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Chapter 3

HSS3332 Chapter 3: Week 3 readings


Department
Health Sciences
Course Code
HSS 3332
Professor
Sarah Fraser
Chapter
3

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Jason Steffener Guest Lecture Reading: Alterations in the Bold FMRI Signal With Ageing and Disease
- FMRI is a powerful non-invasive technique for studying brain functions
- Important for determining the mechanisms of sensorimotor processes or high-level complex behaviour.
- Can also give insight into neural mechanisms that underlie normal development and ageing, as well as
psychiatric disorders.
- The physiological basis of its basic unit of measurement is called the BOLD signal
- The BOLD signal depends on blood-flow relationships between neural activity and the concentration of
deoxyhemoglobin in the surrounding microvasculature.
- Neural event in the brain increase in local blood flow decrease in the concentration of deoxygenated
hemoglobin surrounding the activated region increase in the BOLD signal
- The BOLD signal is a ratio between the non-pragmatic oxygenated hemoglobin to the pragmatic deoxygenated
hemoglobin
- The ratio is altered by neural activity’s influence of cerebral blood flow (CBF), cerebral blood volume (CBV),
and cerebral blood oxygen consumption (CMRO2).
- BOLD signal is an indirect measure of neural activity
- Process of neural activity influencing hemodynamic properties of surrounding vasculature = neurovascular
coupling
- The BOLD response to successive neural events, to a certain extent can be predicted by arithmetic addition of
the responses to single neural events (considering time delay between them). This relationship might vary
between different brain regions.
Mediators of Neurovascular Coupling
- The brain posses an intrinsic mechanism by which its vascular supply can be varied locally in correspondence
with the local variations of functional activity
- Local Metabolites
K+ and H+ have dilatory effects that increase the extracellular fluid during a series of neuronal action
potentials (K+ diffuses out of terminals during rapid repolarization stage of an action potential, which
increases the vicinity of active neurons
The increased K+ affects adjacent resistance vessels (increase in dilation of resistance arterioles)
K+ channels on arterial smooth muscle cells open and cause hyperpolarization relaxation
Voltage-dependent K+ channel may be necessary for the initial transient vasodilation, whereas a
second, ATP=dependent channel is responsible for the sustained dilation
There is evidence that the function of all of the types of K+ channel that are responsible for vasodilation
can be altered by the main risk factors for cerebrovascular disease (hypertension, diabetes,
hypercholesterolemia)
- Nitric Oxide
Endothelia NO does not play an important part in neurovascular coupling
NO’s role in neurovascular coupling is widely accepted but the exact mechanism is not clear
NO serves as a retrograde messenger in synapses (source can be leakage from synaptic clefts or
diffusion from active synapses to arterioles)
NO can be produced by specialized per-arteriolar neurons that are activated by direct stimulation from
collateral axons, or by leaked neurotransmitters from active synapses.
Neuronal NO synthase (NOS) containing neurons lie close to pyramidal cells and vary in density
consistent with the variation of microvasculature density.
Control of CBF by NO is implemented by either simple diffusion or through specialized networks and
the mechanism determines the degree to which the activity of clusters of neurons will produce similar
amplitudes and temporal profiles of CBF changes
There is a uniform distribution of NO-producing neurons in different cortical areas.
Not known whether NO is a direct mediator of CBF or has only modulatory effects.
A study in rats indicated that NO has modulatory effects
- Glutamate and astrocytes
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Glutamate leaks from active synapses, activates glutamate receptors on astrocyte membranes and
elevates the intracellular calcium concentrations production and release of eicosanoids (potent
vasodilators)
Astrocytes might also affect CBF by delivering K+ from the vicinity of active synapses to the arteriolar
wall (‘siphoning’), by production of lactate during glutamate recycling or by production of endothelial
NO, although the importance of these mechanisms is not clear.
Astrocytes re really significant to the interpretation of fMRI in certain populations
Any brain insult results in some gliosis (largely astrocytic), which might disrupt the orderly
neuronal-astrocytic-vascular coupling that is present in the normal brain. This means that reduced
CBF in gliotic areas might not reflect reduction in neural activity, as it would mean in intact brains.
The expression of different neurotransmitter receptors on astrocytes seems to vary during
development, indicating that different mechanisms might be active throughout life affecting the
observed activity-induced CBF changes.
Some common medications (including NSAIDs) might alter neurovascular coupling.
If neurovascular coupling relies on the interaction of specific neurotransmitters with astrocytes, then
specific neurological diseases that diminish or enhance the activity of one or more neurotransmitter
(i.e. Parkinson’s, or Alzheimer’s) might affect neurovascular coupling beyond their direct effect on
neuronal activity.
- Other Neurotransmitters
Acetylcholine increases blood flow in specific cortical (mainly frontparietal) and subcortical areas. This
