MRI: Applications in NeuroscienceMRI: Applicationsin • Yaniv Assaf Tel AvivUniversity, Tel Aviv,Israel Sagol Department of Neurobiology, Departmentof Faculty Life of Sciences School of of School

Funding Applications of MRI in neuroscience

• | & behavior 9 min.

• Neurophysiology |conduction velocity 3 min.

• |connectome 3 min. cortical layers 3 min. Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Brain Plasticity

Neuroplasticity – the ability of the brain to change itself, functionally and structurally as a results of cognitive experience. Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Structural Plasticity

T. Trachtenberg et al., Nature 420, 788 (2002). Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Neuro-plasticity in Adults

Experience Maguire et-al, PNAS 2000 LTP Lerch et-al, Neuroimage, Draganski et-al, Nature 2004 2011

Stem cell

Bermudez et-al, Cereb. Cortex 2008

Oligodendrocyte Astrocyte Neuron Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Open Questions

• Micro vs. macro-structural plasticity

• What are the biological correlates of structural plasticity?

• Previous MRI experiments were done on few weeks of training – what happens at a shorter time? Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Diffusion Tensor Imaging

Mean Diffusivity (MD) Fractional Anisotropy (FA) Tractography

The MD:

 Robust

 Homogeneous Across the brain

 Fast Acquisition

 Well defined in GM and WM

 Simple Interpretation

FA  0.0 0.2 0.4 0.6 0.8 1.0 MD 0.0 0.6 1.2 1.8 2.4 3.0 X10-3 mm2/s Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Morris Water Maze

• The most widely used paradigm in behavioral • Well localized in the brain • Relatively fast training (5 days) N • Controllable W E • Known to cause plasticity, S enhance and Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Experimental Design

Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6

Day 1 90 Day 35214 80 70 60 50 40

30 Latency (s) Latency 20 10 Day 5 0 Day 1 Day 2 Day 3 Day 4 Day 5

60s 30s 6.6s 3.6s Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Effect of Learning

P<0.005 MD % Change % MD

Learning Active Passive Control Control

p-value 0.05 Sensory (BF) cortex 0.025 0.01 0.0075 0.005 Entorhinal Cortex 0.0025 Piriform Cortex 0.001 0.00075 Amygdala 0.0005 0.0001 Cingulate Cortex

Blumenfeld-Katzir et al., PLoS One, 2011 Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers The Need for Speed

MRI1 Round 1 Round 2 Round 3 Round 4 MRI2 x4 x4 x4 x4

90min 1 2

3 4 (seconds) Time

Trial number Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Effect of Learning and Memory p-value

77.5%.5% 0.05 P<0.005 0.025 55.0%.0% 0.01 22.5%.5% 0.0075 00.0%.0% 0.005 0.0%

MD MD Change --2.5%2.5%

0.0025 MD Change -2.5%

% % % ADC ADC % Change 0.001 % --5.0%55.0%.0% 0.00075 0.0005 --7.5%77.5%.5% Learning Active Passive 0.0001 CGCG1LG1 CGCG212 CGLGLG2 Control Control

8.0% R=0.7, p<0.001 6.0%

4.0%

2.0%

0.0%

change 0 0.05 0.1 0.15 0.2 -2.0%

-4.0%

% MD % -6.0%

-8.0% Improve Rate

Sagi, Tavor et al., Neuron 2012 Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Gender Effect

6

4 2 0.01

0 1 2

-2 0.005 ADC % Change % % MD change -4

-6 0.001 Gender Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Sources for MD reduction

• ? A B • Increase in neurite density:

C D 0.160 – CHARMED shows increase 0.155 0.150

0.145 in restricted diffusion Fr 0.140 following training 0.135 0.130 pre post pre post • No apparent changes in 1st week 2nd week T2* ( no blood volume/flow effects)

Tavor et al, Neuroimage 2013 Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Structural Remodeling

+MWM Naive

Green – GFAP (astrocytes) Red – NeuN (Neurons)

Naive +MWM Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Dynamics of the structural plasticity

Sequence learning of the first 50 notes of Fur Elise: • MRI Accuracy • Stage 1: Learning & Accuracy – 60 min.Timing • MRI • Stage 2: Timing – 60 min.

