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Functional Neuroimaging: The “Dis”-Connectome

Salil Soman, MD, MSMike Moseley, PhD

Stanford University S. Seung

Wikipedia

fMRI / DTI - Core of the Connectome

V. Wadeen S. Seung

...Will the Connectome Create New Markets...? The “Connectome” Now on iTunes

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Now! The “Armchair” Connectome The “Connectome” Magnet- PRISMA

The GE-NFL Initiative

NEW YORK, March 11, 2013 -- (NYSE: GE) -- GE and the NFL today announced the Head Health Initiative, a four-year, $60

million collaboration to speed diagnosis and improve treatment for mild traumatic brain injury. The goal of the research and innovation program, guided by healthcare

experts, is to improve the safety of athletes, members of the military and society overall.

The 2013 “BRAIN” Roadmap

http://www.youtube.com/watch?v=EI-VcvwgCgE

“Clarity” Drives “BRAIN” TBI and the “Dis-Connectome”

Role of Advanced MR?

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• Mod to severe detectable with classic MR methods.

• Mild TBI in general has a good prognosis.

• But 15 -30% patients have cognitive, physiological and clinical symptoms at 3 months post injury.

• Majority of patients have negative conventional MR.

• Identify this group at risk for long term disability and early therapy.

WHY ADVANCED MRI?

http://emedicine.medscape.com/article/344973-overview

TBI Background

Wikipedia

Multi-Contrast MR – Key to the Connectome

Structural Imaging

MR Volumetric Analyses

SPM and Freesurfer

VBM Group AnalysesStructural Imaging

Voxel Based Morphometry (VBM) t-test analyses of regional changes over patient populations. Freesurfer/NeuroQuant.

Zhou et al., Mild Traumatic Brain Injury: Longitudinal Regional Brain Volume Changes, Radiology. 2013 J 267(3) 880 90

One year after mild TBI, brain atrophy seenanterior cingulate WM bilaterally left cingulate gyrus isthmus WM, right precuneal GM

VBM Group AnalysisStructural Imaging

Frontal Regions Susceptibile to InjuryTBI Background

http://www.dialogues-cns.com/figures/DialoguesClinNeurosci-13-287-g003.jpg

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http://www.gvsu.edu/cms3/assets/2A1BD006-C757-0356-A2F497F9DC021F20/rsz_astrocyteslstockpd.jpg

TBI Background

http://blog.mcleishorlando.com/blog/wp-content/uploads/2013/03/Axonal_Shear.jpg

“Micro-Structural” MRI for TBI?

Acquisition

Reconstruction

Modeling

Diffusion Tensor Imaging DTI

V. Wedeen

MicroStructural Imaging

Proton Diffusion in GM

10 umOlympus Medical

Proton Diffusion in WM

Olympus Medical 10 um

ADC ADC xx ADC xy ADC xz

ADC xy ADC yy ADC yz

ADCxz ADC yz ADC zz

Tensor

Y

XZ

Magnet axis Fiber axis

Diffusion Tensor Imaging

MicroStructural Imaging

Magnet axis

ADC FA x

y

z

DTI

“FA”

map

Diffusion

Model

Diffusion

Pathways

Fiber

Tractography

Color

“FA”

map

One Way to Display DTI: TractographyOne Way to Display DTI: TractographyMicroStructural Imaging

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DWI inStroke

DWI vs. DTI: Which is Which?DWI vs. DTI: Which is Which?

DWI“ADC”DWI“ADC”

DTI“FA”

DWI inScreening

CNS

Non-NeuroDWI

DWI inMSK

FA in CNSdisease

Fiber tracking

DTI FA

DTI in cognition

Technique Development

Hulkower MB, Poliak DB, Rosenbaum SB, et al. A Decade of DTI in Traumatic Brain Injury: 10 Years and 100 Articles Later. AJNR. American journal of neuroradiology. Jan 10 2013.

• The most commonly identified regions of abnormal FA or MD in DTI studies of TBI:• Corpus callosum, • Frontal lobe, • Internal capsule, • Cingulum

DTI and TBI

DTI Multi-Subject Statistical AppsDTI Modeling and Statistics

http://fsl.fmrib.ox.ac.uk/fslcourse/lectures/fdt.pdf

Tract-Based Spatial Stats (TBSS)FSL (FMRIB)

DTI Modeling and Statistics

S.M. Smith, M. Jenkinson, H. Johansen-Berg, D. Rueckert, T.E. Nichols, C.E. Mackay, K.E. Watkins, O. Ciccarelli, M.Z. Cader, P.M. Matthews, and T.E.J. Behrens. Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data. NeuroImage,

31:1487-1505, 2006.

