1. How Neurons Become BOLD
Jody Culham
Brain and Mind Institute
Department of Psychology
Western University
How Neurons Become BOLD
Last Update: September 26, 2016
Last Course: Psychology 9223, F2016, Western University

2. Section 1 The BOLD Signal

3. Hemoglobin (Hb)

4. Deoxygenated Blood  Signal Loss
Seiji Ogawa
Oxygenated blood?
Diamagnetic
Doesn’t distort surrounding magnetic field
No signal loss…
rat breathing pure oxygen
rat breathing normal air (less than pure oxygen)
Deoxygenated blood?
Paramagnetic
Distorts surrounding magnetic field
Signal loss !!!
Images from Huettel, Song & McCarthy, 2004, Functional Magnetic Resonance Imaging
based on two papers from Ogawa et al., 1990, both in Magnetic Resonance in Medicine

5. BOLD signal At Rest: Active: Blood Oxygen Level Dependent signal
neural activity   blood flow   oxyhemoglobin   T2*   MR signal
At Rest:
Mxy
Signal
Mo sin
T2* task
T2* control
Stask S
Scontrol
Active:
time
TEoptimum
Source: Jorge Jovicich
Figure Source: Huettel, Song & McCarthy, 2004, Functional Magnetic Resonance Imaging

6. Perhaps it should be BDLD? Blood DE-oxygenation level-dependent signal?
Technically, “BOLD” is a misnomer
The fMRI signal is dependent on deoxygenation rather than oxygenation per se
The more deoxy-Hb there is the lower the signal
fMRI Signal
Time
Amount of deoxy-Hb
“BDLD” idea from Bruce Pike, MNI

7. Susceptibility A single bobby pin  susceptibility artifacts
(drops in signal and distortions nearby)

8. Hbdeoxy ~= bobby pins Brain at rest T2*-weighted signal Initial Dip
Vaso-
dilation

9. BOLD Time Course Blood Oxygenation Level-Dependent Signal
Positive BOLD response
Initial Dip
Overshoot
Post-stimulus Undershoot 1 2 3
BOLD Response (% signal change)
Time
Stimulus

10. Evolution of BOLD Response
Hu et al., 1997, MRM

11. Initial Dip (Hypo-oxic Phase)
Transient increase in oxygen consumption, before change in blood flow
Menon et al., 1995; Hu, et al., 1997
Smaller amplitude than main BOLD signal
10% of peak amplitude (e.g., 0.1% signal change)
Potentially more spatially specific
Oxygen utilization may be more closely associated with neuronal activity than positive response
Slide modified from Duke course

12. Rise (Hyperoxic Phase)
Results from vasodilation of arterioles, resulting in a large increase in cerebral blood flow
Inflection point can be used to index onset of processing
Slide modified from Duke course

13. Slide modified from Duke course
Peak – Overshoot
Over-compensatory response
More pronounced in BOLD signal measures than flow measures
Overshoot found in blocked designs with extended intervals
Signal saturates after ~10s of stimulation
Slide modified from Duke course

14. Slide modified from Duke course
Sustained Response
Blocked design analyses rest upon presence of sustained response
Comparison of sustained activity vs. baseline
Statistically simple, powerful
Problems
Difficulty in identifying magnitude of activation
Little ability to describe form of hemodynamic response
Slide modified from Duke course

15. Slide modified from Duke course
Undershoot
Cerebral blood flow more locked to stimuli than cerebral blood volume
Increased blood volume with baseline flow leads to decrease in MR signal
More frequently observed for longer-duration stimuli (>10s)
Short duration stimuli may not evidence
May remain for 10s of seconds
Slide modified from Duke course

16. Trial-to-Trial Variability
Huettel, Song & McCarthy, 2004,
Functional Magnetic Resonance Imaging

17. Variability of HRF Between Subjects
Aguirre, Zarahn & D’Esposito, 1998
HRF shows considerable variability between subjects
different subjects
Within subjects, responses are more consistent, although there is still some variability between sessions
same subject, same session
same subject, different session

18. Variability of HRF Between Areas
Possible caveat: HRF may also vary between areas, not just subjects
Buckner et al., 1996:
noted a delay of .5-1 sec between visual and prefrontal regions
vasculature difference?
processing latency?
Bug or feature?
Menon & Kim – mental chronometry
Buckner et al., 1996

19. Variability Between Subjects/Areas
greater variability between subjects than between regions
deviations from canonical HRF cause false negatives (Type II errors)
Consider including a run to establish subject-specific HRFs from robust area like M1
Handwerker et al., 2004, Neuroimage

