BOLD Contrast: Functional Imaging with MRI Mark Elliott, PhD Associate Director of CMROI, Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, PA

Overview Mechanisms of functional imaging with MRI Methodology of fMRI Issues for animal studies Spatial and temporal sensitivy of fMRI

Methods for Imaging Neural Activity metabolic response FDG PET - ATP tightly regulated - glucose consumption electrical activity - excitatory - inhibitory - soma action potential - oxygen consumption H215O PET hemodynamic response - blood flow fNIR - blood volume electrophysiology - blood oxygenation fMRI EEG MEG Perfusion MRI

Vascular Sensitivity of fMRI and fNIR Venous Arterial II I fNIR Intravascular Perfusion MRI II IV fMRI III I Extravascular III IV Vessel Size

Mix of blood volume, blood flow, and O2 metabolism Vascular Response fMRI vs fNIR fMRI fNIR Spatial Resolution 8-27 mm3 “Blobs” 1-10 cm3 Temporal Resolution Slow (1-2 sec) Fast (50 Hz) important? Measurement parameter Mix of blood volume, blood flow, and O2 metabolism [Hb] and [HbO]

Mechanisms of fMRI Signal: BOLD Contrast Neural Activity CMR02 “Flooding the garden to feed the thirsty flower” - ??? CBF BOLD ( CBF - CMR02) spatial dimension Hemodynamic response is a surrogate marker for neural activity BOLD = Blood Oxygenation Level-Dependent BOLD signal is a complex interaction of CBF + CBV + CMRO2: CBF >> CMRO2  less deoxyhemoglobin with activation CBF is monitored indirectly “Tracer” is primarily venous “Tracer” is endogenous

Magnetic Susceptibility Affects Background Magnetic Field : permeability r : relative permeability M: magnetic susceptibility For biological tissues, | M | << 1 Diagmagnetic: M < 0 Paramagnetic: M > 0 The interface between regions with different M behaves like a magnetized dipole, perturbing the local B field.  M creates larger B B1  B2 B1 M1 B2 M2

BOLD Contrast: Changes in Magnetic Susceptibility of Blood Blood and brain tissue are diamagnetic. Hb0 is diamagnetic. Hb is strongly paramagnetic. HbO is paramagnetic. Increased Neuronal activity: blood flow increases ≈ 30% 02 consumption increases ≈ 5% [Hb0]  [Hb]  Decrease in [Hb] reduces the M between blood and brain tissue Magnetic field becomes more uniform  MRI signal affected

Hemoglobin Saturation Affects Magnetic Field Homogeniety Rat brain, 7T from Ogawa, 1990 Field Map vs. Hemoglobin Saturation Hypoxia Normoxia from Bandettini and Wong, 1995

Summary: BOLD Contrast in fMRI Verbal Fluency Task Broca’s area Wernicke’s area BOLD = Blood Oxygenation Level-Dependent Oversupply of CBF raises [HbO] in regions of increased CMRO2 Susceptibility mismatch between blood and tissue is reduced Magnetic field becomes more homogeneous Temporal T2* contrast generated in T2* sensitive MRI

fMRI Methodology: Acqusition structural T1 weighted ~ 5 min Temporal series of EPIs . . . . 1x1x1 mm voxels EPI functional T2* weighted ~ 2 sec/volume ~ 300 images ~ 10 min time 3x3x3 mm voxels

fMRI Methodology: Stimulus Blocked Design, Event-Related Design, and ISI ISI Fixed ISI On Blocked Design Off On Off Event Related Event related designs can have either fixed or variable inter-stimulus interval (ISI) ISI Variable ISI Variable ISI allows for more stimuli per time. Increased statistical power in analysis.

fMRI Methodology: Analysis “Non-Activation” Signal Stimulus . . . . Processing “Activation” Signal Processing Stimulus

Brain Activation Maps Statistical Parametric Mapping T2*-weighted Snapshot Image Average Difference Statistical Significance Thresholded Overlay on Anatomic ON task OFF signal courtesy J. Detre

Hemodynamic Response Function The “HRF” - the theoretical impulse response of BOLD contrast to brief neuronal activity Peak Contrast Amplitude FWHM Onset Time Stimulus Time to Peak

fMRI Model: HRF Linear System Linear Model Assumption y = h  x Expected signal (y) is convolution of the stimulus signal (x) with the HRF (h) stimulus (x) HRF (h) signal (y) Signal is predicted for any arbitrary sequence of stimuli

Applications of fMRI Cognitive Neuroscience Localization of sensorimotor and cognitive function Brain-behavior correlations Clinical Neuroscience Presurgical mapping Differential diagnosis of cognitive disorders Recovery of function/neuroplasticity Photic Stimulation

Implications for Animal fMRI Pharmacological effects on neuronal metabolism and hemodynamic response Small voxel sizes reduce SNR Smaller volumes enable higher field magnets (7 and 9.4T) Passive stimulus delivery (training possible in some models)

T2* Signal Loss in the Pre-Frontal Cortex Air is highly paramagnetic (like Hb) Air-tissue interface has “static” M Background signal “drop-out” F B0 E 1 S B0 2 Bn = Normal component Bn = Tangential component This rotation angle a is called the flip angle and it is proportional to the amplitude of B1 and to the pulse duration. If the flip angle is 90 degrees, all the magnetization will lie in the transverse plane. A flip angle of 180 degrees will invert the magnetization. F = frontal sinus E = ethmoidal sinus S = sphenoidal sinus Normal component is unchanged by  B1n = B2n Tangential component is altered by  B1n = 1 / 2 B2n

Signal Dropout in T2* Weighted Images In 2D imaging, images are acquired slice by slice. The slice is selected using a slice selection gradient, which is a gradient in the direction perpendicular to the slices (normally z direction). The slice selection gradient is switch on during the application of the RF pulse. Similarly to the read-out gradient, it will generate a frequency distribution, along z. For a slice thickness dz, a band of frequencies need to be excited as shown here. Increasing TE

Spatial Extent of BOLD Neural Activity CMR02 Hb Saturation (%, approx.) resting active arterioles 90 90 capillaries 80 90 veins 60 90 CBF BOLD ( CBF - CMR02) microvessels draining veins Positive T2* contrast derived from CBF > CMR02 Venous compartment experiences largest Hb (and T2*) Draining veins are less spatially specific to site of neural activity

Extravascular BOLD Signal B0 “inhomogeneity” from vessel extends into extravascular (EV) space EV Magnetic Field Gradient microvessel macrovessel Diffusion of water molecules through B0 gradients Large vessels: static dephasing, T2* effect Small vessels: dynamic dephasing, T2 and T2* effect Spin-echo fMRI less sensitive to large vessel (venous) extravascular space water diffusion from Principles of Functional MRI, Seong-Gi Kim

Echo Time and Field Strength Effects on BOLD Contrast BOLD contrast increase with echo time (TE) SNR decreases with echo time Optimal CNR when TE  resting T2* BOLD contrast increases with magnetic field SNR increases with magnetic field 1.5T % Signal TE (msec) 3T % Signal TE (msec) from Stroman et al, Proc. ISMRM, Glasgow (2001)

Field Strength Effect on BOLD Spatial Sensitivity T2* of blood shortens quadratically with B0 Field dependence of T2,blood  T2,tissue - Decreased venous contribution Diffusion weighted BOLD Intravascular BOLD component model simulation Rat brain, 9.4T from S.P. Lee et al, (2003)