Physiology Review

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Physiology Review

• A work in Progress

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National Boards Part I

• Physiology section
• Neurophysiology (23)
• Membrane potentials, action potentials, synpatic
  transmission
• Motor function
• Sensory function
• Autonomic function
• Higher cortical function
• Special senses

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National Boards Part I

• Physiology (cont)
• Muscle physiology (14)
• Cardiac muscle
• Skeletal muscle
• Smooth muscle
• Cardiovascular physiology (17)
• Cardiac mechanisms
• Eletrophysiology of the heart
• Hemodynamics
• Regulation of circulation
• Circulation in organs
• Lymphatics
• Hematology and immunity

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National Boards Part I

• Physiology (cont)
• Respiratory physiology (10)
• Mechanics of breathing
• Ventilation, lung volumes and capacities
• Regulation of respiration
• O2 and CO2 transportation
• Gaseous Exchange
• Body Fluids and Renal physiology (11)
• Regulation of body fluids
• Glomerular filtration
• Tubular exchange
• Acid-base balance

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National Boards Part I

• Physiology (cont)
• Gastrointestinal physiology (10)
• Ingestion
• Digestion
• Absorption
• Regulation of GI function
• Reproductive physiology (4)
• Endocrinology (8)
• Secretion of hormones
• Action of hormones
• Regulation
• Exercise and Stress Physiology (3)

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Neurophysiology

• Membrane potential
• Electrical potential across the membrane
• Inside more negative than outside
• High concentration of Na outside cell
• High concentration of K inside cell
• PO4 SO4 Protein Anions trapped in the cell
  create negative internal enviiornment

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Membrane physiology

• Passive ion movement across the cell membrane
• Concentration gradient
• High to low
• Electrical gradient
• Opposite charges attract, like repel
• Membrane permeability
• Action potential
• Pulselike change in membrane permeability to Na,
  K, (Ca)

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Membrane physiology

• In excitable tissue an action potential is a
  pulse like ? in membrane permeability
• In muscle permeability changes for
• Na
• ? at onset of depolarization, ? during
  repolarization
• Ca
• ? at onset of depolarization, ? during
  repolarization
• K
• ? at onset of depolarization, ? during
  repolarization

9
Passive ion movement across cell

• If ion channels are open, an ion will seek its
  Nerst equilibrium potential
• concentration gradient favoring ion movement in
  one direction is offset by electrical gradient

10
Resting membrane potential (Er)

• During the Er in cardiac muscle, fast Na and
  slow Ca/Na are closed, K channels are open.
• Therefore K ions are free to move, and when they
  reach their Nerst equilibrium potential, a stable
  Er is maintained

11
Na/K ATPase (pump)

• The Na/K pump which is energy dependent
  operates to pump Na out K into the cardiac
  cell at a ratio of 32
• therefore as pumping occurs, there is net loss of
  one charge from the interior each cycle,
  helping the interior of the cell remain negative
• the protein pump utilizes energy from ATP
• Digitalis binds to inhibits this pump

12
Ca exchange protein

• In the cardiac cell membrane is a protein that
  exchanges Ca from the interior in return for
  Na that is allowed to enter the cell.
• The function of this exchange protein is tied to
  the Na/K pump
• if the Na/K pump is inhibited, function of this
  exchange protein is reduced more Ca is
  allowed to accumulate in the cardiac cell ?
  contractile strength.

13
Action potential

• Pulselike change in membrane permeability to Na,
  K, (Ca)
• Controlled by gates
• Voltage dependent
• Ligand dependent
• Depolarization
• Increased membrane permeability to Na (Ca)
• Na influx
• Repolarization
• Increased membrane permeability to K
• K efflux

14
Refractory Period

• Absolute
• During the Action Potential (AP), cell is
  refractory to further stimulation (cannot be
  restimulated)
• Relative
• Toward the end of the AP or just after
  repolarization a stronger than normal stimulus
  (supranormal) is required to excite cell

15
All-or-None Principle

• Action potentials are an all or none phenomenon
• Stimulation above threshold may cause an
  increased number of action potentials but will
  not cause a greater action potential

16
Propagation

• Action potentials propagate (move along) as a
  result of local currents produced at the point of
  depolarization along the membrane compared to the
  adjacent area that is still polarized
• Current flow in biologic tissue is in the
  direction of positive ion movement or opposite
  the direction of negative ion movement

17
Conduction velocity

• Proportional to the diameter of the fiber
• Without myelin
• 1 micron diameter 1 meter/sec
• With myelin
• Accelerates rate of axonal transmission 6X and
  conserves energy by limiting depolarization to
  Nodes of Ranvier
• Saltatory conduction-AP jumps internode to
  internode
• 1micron diameter 6 meter/sec

