DCM

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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 analysis16
September 2009
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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

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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 www.fmri4newbies.com
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Image Ralf Deichmann
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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
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Step 3 Measure emitted radio waves
Images fmri4newbies.com
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T2 weighted images

• Two factors contribute to the decay of transverse
  magnetization1) molecular interactions ?
  dephasing of spins2) 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

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Functional MRI (fMRI)

• Uses echo planar imaging (EPI) for fast
  acquisition of T2-weighted images.
• Spatial resolution
• 3 mm (standard 1.5 T scanner)
• lt 200 µm (high-field systems)
• Sampling speed
• 1 slice 50-100 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?
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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
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The BOLD contrast
deoxy-Hb/oxy-Hb ?
rCBF ??
?
?
neurovascularcoupling
synaptic activity ?
neuronal metabolism ?
DEsposito 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
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The BOLD contrast
REST

• neural activity ? ? blood flow ? ? oxyhemoglobin
  ? ? T2 ? ? MR signal

ACTIVITY
Source Jorge Jovicich, fMRIB Brief Introduction
to fMRI
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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

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BOLD signal is a nonlinear function of rCBF
Stephan et al. 2007, NeuroImage
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Three important questions

1. Is the BOLD signal more strongly related to
   neuronal action potentials or to local field
   potentials (LFP)?
2. How does the BOLD signal reflect the energy
   demands of the brain?
3. What does a negative BOLD signal mean?

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Neurophysiological basis of the BOLD signal soma
or synapse?
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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.
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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
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BOLD LFPs
blue LFP red BOLD grey predicted BOLD
Logothetis Wandell 2004, Ann. Rev. Physiol.
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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
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Current conclusion BOLD signal seems to be more
strongly correlated to postsynaptic activity

• BOLD can be correlated both to 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
  reflects the input to a neuronal population as
  well as its intrinsic processing, rather than its
  spiking output.

Lauritzen 2005, Nat. Neurosci. Rev.
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Three important questions

1. Is the BOLD signal more strongly related to
   neuronal action potentials or to local field
   potentials (LFP)?
2. How does the BOLD signal reflect the energy
   demands of the brain?
3. What does a negative BOLD signal mean?

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Is the BOLD signal driven by energy demands or
synaptic processes?
deoxy-Hb/oxy-Hb ?
rCBF ??
?
?
neurovascularcoupling
synaptic activity ?
neuronal metabolism ?
DEsposito et al. 2003
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Energetic consequences of postsynaptic activity
Also, ATP needed for restoring ionic gradients,
transmitter reuptake etc.
Glutamate reuptake and recycling by astrocytes
requires glucose metabolism
Attwell Iadecola 2002, TINS.
Courtesy Tobias Sommer
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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 or feedforward synaptic
processes...
Schwartz et al. 1979, Science
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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).
• No compensatory increase in blood flow during
  hypoxia (Mintun et al. 2001).

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
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Blood flow might be directly driven by excitatory
postsynaptic processes
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Glutamatergic synapses A feedforward system for
eliciting the BOLD signal?
Lauritzen 2005, Nat. Neurosci. Rev.
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Forward control of blood flow
Courtesy Marieke Scholvinck
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O2 levels determine whether synaptic activity
leads to arteriolar vasodilation or
vasoconstriction
Gordon et al. 2008, Nature
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Three important questions

1. Is the BOLD signal more strongly related to
   neuronal action potentials or to local field
   potentials (LFP)?
2. How does the BOLD signal reflect the energy
   demands of the brain?
3. What does a negative BOLD signal mean?

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Negative BOLD is correlated with decreases in LFPs
positive BOLD
positive BOLD
Shmuel et al. 2006, Nat. Neurosci.
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Impact of inhibitory postsynaptic potentials
(IPSPs) on blood flow
Lauritzen 2005, Nat. Neurosci. Rev.
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Negative BOLD signals due to IPSPs?
Lauritzen 2005, Nat. Neurosci. Rev.
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Potential physiological influences on BOLD
cerebrovascular disease
structural lesions (compression)
blood flow
medications
autoregulation (vasodilation)
blood volume
hypoxia
volume status
BOLD contrast
hypercapnia
biophysical effects
anesthesia/sleep
anemia
smoking
oxygen utilization
degenerative disease
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Drug effects
Coronary heart disease
Analgetics (NSAIDs)
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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.

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Thank you