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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

Neuronal

CMRglc

CMRO2

CBF

Neuroscience


Let s back up what do we know for sure about fmri
Let’s back up…What do we know for sure about fMRI?


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.


Hemoglobin molecule1
Hemoglobin Molecule deoxyhemoglobin


B lood o xygenation l evel d ependent imaging
B deoxyhemoglobinlood Oxygenation Level Dependent Imaging

Baseline

Task

from Mosley & Glover, 1995


Brain or vein
Brain or Vein? deoxyhemoglobin


Large vessel contributions to bold contrast

Virchow-Robin Space deoxyhemoglobin

Large Vessel Contributions to BOLD Contrast


Intravascular deoxyhemoglobin

Perivascular

Extravascular


Isotropic diffusion weighted spiral imaging at 4t

3 deoxyhemoglobin

z = 1.64

Large

Small

Isotropic Diffusion Weighted Spiral Imaging at 4T

Courtesy of Dr. Allen Song, Duke University


a deoxyhemoglobin

b

9 sec

9 sec


BOLD activation (b factor = 0) deoxyhemoglobin

Diffusion-weighted (b factor = 54)

Diffusion-weighted (b factor = 108)

ADC masked by BOLD activation

Subject 41057, Slice 12, 4.0 Tesla


BOLD activation (b factor = 0) deoxyhemoglobin

Diffusion-weighted (b factor = 54)

Diffusion-weighted (b factor = 108)

ADC masked by BOLD activation

Subject 41037, Slice 183, 4.0 Tesla


BOLD activation (b factor = 0) deoxyhemoglobin

Diffusion-weighted (b factor = 54)

Diffusion-weighted (b factor = 108)

ADC masked by BOLD activation

Subject 41037, Slice 177, 4.0 Tesla


BOLD activation (b factor = 0) deoxyhemoglobin

ADC masked by BOLD activation

Subject 41037, Slice 177, 4.0 Tesla


Negative dips
Negative dips deoxyhemoglobin


Phosphorescence Decay Time deoxyhemoglobin

(Oxyphor R2 oxygen tension-sensitive phosphorescent probe)

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


Phosphorescence Decay Time deoxyhemoglobin

(Oxyphor R2 oxygen tension-sensitive phosphorescent probe)

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


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

deoxy Hb

Oxy Hb


Berwick et al, JCBFM, 2002 deoxyhemoglobin

Optical imaging of rat barrel cortex

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


Functional Imaging of the Monkey Brain deoxyhemoglobin

N. Logothetis, Nature Neuroscience, 1999


Early Response in fMRI deoxyhemoglobin

Hu, Le, Ugurbil MRM, 1997


Early Response in fMRI deoxyhemoglobin

Hu, Le, Ugurbil MRM, 1997


What triggers blood flow
What triggers blood flow? deoxyhemoglobin


Arterioles 10 300 microns precapillary sphincters capillaries 5 10 microns venules 8 50 microns
Arterioles (10 - 300 microns) deoxyhemoglobinprecapillary sphinctersCapillaries (5-10 microns)Venules (8-50 microns)


Tissue factors
Tissue factors deoxyhemoglobin

  • K+

  • H+

  • Adenosine

  • Nitric oxide


Neuronal Control of the Microcirculation deoxyhemoglobin

C. Iadecola, Nature Neuroscience, 1998

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


Pial Arteries deoxyhemoglobin

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 vessels

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


Uncoupling
Uncoupling… vessels


glucose vessels

glucose

Glucose 6 phosphate

Net +2 ATP

Fructose – 1,6-phosphate

pyruvate

lactate

TCA

cycle

O2

Net +36 ATP

CO2 + H20



Shulman and Rothman PNAS, 1998 vessels

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.






Attwell and Laughlin, JCBFM, 2001 vessels

Brain Energetics


Attwell and Laughlin, JCBFM, 2001 vessels

Brain Energetics





Lauritzen, JCBFM, 2001 vessels

Climbing Fiber Stimulation


Lauritzen, JCBFM, 2001 vessels

Climbing Fiber Stimulation


Lauritzen, JCBFM, 2001 vessels

Parallel Fiber Stimulation


Lauritzen, JCBFM, 2001 vessels

Harmaline IP synchronizes inferior olive





Whisker Barrel Model vessels

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


Rat Single Whisker Barrel fMRI Activation vessels

7 Tesla

200 m x 200 m x 1000 m

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


Berwick et al, JCBFM, 2002 vessels

Optical imaging of rat barrel cortex

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


Berwick et al, JCBFM, 2002 vessels

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



LMY1 vessels


LSOP5 vessels

LPT6

LPT7

LTO4

LTO10

DWT1


PT6 vessels

LG

PT7

FG

SOP5

V1-V2

Pole

TO4

MT

TO10






NBH1 vessels

Attend House

CDOB1

Attend Face






a vessels

9 sec

9 sec

b



41088 vessels

41088



RTP2-5 vessels

LTTP2-2


N200 vessels

P200

-

+

-

+

Excitatory

Inhibitory

Face-specific cell

Word-specific cell


Rat Olfactory Bulb Structural MRI vessels

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 vessels

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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