18
Synapes

• Specialized junctions for transmission of
  impulses from one nerve to another
• Electrical signal causes release of chemical
  substances (neurotransmitters) that diffuse
  across the synapse
• Slows neural transmission
• Amount of neurotransmitter (NT) release
  proportional to Ca influx

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Neurotransmitters

• Acetylcholine
• Catacholamines
• Norepinephrine
• Epinephrine
• Serotonin
• Dopamine
• Certain amino acids
• Variety of peptides

20
Neurons

• May release more than one substance upon
  stimulation
• Neurotransmitter like norepinephrine
• Neuromodulator like neuropeptide Y (NPY)

21
Postsynaptic Cell Response

• Varies with the NT
• Excitatory NT causes a excitatory postsynaptic
  potential (EPSP)
• Increased membrane permeability to Na and/or
  Ca influx
• Inhibitory NT causes an inhibitory postsynaptic
  potential (IPSP)
• Increased membrane permeability to Cl- influx or
  K efflux
• Response of Postsynpatic Cell reflects
  integration of all input

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Response of Postsynaptic Cell

• Stimulation causing an AP
• ? EPSP gt ? IPSP gt threshold
• Stimulation leading to facilitation
• ? EPSP gt ? IPSP lt threshold
• Inhibition
• ? EPSP lt ? IPSP

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Somatic Sensory System

• Nerve fiber types (Type I, II, III, IV) based on
  fiber diameter (Type I largest, Type IV smallest)
• Ia - Annulospiral (1o) endings of muscle spindles
• Ib - From golgi tendon organs
• II
• Flower spray (2o) endings of muscle spindles
• High disrimination touch ( Meissners)
• Pressure
• III
• Nociception, temperature, some touch (crude)
• IV- nociception and temperature (unmyelinated)
  crude touch and pressure

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Transduction

• Stimulus is changed into electrical signal
• Different types of stimuli
• mechanical deformation
• chemical
• change in temperature
• electromagnetic

25
Sensory systems

• All sensory systems mediate 4 attributes of a
  stimulus no matter what type of sensation
• modality
• location
• intensity
• timing

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Receptor Potential

• Membrane potential of the receptor
• A change in the receptor potential is associated
  with opening of ion (Na) channels
• Above threshold as the receptor potential becomes
  less negative the frequency of AP into the CNS
  increases

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Labeled Line Principle

• Different modalities of sensation depend on the
  termination point in the CNS
• type of sensation felt when a nerve fiber is
  stimulated (e.g. pain, touch, sight, sound) is
  determined by termination point in CNS
• labeled line principle refers to the specificity
  of nerve fibers transmitting only one modality of
  sensation

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Adaptation

• Slow-provide continuous information
  (tonic)-relatively non adapting-respond to
  sustained stimulus
• joint capsul
• muscle spindle
• Merkels discs
• punctate receptive fields
• Ruffini end organs (corpusles)
• activated by stretching the skin

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Adaptation

• Rapid (Fast) or phasic
• react strongly when a change is taking place
• respond to vibration
• hair receptors 30-40 Hz
• Pacinian corpuscles 250 Hz
• Meissners corpuscles- 30-40 Hz
• (Hz represents optimum stimulus rate)

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Sensory innervation of Spinal joints

• Tremendous amount of innervation with cervical
  joints the most heavily innervated
• Four types of sensory receptors
• Type I, II, III, IV

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Type I mechanoreceptors

• Outer layers of joint capsul
• fire at a degree proportional to joint movement
  or traction
• low threshold
• dynamic-fire with movement
• slow adapting
• tonic effects on lower motor neuron pools

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Type II Mechanoreceptors

• Deeper layers of joint capsul
• low threshold
• rapidly adapting
• completely inactive in imobilized joints
• functions in joint movement monitering
• phasic effects on lower motor neuron pools

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Type III Mechanoreceptors

• Recently found in spinal joints
• very high threshold
• slow adaptation
• joint version of Golgi tendon organ

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Type IV receptors

• Nociceptors
• very high threshold
• completely inactive in physiologic normal joint
• activation with joint narrowing, increased capsul
  pressure, chemical irratation

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Tactile information

• The ability to recognize objects placed in the
  hand on the basis of touch alone is one of the
  most important complex functions of the
  somatosensory system. (Gardner Kandel)
• .

