1. The physiology of the BOLD signal
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
Methods & models for fMRI data analysis in neuroeconomics November 2010

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

4. Image: Ralf Deichmann

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 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. 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: 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*)
dropout T1
But 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 blood
Oxygenated hemoglobine:
Diamagnetic (non-magnetic)
 No signal loss… B0
Deoxygenated hemoglobine:
Paramagnetic (magnetic)
 signal loss !
Images: Huettel, Song & McCarthy 2004, Functional Magnetic Resonance Imaging

10. neurovascular coupling
The BOLD contrast
deoxy-Hb/oxy-Hb 
rCBF  ? ?
neurovascular coupling
neuronal metabolism 
synaptic activity 
D’Esposito et al. 2003
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 REST ACTIVITY
neural activity   blood flow   oxyhemoglobin   T2*   MR signal
ACTIVITY
Source: Jorge Jovicich, fMRIB Brief Introduction to fMRI

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
Peak

13. BOLD signal is a nonlinear function of rCBF
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
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 large
database of microelectrode
recordings (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 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

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

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 LFPs
Thomsen 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 coupling
neuronal 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 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)...
Schwartz et al. 1979, Science

24. Energetic consequences of synaptic activity
Glutamate reuptake and recycling by astrocytes requires glucose metabolism
Also, 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, 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. 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 BOLD
positive BOLD
Shmuel 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.

34. Potential physiological influences on BOLD
cerebrovascular
disease
structural lesions
(compression)
medications
blood
flow
blood
volume
autoregulation
(vasodilation)
hypoxia
volume status
BOLD
contrast
hypercapnia
biophysical effects
anesthesia/sleep
anemia
smoking
oxygen
utilization
degenerative disease

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

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