• MRI

IFG

MTG

Premotor

Lingual

STG

MTG Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers White Matter Plasticity

Draganski et al, Nature 2004

Scholtz, et al, Nature Neuroscience 2009 Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers White Matter Plasticity Following Spatial Navigation Task

The Fornix

Passive Active Learning Passive Active Learning control control control control

Hofstetter et al., J of Neurosci 2013 Applications of MRI in neuroscience

• Neuroplasticity |brain & behavior 9 min.

• Neurophysiology |conduction velocity 3 min.

• Neuroanatomy |connectome 3 min. cortical layers 3 min. Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers White Matter Microstructure

• The Axon Diameter Distribution (ADD) is an important morphological feature of the white matter

• The ADD implies on the conduction velocity of nerve fascicles, latency of action potentials

Axon diameter

Ruch TC, Patton HD (eds.) (1982): and Biophysics, 20th ed., 1242 pp. W. B. Saunders, Philadelphia Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers AxCaliber

CSF compartment

Hindered compartment

Restricted compartment

4. Assaf Y., et al. (2008). Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers AxCaliber

1 0.8 Longer Diffusion Time Short Diffusion Time 0.6

0.4 Signal 0.2

0 Small 0 20 40 60 80 100 Time (ms) 1 0.8 0.6

0.4

Signal Medium 0.2 0 0 20 40 60 80 100 Time (ms) 1 0.8

0.6 Large

0.4 Signal 0.2 0 0 20 40 60 80 100 Time (ms) Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers

AxCaliber Probability 0 1 2 3 4 axon diameter (mm)

Barazany D, Basser PJ, Assaf Y. In vivo measurement of axon diameter distribution in the corpus callosum of rat brain. Brain 2009;132(Pt 5):1210-1220. Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers AxCaliber analysis

D=27.8 D=47.8 D=67.8 D=87.8

DataLow b-val Fitting

Eh

ECSF

Er

ADD

D=27.8 D=47.8 D=67.8 D=87.8

Hi b-val Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers AxCaliber analysis

N=19

5. Aboitiz F., et al. (1992)., Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Visual ERPs

Left Hemisphere ERP Right Hemisphere ERP

158.2ms IHTT=5.2ms 163.4ms

ERP = Event Related Potential Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Computing Conduction Velocity

Length (mm) = ACV IHTT (ms)

EEG data

= ADD Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers and AxCaliber correlations

r = 0.81 r = 0.70

Tactile modality P<0.001 Visual modality P=0.002

The axon diameter to the ACV ratio was 8.75 m/s for each mm.

5. Aboitiz F., et al. (1992)., Axon Diameter in MS Applications of MRI in neuroscience

• Neuroplasticity |brain & behavior 9 min.

• Neurophysiology |conduction velocity 3 min.

• Neuroanatomy |connectome 3 min. cortical layers 3 min. Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers What is a CONNECTOME?

CONNECTOME The mass array of neural connections that forms the dense network between all components of the

- The connectome is map/graph - The connectome spans across different scales Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Why the connectome is important?

• To understand a network we need to know its topology (i.e. who connects to who) • Understand brain function: structure to function relations • The connectome affects our cognition and behavior • As genes encodes our body, connectome might encode ourselves/our minds Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers

To see or not to see – that is the question

Do we really needs to see the synapse to know it is there? Do we really needs to see every connection to characterize the connectome? Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Connectome analysis

(1) Fiber tracks  (2) Connectivity Matrix  (3) Network Analysis  (4) Mean Short Path

• Max-component adjacency matrix • ~1 billion entries.. Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers The MAMI database

The Mammalian MRI (MaMI) database contains MRI scans of 87 different species across the mammalian class covering almost all mammalian orders :

