Shulman and Rothman PNAS, 1998 In this period of intense research in the neurosciences, nothing is...

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.


Psychology

CMRglc

NeuronalNeuroenergetics

MentalImage Signal

NeuroscienceCMRO2

CBF

Let’s back up…What do we know for sure about

fMRI?

280 million Hb molecules per red blood cell

Hemoglobin Molecule

L. Pauling and C. Coryell The Magnetic Properties and Structure of Hemoglobin, Oxyhemoglobin and Carbonmonoxy hemoglobin, PNAS, vol. 22, pp. 210-216, 1936.

Different magnetic properties of hemoglobin and deoxyhemoglobin

Hemoglobin Molecule

Baseline

Task

from Mosley & Glover, 1995

Blood Oxygenation Level Dependent Imaging

Brain or Vein?

Large Vessel Contributions to BOLD Contrast

Virchow-Robin Space

Intravascular

Perivascular

Extravascular

3

z = 1.64 Small

Large

Courtesy of Dr. Allen Song, Duke University

Isotropic Diffusion Weighted Spiral Imaging at 4T

9 sec

9 sec

a

b

Diffusion-weighted (b factor = 54)


Subject 41057, Slice 12, 4.0 Tesla

ADC masked by BOLD activation

BOLD activation (b factor = 0)

BOLD activation (b factor = 0) ADC masked by BOLD activation


Negative dips

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

Oxy Hbdeoxy Hb

Berwick et al, JCBFM, 2002

Optical imaging of rat barrel cortexHb02= oxyhemoglobin, Hbr = deoxyhemoglobin, Hbt = total blood flow

N. Logothetis, Nature Neuroscience, 1999

Functional Imaging of the Monkey Brain

Hu, Le, Ugurbil MRM, 1997

Early Response in fMRI

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

C. Iadecola, Nature Neuroscience, 1998Commentary upon Krimer, Muly, Williams and Goldman-Rakic, Nature Neuroscience, 1998

Neuronal Control of the Microcirculation

Krimer, Muly, Williams, Goldman-Rakic, Nature Neuroscience, 1998

Pial Arteries

10 m

Noradrenergic Dopamine


Dopamanergic terminals associated with small cortical blood vessels

10 m


Dopamanergic terminals associated with small cortical blood vessels

2 m

2 m

400 nm

400 nm


Perivascular iontophoretic application of dopamine

18-40 s 40-60 s

Let’s back up again…Why isn’t all the oxyHb used up?

Uncoupling…

glucose

pyruvate

Glucose 6 phosphate

Fructose – 1,6-phosphate

TCAcycle

lactate

Net +2 ATP

Net +36 ATP

glucose

O2

CO2 + H20


Stimulation Change CMRglc Change CMRO2 SourceVisual 51 5 Fox et al. 1988

28 28 Marrett et al. 199329 29 Marrett et al. 1993

16 Davis et al. 199823 Chen et al. 199324 Reivich et al. 1984

Mean 31 20

Cognitive 12 Roland et al. 1987Seizure 400 267 Borgstrom et al. 1976


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




Mean 31 20


Heeger, Nature Neuroscience 2002

Ito et al. JCBFM, 2001




Mean 31 20


Relationship of BOLD to neuronal activity

Attwell and Laughlin, JCBFM, 2001

Brain Energetics

Rees et al. Nature Neuroscience 2000

Heeger, Nature Neuroscience 2000

Lauritzen, JCBFM, 2001


Climbing Fiber Stimulation


Parallel Fiber Stimulation


Harmaline IP synchronizes inferior olive

Smith et al. PNAS, 2002

Hyder et al. PNAS, 2002




Mean 31 20


Spatial co-localization?

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. Stimulus-related 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

Whisker Barrel Model

Yang, Hyder, Shulman PNAS, 93: 475-478, 1996

Rat Single Whisker Barrel fMRI Activation

7 Tesla200 m x 200 m x 1000 m


Optical imaging of rat barrel cortexHb02= oxyhemoglobin, Hbr = deoxyhemoglobin, Hbt = total blood flow


(a) Outside activated region, (b) ipsilateral whisker

Relationship between field potentials and functional MRI

-1

0

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-5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12

100ms

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-5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12

100ms

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-5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12

100ms

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1500ms

Stimulus Onset Asynchrony

(15-17 seconds)

100ms

500ms

1500ms


(15-17 seconds)

100ms

500ms


(15-17 seconds)

100ms

500ms

100ms

500ms

- 1 5 0

- 1 0 0

- 5 0

0

5 0

1 0 0

1 5 0

2 0 0

2 5 0

- 1 0 0 0 1 0 0 2 0 0 3 0 0 4 0 0 5 0 0

1 0 0 m s5 0 0 m s1 5 0 0 m s

L P O - 3

- 4 0 0

- 3 0 0

- 2 0 0

- 1 0 0

0

1 0 0

2 0 0

- 1 0 0 0 1 0 0 2 0 0 3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0 9 0 0

