BOLD fMRIFMRI Undergraduate Course (PSY 181F) FMRI Graduate Course (NBIO 381, PSY 362)

Dr. Scott Huettel, Course Director

Why do we need to know physics/physiology of fMRI?To understand the implications of our resultsInterpreting activation extent, timing, etc.Determining the strength of our conclusionsExploring new and unexpected findings

To understand limitations of our methodChoosing appropriate experimental designCombining information across techniques to overcome limitations

To take advantage of new developmentsEvaluating others approaches to problemsEmploying new pulse sequences or protocols

Contrast AgentsDefined: Substances that alter magnetic susceptibility of tissue or blood, leading to changes in MR signalAffects local magnetic homogeneity: decrease in T2*

Two typesExogenous: Externally applied, non-biological compounds (e.g., Gd-DTPA)Endogenous: Internally generated biological compound (e.g., deoxyhemoglobin, dHb)

External Contrast AgentsMost common are Gadolinium-based compounds introduced into bloodstreamVery large magnetic moments, but do not cross blood-brain barrier

Create field gradients within/around vesselsReduces T1 values in blood (can help visualize tumor, etc.)Changes local magnetic fields

Large signal changesDelay until agent bolus passes through MR imaging volumeWidth of response depends on delivery of bolus and vascular filteringDegree of signal change depends on total blood volume of area

IssuesPotential toxicity of agents (short-term toxicity, long-term accumulation)Cause headaches, nausea, pain at injection

Common Contrast Agents

Belliveau et al., 1990CBV Maps (+24%)Slice LocationNMR intensity change (CBV)

Potential for Endogenous Contrast through Hemodynamics

Blood Deoxygenation affects T2* DecayThulborn et al., 1982

Ogawa et al., 1990aSubjects: 1) Mice and Rats, 2) Test tubesEquipment: High-field MR (7+ T)Results 1:Contrast on gradient-echo images influenced by proportion of oxygen in breathing gasIncreasing oxygen content reduced contrastNo vascular contrast seen on spin-echo imagesResults 2:Examined signal from tubes of oxygenated and deoxygenated blood as measured using gradient-echo and spin-echo images

Gradient EchoOgawa 1990OxyhemoglobinSpin EchoDeoxyhemoglobin????

Gradient EchoOgawa 1990OxyhemoglobinSpin EchoDeoxyhemoglobin

Ogawa et al., 1990b100% O290% O2, 10% CO2Breathing a mix including CO2 results in increased blood flow, in turn increasing blood oxygenation.There is no increased metabolic load (no task).Therefore, BOLD contrast is reduced.Under anesthesia, rats breathing pure oxygen have some BOLD contrast (black lines).

Ogawa 19900.75% Halothane, 0.25cm/s(BOLD contrast)3% Halothane, 0.12cm/s(reduced BOLD)100% N2(enormous BOLD)BOLD does not simply reflect blood flow or neuronal activity

BOLD Endogenous ContrastBlood Oxyenation Level Dependent ContrastDeoxyhemoglobin is paramagneticMagnetic susceptibility of blood increases linearly with increasing oxygenation

Oxygen is extracted during passage through capillary bedBrain arteries are fully oxygenated Venous (and capillary) blood has increased proportion of deoxyhemoglobinDifference between oxy and deoxy states is greater for veins BOLD sensitive to venous changes

Effects of TE and TR on T2* Contrast50 ms1 sTETR

Kwong et al., 1992 VISUAL MOTOR

Ogawa et al., 1992High-field (4T) in humansPatterned visual stimulation at 10 HzGradient-echo (GRE) pulse sequence used Surface coil recordedSignificant image intensity changes in visual cortexImage signal intensity changed with TE changeWhat form of contrast?

Blamire et al., 1992This was the first event-related fMRI study. It used both blocks and pulses of visual stimulation.Hemodynamic response to long stimulus durations.Hemodynamic response to short stimulus durations.Gray MatterWhite matterOutside Head

Relation of BOLD Activity to Neuronal Activity

1. Information processing reflects collected neuronal activityPossibility #1: fMRI response varies with pooled neuronal activity in a brain regionBehavior/cognition determined by pooled activity

Possibility #2: Single neurons govern behavior, making fMRI activation epiphenomenal

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

2. Co-localizationBOLD response reflects activity of neurons that are spatially co-localizedBased on what you know, is this true?

3. Measuring DeoxyhemoglobinfMRI measurements are of amount of deoxyhemoglobin per voxel

We assume that amount of deoxygenated hemoglobin is predictive of neuronal activity

4. Uncoupling of CBF & CMRO2Cerebral Blood Flow (CBF) and Cerebral Metabolic Rate of Oxygen (CMRO2) are coupled under baseline conditionsPET measures CBF well, CMRO2 poorlyfMRI measures CMRO2 well, CBF poorly

CBF about .5 ml/g/min under baseline conditionsIncreases to max of about .7-.8 ml/g/min under activation conditions (+ 30%)

CMRO2 only increases slightly with activationMay only increase by 10-15% or lessNote: A large CBF change may be needed to support a small change in CMRO2

The Hemodynamic Response

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.

