BOLD fMRI

FMRI Undergraduate Course (PSY 181F) FMRI Graduate Course (NBIO 381, PSY 362) Dr. Scott Huettel, Course Director

FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

Why do we need to know physics/physiology of fMRI?

• 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 fMRI 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, dHb)

FMRI – Week 6 – BOLD fMRI 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 fMRI Scott Huettel, Duke University

Common Contrast Agents

FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

FMRI – Week 6 – BOLD fMRI

Belliveau et al., 1990

Slice Location NMR intensity change (CBV) CBV Maps (+24%)

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FMRI – Week 6 – BOLD fMRI

Potential for Endogenous Contrast through Hemodynamics

Scott Huettel, Duke University

FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

Blood Deoxygenation affects T

2 *

Decay

FMRI – Week 6 – BOLD fMRI

Thulborn et al., 1982

Scott Huettel, Duke University

Ogawa et al., 1990a

• 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 fMRI Scott Huettel, Duke University

FMRI – Week 6 – BOLD fMRI

Spin Echo ?

Gradient Echo ?

?

?

Ogawa 1990

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Spin Echo Gradient Echo

FMRI – Week 6 – BOLD fMRI

Ogawa 1990

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100% O 2

Ogawa et al., 1990b

Under anesthesia, rats breathing pure oxygen have some BOLD contrast (black lines).

90% O 2 , 10% CO 2

FMRI – Week 6 – BOLD fMRI

Breathing a mix including CO 2 in increased blood flow, in turn results increasing blood oxygenation.

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, 0.25cm/s (BOLD contrast) 3% Halothane, 0.12cm/s (reduced BOLD)

FMRI – Week 6 – BOLD fMRI

100% N 2 (enormous BOLD) Ogawa 1990

Scott Huettel, Duke University

BOLD Endogenous Contrast

• Blood Oxyenation Level Dependent – Deoxyhemoglobin is paramagnetic Contrast – 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 fMRI Scott Huettel, Duke University

Effects of TE and TR on T2* Contrast

MR Signal T 2 Decay FMRI – Week 6 – BOLD fMRI

50 ms TE

MR Signal T 1 Recovery

1 s TR

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Kwong et al., 1992

 VISUAL 

FMRI – Week 6 – BOLD fMRI

 MOTOR 

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FMRI – Week 6 – BOLD fMRI

Ogawa et al., 1992

• High-field (4T) 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?

Scott Huettel, Duke University

Blamire et al., 1992

This was the first event-related fMRI study. It used both blocks and pulses of visual stimulation.

Hemodynamic response to long stimulus durations.

Gray Matter Hemodynamic response to short stimulus durations.

White matter Outside Head

Scott Huettel, Duke University FMRI – Week 6 – BOLD fMRI

Relation of BOLD Activity to Neuronal Activity

FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

1. Information processing reflects collected neuronal activity

• Possibility #1: fMRI response varies with pooled neuronal activity in a brain region – Behavior/cognition determined by pooled activity • Possibility #2: Single neurons govern behavior, making fMRI activation epiphenomenal

FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

BOLD response reflects pooled local field potential activity (e.g., Logothetis et al, 2001)

FMRI – Week 6 – BOLD fMRI 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 fMRI Scott Huettel, Duke University

FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

3. Measuring Deoxyhemoglobin

• fMRI measurements are of amount of deoxyhemoglobin per voxel • We assume that amount of deoxygenated hemoglobin is predictive of neuronal activity

FMRI – Week 6 – BOLD fMRI 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 – fMRI measures CMRO 2 poorly 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 fMRI Scott Huettel, Duke University

The Hemodynamic Response

FMRI – Week 6 – BOLD fMRI 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 fMRI Scott Huettel, Duke University

Basic Form of Hemodynamic Response

FMRI – Week 6 – BOLD fMRI 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 -10 -5 0 -10

FMRI – Week 6 – BOLD fMRI

5 10 15 -5 20 25 0

Scott Huettel, Duke University

5 10 15 20 25

Early Evidence for the Initial Dip

FMRI – Week 6 – BOLD fMRI A B C

Menon et al, 1995

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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 1.5T

– 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 fMRI Scott Huettel, Duke University

Yacoub et al., 2001

FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

Negative BOLD response caused by impaired oxygen supply

• Subject: 74y male with transient ischemic attack (6m 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 fMRI

FMRI – Week 6 – BOLD fMRI 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 • HDR as a relative measure

FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

The Hemodynamic Response Lags Neural Activity

Experimental Design Convolving HDR Time-shifted Epochs Introduction of Gaps

FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

Amplitude of the HDR

• Peak signal change dependent on: – Brain region Kwong et al, 1992 – Task parameters  – Voxel size – Field Strength

FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

Percent Signal Change

505 -10 -5 500 0 205 5 1% 10 15 • Peak / mean(baseline) • Often used as a basic measure of “amount of processing” 20 25 • Amplitude variable across subjects, age groups, etc.