1 0 0 m s5 0 0 m s1 5 0 0 m s

L P O - 4

-1

0

1

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-5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12

100ms

500ms

1500ms

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-5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12

100ms

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-5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12

100ms

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1500ms


(15-17 seconds)

100ms

500ms

1500ms


(15-17 seconds)

100ms

500ms


(15-17 seconds)

100ms

500ms

100ms

500ms

LTO10

DWT1

LSOP5

LPT6

LPT7

LTO4

Time (msec)

SOP5

PT6

PT7

TO4

TO10

LG

FG

Pole

V1-V2

MT

Timing of activations compared to neuronal activation

Subdural Electrode Strips

Face-Specific N200

2 A

-500

0

500

-100 0 100 200 300 400 500 600

Faces

Flowers

Nouns

Scr Faces

Target

-500

0

500

-100 0 100 200 300 400 500 600

Faces

Flowers

Nouns

Scr Faces

Target

10

11

0 100 200 300 400 500 600

Faces

Cars

Scr Faces

Numbers

Butterflies

0 100 200 300 400 500 600

Faces

Cars

Scr Faces

Numbers

Butterflies

Faces

Cars

Scr Faces

Numbers

Butterflies

B C

LMT 11

LMT 12

LMT 10

LMT 9 RMT 1

RMT 4

RMT 3

RMT 2

2 A

-500

0

500

-100 0 100 200 300 400 500 600

Faces

Flowers

Nouns

Scr Faces

Target

-500

0

500

-100 0 100 200 300 400 500 600

Faces

Flowers

Nouns

Scr Faces

Target

10

11

10

11

0 100 200 300 400 500 600

Faces

Cars

Scr Faces

Numbers

Butterflies

0 100 200 300 400 500 600

Faces

Cars

Scr Faces

Numbers

Butterflies

Faces

Cars

Scr Faces

Numbers

Butterflies

B C

LMT 11

LMT 12

LMT 10

LMT 9 RMT 1

RMT 4

RMT 3

RMT 2

RPTO 8

-300

-250

-200

-150

-100

-50

0

50

100

150

-100 0 100 200 300 400 500 600 700 800 900

Time (msec)

Fruits Face-Cap Tools Scr Faces Circles (Targets)

Face-House Attention Task

-300

-100

100

300

-100 100 300 500 700 900 1100 1300 1500 1700 1900

Attend House

Attend Face

NBH1

CDOB1

Negative activations

Harel et al. JCBFM, 2002

9 sec

9 sec

a

b

180° phase-reversed responses to faces among objects

41088

-8

-4

0

4

8

12

0 18 36 54 72 90 108 126 144 162 180 198 216 234 252 270 288 306

Positive ActivationNegative Activation

41088

Is there evidence for inhibition?

-300

-200

-100

0

100

200

300

-100 0 100 200 300 400 500 600 700 800 900

LTTP2-2Letterstring -Specific

RTTP2-5Face -Specific

P200

N200

JRNFaceNoun

RTP2-5 LTTP2-2

-150

-100

-50

0

50

100

0 100 200 300 400 500

FacesNouns

LOTM 8Letterstring - Specific

P200

N200

JGD

-150

-100

-50

0

50

100

150

0 100 200 300 400 500

FacesNouns

LTOI 10Letterstring - Specific

P200

N200

JWR

-100

-80

-60

-40

-20

0

20

40

60

80

100

0 100 200 300 400 500 600 700 800

FacesNouns

LTTP 2Face - Specific

P200

N200

SGN

-250

-200

-150

-100

-50

0

50

100

150

0 100 200 300 400 500 600 700 800

FacesNouns

RTTP 2Face - Specific

P200

N200

LSH

-150

-100

-50

0

50

100

0 100 200 300 400 500

FacesNouns

LOTM 8Letterstring - Specific

P200

N200

JGD

-150

-100

-50

0

50

100

150

0 100 200 300 400 500

FacesNouns

LTOI 10Letterstring - Specific

P200

N200

JWR

-100

-80

-60

-40

-20

0

20

40

60

80

100

0 100 200 300 400 500 600 700 800

FacesNouns

LTTP 2Face - Specific

P200

N200

SGN

-250

-200

-150

-100

-50

0

50

100

150

0 100 200 300 400 500 600 700 800

FacesNouns

RTTP 2Face - Specific

P200

N200

LSH

-

+

Excitatory

Inhibitory

+

-

Face-specific cell Word-specific cell

N200 P200

Rat Olfactory Bulb Structural MRI

Yang, Renken, Hyder, Siddeek, Greer, Shepherd, Shulman PNAS, 95: 7715-7720, 1998

7 Tesla100 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 Tesla200 m x 200 m x 1000 m

Shulman and Rothman PNAS, 1998 In this period of intense research in the neurosciences, nothing is...

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