the basis of the bold signal
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The Basis of the BOLD Signal. Paul Forbes & Camilla Nord. Outline. Physics (Paul) Physiology (Camilla). Physics of the BOLD signal. BOLD and NMR. To understand the basis of the BOLD signal we first need to understand Nuclear Magnetic Resonance (NMR). Nuclear Magnetic Resonance. Nuclear - PowerPoint PPT PresentationTRANSCRIPT
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The Basis of the BOLD SignalPaul Forbes & Camilla Nord
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Outline
• Physics (Paul)• Physiology (Camilla)
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Physics of the BOLD signal
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BOLD and NMR
• To understand the basis of the BOLD signal we first need to understand Nuclear Magnetic Resonance (NMR)
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Nuclear Magnetic Resonance
• Nuclear• Magnetic• Resonance
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Nuclear Magnetic Resonance
• Nuclear• Magnetic• Resonance
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Human body
Fat and water (tissue)
Hydrogen atoms
Hydrogen nucleus
Single proton
SPIN
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Nuclear Magnetic Resonance
• Nuclear• Magnetic• Resonance
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What is spin?• A magnetic quantity that gives the proton a small magnetic field
around it• Thus, the proton produces a nuclear magnetic resonance (NMR)
signal • We have lots of spins so we can describe them with classical
mechanics (not quantum mechanics - see Ehrenfest theorem)
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Alignment of spin
• In the absence of an external magnetic field the nuclei will point in random directions
• Upon the application of a field the nuclei align either parallel of anti-parallel with the fields
B0
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Alignment of spin
• Some align “spin up” and some align “spin down”• Spin up = high energy state / unstable• Spin down = low energy state / stable
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Precession
• Protons precess when aligned in a field • The spin vector rotates around the direction
of the external field
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Larmor FrequencyAngular frequency at which the nuclei precess = Larmor frequency,
gyromagnetic ratio
External magnetic field strength
The frequency of precession (in Hz) depends on the magnetic field strength
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Nuclear Magnetic Resonance
• Nuclear• Magnetic• Resonance
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Nuclear Magnetic Resonance
• Nuclei are aligned and precessing• Pulse of electromagnetic radiation
is applied - radio frequency pulse• The frequency of this pulse exactly
matches the frequency of precession(Larmor frequency)
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Nuclear Magnetic Resonance
• Nuclei in the low energy state absorb this energy and flip to the high energy state (“spin up”) – phase transition
• They also precess in phase with each other
• Resonance effect
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Nuclear Magnetic Resonance• The nuclei precessing in phase is fundamental
to MRI signal
as it sets up a tranverse magnetic field
which forms the basis of the MRI signal
B0
Btranverse
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Physics to physiology
- so why is this significant in terms the BOLD signal?
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Relaxation
- In terms of fMRI we are interested in the apparent relaxation time T2*
- This occurs when the spins dephase - We are interested in the rate at which the spins
dephase (desync)
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The BOLD signal
• oxyHb is diamagnetic = slow dephasing / T2*
• deoxyHb is paramagnetic = fast dephasing / T2*
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1. BOLD Contrast (Nick Todd)
B0
Tissue
Vessel
Oxygenated Hb
Deoxygenated Hb
voxel
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22 22
1. BOLD Contrast (Nick Todd)
B0
Tissue
Vessel
Oxygenated Hb
Deoxygenated Hb
voxel
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23 23
1. BOLD Contrast (Nick Todd)
B0
Tissue
Vessel
Oxygenated Hb
Deoxygenated Hb
voxel
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24 24
1. BOLD Contrast (Nick Todd)
B0
Tissue
Vessel
Oxygenated Hb
Deoxygenated Hb
voxel
BOLD Contrast
Oxygenated Hb
Deoxygenated Hb
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Physiology of the BOLD signal
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Key determinants of the BOLD signal
Arthurs & Boniface, 2002
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QuestionsBasis of BOLD signal: action potentials or LFPs?
