Introduction to Neurophysiology

Report
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Electrical Properties of Neurons
Neuromuscular Junction
Central Neurons
Cerebral metabolism
Autoregulation
Elevated ICP
Response to Injury
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Membrane potential is caused by the separation of
charge across the cell membrane (negative inside).
The action potential is generated by sequential
opening of ion channels based on the membrane
voltage.
Sodium and potassium gradients determine the
membrane voltage.
At rest, there is a small passive flux of sodium into
the cell and potassium out.
The Na/K/ATPase pump maintains the gradient.
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In response to a variety of stimuli, the
membrane begins to depolarize.
Voltage sensitive Na channels open, allowing
more Na inside.
The channels only remain open for a short time
and then inactivated.
Meanwhile, the K channels open in response to
the voltage change, K flows out and the
membrane repolarizes.
The Na/K/ATPase pump is responsible for
resetting the concentration gradients.
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The nature of the action potential allows for two
important properties: summation and propagation.
Summation is the effect of multiple small
depolarizations below threshold to add together to
reach threshold.
Propagation of the action potential occurs when a
local depolarization beyond threshold causes
adjacent sodium channels to open sufficiently to
cause depolarization.
The action potential can not spread backwards as
the membrane is depolarized and needs to be reset
first.
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Transmission between neurons or to muscles
requires a conversion from electrical to
chemical signals.
In general, the action potential propagates to an
end terminal (aka pre-synaptic).
This causes Ca influx which causes the release
of a chemical agent that floats across the
synapse and binds with post-synaptic
receptors.
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The receptors cause ion channels to open (or close)
which changes the membrane conductance and
depolarize the cell.
A variety of small molecules can act as a transmitter:
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Ach, GABA, Glycine, Glutamate
Serotonin, Dopamine, Norepinephrine
However, the action of a transmitter does not depend
on the nature of the chemical but on the properties of
the receptor.
The receptor can be direct (transmitter binds directly to
the ion channel) or indirect gated (receptor causes a
cascade of second messengers that effect the ion
channel).
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The muscle uses acetylcholine as its
transmitter.
The transmitter (direct) gated channels in the
muscle are permeable to both Na and K.
These channels are also not responsive to
voltage which means that they are not
regenerative.
The depolarization varies with the amount of
transmitter released.
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Central neurons differ from motor neurons as they
receive input from many presynaptic neurons,
some can be inhibitory, and different
neurotransmitters can have similar post-synaptic
effects.
Each central neuron can be considered a
summation machine.
Hundreds of axons synapse with hundreds of
dendrites on each neuron.
Each synapse is typically unable to propagate an
action potential through a cell body to the axon.
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This means that in order to transmit a signal,
the neuron has to be stimulated by multiple
synapses each opening a small number of
Na/K channels (aka EPSP) until threshold is
reached.
Inhibition of the action potential can be caused
by neurotransmitters that open Cl channels;
causing flow into the cell, making the inside
more negative (aka IPSP)
If ∑EPSP - ∑IPSP > Threshold then AP = 1
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Else AP =0
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Glutamate is the major direct gated excitatory
transmitter.
It binds to four different classes of receptors:
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Kainate and Quisqualate A
AMPA
NMDA
NMDA is special because it opens Ca channels
as well as Na and K and is voltage gated.
The Ca influx seems to act as a second
messenger intracellularly.
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The major inhibitory transmitters are GABA
and glycine.
These cause an increase in Cl conductance
which hyperpolarizes the cell.
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Other neurotransmitters such as norepinephrine,
acetylcholine and histamine act through a second
messenger system.
Norepinephrine typically uses cAMP system.
Acetylcholine uses IP3/DAG/Ca/PKC systems.
Histamine uses the arachidonic acid pathways.
The major action is via ion channel
phosphorylation that can either open or close the
channel.
The second messengers can also affect gene
expression.
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Glucose is the sole energy substrate of the brain,
unless there is ketosis.