20. Factors That Affect HRF
drugs: alcohol, caffeine
digestion: fat consumption
aging
disease: dementia
Effect of caffeine
Liu et al, 2004, NeuroImage
Reviewed in Handwerker et al. 2012, NeuroImage

21. Sampling Rate
Huettel, Song & McCarthy, 2004, Functional Magnetic Resonance Imaging

22. Linearity of BOLD response
“Do things add up?”
red = 2 - 1
green = 3 - 2
Sync each trial response to start of trial
Tzvi
Not quite linear
but good enough!
Source: Dale & Buckner, 1997

23. Section 2 From Neurons to BOLD

24. From Neurons to BOLD Voltage (mV) BOLD Signal Change (%) Time (ms)
Positive BOLD Response 40 1
Voltage (mV)
Depolarization
BOLD Signal Change (%)
Repolarization
-55
-70
Refractory period
Undershoot
Time (ms)
Time (s)
Any similarity in the shapes of the curves for action potentials and the BOLD response is purely coincidental (but still kinda cool)

25. Stimulus to BOLD
Source: Arthurs & Boniface, 2002, Trends in Neurosciences

26. Neural Networks

27. Post-Synaptic Potentials
The inputs to a neuron (post-synaptic potentials) increase (excitatory PSPs) or decrease (inhibitory PSPs) the membrane voltage
If the summed PSPs at the axon hillock push the voltage above the threshold, the neuron will fire an action potential

28. What does electrophysiology measure?
Raw microelectrode signal
Filter out low frequencies  Action Potentials (APs)
Filter out high frequencies  Local Field Potentials (LFPs)
Source:

29. BOLD Correlations Local Field Potentials (LFP)
24 s stimulus
12 s stimulus
Local Field Potentials (LFP)
reflect post-synaptic potentials
similar to what EEG (ERPs) and MEG measure
Multi-Unit Activity (MUA)
reflects action potentials
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
4 s stimulus
Source: Logothetis et al., 2001, Nature

30. Correlations between BOLD and LFP frequencies
α (8-12 Hz)
β (18-30 Hz)
Total LFP (0-100 Hz)
γ ( Hz)
gamma shares most info with BOLD

31. Even Simple Circuits Aren’t Simple
gray matter (dendrites, cell bodies
& synapses)
Lower tier area
(e.g., thalamus)
white matter
(axons)
Will BOLD activation from the blue voxel reflect:
output of the black neuron (action potentials)?
excitatory input (green synapses)?
inhibitory input (red synapses)?
inputs from the same layer (which constitute ~80% of synapses)?
feedforward projections (from lower-tier areas)?
feedback projections (from higher-tier areas)?
Middle tier area
(e.g., V1, primary visual cortex)
Higher tier area
(e.g., V2, secondary visual cortex) …

32. Stimulation Affects Local Region and Connected Areas
Optogenetic stimulation of mouse motor cortex leads to large BOLD response there and smaller BOLD response in thalamus
Leopold (2010) comment on Lee et al., 2010, Nature

33. Comparing Electrophysiolgy and BOLD
Data Source: Disbrow et al., 2000, PNAS
Figure Source, Huettel, Song & McCarthy, Functional Magnetic Resonance Imaging

34. fMRI Measures the Population Activity
Ideas from: Scannell & Young, 1999,
Proc Biol Sci
fMRI for Dummies

35. Verb generation after 15 min practice
Effects of Practice
Verb generation
Verb generation after 15 min practice
Raichle & Posner, Images of Mind cover image
Bug or feature?
fMRI adaptation enables us to study the tuning of neurons
fMRI for Dummies

36. Stimulus to BOLD
Source: Arthurs & Boniface, 2002, Trends in Neurosciences

37. Brain and Blood The brain is ~2% of the body by weight
…but it uses about 20% of the body’s oxygen supply and 20-25% of its glucose supply

38. Vascular system

39. Vascular system

40. Contents of a Voxel Capillary beds within the cortex
Source: Duvernoy, Delon & Vannson, 1981, Brain Research Bulletin
Source: Logothetis, 2008, Nature

41. Vasculature: Brain vs. Vein
Source: Menon & Kim, TICS

42. Source: Ono et al., 1990, Atlas of the Cerebral Sulci
“Brain vs. Vein”
large vessels produce BOLD activation further from the true site of activation than small vessels (especially problematic for high-resolution fMRI)
large vessels line the sulci and make it hard to tell which bank of a sulcus the activity arises from
the % signal change in large vessels can be considerably higher than in small vessels (e.g., 10% vs. 2%)
activation in large vessels occurs up to 3 s later than in small ones
Source: Ono et al., 1990, Atlas of the Cerebral Sulci

43. Vessel Valves
Source: Harrison et al. (2002). Cerebral Cortex.

44. Vasodilation
vasodilation could be induced by either electrical stimulation or release of Ca2+
stim
Time
max dilation ~3-6 s after stim
two photon microscopy
biggest changes in arteriole dilation occurred near stimulation; however, effects could also be observed several mm upstream
Source: Adapted from Takano et al., 2006, Nat Neurosci, by Huettel, et al., 2nd ed.

