Modulations in neural circuit dynamics and microstructures can translate to functional enhancements (e.g., upon plasticity), or, conversely, to severe functional deficits (e.g., upon neurodegeneration). We are interested in identifying and investigating the links between such longitudinal functional modulations, their underlying micro-architectural modifications, and the ensuing behavioral responses in vivo. To this end, we harness ultrahigh field Magnetic Resonance Imaging (MRI) coupled to specificity-endowing modalities such as optogenetics and optical microscopy. These offer the opportunity of eliciting activity in circuits of interest, and concomitantly monitoring the ensuing activity in 3D. We further develop and apply novel methodologies based on nonBOLD mechanisms, which can potentially provide much insight into the nature of the activity, as well as probe rather fast dynamics. Microstructures are unraveled via MR methodologies tailored to probe cellular-scale size distributions (in white matter) as well as highly heterogeneous morphologies (in gray matter). These measurements are performed in vivo using state of the art 9.4T and 16.4T scanners, in both anesthetized and behaving rodents, as well as in animal models of neurodegeneration and plasticity. Our long term goals are to understand the mechanisms by which modifications in the tissue’s microstructure transcend globally and modulate function and behavior, and to explore the potential of these as early disease biomarkers.

1. Deciphering distributed neural circuits via advanced fMRI coupled with optogenetics

Complex behaviors ultimately arise from neural activity in widespread, distributed systems in the brain. We are interested in deciphering such networks in awake behaving rodents via optogenetics and advanced ultrafast fMRI. To achieve this goal, we are currently developing optogenetics- and MRI-compatible behavioral paradigms for awake rodents, as well as advanced ultrafast MRI acquisition strategies that will enable the resolution of relatively fast dynamics. The long term goals include the identification of distributed circuits and the investigation of their causal dynamics.

2. Functional MRI via non-BOLD mechanisms

The success of functional-MRI (fMRI) stems from its ability to portray active brain regions upon prescribing a specific task. However, fMRI relies on the Blood-Oxygenation-Level-Dependent (BOLD) mechanism, which is a surrogate marker for neural activity via neurovasculature couplings. A major goal of the Lab will therefore be to harness MRI’s versatility – especially at the ultrahigh fields – towards capturing signatures for neural activity more directly. Specifically, we are interested in detecting cellular swellings upon activation, as well as neurotransmitter releases in the activated regions. Both phenomena can be considered epitomes of neural activity, and their direct detection is expected to provide much insight into the nature of the ensuing activity. We are investigating these phenomena – as well as BOLD neurophysiology – via MRI coupled to orthogonal modalities such as optical microscopy and optogenetics, in numerous settings from organotypic cultures (where hemodynamics are absent) to in vivo rodents.

3. Microstructural determinants of functional modulations leading to behavioral changes in healthy and diseased CNS

Modulations in brain function (e.g., enhancements arising from plasticity or aberrations arising from neurodegeneration) are intimately correlated with underlying micro-architectural modifications in the neural tissues. We are interested in studying the links between the two, in vivo, in a longitudinal fashion in animal models of plasticity on the one hand and neurodegeneration on the other hand. We investigate functional modulations (such as neural network reorganizations) using optogenetics as the specific source of stimulation, and BOLD- and nonBOLD-fMRI as the functional readouts. We augment this functional information with advanced in vivo MRI methodologies that are selectively designed to probe even subtle changes in microstructures arising from plasticity or, conversely, neurodegenerative processes. We target microstructural changes in white matter, where we study variations in axonal size distributions (that govern the conduction velocity) as well as in gray matter, where we study changes in randomly oriented tissue components. We further aim to investigate the diagnostic potential arising from the identification of structural changes preceding functional/behavioral modifications.

