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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.

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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 analysis in neuroeconomicsNovember 2010


Ultrashort introduction to mri physics
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


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



T1

T2

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


T2 = time constant of how quickly the protons emit energy when recovering to equilibrium

T1 = time constant of how quickly the protons realign with the magnetic field

fat has low signal  dark

fat has high signal  bright

CSF has high signal  bright

CSF has low signal  dark

T1-WEIGHTED ANATOMICAL IMAGE

T2-WEIGHTED ANATOMICAL IMAGE

Step 3: Measure emitted radio waves

Images:

fmri4newbies.com


T2 weighted images
T2* weighted images

  • Two factors contribute to the decay of transverse magnetization:1) 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


Functional mri fmri
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: 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”?


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


The BOLD contrast

deoxy-Hb/oxy-Hb 

rCBF 

?

?

neurovascularcoupling

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


The BOLD contrast

REST

  • neural activity   blood flow   oxyhemoglobin   T2*  MR signal

ACTIVITY

Source: Jorge Jovicich, fMRIB Brief Introduction to fMRI


The temporal properties of the bold signal

Peak

Brief

Stimulus

Undershoot

Initial

Undershoot

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


u

stimulus functions

neural state

equation

t

hemodynamic

state

equations

Balloon model

BOLD signal change equation

BOLD signal is a nonlinear function of rCBF

Stephan et al. 2007, NeuroImage


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?



BOLD & action potentials synapse?

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.


Action potentials vs. postsynaptic activity synapse?

  • 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 thatBOLD activity is more closely related to LFPs than MUA

Logothetis et al., 2001, Nature


BOLD & LFPs synapse?

blue: LFP

red: BOLD

grey: predicted BOLD

Logothetis & Wandell 2004, Ann. Rev. Physiol.


Dissociation between action potentials and rCBF synapse?

  • 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


Current conclusion: BOLD signal synapse?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.


Three important questions synapse?

  • 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?


Is the BOLD signal driven by energy demands or synaptic processes?

deoxy-Hb/oxy-Hb 

rCBF 

?

?

neurovascularcoupling

neuronal metabolism 

synaptic activity 

D’Esposito et al. 2003


Localisation of neuronal energy consumption processes?

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


Energetic consequences of processes?synaptic 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


Increased rCBF due to lack of energy? processes?

  • 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



Glutamatergic synapses a feedforward system for eliciting the bold signal
Glutamatergic synapses: postsynaptic processesA feedforward system for eliciting the BOLD signal?

Lauritzen 2005, Nat. Neurosci. Rev.


Forward control of blood flow
Forward control of blood flow postsynaptic processes

Courtesy: Marieke Scholvinck


O postsynaptic processes2 levels determine whether synaptic activity leads to arteriolar vasodilation or vasoconstriction (via prostaglandines)

Gordon et al. 2008, Nature


Three important questions postsynaptic processes

  • 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?


Negative BOLD is correlated with decreases in LFPs postsynaptic processes

positive BOLD

positive BOLD

Shmuel et al. 2006, Nat. Neurosci.


Impact of inhibitory postsynaptic potentials ipsps on blood flow
Impact of inhibitory postsynaptic potentials (IPSPs) on blood flow

Lauritzen 2005, Nat. Neurosci. Rev.


Negative bold signals due to ipsps
Negative BOLD signals due to IPSPs? blood flow

Lauritzen 2005, Nat. Neurosci. Rev.


Potential physiological influences on BOLD blood flow

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


Drug effects

Nitrates (against coronary blood flowheart disease)

Drug effects

Analgetics (NSAIDs)


Summary
Summary blood flow

  • 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.


Thank you
Thank you blood flow


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