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slide2

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.

slide3

Shulman and Rothman PNAS, 1998

Psychology

Image Signal

Mental

Neuroenergetics

Neuronal

CMRglc

CMRO2

CBF

Neuroscience

hemoglobin molecule
Hemoglobin Molecule

280 million Hb molecules per red blood cell

different magnetic properties of hemoglobin and deoxyhemoglobin
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.

b lood o xygenation l evel d ependent imaging
Blood Oxygenation Level Dependent Imaging

Baseline

Task

from Mosley & Glover, 1995

slide13

Intravascular

Perivascular

Extravascular

isotropic diffusion weighted spiral imaging at 4t

3

z = 1.64

Large

Small

Isotropic Diffusion Weighted Spiral Imaging at 4T

Courtesy of Dr. Allen Song, Duke University

slide15

a

b

9 sec

9 sec

slide16

BOLD activation (b factor = 0)

Diffusion-weighted (b factor = 54)

Diffusion-weighted (b factor = 108)

ADC masked by BOLD activation

Subject 41057, Slice 12, 4.0 Tesla

slide17

BOLD activation (b factor = 0)

Diffusion-weighted (b factor = 54)

Diffusion-weighted (b factor = 108)

ADC masked by BOLD activation

Subject 41037, Slice 183, 4.0 Tesla

slide18

BOLD activation (b factor = 0)

Diffusion-weighted (b factor = 54)

Diffusion-weighted (b factor = 108)

ADC masked by BOLD activation

Subject 41037, Slice 177, 4.0 Tesla

slide19

BOLD activation (b factor = 0)

ADC masked by BOLD activation

Subject 41037, Slice 177, 4.0 Tesla

slide21

Phosphorescence Decay Time

(Oxyphor R2 oxygen tension-sensitive phosphorescent probe)

Vanzetta and Grinvald, Science, 286: 1555-1558, 1999

slide22

Phosphorescence Decay Time

(Oxyphor R2 oxygen tension-sensitive phosphorescent probe)

Vanzetta and Grinvald, Science, 286: 1555-1558, 1999

slide24

Berwick et al, JCBFM, 2002

Optical imaging of rat barrel cortex

Hb02= oxyhemoglobin, Hbr = deoxyhemoglobin, Hbt = total blood flow

slide25

Functional Imaging of the Monkey Brain

N. Logothetis, Nature Neuroscience, 1999

slide26

Early Response in fMRI

Hu, Le, Ugurbil MRM, 1997

slide27

Early Response in fMRI

Hu, Le, Ugurbil MRM, 1997

arterioles 10 300 microns precapillary sphincters capillaries 5 10 microns venules 8 50 microns
Arterioles (10 - 300 microns)precapillary sphinctersCapillaries (5-10 microns)Venules (8-50 microns)
tissue factors
Tissue factors
  • K+
  • H+
  • Adenosine
  • Nitric oxide
slide31

Neuronal Control of the Microcirculation

C. Iadecola, Nature Neuroscience, 1998

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

slide32

Pial Arteries

Noradrenergic

Dopamine

10 m

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

slide33

Dopamanergic terminals associated with small cortical blood vessels

10 m

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

slide34

Dopamanergic terminals associated with small cortical blood vessels

2 m

400 nm

2 m

400 nm

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

slide35

Perivascular iontophoretic application of dopamine

18-40 s

40-60 s

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

slide38

glucose

glucose

Glucose 6 phosphate

Net +2 ATP

Fructose – 1,6-phosphate

pyruvate

lactate

TCA

cycle

O2

Net +36 ATP

CO2 + H20

slide40

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.

slide50

Lauritzen, JCBFM, 2001

Climbing Fiber Stimulation

slide51

Lauritzen, JCBFM, 2001

Climbing Fiber Stimulation

slide52

Lauritzen, JCBFM, 2001

Parallel Fiber Stimulation

slide53

Lauritzen, JCBFM, 2001

Harmaline IP synchronizes inferior olive

slide57

Whisker Barrel Model

How neuronal activity changes cerebral blood flow is of biological andpractical importance. The rodent whisker-barrel system has special meritsas a model for studies of changes in local cerebral blood flow (LCBF).

Whisker-activated changes in flow were measuredwith intravascular markers at the pia. LCBF changes were always prompt andlocalized over the appropriate barrel. Stimulus-related changes inparenchymal flow monitored continuously with H2 electrodes recorded shortlatency flow changes initiated in middle cortical layers. Activation thatincreased flow to particular barrels often led to reduced flow to adjacentcortex.

The matching between acapillary plexus (a vascular module) and a barrel (a functional neuronalunit) is a spatial organization of neurons and blood vessels that optimizeslocal interactions between the two. The paths of communication probablyinclude: neurons to neurons, neurons to glia, neurons to vessels, glia tovessels, vessels to vessels and vessels to brain. Matching a functionalgrouping of neurons with a vascular module is an elegant means of reducingthe risk of embarrassment for energy-expensive neuronal activity (ionpumping) while minimizing energy spent for delivery of the energy (cardiacoutput). For imaging studies this organization sets biological limits tospatial, temporal and magnitude resolution. Reduced flow to nearby inactivecortex enhances local differences

Woolsey et al. Cerebral Cortex, 95: 7715-7720, 1996

slide58

Rat Single Whisker Barrel fMRI Activation

7 Tesla

200 m x 200 m x 1000 m

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

slide59

Berwick et al, JCBFM, 2002

Optical imaging of rat barrel cortex

Hb02= oxyhemoglobin, Hbr = deoxyhemoglobin, Hbt = total blood flow

slide60

Berwick et al, JCBFM, 2002

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

slide67

LSOP5

LPT6

LPT7

LTO4

LTO10

DWT1

slide68

PT6

LG

PT7

FG

SOP5

V1-V2

Pole

TO4

MT

TO10

slide75

NBH1

Attend House

CDOB1

Attend Face

slide80

a

9 sec

9 sec

b

slide82

41088

41088

slide84

RTP2-5

LTTP2-2

slide86

N200

P200

-

+

-

+

Excitatory

Inhibitory

Face-specific cell

Word-specific cell

slide88

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

slide89

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

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