Two terms are common in reference to metabolic
turnover of glucose and oxygen: the cerebral
metabolic rate of oxygen and the cerebral
metabolic rate of glucose.
In awake adults the cerebral metabolic rate of
oxygen is approximately 3.3 mg/100 g/min and
the cerebral metabolic rate of glucose is 5.5
mg/100 g/min.
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Of the total energy generated, 50% is used for
interneuronal communication, generation, release, and
uptake of neurotransmitters; 25% is used for
maintenance and restoration of Ionic gradients across the
cell membrane; and the remaining 25% is used for
molecular transport, biosynthesis, and other as yet
unidentified processes.
Most of the energy generated is consumed by neurons.
Glial cells that make up almost 50% of the brain have a
much lower metabolic rate than neurons and account for
less than 10% of total cerebral energy expenditure.
The brain accounts for only two to 3% of total body
weight and does not do any mechanical work, yet it
receives 20% of all cardiac output.
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Substrate availability is determined by three
factors: concentration of substrate in blood, flow
volume, and rate of substrate passage across the
blood brain barrier.
Usually the brain is able to maintain an adequate
supply of substrates by regulation of cerebral
blood flow.
Control of cerebral blood flow by adjustment in
vessel diameter is common referred to as
autoregulation of blood flow.
Several mechanisms active under different
circumstances have been described.
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Cerebral blood flow is functionally coupled to
cerebral metabolism, changing proportionally
with increasing or decreasing regional or global
metabolic demands.
Because 95% of the energy in the normal brain is
generated by oxidative metabolism, cerebral
metabolic rate of oxygen is considered a sensitive
measure of cerebral metabolism.
In general, the brain responds to alterations in
metabolism by changes in flow and thus has a
tendency to keep AVDO2 relatively constant.
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Changes in cerebral perfusion pressure will be followed
by changes in cerebral blood flow unless diameter
regulation takes place.
This type of autoregulation is termed pressure
autoregulation and is the type of autoregulation referred
to in most papers on autoregulation after head injury.
The limits of pressure autoregulation range from 40 to
150 mm of mercury of perfusion pressure.
Beyond these limits, vessel caliber follows flow passively
leading to collapse of vessels at low pressure and forced
dilatation or pressure breakthrough at high pressures.
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Cerebral blood flow can vary with changes in the
viscosity of blood.
Increased viscosity increases cerebral vascular
resistance.
This causes the vessels to dilate to decrease
vascular resistance.
Thereby, cerebral blood flow is kept constant.
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It is likely that a similar mechanism is involved in all
three types of autoregulation.
Removal of the endothelium significantly reduces the
contractions generated in response to various
vasoconstrictors and hypoxia.
The observation that rapid elevation of transmural
pressure triggers vasoconstriction and that this
response is prevented by removal of the endothelium
led to the idea that pressure on autoregulation may be
endothelium mediated.
Two major endothelium derived contracting factors
have been identified: thromboxane A2 and endothelin.
Vascular caliber and cerebral blood flow are
also responsive to changes in arterial CO2, a
mechanism commonly referred to as CO2
reactivity.
 Cerebral blood flow changes 2 to 3% for each
mm Hg of CO2 between 20 to 60 mmHg.
 Hypercarbia results in vasodilatation and
higher cerebral blood flow, and hypocarbia
results in vasoconstriction and lower cerebral
blood flow.
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Vessels respond to pH in the perivascular space.
Over 24 hours the pH in the perivascular space and the
diameter of cerebral blood vessels return to baseline.
With CO2 reactivity, changes in cerebral blood flow
are compensated for by changes in AVDO2, so that a
constant supply of substrates is maintained at the level
set by metabolism.
This means that if a low CO2 causes vasoconstriction,
the AVDO2 increases to compensate for the fall in
delivery.
In contrast, a constant AVDO2 is a common feature of
metabolic, pressure, and viscosity autoregulation.
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The cerebral metabolic rate of oxygen in comatose patients is
typically reduced from a normal value of 3.2 mL per 100 g
per minute to between 1.2 and 2.3 mL per 100 g per minute.