Automated White Matter Tract Segmentation (TRACULA)

Freesurfer

TRActs Constrained by UnderLying Anatomy

DTI Modeling and Statistics

FreeSurfer Module FreeSurfer.net

T1 T2 iso trace FA Colormap FLAIR

SWI

Adult atlas MRIStudio.org

DTI Modeling and Statistics

T1 T2 iso trace FA Colormap

Pediatric atlas (24M)

T1 T2 iso trace FA Colormap

Neonatal atlas

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• The number of b values can provide additional data for modeling the microstructure of the brain.

• Conventional DTI sequences tend to use the single b value of 1000, plus some number of b0 images.

• Having additional b value images other than b0 enables a number of different modeling techniques.

• Conventional DTI is not enough!

“Higher Order” DTIWhy Make This Harder?

Higher Order DTI DTI is NOT Simple : Need Higher Order Tensors

Diffusion Kurtosis Imaging DKI• Assumes substantially non-gaussian distribution of water

diffusion

• May better evaluate diffusion properties outside of highly organized large white matter tracts.

Zhuo J, Xu S, Proctor JL, et al. Diffusion kurtosis as an in vivo imaging marker for reactive astrogliosis in traumatic brain injury. NeuroImage. Jan 2 2012;59(1):467-477.

Higher Order DTI

• within 1 year after mTBI exhibited altered DTI-and DKI measures in thalamus and internal capsule (c/w controls)

• > 1 year after mTBI had differences in splenium of the corpus callosum and the centrum semiovale.

• Cognitive impairment was correlated with Mean Kurtosis (MK) in the thalamus and the internal capsule.

Zhuo J, Xu S, Proctor JL, et al. Diffusion kurtosis as an in vivo imaging marker for reactive astrogliosis in traumatic brain injury. NeuroImage. Jan 2 2012;59(1):467-477.

DKI in TBI

DTI in TBI

Diffusion Full-Space Imaging – 150 Directions –12 minutes minimum

DSI, QSI, RSI – The Ultimate DTI?

Higher Order DTI

http://dsi-studio.labsolver.org

Neurite Orientation Dispersion and Density Imaging

Neurite Modeling (NODDI)Higher Order DTI

UCL Package

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Quantitative Susceptibility MappingWhat and Why?

Microstructural Imaging - QSM

•DTI is a sensitive measure of WM directions / connectivity but needs more work for measuring integrity. •QSM is faster with higher resolution and 3D for WM mapping.•QSM natural extension of GRE and is both bleed/WM sensitive.

• Higher• More paramagnetic

microstructures

• Lower• More diamagnetic

microstructures

Physical Properties of QSM

Microstructural Imaging - QSM

“The total susceptibility of a cerebral microbleed measuredby using QSM is a physical property that is independent

of echo time.”

Liu T, Surapaneni K, Lou M, et al. Cerebral microbleeds: burden assessment by using quantitative susceptibility mapping. Radiology. Jan 2012;262(1):269-278.

QSM Shows Bleeds Independent of TE

Microstructural Imaging - QSM

Negative Correlation between TBI patient only left (not right) lateral orbitofrontal cortex susceptibility and performance on Verbal Test, controlling for age

Soman et al. Preliminary results 2013.

QSM in TBI

Microstructural Imaging - QSM

A B C

D E F

QSM is Ideal for VBM

Microstructural Imaging - QSM

fMRI is BOLDfMRI is BOLD

FeFe

NN

NN

O = OO = O

oxyhemoglobinoxyhemoglobin

FeFe

NN

NN

deoxyhemoglobindeoxyhemoglobin

HbO2HbO2 HbHb

Hb4 unpaired electrons

paramagneticHigh ² �

Hb4 unpaired electrons

paramagneticHigh ² �

HbO2diamagnetic

Low ² �

HbO2diamagnetic

Low ² �

Functional MRI - fMRI

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The Brain Does Not Sleep - Resting State fMRIThe Brain Does Not Sleep - Resting State fMRIFunctional MRI - fMRI

Resting State RS-fMRI The Other Connectivity

Functional Imaging

Zhou Y, et al. Default-mode network disruption in mild traumatic brain injury. Radiology. Dec 2012;265(3):882-892.

