Shulman and Rothman PNAS, 1998
In this period of intense research in the neurosciences, nothing is more promising than
functional magnetic resonance imaging (fMRI) and positron emission tomography (PET)
methods, which localize brain activities. These functional imaging methodologies map
neurophysiological responses to cognitive, emotional, or sensory stimulations. The rapid
experimental progress made by using these methods has encouraged widespread optimism
about our ability to understand the activities of the mind on a biological basis. However, the
relationship between the signal and neurobiological processes related to function is poorly
understood, because the functional imaging signal is not a direct measure of neuronal
processes related to information transfer, such as action potentials and neurotransmitter
release. Rather, the intensity of the imaging signal is related to neurophysiological
parameters of energy consumption and blood flow. To relate the imaging signal to specific
neuronal processes, two relationships must be established…
The first relationship is between the intensity of the imaging signal and the rate of
neurophysiological energy processes, such as the cerebral metabolic rates of glucose
(CMRglc) and of oxygen (CMRO2).
The second and previously unavailable relationship is between the neurophysiological
processes and the activity of neuronal processes. It is necessary to understand these
relationships to directly relate functional imaging studies to neurobiological research that
seeks the relationship between the regional activity of specific neuronal processes and
mental processes.
Shulman and Rothman PNAS, 1998
Psychology
Image Signal
Mental
Neuroenergetics
CMRglc
CMRO2
CBF
Neuronal
Neuroscience
Let’s back up…
What do we know for sure about
fMRI?
Hemoglobin Molecule
280 million Hb molecules per red blood cell
Different magnetic properties of
hemoglobin and deoxyhemoglobin
L. Pauling and C. Coryell
The Magnetic Properties and Structure of Hemoglobin, Oxyhemoglobin and
Carbonmonoxy hemoglobin, PNAS, vol. 22, pp. 210-216, 1936.
Hemoglobin Molecule
Blood Oxygenation Level Dependent Imaging
Baseline
Task
from Mosley & Glover, 1995
Brain or Vein?
Large Vessel Contributions to
BOLD Contrast
Virchow-Robin Space
Intravascular
Perivascular
Extravascular
Isotropic Diffusion Weighted
Spiral Imaging at 4T
3
z = 1.64
Large
Small
Courtesy of Dr. Allen Song, Duke University
a
9 sec
9 sec
b
BOLD activation (b factor = 0)
Diffusion-weighted (b factor = 108)
Diffusion-weighted (b factor = 54)
ADC masked by BOLD activation
Subject 41057, Slice 12, 4.0 Tesla
BOLD activation (b factor = 0)
Diffusion-weighted (b factor = 108)
Diffusion-weighted (b factor = 54)
ADC masked by BOLD activation
Subject 41037, Slice 183, 4.0 Tesla
BOLD activation (b factor = 0)
Diffusion-weighted (b factor = 108)
Diffusion-weighted (b factor = 54)
ADC masked by BOLD activation
Subject 41037, Slice 177, 4.0 Tesla
BOLD activation (b factor = 0)
ADC masked by BOLD activation
Subject 41037, Slice 177, 4.0 Tesla
Negative dips
Phosphorescence Decay Time
(Oxyphor R2 oxygen tension-sensitive phosphorescent probe)
Vanzetta and Grinvald, Science, 286: 1555-1558, 1999
Phosphorescence Decay Time
(Oxyphor R2 oxygen tension-sensitive phosphorescent probe)
Vanzetta and Grinvald, Science, 286: 1555-1558, 1999
Vanzetta and Grinvald, Science, 286: 1555-1558, 1999
deoxy Hb
Oxy Hb
Berwick et al, JCBFM, 2002
Optical imaging of rat barrel cortex
Hb02= oxyhemoglobin, Hbr = deoxyhemoglobin, Hbt = total blood flow
Functional Imaging of the Monkey Brain
N. Logothetis, Nature Neuroscience, 1999
Early Response in fMRI
Hu, Le, Ugurbil MRM, 1997
Early Response in fMRI
Hu, Le, Ugurbil MRM, 1997
What triggers blood flow?
Arterioles (10 - 300 microns)
precapillary sphincters
Capillaries (5-10 microns)
Venules (8-50 microns)
Tissue factors
•
•
•
•
K+
H+
Adenosine
Nitric oxide
Neuronal Control of the Microcirculation
C. Iadecola, Nature Neuroscience, 1998
Commentary upon Krimer, Muly, Williams and Goldman-Rakic, Nature Neuroscience, 1998
Pial Arteries
Noradrenergic
Dopamine
10 m
Krimer, Muly, Williams, Goldman-Rakic, Nature Neuroscience, 1998
Dopamanergic terminals associated with small cortical blood vessels
10 m
Krimer, Muly, Williams, Goldman-Rakic, Nature Neuroscience, 1998
Dopamanergic terminals associated with small cortical blood vessels
2 m
400 nm
2 m
400 nm
Krimer, Muly, Williams, Goldman-Rakic, Nature Neuroscience, 1998
Perivascular iontophoretic application of dopamine
18-40 s
40-60 s
Krimer, Muly, Williams, Goldman-Rakic, Nature Neuroscience, 1998
Let’s back up again…
Why isn’t all the oxyHb used up?