ATP generation from oxidative metabolism is impaired by
either low supply (low cerebral blood flow or hypoxia) or
dysfunctional processing (mitochondrial failure).
Cerebral acidosis occurs frequently after severe head injury.
Acidosis shifts the oxygen dissociation curve to the right, so
that oxygen can be extracted more completely from
hemoglobin.
Acidosis optimizes the pH for glycolysis and causes
vasodilatation of blood vessels thus maximizing the available
blood flow.
Functional recovery of tissue in the presence of high lactate
is usually poor however.
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Experimental data suggest that the brain becomes more
vulnerable to ischemia after head injury.
Common metabolic and biochemical derangements or
abnormal neurotransmitter receptor interactions, which
reach a lethal threshold when the insults are combined,
explain this increased vulnerability.
Under declining cerebral blood flow (due to failure of
pressure autoregulation or severe hypotension), the
brain can initially protect itself from ischemia and
maintain metabolic supply by increasing extraction of
the required oxygen from the flow.
Clinically this results in an increase AVDO2.
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Metabolic autoregulation
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In the presence of injury, blood flow increases.
It has been assumed that normal cerebral metabolism is
depressed after severe head injury and this increased flow
was luxury.
Cerebral blood flow is functionally coupled to cerebral
metabolic rate of glucose.
Therefore increased cerebral blood flow is not necessarily
luxury but may occur in response to increase glucose
turnover or hyperglycolysis.
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Pressure autoregulation
Autoregulation is usually temporarily dysfunctional for
the first few days, with no apparent effect on outcome.
 Based on clinical trials, it has been suggested that
brainstem lesions damaging a brain stem autoregulatory
center may be responsible.
 Endothelial damage may also be responsible for the
perturbation of pressure autoregulation.
 Oxygen radicals that are generated after the initial injury
may cause this endothelial damage.
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Viscosity autoregulation
Cerebral blood flow increases in response to bolus
administration of mannitol which reduces viscosity.
 When pressure autoregulation is intact, the lower viscosity
increases flow which causes the vessels to constrict and
reduce total blood volume.
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Carbon dioxide reactivity
 CO2 reactivity is usually preserved after severe
head injury.
 It may be low early after injury, but in most cases,
returns to a normal by 24 hours after injury.
 Patients with severely impaired CO2 reactivity
usually die or are left with severe neurological
defects.
 The pathological mechanisms leading to disturbed
CO2 regulation are poorly understood. Free
radicals may play a role.
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Cerebral blood flow is influenced by vascular
diameter, blood viscosity, and cerebral perfusion
pressure, whereas cerebral blood volume is
determined by vascular diameter only.
A decrease in cerebral metabolism results in a
coupled decrease in cerebral blood flow obtained by
vasoconstriction (metabolic autoregulation).
Cerebral blood volume decreases because of
reduced vascular diameter, and AVDO2 remains
constant because cerebral blood flow is tuned to
metabolic demand.
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A reduction in cerebral perfusion pressure leads to
compensatory vasodilatation with intact
autoregulation.
Cerebral blood flow thus remains the same, but
cerebral blood volume increases because of the
larger vascular diameter.
Again, metabolism and cerebral blood flow are
matched, and AVDO2 stays the same.
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Under certain circumstances, cerebral perfusion
pressure decreases with defective autoregulation.
In this scenario, cerebral blood flow and cerebral
blood volume follow the decrease in perfusion
pressure passively.
AVDO2 increases, because cerebral blood flow is no
longer adequate to meet the metabolic demand.
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Hypocapnia leads to a reduction in cerebral blood
volume due to vasoconstriction.
Cerebral blood flow is also decreased and
accompanied by increased oxygen extraction when
cerebral blood flow is insufficient to meet the
metabolic demand.
Hyperventilation causes a fall in ICP but at the cost
of ischemia.
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By definition, intracranial pressure is the cerebral spinal
fluid pressure.
Four parameters describe the static and dynamic CSF
pressure: the rate of CSF production, the variable
compliance given by the exponential relationship of CSF
pressure to volume, the outflow resistance, and the
intradural sinus pressure.