Noam Shemesh, PhD
Principal Investigator
noam.shemesh@neuro.fchampalimaud.org

Biography

Andrada Ianus, PhD
Research Associate
andrada.ianus@neuro.fchampalimaud.org

Cristina Chavarrías, PhD
Postdoctoral Fellow
cristina.chavarrias@neuro.fchampalimaud.org

Daniel Nunes, PhD
Postdoctoral Fellow
daniel.nunes@neuro.fchampalimaud.org

Ekaterina Vinnik, MD, PhD
Postdoctoral Fellow
ekaterina.vinnik@neuro.fchampalimaud.org

Francisca Fernandes
Masters Student
francisca.fernandes@neuro.fchampalimaud.org

Frederico Severo
Research Technician
frederico.severo@neuro.fchampalimaud.org

Inês Santiago, MD
PhD Student
ines.santiago@neuro.fchampalimaud.org

Madalena Fonseca
2013 INDP PhD Student
madalena.fonseca@neuro.fchampalimaud.org

Rui Simões, PhD
Postdoctoral Fellow
rui.simoes@research.fchampalimaud.org

Sónia Gonçalves, PhD
Visiting Scientist
sonia.goncalves@research.fchampalimaud.org

Tal Shemesh, PhD
Postdoctoral Fellow
tal.shemesh@neuro.fchampalimaud.org

Teresa Serradas Duarte
PhD Student
teresa.serradasduarte@neuro.fchampalimaud.org

Lab Administration

Vesna Petojevic
Lab Administrator
vesna.petojevic@neuro.fchampalimaud.org

Álvarez GA, Shemesh N, Frydman L. (2017) Internal gradient distributions: A susceptibility-derived tensor delivering morphologies by magnetic resonance. Sci Rep 7 (1), 3311 (doi:10.1038/s41598-017-03277-9)

Brian Hansen, Ahmad R. Khan, Noam Shemesh, Torben E. Lund, Ryan Sangill, Simon F. Eskildsen, Leif Østergaard, Sune N. Jespersen (2017) White matter biomarkers from fast protocols using axially symmetric diffusion kurtosis imaging NMR Biomed. (doi:10.1002/nbm.3741)

Hansen B, Shemesh N, Jespersen SN (2016) Fast imaging of mean, axial and radial diffusion kurtosis NeuroImage 142 , 381-393 (doi:10.1016/j.neuroimage.2016.08.022)

Zhang Z, Shemesh N, Frydman L (2016) Efficient spectroscopic imaging by an optimized encoding of pretargeted resonances. Magn Reson Med ([Epub ahead of print]) (doi:10.1002/mrm.26161)

Shemesh N, Jespersen SN, Alexander DC, Cohen Y, Drobnjak I, Dyrby TB, Finsterbusch J, Koch MA, Kuder T, Laun F, Lawrenz M, Lundell H, Mitra PP, Nilsson M, Özarslan E, Topgaard D, Westin CF. (2015) Conventions and nomenclature for double diffusion encoding NMR and MRI. Magn Reson Med ([Epub ahead of print]) (doi:10.1002/mrm.25901)

Shemesh N, Álvarez GA, Frydman L (2015) Size Distribution Imaging by Non-Uniform Oscillating-Gradient Spin Echo (NOGSE) MRI PLoS ONE 10 (7), e0133201 (doi:10.1371/journal.pone.0133201)

Noam Shemesh, Jens T. Rosenberg, Jean-Nicolas Dumez, Jose A. Muniz, Samuel C. Grant & Lucio Frydman (2014) Metabolic properties in stroked rats revealed by relaxation-enhanced magnetic resonance spectroscopy at ultrahigh fields Nat Commun 5 (4958) (doi:10.1038/ncomms5958)

Shemesh N, Rosenberg JT, Dumez JN, Grant SC, Frydman L. (2014) Metabolic T1 dynamics and longitudinal relaxation enhancement in vivo at ultrahigh magnetic fields on ischemia J Cereb Blood Flow Metab (doi:10.1038/jcbfm.2014.149)

Álvarez GA, Shemesh N, Frydman L. (2014) Diffusion-assisted selective dynamical recoupling: A new approach to measure background gradients in magnetic resonance J Chem Phys 140 (084205 ), 1-9 (doi:10.1063/1.4865335.)