might be due to the direct contact of the cerebral microcirculation by the cholinergic terminals of basal
forebrain neurons, or to the presence of cholinergic receptors on NOS-containing neurons.
Other neurotransmitters might also contribute to the regulation of local CBF, either by direct stimulation
of smooth muscle cells in arteriolar walls or through stimulation of other cells.
GABA neurons co-localize with intraparenchymal blood vessels in a manner that indicates a possible
interaction with vascular smooth muscle, directly mediated by astrocytes.
Any disease state or age-related change that affects these neurotransmitter systems could also alter
neurovascular coupling, and consequently the BOLD response, in a manner that is independent of its
effects on neural activity.
Altered Cerebrovascular Dynamics
- The cerebrovascular system undergoes important changes in multiple components in a continuum throughout
the human lifespan, beginning as early as the fourth decade.
- Vascular pathology in normal ageing can be silent or it can lead to stroke
- Ultrastructure
Change in the structural integrity of the cerebral vasculature due to ageing is the result of
arteriosclerotic changes (thickening of vessel walls, necrosis of smooth muscle cells, and thickening of
basement membrane)
Age is an independent risk factor
Changes decrease elasticity of affected vessels
Venous alterations that come with ageing (a.k.a periventricular venous collagenosis) is found in 65% of
subjects over the age of 60
Atherosclerosis
can occlude cerebral vessel post-stenotic compensatory dilation reduced vascular reactivity
and possibly redistribution of blood floe in the area surrounding the brain region that is supplied by
the occluded vessel.
Therefore, even brain areas that are distant from the injured brain area, can have altered blood-flow
- Resting cerebral blood flow
Ageing is associated with a significant decrease in resting CBF in the cortical and subcortical
parenchyma
Transcranial Doppler ultrasound
Similar findings in large cerebral arteries, such as decrease in blood flow velocity in the middle,
posterior, and anterior cerebral arteries with advancing age
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Fluctuating levels of CO2 can also influence baseline CBF
Measuring the BOLD response, the inactive state of a given region of interest is as relevant as the active
state
BOLD is not an absolute measure, it is relative and it uses the resting CBF as the baseline
Differences in the resting CBF between populations can have important implications for across-
population comparisons.
- Cerebral metabolic rate of O2 consumption
BOLD signal depends on the level of oxyhemoglobin (regulated by CBF) and the level of
deoxyhemoglobin (influenced by CMRO2)
Increasing neural activity increased CMRO2 increased levels of deoxyhemoglobin decrease in
BOLD signal
Age is known to influence CMRO2
Significantly lower resting CMRO2 in cortical and subcortical regions of older subjects compared with
younger subjects, which exceeded age-related changes in CBF.
- Vascular reactivity
Age-associated decrease in the vascular reactivity of cerebral vessels to various chemical modulators
including CO2 concentration
Increased blood CO2 dilation of cerebral arterioles
A significant decrease in the total vascular response from a hypocapnic to a hypercapnic state was
observed in older adults compared with younger adults
Mechanisms of age-related changes have not been elucidated but it is often suggested that they are
secondary to a lack of compliance of the ageing vasculature.
Gliosis accompanying tissue scarring from stroke or traumatic injury, and disruption of long-range
aminergic and cholinergic fibers that innervate the vasculature can also affect vascular reactivity.
Non-uniform distribution of atherosclerosis in the brain
The BOLD Signal in Ageing and Disease
- Normal ageing
Study spatial and temporal characteristic of the BOLD hemodynamic response function (HRF) during a
task that is expected to result in equivalent neural activity in younger and older subjects (simple motor
or visual task)
If there are changes in HRF between groups during a task that is assumed to induce no age-related
change in neural activity, then they can be attribute to an alteration in neurovascular coupling.
Any changes between younger and older subjects un motor cortex would be due to vascular changes in
normal ageing, not changes in neural activity.
Older subjects had a decreased signal-to-noise ratio in the BOLD signal when compared to younger
individuals.
This indicates that some property of the coupling between neural activity and BOLD signal changes
with age, even for simple motor responses in primary motor cortex
- Cerebrovascular disease
Decrease in the rate of rise and the maximal BOLD HRF to a finger- or hand-tapping task in both the
sensorimotor cortex of the hemisphere that was affected by the stroke and in the unaffected hemisphere.
The assumptions was made that the BOLD change was secondary to an alteration in the CBF, as the
other contributing factors to the HRF, the CBF, and CMRO2, were unlikely to be different between the
two groups.
Severe extra0cranial carotid stenosis neurovascular uncoupling that presented as a negative BOLD
signal response during performance of a simple motor task.
The negative BOLD signal only occurred in the affected hemisphere
Implications For FMRI Studies
- Disorders of vascular structure and disorders that might be considered free of vascular pathology (Alzheimer’s,
or Parkinson’s) could result in altered vascular physiology that is unrelated to changes in neural activity.
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