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

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

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

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

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

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

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

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

The Haemodynamic Response Function (HRF)

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

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?

Electrophysiological BOLD-correlates

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

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

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

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)

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

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?

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.

Blood flow might be directly driven by excitatory postsynaptic processes

Feedforward system Glutamate

Active control of blood flow Courtesy: Marieke Scholvinck

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

Glutamate transport in astrocytes triggers glucose metabolism Courtesy: Tobias Sommer

Synaptic inhibition can modulate blood flow

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

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.

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

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

Medication effects Coronary heart disease Painkillers