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Stereognosis

• The ability to perceive form through touch
• tests the ability of dorsal column-medial
  lemniscal system to transmit sensations from the
  hand
• also tests ability of cognitive processes in the
  brain where integration occurs

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Receptors in skin

• Most objects that we handle are larger than the
  receptive field of any receptor in the hand
• These objects stimulate a large population of
  sensory nerve fibers
• each of which scans a small portion of the object
• Deconstruction occurs at the periphery
• By analyzing which fibers have been stimulated
  the brain reconstructs the pattern

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Tactile

• No single sensory axon or class of sensory axons
  signals all relevant information
• Spatial properties are processed by populations
  of receptors that form many parallel pathways
• CNS constructs a coherent image of an object from
  fragmented information conveyed in multiple
  pathways

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Mechanoreceptors

• Rapidly adapting cutaneous
• Meissners corpuscles in glabrous (non hairy)
  skin
• signals edges
• Hair follicle receptors in hairy skin
• Pacinian corpuscles in subcutaneous tissue
• Slowly adapting cutaneous
• Merkels discs have punctate receptive fields
• senses curvature of an objects surface
• Ruffini end organs activated by stretching the
  skin
• even at some distance away from receptor

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Somatic Sensory Cortex

• Receives projections from the thalamus
• Somatotopic organization (homoculus)
• Each central neuron has a receptive field
• size of cortical representation varies in
  different areas of skin
• based on density of receptors
• lateral inhibition can aid two point
  discrimination

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Somatosensory Cortex

• Two major pathways
• Dorsal column-medial lemniscal system
• Most aspects of touch, proprioception
• Anterolateral system
• Sensations of pain (nociception) and temperature

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Somatosensory Cortex (SSC)

• Inputs to SSC are organized into columns by
  submodality
• cortical neurons defined by receptive field
  modality
• most nerve cells are responsive to only one
  modality e.g. superficial tactile, deep
  pressure, temperature, nociception
• some columns activated by rapidly adapting
  Messiners, others by slowly adapting Merkels,
  still others by Paccinian corp.

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Somatosensory cortex

• Brodman area 3, 1, 2 (dominate input)
• 3a-from muscle stretch receptors (spindles)
• 3b-from cutaneous receptors
• 2-from deep pressure receptors
• 1-rapidly adapting cutaneous receptors
• These four areas are extensively interconnected
  (serial parallel processing)
• Each of the 4 regions contains a complete map of
  the body surface

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Somatosensory Cortex

• Detailed features of a stimulus are communicated
  to the brain
• in early stages of cortical processing the
  dynamic properties of central neurons and
  receptors are similar (eg rapidly adapting
  cutaneous receptors connected to rapidly adapting
  2nd and 3rd order neurons)
• in the later stages of cortical processing the
  central nerve cells have complex feature
  detecting properties and integrate various
  sensory inputs

45
Somatosensory Cortex

• 3 different types of neurons in BM area 1,2 have
  complex feature detection capabilities
• Motion sensitive neurons
• respond well to movement in all directions but
  not selectively to movement in any one direction
• Direction-sensitive neurons
• respond much better to movement in one direction
  than in another
• Orientation-sensitive neurons
• respond best to movement along a specific axis

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Pain Analgesia

• Noxious Insults to Body stimulate Nociceptors
• Nociceptors are activated by
• Mechanical Stimuli
• Thermal Stimuli
• Chemical Stimuli

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Other Somatosensory Cortical Areas

• Posterior parietal cortex (BM 5 7)
• BM 5 integrates tactile information from
  mechanoreceptors in skin with proprioceptive
  inputs from underlying muscles joints
• BM 7 receives visual, tactile, proprioceptive
  inputs
• intergrates stereognostic and visual information
• Projects to motor areas of frontal lobe
• sensory initiation guidance of movement

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Secondary SSC (S-II)

• Secondary somatic sensory cortex (S-II)
• located in superior bank of the lateral fissure
• projections from S-1 are required for function of
  S-II
• projects to the insular cortex, which innervates
  regions of temporal lobe believed to be important
  in tactile memory

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Sensations of Pain

• Pricking
• Burning
• Aching
• Stinging
• Soreness

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Pain vs. Nociception

• Nociception-reception of signals in CNS evoked by
  stimulation of specialized sensory receptors
  (nociceptors) that provide information about
  tissue damage
• Pain-perception of adversive or unpleasant
  sensation that originates from a specific region
  of the body

51
Perception of Pain

• All perception involves an abstraction and
  elaboration of sensory inputs
• highly subjective nature of pain is one the
  factors that makes it difficult to define and
  treat clinically

52
Nociceptors

• Least differentiated of all sensory receptors
• Can be sensitized by tissue damage
• hyperalgesia
• repeated heating
• axon reflex may cause spread of hyperalgesia in
  periphery
• sensitization of central nociceptor neurons as a
  result of sustained activation

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Sensitization of Nociceptors

• Potassium from damaged cells-activation
• Serotonin from platelets- activation
• Bradykinin from plasma kininogen-activate
• Histamine from mast cells-activation
• Prostaglandins leukotriens from arachidonic
  acid-damaged cells-sensitize
• Substance P from the 1o afferent-sensitize