Implications of neurovascular coupling, capillaries vs veins, and other physiological factors on interpretation of BOLD signal
Interpretations: How is inhibitory neuronal activity reflected? And how does one interpret a negative BOLD signal?
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What’s in a voxel?
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Vascular basis of BOLD signal➢ = Neural activity-dependent changes in
relative concentration of oxygenated and deoxygenated blood○ Deoxyhaemoglobin is paramagnetic
(as decreases, causes increase in BOLD signal), unlike oxygenated haemoglobin
○ Paradox? → CBF○ Decoupling more O2 provided
than neccessary➢ Varies widely across cortical areas; between
species. What if it varied between the groups you were testing?
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Additional physiological factors○ blood volume○ vascular geometry○ haematocrit○ basal oxygenation levels
○ ‘brain vs vein debate: capillary vs large draining veins downstream from neuronally active regions■ could displace signal
changes Spin-echo fMRI technique minimizes, but decreased StN ratio
Relative contribution to T2* weighted GRE fMRI from capillaries vs. larger blood vessels (veins) as a function of the frequency on the vessel wall for a cylinder mimicking blood vessels. (Ugurbil, 2011)
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Does the BOLD signal reflect energy demands?
• Originally thought that increase in blood flow due to energy requirements
• But most of energy used in post-synaptic signalling; maintaining APs
• So…energy use does not directly increase blood flow
• Increase in glucose and O2 demands causes release of vasodilators
• Adenosine• Arachidonic Acid metabolites • Nitric Oxide (NO)
• Global blood flow changes also associated with DA, NA, 5-HT(Attwell & Iadecola, 2002)
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Does the BOLD signal reflect firing rate?
➢ V5 neurons- direction-specific
➢ fMRI responses in MT+ also increase linearly with motion coherence (field of moving dots)
➢ Proportional to the slopes of single-neuron firing rates in monkeys
fMRI responses in human V1 are proportional to average firing rates in monkey V1.
(Rees et al, 2000; Heeger at al, 2000)
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Or does it reflect another neural property?
➢ i.e., APs or LFPs?
➢ Logothetis et al 2001: Simultaneous intracortical recordings of neural signals & fMRI responses
➢ Largest magnitude changes in LFP correlated with haemodynamic response
BOLD signal reflects input and intracortical processing.
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BOLD signal/AP correlation depends on location!
• Rees/Heeger findings resulted from recordings in areas where inputs, intracortical activity, and outputs (recordings) are all highly correlated, so all increase with stimulus contrast
• Would not have worked in other areas, such as…
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Cerebellar APs and the BOLD signal
➢ GABA-A receptor blockade in rats
➢ Increase in spiking activity (Purkinje cells)○ caused no change in
neurovascular coupling that forms basis of BOLD signal
○ || fibre stimulation causes increase in BOLD, inhibit Purkinje cells
Effect of picrotoxin on evoked cerebellar blood flow responses, local field potentials, synaptic activity, and neurovascular coupling during inferior olive stimulation (Thomsen et al, 2004)
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One possible explanation: Ca2+
a. Excitation increases Ca2+b. Inhibition decreases Ca2+c. …but not always, depending on
inhibitory interneuron and its complement of enzymes & vasoactive substances, e.g. cerebellum (INs increase blood flow because of high NO content)
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Why does this matter?
• Implications for group differences in patient studies (as well as differences between neural regions, development ages, etc.- anything you can think of)
• Concerns over interpretation of BOLD response in autism
• Alterations in signalling pathways (eg, NO), neurotransmitter differences• potential for nonlinear shifts in
BOLD response• Signalling changes- changes in
BOLD w/o neuronal changes
Reynell & Harris 2013
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Interim summary
➢ fMRI BOLD signals are dependent on variability and inter-relationships of several factors. ➢ This includes multiple cellular mechanisms that could affect vasodilation
other than direct neuronal activity, and is relevent for studies examining group differences
➢ Debate currently favours relatively direct correlation between fMRI signals and population synaptic activity (including inhibitory and excitatory activity) with a secondary and potentially more variable correlation with cellular action potentials.