Shemesh N, Alvarez GA, Frydman L. (2013) Measuring small compartment dimensions by probing diffusion dynamics via Non-uniform Oscillating-Gradient Spin-Echo (NOGSE) NMR. J Magn Reson 237 , 49–62 (doi:10.1016/j.jmr.2013.09.009)

Shemesh N, Dumez JN, Frydman L. (2013) Longitudinal relaxation enhancement in 1HNMR of tissue metabolites via spectrally-selective excitation. Chemistry 19 (39), 13002-8 (doi:10.1002/chem.201300955)

Álvarez GA, Shemesh N, Frydman L. (2013) Coherent Dynamical Recoupling of Diffusion-Driven Decoherence in Magnetic Resonance Phys Rev Lett 111 (080404), 1:6 (doi:10.1103/PhysRevLett.111.080404)

Assaf Y1, Alexander DC, Jones DK, Bizzi A, Behrens TE, Clark CA, Cohen Y, Dyrby TB, Huppi PS, Knoesche TR, Lebihan D, Parker GJ, Poupon C; CONNECT consortium, Anaby D, Anwander A, Bar L, Barazany D, Blumenfeld-Katzir T, De-Santis S, Duclap D, Figini M, Fi (2013) The CONNECT project: Combining macro- and micro-structure. NeuroImage 80 , 273–282 (doi:10.1016/j.neuroimage.2013.05.055)

Solomon E, Shemesh N, Frydman L. (2013) Diffusion weighted MRI by spatiotemporal encoding: analytical description and in vivo validations. J Magn Reson 232 , 76–86 (doi:10.1016/j.jmr.2013.02.014)

Wiley-VCH, Ed. C.A. Schalley (2012) Diffusion NMR in Supramolecular Chemistry and Complexed Systems Analytical Methods in Supramolecular Chemistry, 2nd edition Volume 1 & 2 (doi:10.1002/9783527644131.ch6)

Shemesh N, Westin CF, Cohen Y. (2012) Magnetic resonance imaging by synergistic diffusion-diffraction patterns. Phys Rev Lett 108 (5), 058103 (doi:10.1103/PhysRevLett.108.058103)

Sadan O, Shemesh N, Barzilay R, Dadon-Nahum M, Blumenfeld-Katzir T, Assaf Y, Yeshurun M, Djaldetti R, Cohen Y, Melamed E, Offen D. (2012) Mesenchymal stem cells induced to secrete neurotrophic factors attenuate quinolinic acid toxicity: a potential therapy for Huntington's disease. Exp Neurol. 234 (2), 417–427 (doi:10.1016/j.expneurol.2011.12.045)

Shemesh N, Barazany D, Sadan O, Bar L, Zur Y, Barhum Y, Sochen N, Offen D, Assaf Y, Cohen Y. (2012) Mapping apparent eccentricity and residual ensemble anisotropy in the gray matter using angular double-pulsed-field-gradient MRI Magn Reson Med 68 (3), 794–806 (doi:10.1002/mrm.24490)

Ozarslan E, Shemesh N, Koay CG, Cohen Y, Basser PJ. (2011) NMR characterization of general compartment size distributions. New J Phys 13 ( 015010), 1-17 (doi:10.1088/1367-2630/13/1/015010)

Shemesh N, Cohen Y. (2011) Overcoming apparent-Susceptibility-Induced Anisotropy (aSIA) by bipolar double-Pulsed-Field-Gradient NMR. J Magn Reson 212 (2), 362–369 (doi:10.1016/j.jmr.2011.07.015)

Shemesh N, Ozarslan E, Basser PJ, Cohen Y. (2011) Accurate noninvasive measurement of cell size and compartment shape anisotropy in yeast cells using double-pulsed field gradient MR. NMR Biomed. 25 (2), 236–246 (doi:10.1002/nbm.1737)

Shemesh N, Adiri T, Cohen Y. (2011) Probing microscopic architecture of opaque heterogeneous systems using double-pulsed-field-gradient NMR. J Am Chem Soc 133 (15), 6028-35 (doi:10.1021/ja200303h)

Shemesh N, Cohen Y. (2011) Microscopic and compartment shape anisotropies in gray and white matter revealed by angular bipolar double-PFG MR Magn Reson Med 65 (5), 1216-1227 (doi:10.1002/mrm.2273)

