BOLD fMRIBIAC Graduate fMRI CourseOctober 5, 2005

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

Developments for BOLD MRIEchoplanar imaging methodsProposed by Mansfield in 1977

Ready availability of high-field scannersTechnological developmentsClinical applicability insurance reimbursement clinical prevalence

Discovery of BOLD contrast mechanism

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., dHb)

External Contrast AgentsMost common are Gadolinium-based compounds introduced into bloodstreamVery large magnetic momentsDo not cross blood-brain barrierCreate field gradients within/around vesselsReduces T1 values in blood (can help visualize tumor, etc.)Changes local magnetic fieldsLarge signal changes: 30-50%Delay 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 areaIssuesPotential toxicity of agents (short-term toxicity, long-term accumulation)Cause headaches, nausea, pain at injection

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

Common Contrast Agents

CompoundLongitudinal RelaxivityTransverse RelaxivityMagnetic SusceptibilityGdCl2111MnCl20.963.830.51GdDTPA0.520.51DyDTPA0.030.041.78GDTPA albumin1.6--Iron oxide particle (3nm)0.410.6340.7Iron oxide particle (253nm)4.415.5148

Potential for Endogenous Contrast through Hemodynamics

Blood Deoxygenation affects T2 RecoveryIncreasing Blood OxygenationDecreasing Relaxation TimeT2T1Thulborn 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(BOLD contrast)3% Halothane(reduced BOLD)100% N2(enormous BOLD)BOLD does not simply reflect blood flow

BOLD Endogenous ContrastBlood Oxyenation Level Dependent ContrastDeoxyhemoglobin is paramagnetic, oxyhemoglobin is less so.Magnetic susceptibility of blood increases linearly with increasing oxygenation

Oxygen is extracted during passage through capillary bedArteries 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

50 ms1 sEffects of TE and TR on T2* ContrastTETR

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 activityfMRI response varies with pooled neuronal activity in a brain regionBehavior/cognitive ability determined by pooled activity

Alternatively, if single neurons governed behavior, fMRI activation may be epiphenomenal

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

Calcarine SulciFusiform GyrifMRI Hemodynamic Response1500ms500ms100ms

CalcarineFusiform500ms100ms1500ms

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

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

Basic Form of Hemodynamic ResponseSustained Response

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7.14 Summary of BOLD signal generation. (Part 1)

7.14 Summary of BOLD signal generation. (Part 2)

Baseline PeriodWhy include a baseline period in epoch?Corrects for scanner drift across time

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

Rise (Hyperoxic Phase)Results from vasodilation of arterioles, resulting in a large increase in cerebral blood flowInflection point can be used to index onset of processing

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Peak OvershootOver-compensatory responseMore pronounced in BOLD signal measures than flow measuresOvershoot found in blocked designs with extended intervalsSignal saturates after ~10s of stimulation

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Sustained ResponseBlocked design analyses rest upon presence of sustained responseComparison of sustained activity vs. baselineStatistically simple, powerfulProblemsDifficulty in identifying magnitude of activationLittle ability to describe form of hemodynamic responseMay require detrending of raw time course

UndershootCerebral blood flow more locked to stimuli than cerebral blood volumeIncreased blood volume with baseline flow leads to decrease in MR signalMore frequently observed for longer-duration stimuli (>10s)May not be present for short duration stimuli May remain for 10s of seconds

Issues in HDR AnalysisDelay in the HDR Hemodynamic activity lags neuronal activityAmplitude of the HDR Variability in the HDR HDR as a relative measure

The Hemodynamic Response Lags Neural ActivityExperimental Design

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

500505200205

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

Kwong et al, 1992

Variability in the Hemodynamic ResponseAcross SubjectsAcross Sessions in a Single SubjectAcross Brain RegionsAcross Stimuli

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

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