Uncoupling…
glucose
glucose
Glucose 6 phosphate
Net +2 ATP
Fructose – 1,6-phosphate
pyruvate
lactate
O2
CO2 + H20
TCA
cycle
Net +36 ATP
Shulman and Rothman PNAS, 1998
Stimulation
Visual
Mean
Cognitive
Seizure
Change CMRglc
51
28
29
Change CMRO2
5
28
29
16
23
24
31
20
400
12
267
Source
Fox et al. 1988
Marrett et al. 1993
Marrett et al. 1993
Davis et al. 1998
Chen et al. 1993
Reivich et al. 1984
Roland et al. 1987
Borgstrom et al. 1976
Shulman and Rothman PNAS, 1998
Proposed pathway of glutamate / glutamine neurotransmitter cycling between neurons and glia, whose flux has
been quantitated recently by 13C MRS experiments. Action potentials reaching the presynaptic neuron cause
release of vesicular glutamate into the synaptic cleft, where it is recognized by glutamate receptors post-synaptically
and is cleared by Na+ -coupled transport into glia. There it is converted enzymatically to glutamine, which passively
diffuses back to the neuron and, after reconversion to glutamate, is repackaged into vesicles. The rate of the
glutamate-to-glutamine step in this cycle (Vcycle), has been derived from recent 13C experiments.
Sibson et al. PNAS, 1998
Stimulation
Visual
Mean
Cognitive
Seizure
Change CMRglc
51
28
29
Change CMRO2
5
28
29
16
23
24
31
20
400
12
267
Source
Fox et al. 1988
Marrett et al. 1993
Marrett et al. 1993
Davis et al. 1998
Chen et al. 1993
Reivich et al. 1984
Roland et al. 1987
Borgstrom et al. 1976
Heeger, Nature Neuroscience 2002
Ito et al. JCBFM, 2001
Stimulation
Visual
Mean
Cognitive
Seizure
Change CMRglc
51
28
29
Change CMRO2
5
28
29
16
23
24
31
20
400
12
267
Source
Fox et al. 1988
Marrett et al. 1993
Marrett et al. 1993
Davis et al. 1998
Chen et al. 1993
Reivich et al. 1984
Roland et al. 1987
Borgstrom et al. 1976
Relationship of BOLD to neuronal
activity
Attwell and Laughlin, JCBFM, 2001
Brain Energetics
Attwell and Laughlin, JCBFM, 2001
Brain Energetics
Rees et al. Nature Neuroscience 2000
Heeger, Nature Neuroscience 2000
Lauritzen, JCBFM, 2001
Lauritzen, JCBFM, 2001
Climbing Fiber Stimulation
Lauritzen, JCBFM, 2001
Climbing Fiber Stimulation
Lauritzen, JCBFM, 2001
Parallel Fiber Stimulation
Lauritzen, JCBFM, 2001
Harmaline IP synchronizes inferior olive
Smith et al. PNAS, 2002
Hyder et al. PNAS, 2002
Stimulation
Visual
Mean
Cognitive
Seizure
Change CMRglc
51
28
29
Change CMRO2
5
28
29
16
23
24
31
20
400
12
267
Source
Fox et al. 1988
Marrett et al. 1993
Marrett et al. 1993
Davis et al. 1998
Chen et al. 1993
Reivich et al. 1984
Roland et al. 1987
Borgstrom et al. 1976
Spatial co-localization?
Whisker Barrel Model
How neuronal activity changes cerebral blood flow is of biological and practical
importance. The rodent whisker-barrel system has special merits as a model for studies
of changes in local cerebral blood flow (LCBF).
Whisker-activated changes in flow were measured with intravascular markers at the pia.
LCBF changes were always prompt and localized over the appropriate barrel. Stimulusrelated changes in parenchymal flow monitored continuously with H2 electrodes
recorded short latency flow changes initiated in middle cortical layers. Activation that
increased flow to particular barrels often led to reduced flow to adjacent cortex.