When compared with DMN patterns in the control group (A), the patient group (B) showed significantly decreased connectivity in the posterior portion (arrowheads) and increased connectivity in the anterior portion (arrows) of the DMN.

RS-fMRI in TBIFunctional Imaging

RS-fMRI BOLD FluctuationsRelated to CBV

RS-fMRI BOLD FluctuationsRelated to CBV

Related To NetworkDelays (!)

Multispectral Data Fusion

The Dis-Connectome

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Structural Connectivity Mapping

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Diffusion Tensor Imaing Volumetrics Connectivity Matrix

• Diffusion Tensor and volumetric images combined to generate connectivity matrices.

• Matrices then converted to graphs representing brain connectivity.

The Connectome – Putting It All Together

Structural Connectivity MappingThe Connectome – Putting It All Together

Structural Connectivity MappingThe Connectome – Putting It All Together

• Compared to controls, the graph analysis showed reduced overall connectivity, longer average path lengths, and reduced network efficiency.

• A particular impact of TBI is seen on a major network hub, the posterior cingulate cortex.

• Taken together, these results confirm that a network critical to cognitive function shows a shift away from small-world characteristics.

Pandit AS, Expert P, Lambiotte R, et al. Traumatic brain injury impairs small-world topology. Neurology. May 14 2013;80(20):1826-1833.

Controls

TBI

The “Small World Network” - TBIThe Connectome – Putting It All Together

Many Thanks: Keith MainFranco PestilliGautam PrasadNils FolkertNatalie HanAnna Clare MillazzoNanjie GongDeqiang QiuMurat AksoyElizabeth HitchnerJyoti BhatZungho (Wesley) ZunShannon BuckleyBernard NgJonas RichiardiDawn LaGuo Jia GuoFariah Mahzabeen

Solil SomanGreg ZaharchukAllyson RosenBrian WandellWei ZhouAndy QuonMichael GreciusJerry YesavageGeoff KerchnerEric WongChunlei LiuJames HarrisJames BrewerKaren HirschBooil Jo

R21 NS081416

J. Wesson AshfordAnsgar FurstMaheen M. AdamsonRobert DoughertyLaura LazaroniLeah FriedmanJae Mo ParkSamantha HoldsworthLinda IsaacLisa Kinoshita

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Thank you

salsoman@stanford.edu

“Metabolic” PET-MR (mMR)“Metabolic” PET-MR (mMR)

Siemens mMR “Biograph”

Siemens mMR “Biograph”

• The sample consisted of 57 veterans (7 females), mean age of 46.8 yrs. (median: 45.1), 31 mild TBI, 5 moderate TBI and 43 with PTSD.

• Glucose metabolism decreased significantly with increasing TBI severity in the right precuneus and left angular gyrus.

• VOI analyses with FWE multiple comparison correction at p < .05 confirmed the robustness of the effect.

Soman et al. Preliminary results 2013.

PET-MR and TBI

Beyond the Connectome – Room for PET?

SI=ke(-� � G [- �/3] ADC) =ke(-b ADC)

where b=0-1000 sec/mm2

SI=ke(-� � G [- �/3] ADC) =ke(-b ADC)

where b=0-1000 sec/mm2

Proton Diffusion can be Measured as the “ADC”

Proton DiffusionProton Diffusion

0 090 RF 180 RF

0 0

GG GG

b0b0

ADC map

= 40 msec���� msec

b1000b1000 ADCADC

22 22 22

MicroStructural Imaging

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Thalamic Nuclei Evaluation

Krauth et al. A mean three-dimensional atlas of the human thalamus: generation from multiple histological data. Neuroimage. 2010 Feb 1;49(3):2053-62; Squarcina et al. A robust method for investigating thalamic white matter tracts after traumatic brain injury. NeuroImage. Nov 1 2012;63(2):779-788.

• Damage to the structural connections of the thalamus is a frequent feature of traumatic brain injury (TBI) and could be a key factor in clinical outcome

• Multiple thalamic nuclei atlases available.

DTI in TBI