to better probe brain and body, in both healthy and diseased states. By combining a deep knowledge of MR physics with advanced MR hardware and suitable programming skills, our goal is thus to maximize the information, whether of spatial, temporal or spectral nature, that can be extracted from the biological system under study.

Figure Credits: Sónia I. Gonçalves.

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Detection and characterization of pancreatic intraepithelial neoplasia (PanIN)

This project aims to detect and classify pre-malignant lesions for pancreatic cancer (PanIN) using novel pulse sequences with combined magnetic susceptibility and diffusion contrasts, using transgenic mouse models. So far, we have been able to detect PanIN in pancreas extracted from mice, while at the same time, differentiate PanIN from inflammatory changes. We are now in the process of replicating this
method in vivo. For this, we are also developing a protocol using hyoscine butylbromide that might allow performing high resolution abdominal MRI and abdominal DWI in the mouse. We are also optimizing the pulse sequence parameters for optimal lesion detection in vivo.

Figure Credits: Bilreiro et al. Identification of pancreatic intraepithelial neoplasia in the mouse pancreas with MR Microscopy. Proceedings of the 28th Annual Meeting of ISMRM, 2020.

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Diffusion-weighted contrast for fMRI coupled with electrophysiology and optogenetics

In this project, we are focused in studying the differences between BOLD and diffusion-weighted (dfMRI) signals for functional MRI spatially and temporally. Using the forepaw stimulation model in rodents, we have been able to demonstrate that dfMRI signals provide a much more detailed information about the circuitry of the thalamo-cortical pathway in forelimb sensation. To better understand the origins of dfMRI contrast in the brain, we are applying cutting-edge MRI techniques combined with electrophysiology and optogenetics.

Figure Credits:
Nunes D, Ianuş A, Shemesh N (2019). Layer-specific connectivity revealed by diffusion-weighted functional MRI in the rat thalamocortical pathway. NeuroImage 184:646-657.
Nunes D, Gil R, Shemesh N (2020). A rapid-onset diffusion functional MRI signal reflects neuromorphological coupling dynamics. arXiv:2001.08508.

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Characterising tumour microenvironment

This project focuses on characterising the metabolic and microstructural heterogeneity of the tumour microenvironment and its dynamic changes, in order to establish non-invasive markers of progression and metastasis. This is investigated in preclinical models but with a clear bench-to-bedside perspective, using advanced magnetic resonance imaging and spectroscopy methods.

Figure Credits: Rui V. Simões.

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Diffusion fMRI using brain slices

Despite its immense utility in mapping brain function, MRI’s main functional contrast – the Blood-Oxygenation-Level-Dependent (BOLD) mechanism is an indirect marker of neural activity and its underlying neurovascular coupling mechanisms remain poorly understood. Diffusion functional MRI (dfMRI) has been proposed as a more direct method for detecting neural activity with faster dynamics and with more spatial specificity compared to BOLD. However, much controversy surrounds dfMRI, mainly due to potential BOLD contamination. This project aims to validate dfMRI using brain slices, where vascular responses are absent and where pharmacology can be used to modulate neuronal/vascular responses. As well, those slices can be used to tune and optimize dfMRI contrasts.

Figure Credits: Rita Gil.

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Whole-brain fMRI of serotonergic neuron optogenetic activation

This project aims to understand where in the brain the neuromodulator serotonin (5-HT) acts to ultimately modulate cognitive and behavioral functions. To this end, we are combining whole-brain imaging using high field (9.4T) functional magnetic resonance imaging (fMRI) with causal optogenetic manipulations in sedated, awake and behaving mice. This way, we aim to map the effects of 5-HT across the brain and use this information to target causal manipulations to specific 5-HT projections.

Figure Credits: Fonseca MS, Murakami M, Mainen ZF (2015). Activation of dorsal raphe serotonergic neurons promotes waiting but is not reinforcing. Curr. Biol. 25(3):306-315.

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Functional MRI and calcium readout of locus coeruleus optogenetic activation

This research project aims at a better understanding of the physiological phenomena underlying functional MRI. To this end, we combine fMRI with optogenetic stimulation and optical calcium recordings inside the scanner. In particular, we are interested in a small brainstem nucleus called locus coeruleus (LC). LC has connections to almost every region in the forebrain and regulates vital autonomous and cognitive functions – it helps us to stay awake when sleeping would be dangerous, to focus our attention on the most critical events in our environment and to store them in memory. LC is also one of the first structures to degenerate in Alzheimer’s and Parkinson’s disease. Through optogenetic stimulation of LC, and the combined fMRI and calcium readout, we investigate the system-level effects through which LC achieves its broad downstream effects.

