BOLD Functional MRI. Outline !"#$"%%& BMB601 Ang Li 03/01/2011

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1 BOLD Functional MRI BMB601 Ang Li 03/01/2011 Outline Introduction to BOLD functional MRI History of BOLD fmri Principles of the BOLD effect BOLD hemodynamic response %&

2 INTRODUCTION OF FUNCTIONAL MRI Introduction of BOLD Functional MRI Functional neural imaging technique based on the BOLD (Blood Oxygenation Level Dependent) effect. Goal: to map patterns of local changes in MR signal in the brain as an indicator of neural activity associated with particular stimuli or tasks. Measure changes in blood oxygenation Voxel smallest spatial unit for fmri #&

3 Introduction of BOLD Functional MRI Advantages: Minimal invasiveness and radiation exposure Wide availability of hardware standard MRI scanner Both spatial and temporal resolution Disadvantage: Indirect measurement of neural activity Require careful statistical analysis and interpretation HISTORY OF BOLD FMRI '&

4 History of BOLD fmri Initial discovery of magnetic properties of blood (Pauling and Coryell, 1936) Magnetic properties of a blood cell (hemoglobin) depends on whether it has an oxygen molecule Oxyhemoglobin! Diamagnetic Deoxyhemoglobin! Paramagnetic Coupling of glucose metabolism and blood flow in brain using autoradiography (Sokoloff, 1981) Correlation r=0.95 Changes in blood oxygenation changed the T2 of blood (Thulborn, Waterton, Matthews and Radda, 1982) History of BOLD fmri Belliveau (1990) used MRI contrast agent Gadolinium as an exogenous tracer Gadolinium locally disrupts MRI signal Map blood volume during rest and activation Seiji Ogawa (1990) manipulates oxygen content of air breathed by rats Anoxic condition " high image contrast Image contrast caused by magnetic susceptibility between dhb and surrounding tissues Gradient Echo image: dark lines Spin echo image: lines absent Results: deoxyhemoglobin " susceptibility " T2* " signal strengh Gradient Echo Spin Echo ()*+,-./&01232&-4&2567&%889&!&

5 History of BOLD fmri First BOLD-contrast fmri in human visual cortex (Kwong, 1992) Sources: Kwong et al., 1992 PRINCIPLES OF THE BOLD EFFECT :&

6 Contrast Agent Contrast agent: Enhance the contrast between different tissues by altering local relaxation times How contrast agent works: Gadolinium, e.g. Gd-DTPA (blood vessel or brain tumor enhancement) Unpaired electrons, paramagnetic Affect the magnitude and correlation times of the fluctuating field " affects both T1 and T2 T1>>T2, fractional change of T1 >>T2 (T1-agent) Tissue relaxation time Contrast agents with large magnetic moment Reduces T2 more than T1 Alter blood magnetic susceptibility relative to surrounding tissue Local heterogeneity of the field " signal decay " shorten T 2 * Magnetic Field Distortion Shorten T2* Magnetic susceptibility (!) : The degree of magnetization of a material when placed in magnetic field B0 Cubic of material many magnetic dipole moments " dipole field Paramagnetic - dipole align the applied field Diameganetic dipole align opposite to the applied field Sum of dipole moments " net magnetization Induced local magnetization is proportional to applied magnetic field: M=! B0 (!: a few ppm) Field distortions A body placed in a uniform, external magnetic field B0, the net field is distorted both outside and inside the body. Human head: heterogeneous (water, bone, air) " field distortion at the interfaces Large field gradient (> voxel size) " unwanted distortion on image Microscopic field gradient around small vessels (< voxel size) "Signal drop due to the dephasing of the spins " T2* effect ;&

7 BOLD Signal and T2* Deoxyhemoglobin endogenous contrast agent BOLD fmri: detect small local change in T2* T2* relaxation GRE pulse sequence no 180 pulse " dephasing effects of field inhomogeneities are not reversed Signal decays exponentially with increasing TE (decay constant T2*) BOLD Signal and T2* Empirical model by Davis et al., 1998: Change in deoxyhemoglobin content alters R2* R2* depends on blood volume and deoxyhemoglobin concentration!=1.5 good approximation for 1.5T (by Monte Carlo simulation) (Boxerman etal., 1995b)!=1 for higher field, e.g. 7T (Mandeville et al., 1999, Ogawa, Lee and Barrere, 1993a) Limitation Fails to describe the volume exchange effect $&

