BOLD f MRI FMRI Undergraduate Course PSY 181

BOLD f. MRI FMRI Undergraduate Course (PSY 181 F) FMRI Graduate Course (NBIO 381, PSY 362) Dr. Scott Huettel, Course Director FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Why do we need to know physics/physiology of f. MRI? • To understand the implications of our results – Interpreting activation extent, timing, etc. – Determining the strength of our conclusions – Exploring new and unexpected findings • To understand limitations of our method – Choosing appropriate experimental design – Combining information across techniques to overcome limitations • To take advantage of new developments – Evaluating others’ approaches to problems – Employing new pulse sequences or protocols FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Contrast Agents • Defined: Substances that alter magnetic susceptibility of tissue or blood, leading to changes in MR signal – Affects local magnetic homogeneity: decrease in T 2* • Two types – Exogenous: Externally applied, non-biological compounds (e. g. , Gd-DTPA) – Endogenous: Internally generated biological compound (e. g. , deoxyhemoglobin, d. Hb) FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

External Contrast Agents • Most common are Gadolinium-based compounds introduced into bloodstream – Very large magnetic moments, but do not cross blood-brain barrier • Create field gradients within/around vessels – Reduces T 1 values in blood (can help visualize tumor, etc. ) – Changes local magnetic fields • Large signal changes – Delay until agent bolus passes through MR imaging volume – Width of response depends on delivery of bolus and vascular filtering – Degree of signal change depends on total blood volume of area • Issues – Potential toxicity of agents (short-term toxicity, long-term accumulation) – Cause headaches, nausea, pain at injection FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Common Contrast Agents FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Belliveau et al. , 1990 Slice Location NMR intensity change (CBV) CBV Maps (+24%) FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Potential for Endogenous Contrast through Hemodynamics FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Blood Deoxygenation affects T 2* Decay Thulborn et al. , 1982 FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Ogawa et al. , 1990 a • Subjects: 1) Mice and Rats, 2) Test tubes • Equipment: High-field MR (7+ T) • Results 1: – Contrast on gradient-echo images influenced by proportion of oxygen in breathing gas – Increasing oxygen content reduced contrast – No vascular contrast seen on spin-echo images • Results 2: – Examined signal from tubes of oxygenated and deoxygenated blood as measured using gradient-echo and spin-echo images FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Spin Echo b lo in og em h xy Gradient Echo ? ? O l og n i ob m e yh ox e D Ogawa 1990 FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Spin Echo b lo Gradient Echo in og em h xy O l og n i ob m e yh ox e D Ogawa 1990 FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Ogawa et al. , 1990 b 100% O 2 Under anesthesia, rats breathing pure oxygen have some BOLD contrast (black lines). Breathing a mix including CO 2 results in increased blood flow, in turn increasing blood oxygenation. 90% O 2, 10% CO 2 FMRI – Week 6 – BOLD f. MRI There is no increased metabolic load (no task). Therefore, BOLD contrast is reduced. Scott Huettel, Duke University

BOLD does not simply reflect blood flow or neuronal activity… 0. 75% Halothane, 0. 25 cm/s (BOLD contrast) 3% Halothane, 0. 12 cm/s (reduced BOLD) 100% N 2 (enormous BOLD) Ogawa 1990 FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

BOLD Endogenous Contrast • Blood Oxyenation Level Dependent Contrast – Deoxyhemoglobin is paramagnetic – Magnetic susceptibility of blood increases linearly with increasing oxygenation • Oxygen is extracted during passage through capillary bed – Brain arteries are fully oxygenated – Venous (and capillary) blood has increased proportion of deoxyhemoglobin – Difference between oxy and deoxy states is greater for veins BOLD sensitive to venous changes FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Effects of TE and TR on T 2* Contrast MR Signal T 2 Decay T 1 Recovery FMRI – Week 6 – BOLD f. MRI 50 ms 1 s TE TR Scott Huettel, Duke University

Kwong et al. , 1992 VISUAL MOTOR FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Ogawa et al. , 1992 • High-field (4 T) in humans • Patterned visual stimulation at 10 Hz • Gradient-echo (GRE) pulse sequence used – Surface coil recorded • Significant image intensity changes in visual cortex • Image signal intensity changed with TE change – What form of contrast? FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Blamire et al. , 1992 This was the first event-related f. MRI study. It used both blocks and pulses of visual stimulation. Gray Matter Hemodynamic response to long stimulus durations. Hemodynamic response to short stimulus durations. White matter Outside Head FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Relation of BOLD Activity to Neuronal Activity FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

1. Information processing reflects collected neuronal activity • Possibility #1: f. MRI response varies with pooled neuronal activity in a brain region – Behavior/cognition determined by pooled activity • Possibility #2: Single neurons govern behavior, making f. MRI activation epiphenomenal FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

BOLD response reflects pooled local field potential activity (e. g. , Logothetis et al, 2001) FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

2. Co-localization • BOLD response reflects activity of neurons that are spatially co-localized • Based on what you know, is this true? FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

3. Measuring Deoxyhemoglobin • f. MRI measurements are of amount of deoxyhemoglobin per voxel • We assume that amount of deoxygenated hemoglobin is predictive of neuronal activity FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

4. Uncoupling of CBF & CMRO 2 • Cerebral Blood Flow (CBF) and Cerebral Metabolic Rate of Oxygen (CMRO 2) are coupled under baseline conditions – PET measures CBF well, CMRO 2 poorly – f. MRI measures CMRO 2 well, CBF poorly • CBF about. 5 ml/g/min under baseline conditions – Increases to max of about. 7 -. 8 ml/g/min under activation conditions (+ 30%) • CMRO 2 only increases slightly with activation – May only increase by 10 -15% or less – Note: A large CBF change may be needed to support a small change in CMRO 2 FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