54
Nociceptive pathways

• Fast
• A delta fibers
• glutamate
• neospinothalamic
• mechanical, thermal
• good localization
• sharp, pricking
• terminate in VB complex of thalamus

• Slow
• C fibers
• substance P
• paleospinothalamic
• polymodal/chemical
• poor localization
• dull, burning, aching
• terminate RF
• tectal area of mesen.
• Periaqueductal gray

55
Nociceptive pathways

• Spinothalamic-major
• neo- fast (A delta)
• paleo- slow (C fibers)
• Spinoreticular
• Spinomesencephalic
• Spinocervical (mostly tactile)
• Dorsal columns- (mostly tactile)

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Cardinal signs of inflammation

• Rubor-redness
• Calor-heat
• Tumor-swelling
• Dolar-pain

57
Pain Control Mechanisms

• Peripheral
• Gating theory
• involves inhibitory interneruon in cord impacting
  nocicep. projection neurons
• inhibited by C fibers
• stimulated by A alpha beta fibers
• TENS

• Central
• Direct electrical to brain -gt analgesia
• Nociceptive control pathways descend to cord
• Endogenous opiods

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Endogenous opioids

• Periaquedutal gray
• enkephalin projections to Raphe
• Raphe N.
• serotonin projections to the cord
• Inhibitory interneurons in cord
• release enkephalin which can cause pre-synaptic
  inhibition of incoming C A delta fibers
• inhibit 2nd order projection neurons

59
Pain control

• Endogenous opioid peptides and receptors are
  located at key points in the pain modulatory
  system

60
Headache

• Referred pain to surface of head
• Intracranial origins
• meningitis
• inflammation of meninges
• migraine
• vasocontraction/vasodilatation
• irritation of meninges
• e.g. abuse of alcohol
• constipation

61
Headache (cont.)

• Extracranial origins
• Muscle spasm
• connective tissue bridges between muscle dura
  in upper cervical spine
• Irritation of nasal passages and/or sinuses
• eye disorders
• cervical joint dysfunction
• spill over of signals from cervical joints (C2)
  to nucleus of CN V
• traction of dura
• mandibular branch of CN V has a recurrent or
  meningeal branch which innervates part of dura

62
Relationship of Cervical Spine to HA

• CN V sensory innervation of most of head face.
  (Three divisions).
• CN V nucleus of termination extends all the way
  down to level of C2.
• Some of cervical joint afferents synapse directly
  in CN V nuclei.
• C2 afferents synapse both in dorsal horn (DRG)
  CN V nuclei.
• Overlap between CN V C2 can cause headache
  associated w/ cervical dysfunction

63
Muscle Receptors

• Muscle contain 2 types of sensory receptors
• muscle spindles respond to stretch
• located within belly of muscle in parallel with
  extrafusal fibers (spindles are intrafusal
  fibers)
• innervated by 2 types of myelinated afferent
  fibers
• group Ia (large diameter)
• group II (small diameter)
• innervated by gamma motor neurons that regulate
  the sensitivity of the spindle
• golgi tendon organs respond to tension
• located at junction of muscle tendon
• innervated by group Ib afferent fibers

64
Muscle Spindles

• Nuclear chain
• Most responsive to muscle shortening
• Nuclear bag-
• most responsive to muscle lengthening
• Dynamic vs static bag
• A typical mammalian muscle spindle contains one
  of each type of bag fiber a variable number of
  chain fibers (? 5)

65
Muscle Spindles

• sensory endings
• primary-usually 1/spindle include all branches
  of Ia afferent axon
• innervate all three types
• much more sensitive to rate of change of length
  than secondary endings
• secondary-usually 1/spindle from group II
  afferent
• innervate only on chain and static bag
• information about static length of muscle

66
Gamma Motor System

• Innervates intrafusal fibers
• Controlled by
• Reticular formation
• Mesencephalic area appears to regulate rhythmic
  gate
• Vestibular system
• Lateral vestibulospinal tract facilitates gamma
  motor neuron antigravity control
• Cutaneous sensory receptors
• Over skeletal muscle, sensory afferent
  activating gamma motor neurons

67
Golgi tendon organ (GTO)

• Sensitive to changes in tension
• each tendon organ is innervated by single group
  Ib axon that branches intertwines among braided
  collagen fascicles.
• Stretching tendon organ straightens collagen
  bundles which compresses elongates nerve
  endings causing them to fire
• firing rate very sensitive to changes in tension
• greater response associated with contraction vs.
  stretch (collagen stiffer than muscle fiber)

68
CNS control of spindle sensitivity

• Gamma motor innervation to the spindle causes
  contraction of the ends of the spindle
• This allows the spindle to shorten function
  while the muscle is contracting
• Spindle operate over wide range of muscle length
• This is due to simultaneously activating both
  alpha gamma motor neurons during muscle
  contraction. (alpha-gamma coactivation)
• In slow voluntary movements Ia afferents often
  increase rate of discharge as muscle is shortening

