BOLD signal dependence on BOLD signal dependence on blood flow and metabolismblood flow and metabolismR. Hoge, MGH NMR CenterOutlineOutline•physiological events accompanying neuronal activation•factors affecting BOLD signal sensitivity•BOLD response dynamicsPhysiological Events Accompanying Physiological Events Accompanying Neuronal ActivationNeuronal Activationinformationprocessing in neuronselectricalchemicalmetabolismglucoseO2neurotransmitter recycling(glutamate)maintenance of membrane potentialblood flowarteriolar resistancevascular neurotransmitter receptors(dopamine, NO)local and long range neural projections to vasculaturemetabolic byproducts(CO2, H+)blood volumearterialvenoushydrostatic pressure, vascular smooth muscle toneStimulusStimulus--driven glucose uptake:driven glucose uptake:tootell et al. 19882DG autoradiographyduring visual stim. in monkeyDeoxygenated blood attenuates TDeoxygenated blood attenuates T22**--weighted MR imagesweighted MR imagesMRI volume elementO2decrease of venous decrease of venous dHbdHbduring increased perfusion:during increased perfusion:O2Cerebral blood flow is affected by both systemic and focal Cerebral blood flow is affected by both systemic and focal influences:influences:0 200 400 600 800 1000 1200 1400-100102030405060Perfusion (% increase)Time (seconds)stimulation + hypercapnia0100200300400-30-20-1001020304050Time (seconds)Perfusion (% change)hypercapnia onlystimulation + hypocapniastimulation onlyOutlineOutline•physiological events accompanying neuronal activation•factors affecting BOLD signal sensitivity•BOLD response dynamicsFactors affecting BOLD signalFactors affecting BOLD signal•physiology–blood flow, metabolism, blood volume•equipment–magnetic field value•pulse sequence–gradient-echo vs. spin-echo–echo time–resolution0 200 400 600 800 1000 1200 1400-10-505101520CBF (% increase)Time (seconds)0 200 400 600 800 1000 1200 14000123BOLD (% increase)Time (seconds)Oxidative metabolism attenuates the BOLD signal:Oxidative metabolism attenuates the BOLD signal:N=12hypercapniavisual stimulationCBF BOLD0510152025CMRO2(% increase)0 10 20 30 40 50Perfusion (% increase)CBFCBF--CMROCMRO22coupling determines the BOLD coupling determines the BOLD signal during activation:signal during activation:0 10 20 30 40 5001234Perfusion (% increase)BOLD (% increase)0+10 +20-10800204060flow-20-40-60-80∆∆%01020304050BOLD sensitivityM ∼∼[dHb]∆∆%400102030-10-20-30-40∆∆%CMRO2∆∆%40123-1-2-3-4BOLDCMRO2imagingmodel for spatial pattern of BOLD contrastCMRO2quantitation supportedby PET imaging (Marret et al.)Spatial patterns of BOLD, flow, and metabolism:Spatial patterns of BOLD, flow, and metabolism:800204060-20-40-60-80∆∆%∆∆%40123-1-2-3-4+10-10t=0p=0.05+10-10t=0p=0.05BOLDflowpercent change statistical mapImages of Images of ∆∆∆∆%BOLD show different spatial patterns %BOLD show different spatial patterns than BOLD statistical maps:than BOLD statistical maps:Systemic Systemic vasoactive vasoactive effects (respiratory, drug) effects (respiratory, drug) are amplified in BOLD imaging:are amplified in BOLD imaging:Global (~5%)Activation (~35%)• due to lack of metabolic signal attenuation during systemically driven flow increasesflowActivation (~1%)Global (~1%)BOLD+10-10t=0p=0.05If there are If there are stimulusstimulus--correlated systemic effectscorrelated systemic effects, flow , flow contrast will provide much higher specificity than BOLDcontrast will provide much higher specificity than BOLDvisual stim, BOLD visual stim, Flowvisual stim + CO2BOLDvisual stim + CO2FlowOutlineOutline•physiological events accompanying neuronal activation•factors affecting BOLD signal sensitivity•BOLD response dynamicsTemporal Response WaveformsTemporal Response Waveforms•initial dip•overshoot and undershoot•delayed CBV effects•stimulus-dependent response waveformsInitial Initial deoxyhemoglobin deoxyhemoglobin surgesurge((fMRIfMRIinitial dip)initial dip)Shtoyerman, Grinvaldet al.•attributed to early metabolic response•appears to be highly spatially localized•may be idiosyncrasy associated with specific visual input and/or anesthetic stateBOLD overshoot in V1:BOLD overshoot in V1:-10120 50 100 150 200 250 300 350 400Time (seconds)BOLD (% change)48 signal averagesPerfusion overshoot in V1:Perfusion overshoot in V1:0 50 100 150 200 250 300 350 400-50510152025Perfusion (% change)Time (seconds)48 signal averagesSlowSlow--onset CBV response onset CBV response (rat forepaw stimulation)(rat forepaw stimulation)Mandeville et al.MRM 19990204060-30 0 30 60CBFCBV% changetime (sec)BOLD response waveforms for different stimuli at BOLD response waveforms for different stimuli at graded contrast levels:graded contrast levels:0 200 400 600 800 1000 1200 1400-10123Time (seconds)BOLD (% change)0 200 400 600 800 1000 1200 1400-10123Time (seconds)0 200 400 600 800 1000 1200 1400-10123Time (seconds)N=12• not all patterns produced BOLD overshoot• contrast-sensitivity markedly differentno overshoot no overshoot overshootFrequencyFrequency--dependent step responses in V1dependent step responses in V10 100 200 300 400 500-10123Time (seconds)BOLD(% change)7 min. stimulationHeschl's GyrusSuperior Temporal Gyrus2100306003060Response waveforms in auditory areas Response waveforms in auditory areas during highduring high--frequency noise burstsfrequency noise burstscourtesy of Mike HarmsPractical QuestionsPractical Questions•what does BOLD signal mean, in physiological terms?•what factors affect BOLD sensitivity to hemodynamic changes?•how can I compare BOLD responses–within regions (different conditions)–across regions More practical Questions…More practical Questions…•how do temporal response waveforms relate to underlying neurophysiology?•what features of the BOLD response are general, and which are idiosyncratic?–dips, over/undershoots, offset responses…•what factors affect the specificityof BOLD contrast as a marker for neuronal activation?–gross regional specificity, high spatial