The matching between a capillary plexus (a vascular module) and a barrel (a functional
neuronal unit) is a spatial organization of neurons and blood vessels that optimizes local
interactions between the two. The paths of communication probably include: neurons to
neurons, neurons to glia, neurons to vessels, glia to vessels, vessels to vessels and
vessels to brain. Matching a functional grouping of neurons with a vascular module is
an elegant means of reducing the risk of embarrassment for energy-expensive neuronal
activity (ion pumping) while minimizing energy spent for delivery of the energy
(cardiac output). For imaging studies this organization sets biological limits to spatial,
temporal and magnitude resolution. Reduced flow to nearby inactive cortex enhances
local differences
Woolsey et al. Cerebral Cortex, 95: 7715-7720, 1996
Rat Single Whisker Barrel fMRI Activation
7 Tesla
200 m x 200 m x 1000 m
Yang, Hyder, Shulman PNAS, 93: 475-478, 1996
Berwick et al, JCBFM, 2002
Optical imaging of rat barrel cortex
Hb02= oxyhemoglobin, Hbr = deoxyhemoglobin, Hbt = total blood flow
Berwick et al, JCBFM, 2002
(a) Outside activated region, (b) ipsilateral whisker
Relationship between field potentials
and functional MRI
7
6
100ms
5
500ms
4
1500ms
3
2
1
0
-1
-5
-4
-3
-2
-1
0
1
2
3
4
5
6
7
8
9
10 11 12
0
1
2
3
4
5
6
7
8
9
10 11 12
0
1
2
3
4
5
6
7
8
9
10 11 12
7
6
100ms
5
500ms
4
1500ms
3
2
1
0
-1
-5
Stimulus Onset
Asynchrony
(15-17 seconds)
100ms
500ms
-4
-3
-2
-1
7
6
100ms
5
500ms
4
1500ms
3
1500ms
2
1
0
-1
-5
-4
-3
-2
-1
LMY1
LPO - 3
250
200
150
100
50
0
100 ms
500 ms
1500 ms
-50
-100
-150
-100
0
100
200
300
400
500
LPO - 4
200
100
0
-100
-200
-300
100 ms
500 ms
1500 ms
-400
-100 0
100 200 300 400 500 600 700 800 900
7
6
100ms
5
500ms
4
1500ms
3
2
1
0
-1
-5
-4
-3
-2
-1
0
1
2
3
4
5
6
7
8
9
10 11 12
0
1
2
3
4
5
6
7
8
9
10 11 12
0
1
2
3
4
5
6
7
8
9
10 11 12
7
6
100ms
5
500ms
4
1500ms
3
2
1
0
-1
-5
Stimulus Onset
Asynchrony
(15-17 seconds)
100ms
500ms
-4
-3
-2
-1
7
6
100ms
5
500ms
4
1500ms
3
1500ms
2
1
0
-1
-5
-4
-3
-2
-1
LSOP5
LPT6
LPT7
LTO4
LTO10
DWT1
PT6
LG
PT7
FG
SOP5
V1-V2
Pole
TO4
MT
TO10
Time (msec)
Timing of activations compared to
neuronal activation
Subdural Electrode Strips
Face-Specific N200
2A
C
B
500
LMT 12
RMT 4
LMT 11
RMT 3
10
0
RMT 2
LMT 10
Faces
Faces
Flowers
Cars
Nouns
Scr Faces
Scr Faces
Numbers
Target
Butterflies
11
RMT 1
LMT 9
-500
-100
0
100
200
300
400
500
600
0
100
200
300
400
500
600
RPTO 8
Fruits
Face-Cap
Tools
Scr Faces
Circles (Targets)
150
100
50
0
-50
-100
-150
-200
-250
-300
-100
0
100
200
300
400
Time (msec)
500
600
700
800
900
Face-House Attention Task
300
NBH1
100
Attend House
CDOB1
Attend Face
-100
-300
-100
100
300
500
700
900
1100
1300
1500
1700
1900
Negative activations
Harel et al. JCBFM, 2002
Harel et al. JCBFM, 2002
Harel et al. JCBFM, 2002
a
9 sec
9 sec
b
180° phase-reversed responses to
faces among objects
12
Positive Activation
Negative Activation
8
4
0
-4
41088
41088
-8
0
18
36
54
72
90
108
126
144
162
180
198
216
234
252
270
288
306
Is there evidence for inhibition?
300
200
100
RTTP2-5
Face Specific
0
P200
-100
-200
LTTP2-2
Letterstring Specific
-300
-100
0
N200
JRN
Face
Noun
100 200 300 400 500 600 700 800 900
RTP2-5
LTTP2-2
100
80
100
LTTP 2
Face - Specific
60
50
P200
40
LOTM 8
Letterstring - Specific
20
P200
0
0
-20
-50
SGN
Faces
Nouns
-40
-60
-80
N200
-100
100
100
200
300
400
500
600
700
800
100
200
300
400
500
400
500
LTOI 10
Letterstring - Specific
100
P200
50
0
150
RTTP 2
Face - Specific
Faces
Nouns
N200
-150
0
150
JGD
-100
P200
50
0
-50
0
-100
LSH
Faces
Nouns
-150
-50
JWR
-100
-200
N200
-250
N200
-150
0
100
200
300
400
500
600
700
800
0
100
200
Faces
Nouns
300
N200
P200
-
+
+
-
Excitatory
Inhibitory
Face-specific cell
Word-specific cell
Rat Olfactory Bulb Structural MRI
7 Tesla
100 m x 100 m x 1000 m
Yang, Renken, Hyder, Siddeek, Greer, Shepherd, Shulman PNAS, 95: 7715-7720, 1998
Rat Olfactory Bulb fMRI Activation
7 Tesla
200 m x 200 m x 1000 m
Yang, Renken, Hyder, Siddeek, Greer, Shepherd, Shulman PNAS, 95: 7715-7720, 1998