Presentation on theme: "The physiology of the BOLD signal"— Presentation transcript:
1 The physiology of the BOLD signal Klaas Enno Stephan Laboratory for Social and Neural Systems ResearchInstitute for Empirical Research in EconomicsUniversity of ZurichFunctional Imaging Laboratory (FIL)Wellcome Trust Centre for NeuroimagingUniversity College LondonWith many thanks for slides & images to:Meike GrolTobias SommerRalf DeichmannMethods & models for fMRI data analysis in neuroeconomics November 2010
2 Ultrashort introduction to MRI physics Step 1: Place an object/subject in a big magnetStep 2: Apply radio wavesStep 3: Measure emitted radio waves
3 Step 1: Place subject in a big magnet Spin = rotation of a proton around some axisMovement of a positive charge → magnetic momentWhen you put any material in an MRI scanner, the protons align with the direction of the magnetic field.Images:
5 Step 2: Apply radio waves When you apply radio waves (RF pulse) at the appropriate frequency (Larmor frequency), you can change the orientation of the spins as the protons absorb energy.After you turn off the RF pulse, as the protons return to their original orientations, they emit energy in the form of radio waves.Images: Ralf Deichmann
6 Step 3: Measure emitted radio waves T1 = time constant of how quickly the protons realign with the magnetic fieldT2 = time constant of how quickly the protons emit energy when recovering to equilibriumfat has high signal brightCSF has low signal darkT1-WEIGHTED ANATOMICAL IMAGET2-WEIGHTED ANATOMICAL IMAGEfat has low signal darkCSF has high signal brightImages:fmri4newbies.com
7 T2* weighted imagesTwo factors contribute to the decay of transverse magnetization: 1) molecular interactions → dephasing of spins 2) local inhomogeneities of the magnetic fieldThe combined time constant is called T2*.fMRI uses acquisition techniques (e.g. EPI) that are sensitive to changes in T2*.The general principle of MRI:excite spins in static field by RF pulses & detect the emitted RFuse an acquisition technique that is sensitive to local differences in T1, T2 or T2*construct a spatial image
8 But what is it that makes T2* weighted images “functional”? Functional MRI (fMRI)Uses echo planar imaging (EPI) for fast acquisition of T2*-weighted images.Spatial resolution:1.5-3 mm (standard 3 T scanner)< 200 μm (high-field systems)Sampling speed:1 slice: msProblems:distortion and signal dropouts in certain regionssensitive to head motion of subjects during scanningRequires spatial pre-processing and statistical analysis.EPI(T2*)dropoutT1But what is it that makes T2* weighted images “functional”?
9 The BOLD contrast BOLD (Blood Oxygenation Level Dependent) contrast = measures inhomogeneities in the magnetic field due to changes in the level of O2 in the bloodOxygenated hemoglobine:Diamagnetic (non-magnetic) No signal loss…B0Deoxygenated hemoglobine:Paramagnetic (magnetic) signal loss !Images: Huettel, Song & McCarthy 2004, Functional Magnetic Resonance Imaging
10 neurovascular coupling The BOLD contrastdeoxy-Hb/oxy-Hb rCBF ??neurovascular couplingneuronal metabolism synaptic activity D’Esposito et al. 2003Due to an over-compensatory increase of rCBF, increased neural activity decreases the relative amount of deoxy-Hb higher T2* signal intensity
12 The temporal properties of the BOLD signal sometimes shows initial undershootpeaks after 4-6 secsback to baseline after approx. 30 secscan vary between regions and subjectsBriefStimulusUndershootInitialPeak
13 BOLD signal is a nonlinear function of rCBF stimulus functionsutneural stateequationhemodynamicstateequationsBalloon modelBOLD signal change equationBOLD signal is a nonlinear function of rCBFStephan et al. 2007, NeuroImage
14 Three important questions Is the BOLD signal more strongly related to neuronal action potentials or to local field potentials (LFP)?Does the BOLD signal reflect energy demands or synaptic activity?What does a negative BOLD signal mean?
15 Neurophysiological basis of the BOLD signal: soma or synapse?
16 BOLD & action potentials Red curve: “average firing rate in monkey V1, as a function of contrast, estimated from a largedatabase of microelectroderecordings (333 neurons).”Heeger et al. 2000, Nat. Neurosci.Rees et al. 2000, Nat. Neurosci.In early experiments comparing human BOLD signals and monkey electrophysiological data, BOLD signals were found to be correlated with action potentials.
