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The physiology of the BOLD signal Methods & models for fMRI data analysis in neuroeconomics November 2010 Klaas Enno Stephan Laboratory for Social and.

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Presentation on theme: "The physiology of the BOLD signal Methods & models for fMRI data analysis in neuroeconomics November 2010 Klaas Enno Stephan Laboratory for Social and."— Presentation transcript:

1 The physiology of the BOLD signal Methods & models for fMRI data analysis in neuroeconomics November 2010 Klaas Enno Stephan Laboratory for Social and Neural Systems Research Institute for Empirical Research in Economics University of Zurich Functional Imaging Laboratory (FIL) Wellcome Trust Centre for Neuroimaging University College London With many thanks for slides & images to: Meike Grol Tobias Sommer Ralf Deichmann

2 Ultrashort introduction to MRI physics Step 1: Place an object/subject in a big magnet Step 2: Apply radio waves Step 3: Measure emitted radio waves

3 Step 1: Place subject in a big magnet When you put any material in an MRI scanner, the protons align with the direction of the magnetic field. Images: Spin = rotation of a proton around some axis Movement of a positive charge → magnetic moment

4 Image: Ralf Deichmann

5 Images: Ralf Deichmann 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. T2 T1

6 Step 3: Measure emitted radio waves T1 = time constant of how quickly the protons realign with the magnetic field T2 = time constant of how quickly the protons emit energy when recovering to equilibrium fat has high signal  bright CSF has low signal  dark T1-WEIGHTED ANATOMICAL IMAGE T2-WEIGHTED ANATOMICAL IMAGE fat has low signal  dark CSF has high signal  bright Images: fmri4newbies.com

7 T2 * weighted images Two factors contribute to the decay of transverse magnetization: 1) molecular interactions → dephasing of spins 2) local inhomogeneities of the magnetic field The 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 RF –use an acquisition technique that is sensitive to local differences in T1, T2 or T2* –construct a spatial image

8 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: ms Problems: –distortion and signal dropouts in certain regions –sensitive to head motion of subjects during scanning Requires spatial pre-processing and statistical analysis. EPI (T2 * ) T1 dropout But what is it that makes T2* weighted images “functional”?

9 The BOLD contrast B0B0 BOLD (Blood Oxygenation Level Dependent) contrast = measures inhomogeneities in the magnetic field due to changes in the level of O 2 in the blood Oxygenated hemoglobine: Diamagnetic (non-magnetic)  No signal loss… Deoxygenated hemoglobine: Paramagnetic (magnetic)  signal loss ! Images: Huettel, Song & McCarthy 2004, Functional Magnetic Resonance Imaging

10 The BOLD contrast synaptic activity  neuronal metabolism  neurovascular coupling D’Esposito et al rCBF  deoxy-Hb/oxy-Hb  Due to an over-compensatory increase of rCBF, increased neural activity decreases the relative amount of deoxy-Hb  higher T2* signal intensity ? ?

11 The BOLD contrast Source: Jorge Jovicich, fMRIB Brief Introduction to fMRIfMRIB Brief Introduction to fMRI  neural activity   blood flow   oxyhemoglobin   T2*   MR signal REST ACTIVITY

12 The temporal properties of the BOLD signal sometimes shows initial undershoot peaks after 4-6 secs back to baseline after approx. 30 secs can vary between regions and subjects Brief Stimulus Undershoot Initial Undershoot Peak

13 stimulus functions u t neural state equation hemodynamic state equations Balloon model BOLD signal change equation BOLD signal is a nonlinear function of rCBF Stephan et al. 2007, NeuroImage

14 Three important questions 1.Is the BOLD signal more strongly related to neuronal action potentials or to local field potentials (LFP)? 2.Does the BOLD signal reflect energy demands or synaptic activity? 3.What does a negative BOLD signal mean?

15 Neurophysiological basis of the BOLD signal: soma or synapse?

16 In early experiments comparing human BOLD signals and monkey electrophysiological data, BOLD signals were found to be correlated with action potentials. BOLD & action potentials Heeger et al. 2000, Nat. Neurosci. Rees et al. 2000, Nat. Neurosci. Red curve: “average firing rate in monkey V1, as a function of contrast, estimated from a large database of microelectrode recordings (333 neurons).”

17 Local Field Potentials (LFP) reflect summation of post-synaptic potentials Multi-Unit Activity (MUA) reflects action potentials/spiking Logothetis et al. (2001) combined BOLD fMRI and electrophysiological recordings found that BOLD activity is more closely related to LFPs than MUA Logothetis et al., 2001, Nature Action potentials vs. postsynaptic activity

18 BOLD & LFPs Logothetis & Wandell 2004, Ann. Rev. Physiol. blue: LFP red: BOLD grey: predicted BOLD

19 Thomsen et al. 2004, J. Physiol.  rCBF-increase can be independent from spiking activity, but seems to be always correlated to LFPs GABA A antagonist picrotoxine increased spiking activity without increase in rCBF and without disturbing neurovascular coupling per se Lauritzen et al Dissociation between action potentials and rCBF

20 Current conclusion: BOLD signal more strongly correlated to postsynaptic activity Lauritzen 2005, Nat. Neurosci. Rev. 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.

21 Three important questions 1.Is the BOLD signal more strongly related to neuronal action potentials or to local field potentials (LFP)? 2.Does the BOLD signal reflect energy demands or synaptic activity? 3.What does a negative BOLD signal mean?

22 Is the BOLD signal driven by energy demands or synaptic processes? synaptic activity  neuronal metabolism  neurovascular coupling D’Esposito et al rCBF  deoxy-Hb/oxy-Hb  ? ?

23 Schwartz et al. 1979, Science 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 body Compatible 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)...

24 Energetic consequences of synaptic activity Courtesy: Tobias Sommer Glutamate reuptake and recycling by astrocytes requires glucose metabolism Also, ATP needed for restoring ionic gradients, transmitter reuptake etc. Attwell & Iadecola 2002, TINS.

25 Increased rCBF due to lack of energy? 1.Initial dip: possible to get more O 2 from the blood without increasing rCBF (which happens later in time). 2.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, NeuroImage rCBF map during visual stimulation under normal conditions rCBF map during visual stimulation under hypoxia Mintun 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 O 2 levels determine whether synaptic activity leads to arteriolar vasodilation or vasoconstriction (via prostaglandines) Gordon et al. 2008, Nature

30 Three important questions 1.Is the BOLD signal more strongly related to neuronal action potentials or to local field potentials (LFP)? 2.Does the BOLD signal reflect energy demands or synaptic activity? 3.What does a negative BOLD signal mean?

31 Shmuel et al. 2006, Nat. Neurosci. Negative BOLD is correlated with decreases in LFPs positive BOLD

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.

34 BOLDcontrast bloodflow bloodvolume oxygenutilization structural lesions (compression) autoregulation(vasodilation) cerebrovasculardisease medications hypoxia anemia smoking hypercapnia degenerative disease volume status anesthesia/sleep biophysical effects Potential physiological influences on BOLD

35 Drug effects Analgetics (NSAIDs) Nitrates (against coronary heart disease)

36 Summary The 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.

37 Thank you


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