The Hemodynamic Response FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Under normal conditions, oxygen is extracted from red blood cells within the capillaries. But when neurons are active, more oxygenated blood is supplied than needed. This reduces the local quantity of deoxygenated hemoglobin. FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Basic Form of Hemodynamic Response FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Initial Dip (Hypo-oxic Phase) • Transient increase in oxygen consumption, before change in blood flow – Menon et al. , 1995; Hu, et al. , 1997 • Shown by optical imaging studies – Malonek & Grinvald, 1996 • Smaller amplitude than main BOLD signal – 10% of peak amplitude (e. g. , 0. 1% signal change) • Potentially more spatially specific – Oxygen utilization may be more closely associated with neuronal activity than perfusion response FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Early Evidence for the Initial Dip A C B Menon et al, 1995 FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Why is the initial dip controversial? • Not seen in most studies – Spatially localized to Minnesota – May require high field • Increasing field strength increases proportion of signal drawn from small vessels • Of small amplitude/SNR; may require more signal • Yacoub and Hu (1999) reported at 1. 5 T – May be obscured with large voxels or ROI analyses • May be selective for particular cortical regions – Yacoub et al. , 2001, report visual and motor activity • Mechanism unknown – Probably represents increase in activity in advance of flow – But could result from flow decrease or volume increase FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Yacoub et al. , 2001 FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Negative BOLD response caused by impaired oxygen supply • Subject: 74 y male with transient ischemic attack (6 m prior) – Revealed to have arterial occlusion in left hemisphere • Tested in bimanual motor task • Found negative bold in LH, earlier than positive in right FMRI – Week 6 – BOLD f. MRI Rother, et. Duke al. , University 2002 Scott Huettel,

FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Why does the hemodynamic response matter? • Delay in the hemodynamic response (HDR) – Hemodynamic activity lags neuronal activity • • Amplitude of the HDR Variability in the HDR Linearity of the HDR as a relative measure FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

The Hemodynamic Response Lags Neural Activity Experimental Design Convolving HDR Time-shifted Epochs Introduction of Gaps FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Amplitude of the HDR • Peak signal change dependent on: – – Brain region Task parameters Voxel size Field Strength FMRI – Week 6 – BOLD f. MRI Kwong et al, 1992 Scott Huettel, Duke University

Percent Signal Change 505 1% 500 205 200 • Peak / mean(baseline) • Often used as a basic measure of “amount of processing” • Amplitude variable across subjects, age groups, etc. 1% FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Relative vs. Absolute Measures • f. MRI provides relative change over time – Signal measured in “arbitrary MR units” – Percent signal change over baseline • PET provides absolute signal – Measures biological quantity in real units • CBF: cerebral blood flow • CMRGlc: Cerebral Metabolic Rate of Glucose • CMRO 2: Cerebral Metabolic Rate of Oxygen • CBV: Cerebral Blood Volume FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Linearity of the Hemodynamic Response FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Impulse-Response Systems • Impulse: single event that evokes changes in a system – Assumed to be of infinitely short duration • Response: Resulting change in system Impulses Convolution Response = Output FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Linear Systems • Scaling – The ratio of inputs determines the ratio of outputs – Example: if Input 1 is twice as large as Input 2, Output 1 will be twice as large as Output 2 • Superposition – The response to a sum of inputs is equivalent to the sum of the response to individual inputs – Example: Output 1+2+3 = Output 1+Output 2+Output 3 FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Scaling (top) and Superposition (bottom) A B FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

f. MRI Hemodynamic Response Calcarine Sulci 1500 ms 100 ms Fusiform Gyri FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Linear and Non-linear Systems A B C D FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Possible Sources of Nonlinearity • Stimulus time course neural activity – Activity not uniform across stimulus (for any stimulus) • Neural activity Vascular changes – Different activity durations may lead to different blood flow or oxygen extraction • Minimum bolus size? • Minimum activity necessary to trigger? • Vascular changes BOLD measurement – Saturation of BOLD response necessitates nonlinearity – Vascular measures combining to generate BOLD have different time courses From Buxton, 2001 FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Effects of Stimulus Duration • Short stimulus durations evoke BOLD responses – Amplitude of BOLD response often depends on duration – Stimuli < 100 ms evoke measurable BOLD responses • Form of response changes with duration – Latency to peak increases with increasing duration – Onset of rise does not change with duration – Rate of rise increases with duration • Key issue: deconfounding duration of stimulus with duration of neuronal activity FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

The f. MRI Linear Transform FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Boynton et al. , 1996 Varied contrast of checkerboard bars as well as their interval (B) and duration (C). FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

FMRI – Week 6 – BOLD f. MRI Boynton, et al, 1996 Scott Huettel, Duke University

Differences in Nonlinearity across Brain Regions Birn, et al, 2001 FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

SMA vs. M 1 Birn, et al, 2001 FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Caveat: Stimulus Duration ≠ Neuronal Activity Duration FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

$Refractory Periods • Definition: a change in the responsiveness to an event based upon$

Refractory Periods • Definition: a change in the responsiveness to an event based upon the presence or absence of a similar preceding event – Neuronal refractory period – Vascular refractory period FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Dale & Buckner, 1997 • Responses to consecutive presentations of a stimulus add in a “roughly linear” fashion • Subtle departures from linearity are evident FMRI – Week 6 – BOLD f. MRI Scott Huettel, Duke University

Intra-Pair Interval (IPI) 6 sec IPI Inter-Trial Interval (16 -20 seconds) 4 sec IPI 2 sec IPI 1 sec IPI Single. Stimulus FMRI – Week 6 – BOLD f. MRI 500 ms duration Huettel & Mc. Carthy, 2000 Scott Huettel, Duke University