17 Action potentials vs. postsynaptic activity Local Field Potentials (LFP)reflect summation of post-synaptic potentialsMulti-Unit Activity (MUA)reflects action potentials/spikingLogothetis et al. (2001)combined BOLD fMRI and electrophysiological recordingsfound that BOLD activity is more closely related to LFPs than MUALogothetis et al., 2001, Nature
19 Dissociation between action potentials and rCBF GABAA antagonist picrotoxine increased spiking activity without increase in rCBF...... and without disturbing neurovascular coupling per se rCBF-increase can be independent from spiking activity, but seems to be always correlated to LFPsThomsen et al. 2004, J. Physiol.Lauritzen et al. 2003
20 Current conclusion: BOLD signal more strongly correlated to postsynaptic activity BOLD can be correlated both to presynaptic actitivity (action potentials) and to postsynaptic actitivity (as indexed by LFPs)Indeed, in many cases action potentials and LFPs are themselves highly correlated.rCBF-increase can be independent from spiking activity, but so far no case has been found where it was independent of LFPs.This justifies the (present) conclusion that BOLD more strongly reflects the input to a neuronal population as well as its intrinsic processing, rather than its spiking output.Lauritzen 2005, Nat. Neurosci. Rev.
21 Three important questions Is the BOLD signal more strongly related to neuronal action potentials or to local field potentials (LFP)?Does the BOLD signal reflect energy demands or synaptic activity?What does a negative BOLD signal mean?
22 Is the BOLD signal driven by energy demands or synaptic processes? deoxy-Hb/oxy-Hb rCBF ??neurovascular couplingneuronal metabolism synaptic activity D’Esposito et al. 2003
23 Localisation of neuronal energy consumption Salt loading in rats and 2-deoxyglucose mapping→ glucose utilization in the posterior pituitary but not in paraventricular and supraoptic nuclei (which release ADH & oxytocin at their axonal endings in the post. pituitary)→ neuronal energy consumption takes place at the synapses, not at the cell bodyCompatible with findings on BOLD relation to LFPs!But does not tell us whether BOLD induction is due to energy demands (feedback) or synaptic processes (feedforward)...Schwartz et al. 1979, Science
24 Energetic consequences of synaptic activity Glutamate reuptake and recycling by astrocytes requires glucose metabolismAlso, ATP needed for restoring ionic gradients, transmitter reuptake etc.Attwell & Iadecola 2002, TINS.Courtesy: Tobias Sommer
25 Increased rCBF due to lack of energy? Initial dip: possible to get more O2 from the blood without increasing rCBF (which happens later in time).Controversial reports on whether or not there is compensatory increase in blood flow during hypoxia (Mintun et al. 2001; Gjedde 2002).Friston et al. 2000, NeuroImagerCBF map during visual stimulation under normal conditionsrCBF map during visual stimulation under hypoxiaMintun et al. 2001, PNAS
26 Blood flow might be directly driven by excitatory postsynaptic processes
27 Glutamatergic synapses: A feedforward system for eliciting the BOLD signal? Lauritzen 2005, Nat. Neurosci. Rev.
28 Forward control of blood flow Courtesy: Marieke Scholvinck
29 O2 levels determine whether synaptic activity leads to arteriolar vasodilation or vasoconstriction (via prostaglandines)Gordon et al. 2008, Nature
30 Three important questions Is the BOLD signal more strongly related to neuronal action potentials or to local field potentials (LFP)?Does the BOLD signal reflect energy demands or synaptic activity?What does a negative BOLD signal mean?
31 Negative BOLD is correlated with decreases in LFPs positive BOLDpositive BOLDShmuel et al. 2006, Nat. Neurosci.
32 Impact of inhibitory postsynaptic potentials (IPSPs) on blood flow Lauritzen 2005, Nat. Neurosci. Rev.
33 Negative BOLD signals due to IPSPs? Lauritzen 2005, Nat. Neurosci. Rev.
35 Drug effects Nitrates (against coronary heart disease) Analgetics (NSAIDs)
36 SummaryThe BOLD signal seems to be more strongly related to LFPs than to spiking activity.The BOLD signal seems to reflect the input to a neuronal population as well as its intrinsic processing, not the outputs from that population.Blood flow seems to be controlled in a forward fashion by postsynaptic processes leading to the release of vasodilators.Negative BOLD signals may result from IPSPs.Various drugs can interfere with the BOLD response.