8 BOLD Signal and T2* Difference "R2* between the resting (r) and activated (a) states: v = V/V0, activated blood volume normalized to its resting value c = [dhb]a/[dhb]r, normalized concentration of deoxyhemoglobin BOLD Effect Presence of deoxyhemoglobin creates magnetic field gradients " shorten T2* " reduced MR signal Brain activation " increased blood oxygenation level " blood susceptibility closer to the susceptibility of surrounding tissue " reduced field gradient " increased T2* " increased T2*-weighted signal Physiological Basis of the BOLD Effect Combined results of changes in Cerebral Blood Flow, Cerebral Metabolic Rate of Oxygen, and Cerebral Blood Volume CBF Stimulus Neural Activity CMRO2 Bold Signal CBV <&

9 Physiological Basis of the BOLD Effect BOLD effect indirect measurement of neural activity With onset of activation: CBF increases dramatically CBV increases moderately CMRO2 increases by a much smaller amount CBF CMRO2 Local Hb Content Local Hb Content More HbO2 is delivered though the increased CBF (excess O2) Metabolism"O2 extraction; More HbO2 is deoxygenated CBV Local Hb Content Increased blood volume increased the number of local Hb Results: drop in blood oxygenation extraction fraction " increases MR signal Increase in CBV " decrease MR signal (overwhelmed adult brain) Physiological Basis of the BOLD Effect Physiological modeling of the BOLD signal Relating the change in blood oxygenation to the changes in CMRO2 and CBF E = oxygen extraction fraction [O2]art proportional to blood concentration of [Hb] Venous concentration of dhb (steady-state): m = CMRO2(a)/CMRO2(r), f = CBF(a)/CBF(r) c = m/f (normalized concentration of deoxyhemoglobin ) Measurement of Smax : CO2 inhalation experiment 8&

10 BOLD HEMODYNAMIC RESPONSE BOLD Signal Response Time course of BOLD signal with activation: Source: Functional Magnetic Resonance Imaging, 2004 %9&

11 Location of BOLD Signal Changes Largest BOLD signal changes " draining veins (Lai et al., 1993) as venous vessels undergo the largest change in dhb. Typical voxel size: >30 mm 3 ; Signal change: a few % at 1.5T Decrease in voxel size " dramatic increase in the largest BOLD signal change (Frahm, Merboldt, 1993). Activated areas were predominantly found to be in the location of venous vessels with diameters on the order of the pixel size (Hoogenraad, 1999) Improved localization of BOLD signal changes at the expense of sensitivity. High field: largest signal changes are ignored; only weaker signal changes are used for mapping " eliminate signal from draining veins Experiment strategy depends on the objectives To test whether an area of brain is activated not significantly affected by the displacement caused by draining veins. To map precise anatomical location BOLD fmri may not be appropriate. Post-stimulus Undershoot Signal change: change in local deoxyhemogobin content Possible explanations: 1. CMRO2 remains elevated after blood flow has returned to baseline. 2. CBV remains elevated. Mandeville et al., 1996: Rapid return to baseline of CBF but delayed return of CBV Delay in CBV return to baseline results in an accumulation of dhb " signal drops below the baseline Source: Functional Magnetic Resonance Imaging, 2004; Mandeville et al., %%&

12 Initial Dip Transient increase in oxygen consumption, before change in blood flow (Menon et al., 1995). Shown by optical imaging studies Malonek & Grinvald, 1996 Voxel with initial dip Mapped to the gray matter 2% late BOLD signal vs. 1% initial dip Presence of post-stimulus undershoot Voxel without initial dip Widespread in visual courtex 6% positive BOLD signal and no undershoot Time course of fmri signal: Source: Menon et al., 1995 Source: Functional Magnetic Resonance Imaging, 2004; Malonek &Grinvald, Controversial Interpretation of the Initial Dip Not seen in most studies Very weak initial dip at 1.5T (10% of the amplitude of the late positive response) (Yacoub and Hu, 1999) Not found in rats even at high field species difference (Marota et. al. 1999) Nature of initial dip is unclear Usual interpretation: early increase of CMRO2 before blood flow increases, with a corresponding increase in oxygen extraction. Initial flow decrease or volume increase could also lead to initial dip %#&