69
CNS control of spindle sensitivity

• In movement the Ia afferents discharge rate is
  very sensitive to variartions in the rate of
  change of muscle length
• This information can be used by the nervous
  system to compensate for irregularities in the
  trajectory of a movement to detect fatigue of
  local groups of muscle fibers

70
Summary

• Spindles in conjunction with GTOs provide the
  CNS with continuous information about the
  mechanical state of a muscle
• For virtually all higher order perceptual
  processes, the brain must correlate sensory input
  with motor output to accurately assess the bodies
  interaction with its environment

71
Neuronal Pools

• CNS composed of millions of neuronal pools
• number of neurons in these pools vary from a few
  to a vast number
• each pool has its own special characteristics of
  organization which affects the way it processes
  signals
• despite differences in function, pools share many
  similar principles

72
Transmission of signals

• Spatial summation
• increasing signal strength transmitted by
  progressively greater of fibers
• receptor field
• of endings diminish as you move from center to
  periphery
• overlap between fibers
• Temporal summation
• increasing signal strength by ? frequency of IPS

73
Neuronal Pools

• Input fibers
• divide hundreds to thousands of times to synapse
  with arborized dendrites
• stimulatory field
• Output fibers
• impacted by input fibers but not equally
• Excitation-supra-threshold stimulus
• Facilitation-sub-threshold stimulus
• Inhibition-release of inhibitory NT

74
Neuronal Pools

• Divergence
• in the same tract
• into multiple tracts
• Convergence
• from a single source
• from multiple sources
• Neuronal circuit causing both excitation and
  inhibition (e.g. reciprocal inhibition)
• insertion of inhibitory neuron

75
Neuronal Pools

• Prolongation of Signals
• Synaptic Afterdischarge
• postsynaptic potential lasts for msec
• can continue to excite neuron
• Reverberatory circuit
• positive feedback within circuit due to
  collateral fibers which restimulate itself or
  neighboring neuron in the same circuit
• subject to facilitation or inhibition

76
Neuronal Pools

• Continuous signal output-self excitatory
• continuous intrinsic neuronal discharge
• less negative membrane potential
• leakly membrane to Na/Ca
• continuous reverberatory signals
• IPS increased with excitation
• IPS decreased with inhibition
• carrier wave type of information transmission
  excitation and inhibition are not the cause of
  the output, they modify output up or down
• ANS works in this fashion to control HR, vascular
  tone, gut motility, etc.

77
Rhythmical Signal Output

• Almost all result from reverberating circuits
• excitatory signals can increases amplitude
  frequency of rhythmic output
• inhibitory signals can decrease amplitude
  frequency of rhythmic output
• examples include the dorsal respiratory center in
  medulla and its effect on phrenic nerve activity
  to the diaphragm

78
Stability of Neuronal Circuits

• Almost every part of the brain connects with
  every other part directly or indirectly
• Problem of over-excitation (epileptic seizure)
• Problem controlled by
• inhibitory circuits
• fatigue of synapses
• decreasing resting membrane potential
• long-term changes by down regulation of receptors

79
Homeostasis

• Concept whereby body states are regulated toward
  a steady state
• Proposed by Walter Cannon in 1932
• At the same time Cannon introduced negative
  feedback regulation
• an important part of this feedback regulation is
  mediated by the ANS through the hypothalamus

80
Autonomic Nervous System

• Controls visceral functions
• functions to maintain a dynamic internal
  environment, necessary for proper function of
  cells, tissues, organs, under a wide variety of
  conditions demands

81
Autonomic Nervous System

• Visceral largely involuntary motor system
• Three major divisions
• Sympathetic
• Fight flight fright
• emergency situations where there is a sudden ? in
  internal or external environment
• Parasympathetic
• Rest and Digest
• Enteric
• neuronal network in the walls of GI tract

82
ANS

• Primarily an effector system
• Controls
• smooth muscle
• heart muscle
• exocrine glands
• Two neuron system
• Preganglionic fiber
• cell body in CNS
• Postganglionic fiber
• cell body outside CNS

83
Sympathetic Nervous System

• Pre-ganglionic cells
• intermediolateral horn cells
• C8 to L2 or L3
• release primarily acetylcholine
• also releases some neuropeptides (eg. LHRH)
• Post-ganglionic cells
• Paravertebral or Prevertebral ganglia
• most fibers release norepinephrine
• also can release neuropeptides (eg. NPY)

84
Mass SNS discharge

• Increase in arterial pressure
• decreased blood flow to inactive organs/tissues
• increase rate of cellular metabolism
• increased blood glucose metabolism
• increased glycolysis in liver muscle
• increased muscle strength
• increased mental activity
• increased rate of blood coagulation