Gazelle · Sheep · Dikdik Antelope · Ibex · Artiodactyla – 2 families, 8 species Domestic Pig · Wild Boar · Oryx · Cow · Arabian Wolf · African Wild Dog · Domestic Dog Carnivora – 5 families, 9 species · Fennec Fox · Domestic Cat · Hyaena · Chiroptera – 6 families, 16 species Caracal · Meerkat · Ferret · Trident Bat · Free Tailed Bat · Vampire Bat · Short Tailed Bat · Erinaceoporpha – 1 family, 2 species Jamaican Fruit Bat · Egyptian Fruit Bat · Short- nosed Fruit Bat · Long-tongued Fruit Bat · Cave Hyracoidea – 1 family, 1 species Nectar Bat · Mouse Tailed Bat · Pipistrelle Bat · Greater Mouse-eared Bat · Geoffroy's Bat · Lagomorpha – 1 family, 1 species Lyle's Flying Fox · Fish Eating Bat · Yellow- shouldered Bat · European Hedgehog · Long- Marsupialia – 1 family, 3 species eared Hedgehog · Rock Hyrax · Common Rabbit · Red Kangaroo · Wallaby · Bettong · Perssodactyla – 2 families, 2 species Horse · Tapir · African Wild Donkey · Agouti · Prairie Dog · Vole · Porcupine · Capybara · Primates – 4 families, 7 species Mouse · Rat · Wild Rat · Merion · Spiny Mouse · Golden Spiny Mouse · Sand Rat · Blind Mole · Rodentia – 7 families, 13 species Vervet Monkey · Rhesus Macaque · Long Tailed Macaque · Mangabey · Lemur · Marmoset · Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Mammalian Connectome

Human Mangabey Hyena Fruit Bat

Red Kangaroo Rabbit Wild Rat Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Mammalian Connectome

Trident Bat 6 gr

Striped Dolphin 150 Kg Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Connectome Evolution Applications of MRI in neuroscience

• Neuroplasticity |brain & behavior 9 min.

• Neurophysiology |conduction velocity 3 min.

• Neuroanatomy |connectome 3 min. cortical layers 3 min. Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers The Human Cortex Cyto-Architecture

The human cortex has a prominent morphological feature of six distinct layers Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Extreme Resolution T1/T2 MRI demonstrates the layers

MRI Anatomical image stained section of limited field of view

1500

Walters et al. (2003) 1000

500

0

Barazany and Assaf (Cereb Cortex, 2012) Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers

Cortical Inversion Recovery Bands in the Rat Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers Cortical Layer Mal-Development

• Reelin (Reln) protein is involved in signaling cascade that instructs neurons to migrate to their proper position in the developing brain • Reln deficiency causes disturbance or inversion of cortical layers

Tissir et.al (Nat Rev Neurosci, 2003) Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers T1 of Rln-deficient Mice

The IR-MRI layers of reeler mouse have inverted pattern opposed to wild type

IR-MRI is sensitive to brain mal-development and can characterize the different microstructural properties

Barazany et.al (in preparation) Neuroplasticity | Neurophysiology | Neuroanatomy: connectome | Neuroanatomy: Layers The visual cortex of congenitally blind Collaboration with Prof. Amir Amedi (Hebrew University)

Barazany et.al (in preparation)

Acknowledgments

Galit Yovel, TAU Tel Aviv University Yossi Yovel, TAU Naama Friedman, TAU - Daniel Barazany Yoram Cohen, TAU - Shani Ben-Amitay Amir Amedi, HUJI - Shir Hofstetter - Assaf Horowitz Peter Basser, NIH - Shlomi Lifshits Derek Jones, UK - Ido Tavor Karl Zilles, Germany - Shimrit Tzur Moryosef Katrin Amunts, Germany - Omri Zomet Alexnader Leemans, The Netherlands - Eyal Lotan (ExploreDTI) - Yael Piontkevitch - Tamar Blumenfeld-Katzir Heidi Johansen-Berg, UK Douglas R. Fields, NIH