45. Upstream Effects arteriole veins
biggest changes in arteriole dilation occurred near stimulation; however, effects could also be observed several mm upstream
Source: Adapted from Iadecola et al., 1997, J Neurophysiol, by Huettel, et al., 2nd ed.

46. Don’t Trust Sinus Activity
You will sometimes see bogus “activity” in the sagittal sinus

47. The Forgotten Brain Cells
Image from: (see copyright info at bottom of image)
Common (i.e., Wrong) Wisdom
“Glial cells are probably not essential for processing information”
(Kandel, Schwartz & Jessell, Principles of Neural Science 3rd Ed.)

48. Tripartite Synapse
Astrocytes are adjacent to both synapses and blood vessels
well poised to adjust vascular response to neural activity
Astrocytes outnumber neurons by at least 10:1 and comprise ~50% of the total CNS volume
Astrocytes perform a number of critically important functions:
Neurotransmitter uptake and recycling
Neurometabolic regulation
Cerebrovascular regulation
Release of signaling molecules (“gliotransmitters”)
Slide modified from talk by Chase Figley
Source: Figley & Stroman, 2011, EJN

49. Glycolysis
Source: Raichle, 2001, Nature

50. Data Source: Howarth et al., 2012
Energy Budget
Data Source: Howarth et al., 2012
Figure Source, Huettel, Song & McCarthy, Functional Magnetic Resonance Imaging, 3rd ed.

51. Neurovascular Mousetrap
Hillman et al., 2004, Annual Review of Neuroscience

52. Vasoactive Substances
substances that cause the vessels to dilate
potassium ions (K+)
move from intra- to extra-cellular space during synaptic activity
adenosine
increases with high metabolic activity
nitric oxide
released by local and distant activation
gap junctions
calcium (Ca2+)
triggered by neuronal activation
dopamine
Information Source: Huettel, Song & McCarthy, 2nd ed.

53. What about inhibitory synapses?
GABA = inhibitory neurotransmitter
 hyperpolarization (IPSP)
less metabolically demanding than excitatory (glutamatergic) activity
GABA can be taken up presynaptically rather than recycled through astrocytes
Therefore, neurotransmission at inhibitory synapses likely influences the BOLD signal less than at excitatory synapses

54. Not Just Neurons Sirotin & Das, 2009
Leopold, 2009, based on data of Sirotin & Das, 2009, Nature
Sirotin & Das, 2009
awake macaque monkey sees tiny light in dark room
red: keep tight fixation; green: relax
timing of red-green is periodic
measure blood flow in area of peripheral visual cortex
away from foveal representation of fixation point
on some trials visual stimuli were presented to activate the measured area

55. Non-Neuronal Effects Sirotin & Das, 2009
Leopold, 2009, based on data of Sirotin & Das, 2009, Nature
Sirotin & Das, 2009
two components to blood flow in visual cortex (V1)
related to neuronal responses to visual stimuli
related anticipation of neural events

56. Properties of Predictive Response
response follows expected trial timing
when trial timing is changed, monkey performs correctly but this response persists for a few trials
occurs even without stimulation
correlated with pupil diameter
is it just general arousal?
visual cortex response does not occur with predictive sequence of auditory events
suggests it’s more regionally specific than general arousal
occurs in arterial signal

57. Stimulus to BOLD
Source: Arthurs & Boniface, 2002, Trends in Neurosciences

58. Gradient Echo vs. Spin Echo
high SNR
strong contribution of vessels
Spin Echo
lower SNR
weaker contribution of vessels
Source: Logothetis, 2008, Nature

59. The Concise Summary
We sort of understand this (e.g., psychophysics, neurophysiology)
We sort of understand this (MR Physics)
We’re clueless here!

60. Is the fMRI Sky Falling?

61. Don’t Panic
BOLD imaging is well correlated with results from other methods
BOLD imaging can resolve activation at a fairly small scale (e.g., retinotopic mapping)
PSPs and action potentials are correlated so either way, it’s getting at something meaningful
even if BOLD activation doesn’t correlate completely with electrophysiology, that doesn’t mean it’s wrong
may be picking up other processing info (e.g., PSPs, synchrony)
maybe anticipatory changes in blood flow are interesting too