85
Normal Sympathetic Tone

• 1/2 to 2 Impulses/Sec
• Creates enough constriction in blood vessels to
  limit flow
• Sympathocotonia- increased sympathetic activity
  (Hyperactivity)
• Most SNS terminals release norepinephrine
• release of norepinephrine depends on functional
  terminals which depend on nerve growth factor

86
Horners Syndrome

• Interruption of SNS supply to an eye
• from cervical sympathetic chain
• constricted pupil compared to unaffected eye
• drooping of eyelid normally held open in part by
  SNS innervated smooth muscle
• dilated blood vessels
• lack of sweating on that side of face

87
Parasympathetic Nervous System

• Preganglionic neurons
• located in several cranial nerve nuclei in
  brainstem
• Edinger-Westphal nucleus (III)
• superior salivatory nucleus (VII)
• inferior salivatory nucleus (IX)
• dorsal motor (X) (secretomotor)
• nucleus ambiguus (X) (visceromotor)
• intermediolateral regions of S2,3,4
• release acetylcholine

88
Parasympathetic Nervous System

• Postganglionic cells
• cranial ganglia
• ciliary ganglion
• pterygopalatine
• submandibular ganglia
• otic ganglia
• other ganglia located near or in the walls of
  visceral organs in thoracic, abdominal, pelvic
  cavities
• release acetylcholine

89
Parasympathetic nervous system

• The vagus nerves innervate the heart, lungs,
  bronchi, liver, pancreas, all the GI tract from
  the esophagus to the splenic flexure of the colon
• The remainder of the colon rectum, urinary
  bladder, reproductive organs are innervated by
  sacral preganglionic nerves via pelvic nerves to
  postganglionic neurons in pelvic ganglia

90
Enteric Nervous System

• Located in wall of GI tract (100 million neurons)
• Activity modulated by ANS

91
Enteric Nervous system

• Preganglionic Parasympathetic project to enteric
  ganglia of stomach, colon, rectum via vagus
  pelvic splanchnic nerves
• increase motility and tone
• relax sphincters
• stimulate secretion

92
Enteric Nervous System

• Myenteric Plexus (Auerbachs)
• between longitudenal circular muscle layer
• controls gut motility
• can coordinate peristalsis in intestinal tract
  that has been removed from the body
• excitatory motor neurons release Ach sub P
• inhibitory motor neurons release Dynorphin
  vasoactive intestinal peptide

93
Enteric Nervous System

• Submucosal Plexus
• Regulates
• ion water transport across the intestinal
  epithelium
• glandular secretion
• communicates with myenteric plexus
• releases neuropeptides
• well organized neural networks

94
Visceral afferent fibers

• Accompany visceral motor fibers in autonomic
  nerves
• supply information that originates in sensory
  receptors in viscera
• never reach level of consciousness
• responsible for afferent limb of viscerovisceral
  and viscerosomatic reflexes
• important for homeostatic control and adjustment
  to external stimuli

95
Visceral afferents

• Many of these neurons may release an excitatory
  neurotransmitter such as glutamate
• Contain many neuropeptides
• can include nociceptors visceral pain
• distension of hollow viscus

96
Neuropeptides (visceral afferent)

• Angiotension II
• Arginine-vasopressin
• bombesin
• calcitonin gene-related peptide
• cholecystokinin
• galamin
• substance P
• enkephalin
• somatostatin
• vasoactive intestinal peptide

97
Autonomic Reflexes

• Cardiovascular
• baroreceptor
• Bainbridge reflex
• GI autonomic reflexes
• smell of food elicits parasympathetic release of
  digestive juices from secretory cells of GI tract
• fecal matter in rectum elicits strong peristaltic
  contractions to empty the bowel

98
Intracellular Effects

• SNS-postganglionic fibers
• Norepinephrine binds to a alpha or beta receptor
  which effects a G protein
• Gs proteins adenyl cyclase which raises cAMP
  which in turn protein kinase activity which
  increases membrane permeability to Na Ca
• Parasympathetic-postganglionic fibers
• Acetylcholine binds to a muscarinic receptor
  which also effects a G protein
• Gi proteins - adenyl cyclase and has the opposite
  effect of Gs

99
Effects of Stimulation

• EyeS dilates pupils P- constricts
  pupil, contracts ciliary
  muscle increases lens strength
• Glandsin general stimulated by P but S will
  concentrate secretion by decreasing blood flow.
  Sweat glands are exclusively innervated by
  cholinergic S
• GI tractS -, P (mediated by enteric)
• Heart S , P -
• Bld vesselsS constriction, P largely absent

100
Effects of Stimulation

• Airway smooth muscle S dilation P constriction
• Ducts S dilation P constriction
• Immune System S inhibits, P ??