-10 -5 200 0 5

FMRI – Week 6 – BOLD fMRI

1% 10 15 20 25

Scott Huettel, Duke University

FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

Relative vs. Absolute Measures

• fMRI 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 fMRI Scott Huettel, Duke University

Linearity of the Hemodynamic Response

FMRI – Week 6 – BOLD fMRI 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 fMRI Scott Huettel, Duke University

Linear Systems

• Scaling – The ratio of inputs determines the ratio of outputs – Example: if Input Output 1 1 is twice as large as Input 2 , 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 fMRI Scott Huettel, Duke University

Scaling (top) and Superposition (bottom)

A -5 0 5 10 15 20 -5 0 5 10 15 20 -5 0 5 10 15 20 B -5 0 5 10 15 20 25 30 -5 0 5 10 15 20 25 30 -5 0 5 10 15 20 25 30

FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

Calcarine Sulci Fusiform Gyri FMRI – Week 6 – BOLD fMRI

-6 -4 -6 -4 2 1 -2 0 0 -1 7 4 3 6 5 6 3 2 5 4 1 -2 0 0 -1 100ms 500ms 1500ms 1500ms 500ms 100ms 2 4 6 8 10 12 100ms 500ms 1500ms 2 4 6 8 10 12

Scott Huettel, Duke University

Linear and Non-linear Systems

A B

-5 0 5 10 15 20 25 -5 0 5 10 15 20 25

C D

-5 0 5 10 15 20 25 -5 0 5 10 15 20 25

FMRI – Week 6 – BOLD fMRI 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

FMRI – Week 6 – BOLD fMRI

From Buxton, 2001

Scott Huettel, Duke University

Effects of Stimulus Duration

• Short stimulus durations evoke BOLD responses – Amplitude of BOLD response often depends on duration – Stimuli < 100ms 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 fMRI Scott Huettel, Duke University

The fMRI Linear Transform

FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

FMRI – Week 6 – BOLD fMRI

Boynton et al., 1996

Varied contrast of checkerboard bars as well as their interval (B) and duration (C).

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FMRI – Week 6 – BOLD fMRI

Boynton, et al, 1996

Scott Huettel, Duke University

FMRI – Week 6 – BOLD fMRI

Boynton, et al, 1996

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Differences in Nonlinearity across Brain Regions

Birn, et al, 2001

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SMA vs. M1

FMRI – Week 6 – BOLD fMRI

Birn, et al, 2001

Scott Huettel, Duke University

Caveat: Stimulus Duration ≠ Neuronal Activity Duration

Component 7 Component 4 120 100 80 60 40 20 0 6 4 2 0 -2 -4 0 500 1000 1500 500 1000 Component 2 1500 120 100 80 60 40 20 0 500 1000 2 0 -2 4 2 0

FMRI – Week 6 – BOLD fMRI

1000 1500 1500 2000 2000 2000 2500 500 500 1000 1500 2000 2500 120 100 80 60 40 20 0 6 4 2 0 -2 0 120 100 80 60 40 20 0 2 0 -2 4 2 0 -2 0 500 500 1000 Component 5 1500 1000 1000 1500 2000 2000 2000 2500

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 fMRI 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 fMRI Scott Huettel, Duke University

6 sec IPI 4 sec IPI 2 sec IPI 1 sec IPI Single Stimulus 500 ms duration Intra-Pair Interval (IPI)

FMRI – Week 6 – BOLD fMRI

Inter-Trial Interval (16-20 seconds)

Hemodynamic Responses to Closely Spaced Stimuli 2.00

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FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

“Rough Linearity”

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0 6 4 2 1 0 1 2 3 4 5 6 7 8 9 10 Time since onset of second stimulus (sec) 11 12 13

FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University