Figure Credits: Julia M. Huntenburg.

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Neurotransmitter quantification through overlap-resolved CEST

Chemical Exchange Saturation Transfer (CEST) can provide metabolic imaging at high spatial resolution, especially at ultrahigh fields. However, when spectral overlap exists downfield, metabolite maps may be contaminated by other unwanted signals. We developed a new methodology termed overlap-resolved CEST (orCEST), which, through subtraction in CESTasym spectra, provides enhanced specificity capable of imaging and quantifying in a consistent, easy, and reliable way the major excitatory and inhibitory neurotransmitters in the brain, Glutamate and GABA.

Figure Credits: Severo F, Shemesh N (2020). In-vivo Magnetic Resonance Imaging of GABA and Glutamate. arXiv:2001.08515.

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Development and validation of advanced diffusion MRI techniques to study brain development and plasticity

Microscopic tissue properties are of special interest in biology as many cellular and sub-cellular structures occur on those scales. However, these properties are beyond the direct resolution limit of contemporary MRI. Fortunately, the characteristic path length of water diffusion in tissues is on the order of microns (given MR-relevant timescales), making diffusion MRI (dMRI) one of the most valuable reporters for dimensions much smaller than the MRI voxel size in both health and disease. Our research interest is to develop and validate advanced dMRI techniques. Our aim is to identify the benefits and pitfalls of dMRI techniques and illustrate their applicability to study brain development and plasticity. We are also interested on the translation of dMRI techniques to characterise neurological pathologies and the progression of tumours.

Figure Credits: Rafael N. Henriques.

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Identification and monitoring of microstructural changes with high specificity through in vivo MRI

The diagnosis of brain disorders, attributing one-third of all disease burden, is hindered by the lack of an imaging technique that reveals the architecture of living brain tissue at the cellular resolution of the associated pathological processes by means of biophysically relevant and specific biomarkers. Although the current contrast-driven MR modalities might show sensitivity to those microstructural changes, the lack of specificity limits the diagnostic power of MRI or the usefulness of MRI as a research tool for biological sciences that might fuel our further understanding in disease or aging mechanisms. We focus on the development and validation of MRI as a diagnostic and research tool that allows for the in vivo identification and monitoring of microstructural changes in the unexplored depths of the brain by striving to microstructural specificity of MRI through biophysical modelling of proton diffusion.

Figure Credits: Jelle Veraart.

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Functional MR spectroscopy to study brain metabolism under activation

Magnetic resonance spectroscopy (MRS) is a potential powerful tool to study brain metabolism in resting state (to characterize a pathology for example) or upon activation to possibly quantify the variation of main neurotransmitters (Glu, GABA). Functional MRS (fMRS) is challenging and there is still a lot to do to understand the measure itself, to reach its most relevant interpretation. This work aims at exploring fMRS, using different filters and combining it with functional imaging, to better characterize and understand activation in the brain under various stimuli.

Figure Credits: Ligneul C et al (2019). Diffusion-weighted magnetic resonance spectroscopy enables cell-specific monitoring of astrocyte reactivity in vivo. NeuroImage 191:457-469.

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Noam Shemesh, PhD

Andrada Ianuş, PhD

Cristina Chavarrías, PhD

Joana Carvalho, PhD

Rafael Henriques, PhD

Rui Simões, PhD

Sónia Gonçalves, PhD

Tal Shemesh, PhD

Rita Gil

Frederico Severo

Carlos Bilreiro, MD

Rita Alves

Beatriz Cardoso

Francisca Fernandes

Ruxanda Lungu

Joana Cabral, PhD

Vesna Petojevic

Inês Santiago, MD

Madalena Fonseca

Bárbara Costa

Clémence Ligneul, PhD

Teresa Serradas Duarte

Julia Huntenburg, PhD

Jelle Veraart, PhD

Daniel Nunes, PhD

Ekaterina Vinnik, PhD

Guilherme Blazquez Freches