101
Fate of released NT

• Acetylcholine (P) rapidly hydrolysed by
  aetylcholinesterase
• Norepinephrine
• uptake by the nerve terminals
• degraded by MAO, COMT
• carried away by blood

102
Precursors for NT

• Tyrosine is the precursor for Dopamine,
  Norepinephrine Epinephrine
• Choline is the precursor for Acetylcholine

103
Receptors

• Adrenergic
• Alpha
• Beta
• Acetylcholine receptors
• Nicotinic
• found at synapes between pre post ganglionic
  fibers (both S P)
• Muscarinic
• found at effector organs

104
Receptors

• Receptor populations are dynamic
• Up-regulate
• increased of receptors
• Increased sensitivity to neurotransmitter
• Down-regulate
• decreased of receptors
• Decreased sensitivity to neurotransmitter
• Denervation supersensitivity
• Cut nerves and increased of receptors causing
  increased sensitivity to the same amount of NT

105
Higher control of ANS

• Many neuronal areas in the brain stem reticular
  substance and along the course of the tractus
  solitarius of the medulla, pons, mesencephalon
  as well as in many special nuclei (hypothalamus)
  control different autonomic functions.
• ANS activated, regulated by centers in
• spinal cord, brain stem, hypothalamus, higher
  centers (e.g. limbic system cerebral cortex)

106
Neural immunoregulation

• Nerve fibers project into every organ
• involved in monitoring both internal external
  environment
• controls output of endocrine exocrine glands
• essential components of homeostatic mechanisms to
  maintain viability of organism
• local monitoring modulation of host defense
  CNS coordinates host defense activity
• (Immunology today V.216, 281-289, Jun 2000)

107
Central Autonomic Regulation

• Major relay cell groups in brain regulate
  afferent efferent information
• convergence of autonomic information onto
  discrete brain nuclei
• autonomic function is modulated by ?s in
  preganglionic SNS or Para tone and/or ?s in
  neuroendocrine (NE) effectors

108
Central Autonomic Regulation

• different components of central autonomic
  regulation are reciprocally innervated
• parallel pathways carry autonomic info to other
  structures
• multiple chemical substances mediate transduction
  of neuronal infomation

109
Important Central Autonomic Areas

• Nucleus Tractus Solitarius
• Parabrachial Nucleus
• Locus Coeruleus
• Amygdala
• Cerebral Cortex
• Hypothalamus
• Circumventricular Organs (fenestrated caps)

110
Cardiovascular Physiology

• Cardiovascular disease is 1 cause of death
• Major underlying cause is ischemia due to
• atherosclerosis (plaquing)
• white thrombus
• red thrombus
• artery spasm

111
Connective Tissue

• Ordinary
• Loose connective tissue (areolar tissue)
• Dense ordinary connective tissue
• Regular vs. Irregular
• Special
• Adipose tissue (fat)
• Blood cells
• Blood cell forming tissue
• Myeloid or lymphatic tissue
• Cartilage
• Bone

112
Events in Hemostasis

• Hemostasis-prevention of blood loss
• Mechanisms
• vascular spasm
• formation of a platelet plug
• blood coagulation
• fibrous tissue growth to seal

113
Mechanism of Platelet Activation

• When platelets contact damaged area they 1)
  swell
• 2) irregular form w/ irradiating processes
  protruding from surface
• 3) contractile proteins contract causing
  granule release
• 4) secrete ADP and Thromboxane A2

114
Role of Endothelium

• Prevents platelet aggregation
• produces PGI2 (prostacyclin)-
• vasodilator
• stimulates platelet adenyl cyclase which
  suppresses release of granules
• limits platelet extension
• produces factor VIII (clotting)

115
Anticoagulants

• Chelators
• citrate oxalate
• tye up calcium
• Heparin
• enhances the action of antithrombin III
• principal inhibitor of thrombin
• Dicumarol (Warfarin)
• inhibition of vitamin K dependent factors
  produced by the liver
• II, VII, IX, X

116
Anticoagulants vs Lysis of clots

• Anticoagulants
• prevents clots from forming
• chelators-tye up calcium (citrate, oxylate)
• heparin- complexes with Antithrobin III
• dicumarol-inhibition of Vit. K dependent factors
• factors II, VII, IX, X (synthesized by
  hepatocytes
• Lysis of Clots
• Plasmin (from plasminogen)

117
Activators of Plasminogen

• Endogenous Activators
• tissues
• plasma
• urine
• Exogenous Activators
• streptokinase
• tPA (tissue plasminogen activator)

118
Collateralization

• The ability to open up alternate routes of blood
  flow to compensate for a blocked vessel
• Angiogenesis
• Vasodilatation
• Role of the SNS ??
• May impede
• May augment

