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 18 February 2009

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 Protons have “spins” (like gyroscopes). They have an orientation and a frequency. Images: www.fmri4newbies.com

When you put any material in an MRI scanner, the protons align with the direction of the magnetic field.

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.

Images: Ralf Deichmann

T1 T2

After you turn off the RF pulse, as the protons return to their original orientations, they emit energy in the form of radio waves.

Step 3: Measure emitted radio waves

T1

= time constant of how quickly the protons realign with the magnetic field fat has high signal  bright CSF has low signal  dark Images: fmri4newbies.com

T1-WEIGHTED ANATOMICAL IMAGE T2

= time constant of how quickly the protons emit energy when recovering to equilibrium fat has low signal  dark CSF has high signal  bright

T2-WEIGHTED ANATOMICAL IMAGE

T2 * weighted images • Two factors contribute to the decay of transverse magnetization: 1) molecular interactions 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

Functional MRI (fMRI) • Uses

echo planar imaging

(EPI) for fast acquisition of T2*-weighted images.

• Spatial resolution: – 3 mm (standard 1.5 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.

But what is it that makes T2* weighted images “functional”?

EPI (T2 * ) T1 dropout

The BOLD contrast

BOLD

(Blood Oxygenation Level Dependent) contrast = measures inhomogeneities in the magnetic field due to changes in the level of O 2 in the blood

B 0 Oxygenated hemoglobine:

Diamagnetic (non-magnetic)  No signal loss…

Deoxygenated hemoglobine:

Paramagnetic (magnetic)  signal loss !

Images: Huettel, Song & McCarthy 2004, Functional Magnetic Resonance Imaging

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

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 • sometimes shows initial undershoot • peaks after 4-6 secs • back to baseline after approx. 30 secs • can vary between regions and subjects Brief Stimulus Initial Undershoot Peak Undershoot

u

stimulus functions t neural state equation

dx dt

  

A



j m

  1

u j B

(

j

)  

x



Cu f vasodilato ry signal s

 

x

 

s



γ

(

f

 1 )

s s

hemodynamic state equations

flow induc tion

(rCBF)

f

 

s f changes in volume τ v

 

f



v

1

/α v

Balloon model

v changes in dHb τ q

 

f E

(

f,E

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q E

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v

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/α q/v q

0.4

0.2

0 0 1 0.5

0 0 0.2

0 -0.2

-0.4

-0.6

0 BOLD signal is a nonlinear function of rCBF 2 2 4 4 6 6 8 8 2 4 6 8 10 10 12 12 14 RBM N ,  = 0.5

CBM N ,  = 0.5

RBM N ,  = 1 CBM N ,  = 1 RBM N ,  = 2 CBM N ,  = 2 14 10 12 14  (

q

,

v

)

k

1

k

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k

3     

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 

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3  1  BOLD signal

v

   change equation Stephan et al. 2007,

NeuroImage

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?

Neurophysiological basis of the BOLD signal: soma or synapse?

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.

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

Logothetis & Wandell 2004,

Ann. Rev. Physiol.

BOLD & LFPs blue: LFP red: BOLD grey: predicted BOLD

Dissociation between action potentials and rCBF • GABA A antagonist picrotoxine increased spiking activity without increase in rCBF...

• ... and without disturbing neurovascular coupling per se Thomsen et al. 2004,

J. Physiol.

 rCBF-increase can be independent from spiking activity, but seems to be always correlated to LFPs Lauritzen et al. 2003

Current conclusion: BOLD signal seems to be more strongly correlated to postsynaptic activity BOLD seems to reflect the input to a neuronal population as well as its intrinsic processing.

Lauritzen 2005,

Nat. Neurosci. Rev.

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?

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

Localisation of neuronal energy consumption Schwartz et al. 1979,

Science

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...

Lack of energy?

1. Initial dip: possible to get more O 2 from the blood without increasing rCBF (which happens later in time).

2. 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

Lack of energy?

3. Sustained visual stimulation is associated with an increase in rCBF far in excess of O 2 consumption. But over time, O 2 consumption begins to increase as blood flow falls (Mintun et al. 2002).

Mintun et al. 2002,

NeuroImage

Blood flow seems to be controlled by other factors than a lack of energy.

Blood flow might be directly driven by excitatory postsynaptic processes

Glutamatergic synapses: A feedforward system for eliciting the BOLD signal?

Lauritzen 2005,

Nat. Neurosci. Rev.

Courtesy: Marieke Scholvinck Forward control of blood flow

O 2 levels determine whether synaptic activity leads to arteriolar vasodilation or vasoconstriction Gordon et al. 2008,

Nature

Energetic consequences of postsynaptic activity Glutamate reuptake by astrocytes triggers glucose metabolism Courtesy: Tobias Sommer ATP needed for restoring ionic gradients, transmitter reuptake etc.

Attwell & Iadecola 2002,

TINS.

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?

Negative BOLD is correlated with decreases in LFPs

positive BOLD positive BOLD

Shmuel et al. 2006,

Nat. Neurosci.

Impact of inhibitory postsynaptic potentials (IPSPs) on blood flow Lauritzen 2005,

Nat. Neurosci. Rev.

Negative BOLD signals due to IPSPs?

Lauritzen 2005,

Nat. Neurosci. Rev.

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

Drug effects

Coronary heart disease Analgetics (NSAIDs)

• • • • • 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.

MRI physics in a nutshell - I

•

Inside static magnetic field:

Spins of protons align with magnetic field B  longitudinal magnetisation (because spins carry an elementary magnetisation) •

Intended manipulation:

Make spins rotate (precess) about the direction of B (like a gyroscope).

• Precession (Lamor) frequency is proportional to B, e.g. 64 MHz for 1.5 T B

•

MRI physics in a nutshell - II

How do we do it?

RF pulses (Larmor frequency!) push M away from B  transverse magnetization • During precession, each proton emits an RF signal.

• After the RF pulse, M will re align to B within 2-3 secs  “relaxation” • Relaxation has a longitudinal (T1) and a transverse (T2) component  tissue-dependent time constants!

T1 T2

MRI physics in a nutshell - III

• Two factors contribute to the decay of transverse magnetization: 1) molecular interactions 2) local inhomogeneities of the magnetic field → leads to dephasing of the spins • 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 (“how” is the topic of a different talk)