Week 6: Physiological Basis of the BOLD Response Gregory McCarthy, Duke University

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From Neuronal to Hemodynamic Activity
Gregory McCarthy
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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.
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Shulman and Rothman PNAS, 1998
Psychology
Mental
Image Signal
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What brain processes consume energy?

• And what is the source of that energy?

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Neuronal Activity
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Ion channels and pumps
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Synapses and neurotransmitter release.
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Anaerobic and aerobic glycolysis.
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The energy budget of the (rodent) brain.
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Roy and Sherrington (1890)
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Positron emission tomography (PET) imaging.
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The Vascular System
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Arteries
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Microcirculation of the human brain.
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Arterioles (10 - 300 microns)precapillary
sphinctersCapillaries (5-10 microns)Venules
(8-50 microns)
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Models to account for decoupling

• Watering the whole garden for the sake of one
  flower (Grinvald)
• Astrocyte shuttle (Shulman, Magestretti)
• Transit time (Buxton)

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From Malonek and Grinvald et al., 1996
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Phosphorescence Decay Time (Oxyphor R2 oxygen
tension-sensitive phosphorescent probe)
Vanzetta and Grinvald, Science, 286 1555-1558,
1999
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Vanzetta and Grinvald, Science, 286 1555-1558,
1999
deoxy Hb
Oxy Hb
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http//www.weizmann.ac.il/brain/images/ImageGaller
y.htmlInitialDip
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Astrocyte-Neuron Lactate Shuttle
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from Magestretti et al, Science, 2002
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The Initial (Negative) Dip
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Different Concentrations of Hb and dHB
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Berwick et al, JCBFM, 2002
Optical imaging of rat barrel cortex Hb02
oxyhemoglobin, Hbr deoxyhemoglobin, Hbt total
blood flow
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Early Response in fMRI
Hu, Le, Ugurbil MRM, 1997
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Functional Imaging of the Monkey Brain
N. Logothetis, Nature Neuroscience, 1999
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Transit Time and Balloon Model
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Brain or Vein?
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Evoked changes in blood flow
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The relation between sensory stimulation and
local blood flow changes
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The change in diameter of arterioles following
sciatic stimulation.
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Change in arteriole dilation as a function of
distance from active neurons.
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What triggers blood flow?
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Tissue factors

• K
• H
• Adenosine
• Nitric oxide

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Neuronal Control of the Microcirculation
C. Iadecola, Nature Neuroscience, 1998 Commentary
upon Krimer, Muly, Williams and Goldman-Rakic,
Nature Neuroscience, 1998
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Pial Arteries
Noradrenergic
Dopamine
10 ?m
Krimer, Muly, Williams, Goldman-Rakic, Nature
Neuroscience, 1998
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Dopamanergic terminals associated with small
cortical blood vessels
10 ?m
Krimer, Muly, Williams, Goldman-Rakic, Nature
Neuroscience, 1998
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Dopamanergic terminals associated with small
cortical blood vessels
2 ?m
400 nm
2 ?m
400 nm
Krimer, Muly, Williams, Goldman-Rakic, Nature
Neuroscience, 1998
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Perivascular iontophoretic application of
dopamine
18-40 s
40-60 s
Krimer, Muly, Williams, Goldman-Rakic, Nature
Neuroscience, 1998
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Neuroanatomy
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eyeball
optic nerve
spinal cord
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corpus callosum
falx
skull
hypothalamus
occipital lobe
frontal lobe
sinus
thalamus
midbrain
pons
cerebellum
medulla
spinal cord
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central sulcus
parietal lobe
superior parietal lobule
precentral gyrus
parieto-occipital sulcus
occipital lobe
frontal lobe
Sylvian fissure
cerebellum
temporal lobe
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frontal lobe
olfactory nerves
Optic chiasma
Parahippocampal gyrus
circle of Willis
fusiform gyrus
inferior temporal gyrus
basilar artery
brain stem
substantia nigra
vertebral arteries
spinal cord
occipital lobe
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central sulcus
cingulate gyrus
parietal lobe
corpus callosum
occipital lobe
calcarine sulcus
fornix
thalamus
posterior commissure
cerebellum
pons
medulla
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corpus collosum
white matter
lateral ventricles
Sylvian sulcus
thalamus
Insula
temporal lobe
amygdala
mamillary body
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frontal lobe
anterior corpus callosum
caudate
ventricle
thalamus
posterior corpus callosum
occipital lobe
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corona radiata
sagittal stratum
thalamus
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The cytoarchitectonic map of Brodmann