Komlosh ME, Ozarslan E, Lizak MJ, Horkay F, Schram V, Shemesh N, Cohen Y, Basser PJ. (2011) Pore diameter mapping using double pulsed-field gradient MRI and its validation using a novel glass capillary array phantom. J Magn Reson 202 (1), 128–135 (doi:10.1016/j.jmr.2010.10.014)

Shemesh N, Ozarslan E, Komlosh ME, Basser PJ, Cohen Y. (2010) From single-pulsed field gradient to double-pulsed field gradient MR: gleaning new microstructural information and developing new forms of contrast in MRI. NMR Biomed. 23 (7), 757–780 (doi:10.1002/nbm.1550)

Shemesh N, Ozarslan E, Adiri T, Basser PJ, Cohen Y. (2010) Noninvasive bipolar double-pulsed-field-gradient NMR reveals signatures for pore size and shape in polydisperse, randomly oriented, inhomogeneous porous media. J Chem Phys 133 (4), 044705(1-9) (doi:10.1063/1.3454131)

Bar-Shir A, Shemesh N, Nossin-Manor R, Cohen Y. (2010) Long therapeutic window in Spehnopalatine ganglion stimulated ischemic rats: an MRI and MRSI study. J Magn Reson Imaging. 31 (6), 1355–1363 (doi:10.1002/jmri.22110.)

Shemesh N, Ozarslan E, Basser PJ, Cohen Y. (2010) Detecting diffusion-diffraction patterns in size distribution phantoms using double-pulsed field gradient NMR: Theory and experiments J Chem Phys 132 (3), 034703 (doi:10.1063/1.3285299.)

Shemesh N*, Sadan O*, Melamed E, Offen D, Cohen Y. (2009) Longitudinal MRI and MRSI characterization of the quinolinic acid rat model for excitotoxicity: peculiar apparent diffusion coefficients and recovery of N-acetyl aspartate levels. NMR Biomed. 23 (2), 196–206 (doi:10.1002/nbm.1443)

Sadan O, Bahat-Stromza M, Barhum Y, Levy YS, Pisnevsky A, Peretz H, Ilan AB, Bulvik S, Shemesh N, Krepel D, Cohen Y, Melamed E, Offen D. (2009) Protective Effects of Neurotrophic Factor–Secreting Cells in a 6-OHDA Rat Model of Parkinson Disease Stem Cells Dev. 18 (8), 1179-1190 (doi:10.1089/scd.2008.0411)

Shemesh N, Ozarslan E, Bar-Shir A, Basser PJ, Cohen Y. (2009) Observation of restricted diffusion in the presence of a freely diffusing compartment: single- and double-PFG experiments J Magn Reson 200 (2), 214–225 (doi:10.1016/j.jmr.2009.07.005)

Sadan O*, Shemesh N*, Cohen Y, Melamed E, Offen D. (2009) Adult neurotrophic factor-secreting stem cells: a potential novel therapy for neurodegenerative diseases. Isr Med Assoc J. 11 (4), 201-4

Ozarslan E, Shemesh N, Basser PJ. (2009) A general framework to quantify the effect of restricted diffusion on the NMR signal with applications to double pulsed field gradient NMR experiments. J Chem Phys 130 (10), 104702 (doi:10.1063/1.3082078)

Shemesh N, Ozarslan E, Basser PJ, Cohen Y. (2009) Measuring small compartmental dimensions with low-q angular double PGSE NMR: The effect of experimental parameters on signal decay. J Magn Reson 198 (1), 15-23 (doi:10.1016/j.jmr.2009.01.004)

Shemesh N, Cohen Y. (2008) The effect of experimental parameters on the signal decay in double-PGSE experiments: negative diffractions and enhancement of structural information. J Magn Reson 195 (2), 153-61 (doi:10.1016/j.jmr.2008.09.006)

Sadan O, Shemesh N, Barzilay R, Bahat-Stromza M, Melamed E, Cohen Y, Offen D. (2008) Migration of neurotrophic factors-secreting mesenchymal stem cells toward a quinolinic acid lesion as viewed by magnetic resonance imaging. Stem Cells 26 (10), 2542–2551 (doi:10.1634/stemcells.2008-0240)