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What about inhibitory activity?
Majority of cortex = pyramidal cells Hypothesis: inhibitory cells do not
produce change in BOLD because lower metabolic demand from increased efficiency
Figure: Left column, primary motor cortex, ‘no go condition’ show no change from baseline, comp to pre-SMA. (Waldfogel et al, 2000).
•Recent model: inhibition increases BOLD if low level of excitation, but reduces when excitation high- can explain contradictory results (Tagamets & Horowitz, 2001)
•More complex than this?
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Is inhibition just reflected as a negative BOLD signal?
• Unknown. • Motor and visual cortices show NBR as a
result of neuronal inhibition• Many claim that NBR = inhibitory
activity• Monkey V1 show NBR
corresponds with decreased population spiking (comb fMRI/electrophys)
• Cannot draw conclusions without understanding intrinsic correlation• BUT is there another
explanation? Example of seizures. • Cortex vs subcortical
dissocation? Schridde et al, 2008
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Intrinsic connectivity
What is the majority of the brain’s energy devoted to?NOISE (spontaneous fluctuations in the BOLD signal)
Synchrony/coherence with anatomically and functionally connected regions
Potential for clinical biomarkers Techniques: seed-based (AD
hippocampal connectivity); ICA (MDD subgenual cingulate).
•
Zhang & Raichle, 2010
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The ‘Default Mode Network’• Seminal meta-analysis suggested a baseline state of the human
brain using PET (Raichle et al 2001)• Consistent reductions from this baseline observed in goal-
directed behaviour (PET; fMRI). Temporary suspension?• Shown as a negative bold response (NBR)
• Has spurred an entire field of research into rs-fMRI• A priori studies vs. model-based/data-driven
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Designing an fMRI experiment• Because fMRI does not measure neural
activity directly, we must quantify relative changes in activity
• A typical fMRI experiment employs a task to examine differences in the BOLD signal (eg event-related) vs baseline (rest)
–Timing of BOLD signal: intertime interval & jitter
• What if there is no task?
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Interpreting DMN results
•Grecius et al, 2007•Increased DMN functional connectivity with subgenual cingulate, thalamus, precuneus in MDD•Interpretation: Treatment refractoriness, ‘biomarker’
Cowdrey et al, 2012
Increased DMN functional connectivity in anorexia nervosaBlue= recovered AN group average Green= healthy control group
Interpretation: rumination (precuneus) and inhibition (dlPFC)
Carhart-Harris et al, 2012
Increased DMN-task positive network coupling (normally orthogonal) after psilocybin
Interpretation: ‘disturbed ego boundaries’, with implications for schizophrenia
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Using the BOLD signal advantageously
• 87% studies used conventional gradient-echo echoplanar imaging (rest, spin-echo)• can lead to localization
errors without optimised protocol (e.g. pulse sequences)
• Spatial specificity improves with increasing magnetic field strength
• Higher-resolution sequences available• Requires extensive
collaboration with MR physicists
• Do we need this for all studies?• “reading a newspaper with a
microscope”Logothetis, 2008
Lawson et al, 2012
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Next time you read an fMRI study• Are there other physiological effects that
could have produced their result? • Vasodilation differences in region;
disease state• What was their fMRI protocol? Was it
high-res? If no, should it have been?• Do they report a negative BOLD signal?• What is their interpretation? Does it rely
on APs or LFPs?• Depends on their region of interest!• Example critique: Conner et al (2013): Social
proximity to a caregiver during a potentially stressful situation attenuated activity in the hypothalamus, VMPFC, and VLPFC (left) in clinically anxious youths.
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Thank you
Many thanks to Nikolaus Weiskopf for advice, and to you for your attention!
Any questions?