The Monro-Kellie doctrine states that the total volume of
the intracranial contents (cerebral blood volume, CSF,
and brain) is constant.
An increase in one of the three compartments must be
accompanied by an equal decrease in one of the other
compartments; otherwise ICP will increase.
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As long as these volume compensations are sufficient,
ICP remains relatively constant in the range of eight to 10
mmHg.
However, at a certain volume, this buffering capacity is
exhausted, resulting in an exponential increase in
pressure with any further volume addition.
The following five pathways of intracranial volume
increases are: CSF system, cerebral blood volume, blood
brain barrier damage associated edema (vasogenic
edema), neurotoxic edema, and ischemic edema.
CSF components (CSF resistant to outflow and
absorption) account for approximately one third of ICP
elevation.
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Cerebral blood flow is determined by the total
diameter of the cerebral vascular bed.
Approximately 20 mL of blood (one third of the
total cerebral blood volume) is located in the
cerebral resistance vessels.
Because most autoregulatory and CO2
dependent diameter variations take place in
these vessels, cerebral blood volume is
determined mainly by their diameter.
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Trauma causes calcium to enter through
voltage gated channels especially glutamate.
Excessive excitatory transmitters can cause cell
death by:
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Increased Na and Cl causing swelling
Increased intracellular Ca
Intracellular Ca attacks the cell membrane by
activating PLA and PLC.
The fatty acids lead to breakdown of the BBB,
cerebral edema, and generation of arachidonic
acid by-products which affect blood flow.
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ROS are released by the mitochondria because
of Ca mediated disruption of the ETC.
These ROS can cause DNA strand breaks.
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Calpain are nonlysosomal cysteine proteases
activated by increased intracellular Ca.
Activated calpains cause proteolysis of
cytoskeletal proteins, neurofilament proteins
and tubulin.
Calpains also contribute to the process that
leads to cell death.
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Intramitochondrial Ca accumulation impairs
the ETC, leading to less ATP and more ROS.
This causes cell death through energy failure
and oxidative damage.
The increased Ca also causes increased
permeability of the inner membrane leading to
rupture.
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Increased intracellular Ca activates PKC and
calmodulin kinase which phosphorylate
transcription factors.
These induce jun and fos RNA.
The significant is unknown at this time as these
genes are involved in cell death and survival.
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DAI is one of the most important forms of
brain damage.
It is an acceleration/deceleration injury that
can occur without any impact.
Primary axotomy occurs at the time of the
injury and is associated with severe cases.
The majority of axons undergo a progressive
axotomy with intra-axonal perturbations,
cytoskeletal alterations, impaired transport and
axonal disconnection.
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Mild injury results in increase in axolemma
permeability and increased Ca.
This leads to cytoskeletal misalignment and
impaired axonal transport.
Moderate or severe injury leads to massive
increases in axolemma permeability, Ca influx
and calpain activation.
This leads to neurofilament compaction,
microtubule loss, mitochondrial swelling, and
cytochrome c activation.
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The final common pathway for both injury
types is axonal swelling, disconnection and
then eventually downstream wallerian
degeneration.
The delay in effect suggests that there may be a
window of opportunity to mitigate the injury.
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Apoptotic cell death occurs both acutely and
chronically.
It is triggered by the activation of cysteine
proteases, caspases 3, 8 and 9.
Caspase 3 activity is increased in the injured
cortex by 6 hours, peaks at 24 and persists for
about 72 hours.
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Axonal disconnection is followed by limited
regenerative attempts in the CNS.
Shutdown of regeneration is due in part to
intrinsic properties of the neuron and extrinsic
environmental factors affecting axonal
outgrowth.
Scar formation around the injury site and the
presence of myelin surrounding the axons are
believed to be primarily responsible.
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Electrical Properties of Neurons
Neuromuscular Junction
Central Neurons
Cerebral metabolism
Autoregulation
Elevated ICP
Response to Injury

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