Basic Form of Hemodynamic Response

Initial Dip (Hypo-oxic Phase)Transient increase in oxygen consumption, before change in blood flow Menon et al., 1995; Hu, et al., 1997Shown by optical imaging studiesMalonek & Grinvald, 1996Smaller amplitude than main BOLD signal10% of peak amplitude (e.g., 0.1% signal change)Potentially more spatially specificOxygen utilization may be more closely associated with neuronal activity than perfusion response

Early Evidence for the Initial DipCABMenon et al, 1995

Why is the initial dip controversial?Not seen in most studiesSpatially localized to MinnesotaMay require high fieldIncreasing field strength increases proportion of signal drawn from small vesselsOf small amplitude/SNR; may require more signalYacoub and Hu (1999) reported at 1.5TMay be obscured with large voxels or ROI analysesMay be selective for particular cortical regionsYacoub et al., 2001, report visual and motor activityMechanism unknownProbably represents increase in activity in advance of flowBut could result from flow decrease or volume increase

Yacoub et al., 2001

Negative BOLD response caused by impaired oxygen supply Subject: 74y male with transient ischemic attack (6m prior)Revealed to have arterial occlusion in left hemisphereTested in bimanual motor taskFound negative bold in LH, earlier than positive in right

Rother, et al., 2002

Why does the hemodynamic response matter?Delay in the hemodynamic response (HDR) Hemodynamic activity lags neuronal activityAmplitude of the HDR Variability in the HDR Linearity of the HDRHDR as a relative measure

The Hemodynamic Response Lags Neural ActivityExperimental Design

Amplitude of the HDRPeak signal change dependent on:Brain regionTask parameters Voxel sizeField Strength

Kwong et al, 1992

Percent Signal ChangePeak / mean(baseline)Often used as a basic measure of amount of processingAmplitude variable across subjects, age groups, etc.

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Relative vs. Absolute MeasuresfMRI provides relative change over timeSignal measured in arbitrary MR unitsPercent signal change over baselinePET provides absolute signal Measures biological quantity in real unitsCBF: cerebral blood flowCMRGlc: Cerebral Metabolic Rate of GlucoseCMRO2: Cerebral Metabolic Rate of OxygenCBV: Cerebral Blood Volume

Linearity of the Hemodynamic Response

Impulse-Response SystemsImpulse: single event that evokes changes in a systemAssumed to be of infinitely short durationResponse: Resulting change in system =ImpulsesConvolutionResponseOutput

Linear SystemsScalingThe ratio of inputs determines the ratio of outputsExample: if Input1 is twice as large as Input2, Output1 will be twice as large as Output2

SuperpositionThe response to a sum of inputs is equivalent to the sum of the response to individual inputsExample: Output1+2+3 = Output1+Output2+Output3

Scaling (top) and Superposition (bottom)BA

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Possible Sources of NonlinearityStimulus time course neural activityActivity not uniform across stimulus (for any stimulus)

Neural activity Vascular changesDifferent activity durations may lead to different blood flow or oxygen extractionMinimum bolus size?Minimum activity necessary to trigger?

Vascular changes BOLD measurementSaturation of BOLD response necessitates nonlinearityVascular measures combining to generate BOLD have different time coursesFrom Buxton, 2001

Effects of Stimulus DurationShort stimulus durations evoke BOLD responsesAmplitude of BOLD response often depends on durationStimuli < 100ms evoke measurable BOLD responses

Form of response changes with durationLatency to peak increases with increasing durationOnset of rise does not change with duration Rate of rise increases with duration

Key issue: deconfounding duration of stimulus with duration of neuronal activity

The fMRI Linear Transform

Boynton et al., 1996Varied contrast of checkerboard bars as well as their interval (B) and duration (C).

Boynton, et al, 1996

Boynton, et al, 1996

Differences in Nonlinearity across Brain RegionsBirn, et al, 2001

SMA vs. M1Birn, et al, 2001

Caveat: Stimulus Duration Neuronal Activity Duration

Refractory PeriodsDefinition: a change in the responsiveness to an event based upon the presence or absence of a similar preceding eventNeuronal refractory periodVascular refractory period

Dale & Buckner, 1997Responses to consecutive presentations of a stimulus add in a roughly linear fashionSubtle departures from linearity are evident

Huettel & McCarthy, 2000500 ms duration

Hemodynamic Responses to Closely Spaced Stimuli

Rough LinearityTime since onset of second stimulus (sec)Signal Change over Baseline(%)

fmri-fig-07-14-2.jpg fmri-fig-07-16-0.jpg fmri-fig-07-17-1.jpg fmri-fig-07-17-2.jpg Our basic design was derived from electrophysiological studies of refractory periods. We presented either a single short duration visual checkerboard, or a pair of checkerboards separated by an intra-pair interval of either 1, 2, 4, or 6 seconds. A long inter-trial interval ensured that the hemodynamic response returned to baseline before the onset of the next trial. Our hypothesis was that the second stimulus in the pair would have relatively little effect upon the composite waveform at short intervals, like 1 or 2 seconds, but would have a large effect at long intervals. That is, the hemodynamic response would be relatively linearly additive at long-intervals, but non-linear at short intervals.These graphs show the time courses of fMRI activation in calcarine cortex. The yellow line that is repeated in each graph shows the response to a single stimulus. The colored lines show the response to pairs of stimuli. Readily apparent is the contribution of the second stimulus above that of the single stimulus condition. To determine how large of a hemodynamic response was evoked by the second stimulus, we took the residual area between the two curves (the additive effect of the second stimulus), and we time-locked that difference to the onset of the second stimulus.The independent contribution of the second stimulus is shown on this plot.The yellow line shows the response to a single stimulus.Readily apparent are the significant refractory effects. At 1 second intervals, the response to the second stimulus is attenuated in amplitude by about 45% and is increased in latency by about a second. Both amplitude and latency values recover to near single-stimulus values by about six seconds.