1. What do we (not) measure with fMRI?
BOLD physiology
What do we (not) measure with fMRI?
Meike J. Grol
Leiden Institute for Brain and Cognition (LIBC), Leiden, The Netherlands
Leiden University - Institute for Psychological Research (LU-IPR), Leiden, The Netherlands
Department of Radiology, Leiden University Medical Center
F. C. Donders Centre for Cognitive NeuroImaging, Nijmegen, The Netherlands
Zürich SPM Course February 27, 2008

2. Ultrashort MR physics overview
4T magnet
RF Coil
Magnet
RF Coil
source: fmri4newbies.com

3. Step 1: Put Subject in Big Magnet
Protons (hydrogen atoms) have “spins” (like tops). They have an orientation and a frequency.
When you put a material (like your subject) in an MRI scanner, some of the protons become oriented with the magnetic field.
source: fmri4newbies.com

4. Step 2: Apply Radio Waves
When you apply radio waves (RF pulse) at the appropriate frequency, you can change the orientation of the spins as the protons absorb energy.
After you turn off the radio waves, as the protons return to their original orientations, they emit energy in the form of radio waves.
source: fmri4newbies.com

5. Step 3: Measure Radio Waves
T1 measures how quickly the protons realign with the main magnetic field
T2 measures how quickly the protons give off energy as they recover to equilibrium
T2-WEIGHTED ANATOMICAL IMAGE
fat has low signal  dark
CSF has high signal  bright
fat has high signal  bright
CSF has low signal  dark
T1-WEIGHTED ANATOMICAL IMAGE
source:
fmri4newbies.com

6. This is usually not so nice, but...
We also have T2* weighted images: these are sensitive to local magnetic field inhomogeneities.
These T2* weighted images have artifacts near junctions between air and tissue: sinuses, ear canals
sinuses
ear
canals
This is usually not so nice, but...
Based on Robert Cox’s web slides

7. 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 blood?
Non-magnetic
No signal loss… B0
Deoxygenated blood?
Magnetic!
Signal loss!!!
Images from Huettel, Song & McCarthy, 2004, Functional Magnetic Resonance Imaging

8. BOLD signal REST ACTIVITY
neural activity   blood flow   oxyhemoglobin   T2*   MR signal
ACTIVITY
Source: fMRIB Brief Introduction to fMRI
Source: Jorge Jovicich

9. The Haemodynamic Response Function (HRF)

10. Physiology of the BOLD signal
Source: Arthurs & Boniface, 2002, Trends in Neurosciences

11. Three open questions
Is BOLD more informative about spiking/action potentials or local field potentials (LFP)?
How does the BOLD reflect the energy demands of the brain?
What does a negative BOLD signal mean?

12. Electrophysiological BOLD-correlates

13. Action potentials vs. synaptic activity I
Local Field Potentials (LFP)
reflect post-synaptic potentials
similar to what EEG (ERPs) and MEG measure
Multi-Unit Activity (MUA)
reflects action potentials/spiking
similar to what most electrophysiology measures
Logothetis et al. (2001)
combined BOLD fMRI and electrophysiological recordings
found that BOLD activity is more closely related to LFPs than MUA
Source: Logothetis et al., 2001, Nature
Courtesy: Jody Culham

14. Action potentials vs. synaptic activity II
(Mukamel et al., 2005)
(Heeger et al., 2000)
BOLD-Signal strongly correlated with both action potentials and synaptic activity
Courtesy: Tobias Sommer

15. Dissociation between action potentials and CBF
bicuculline increased spiking activity without increase CBF and vice versa
normal neurovascular coupling
 local CBF-increase can be independent from spiking activity, but is always correlated to LFPs
(Thomsen et al. 2004)
(Lauritzen et al. 2003)
Courtesy: Tobias Sommer

16. BOLD seems to be correlated to postsynaptic activity
BOLD seems to reflect the input of a cortical area as well as its intracortical processing
(Lauritzen et al. 2005)

17. Localisation of energy metabolism
Energy metabolism takes place at the synapses, not at the cell body.
Schwartz et al. 1979
Courtesy: Tobias Sommer

18. CBF & Glucose consumption
How does the BOLD reflect the energy demands of the brain?
Neuronal Activity →
O2-consumption (CMRO2)
CBF & Glucose consumption
PET
fMRI
BOLD-contrast
Uncoupling of CBF and CMRO2 “functional hyperaemia“
Does the need for oxygen drive the blood flow?

19. Lack of energy?
the initial dip shows that it is possible to get more
O2 from the blood without increasing the blood flow,
which happens later in time.
Although oxygen usage associated with neuronal activity must colocalize with the activity, the subsequent increase of blood flow occurs in a larger area.
When subjects breath air with reduced oxygen content the oxygen availability in circulating blood is decreased. Surprisingly, the expected compensatory blood flow response was not observed (Mintun et al, 2000).
Blood flow seems to be controlled by factors other than a lack of energy.

20. Blood flow might be directly driven by excitatory postsynaptic processes

21. Feedforward system
Glutamate

22. Active control of blood flow
Courtesy: Marieke Scholvinck

23. Hungry brains 50-75% of energy
GLUTAMATE
Glial cell
3Na + H K Na
Post-synaptic neuron Ca 2
GLU
GLN
ATP 2K
Pre-synaptic neuron
50-75% of energy
use is action potential driven; remainder is spent on housekeeping
Most energy is spent on the reuptake of glutamate and reversing ion movements
(Atwell and Laughlin, 2001)
3Na
Courtesy: Marieke Scholvinck

24. Glutamate transport in astrocytes triggers glucose metabolism
Courtesy: Tobias Sommer

25. Synaptic inhibition can modulate blood flow

26. Leading to negative BOLD signals?
Lauritzen, 2005
Raichle et al, 1998
-> Synaptic inhibition could result in a negative BOLD signal

27. Summary
BOLD seems to be more informative about local field potentials (LFP) than spiking activity. BOLD seems to reflect the input of a cortical area as well as its intracortical processing, not the output level of firing of the neuron.
Blood flow seems to be actively controlled by neurotransmitters leading to vasodilation.
Glutamate transport in astrocytes triggers glucose metabolism
Synaptic inhibition might result in a negative BOLD signal.

28. Fortunately, BOLD is tightly coupled to synaptic activity
But we have to be alert…

29. Potential Physiological Influences on BOLD
cerebrovascular
disease
structural lesions
(compression)
medications
blood
flow
blood
volume
autoregulation
(vasodilation)
hypoxia
volume status
BOLD
contrast
hypercarbia
biophysical effects
anesthesia/sleep
anemia
smoking
oxygen
utilization
degenerative disease

30. Medication effects
Coronary heart disease
Painkillers