119
Blood Coagulation- Thrombosis

• Extrinsic mechanism-initiated by chemical factors
  released by damaged tissues
• Intrinsic mechanism-requires only components in
  blood trauma to blood or exposure to collagen
  (or foreign surface)

120
Clotting factors

• I- fibrinogen
• II- Prothrombin
• III- Thromboplastin
• IV- Calcium
• V- Proaccelerin
• VII- Serum prothombin conversion acclerator
• VIII- antihemophilic factor (A)

121
Clotting factors (cont.)

• IX- antihemophilic factor B christmas factor
• X- Stuart factor
• XI- antihemophilic factor C
• XII- Hageman factor
• XIII- Fibrin-stabilizing factor
• Prekallikrein- Fletcher factor
• High molecular weight kininogen
• Platelets

122
Hepatocytes role in clotting

• Liver synthesizes 5 clotting factors
• I (fibrinogen)
• II (prothrombin)
• VII (SPCA)
• IX (AHF B)
• X (Stuart factor)
• Coumarin (warfarin or cumadin) depresses liver
  formation of II, VII, IX, X by blocking action of
  vitamin K

123
Hemophilia

• Sex linked on X chromosome
• occurs almost exclusively in males
• 85 of cases- defect in factor VIII
• 15 of cases- defect in factor IX
• varying degree of severity from mild ? severe

124
Blood Coagulation

• The key step is the conversion of fibrinogen to
  fibrin which requires thrombin
• thrombin
• fibrinogen---------------gtfibrin

125
Final Common Steps

• Once Fibrinogen has been converted to Fibrin by
  Thrombin it is changed from the soluble monomer
  to the insoluble polymer by the activated Factor
  XIII
• Factor XIII is activated by Thrombin and Ca

126
Heart muscle

• Atrial Ventricular
• striated enlongated grouped in irregular
  anatamosing columns
• 1-2 centrally located nuclei
• Specialized excitatory conductive muscle fibers
  (SA node, AV node, Purkinje fibers)
• contract weakly
• few fibrils

127
Syncytial nature of cardiac muscle

• Syncytium many acting as one
• Due to presence of intercalated discs
• low resistance pathways connecting cardiac cells
  end to end
• presence of gap junctions

128
SA node

• Normal pacemaker of the heart
• Self excitatory nature
• less negative Er
• leaky membrane to Na/CA
• only slow Ca/Na channels operational
• spontaneously depolarizes at fastest rate
• overdrive suppression-inhibits other cells
  automaticity
• contracts feebly
• Stretch on the SA node will increase Ca and/or
  Na permeability which will increase heart rate

129
AV node

• Delays the wave of depolarization from entering
  the ventricle
• allows the atria to contract slightly ahead of
  the ventricles (.1 sec delay)
• Slow conduction velocity due to smaller diameter
  fibers
• In absence of SA node, AV node may act as
  pacemaker but at a slower rate

130
Cardiac Cycle

• Systole
• isovolumic contraction
• ejection
• Diastole
• isovolumic relaxation
• rapid inflow- 70-75
• diastasis
• atrial systole- 25-30

131
Onset of Ventricular Contraction

• Isovolumic contraction
• Tricuspid Mitral valves close
• as ventricular pressure rises above atrial
  pressure
• Pulmonic Aortic valves open
• as ventricular pressure rises above pulmonic
  aortic artery pressure

132
Ejection of blood from ventricles

• Most of blood ejected in first 1/2 of phase
• ventricular pressure peaks and starts to fall off
• ejection is terminated by closure of the
  semilunar valves (pulmonic aortic)

133
Ventricular Relaxation

• Isovolumetric (isometric) relaxation-As the
  ventricular wall relaxes, ventricular pressure
  (P) falls the aortic and pulmonic valves close
  as the ventricular P falls below aortic and
  pulmonic artery P
• Rapid inflow-When ventricular P falls below
  atrial pressure, the mitral and tricuspid valves
  will open and ventricles fill

134
Ventricular Relaxation (cont)

• Diastasis-inflow to ventricles is reduced.
• Atrial systole-atrial contraction actively pumps
  about 25-30 of the inflow volume and marks the
  last phase of ventricular relaxation (diastole)

135
Ventricular Volumes

• End Diastolic Volume-(EDV)
• volume in ventricles at the end of filling
• End Systolic Volume- (ESV)
• volume in ventricles at the end of ejection
• Stroke volume (EDV-ESV)
• volume ejected by ventricles
• Ejection fraction
• of EDV ejected (SV/EDV X 100)
• normal 50-60

136
Terms

• Preload-stretch on the wall prior to contraction
  (proportional to the EDV)
• Afterload-the changing resistance (impedance)
  that the heart has to pump against as blood is
  ejected. i.e. Changing aortic BP during
  ejection of blood from the left ventricle

137
Atrial Pressure Waves

• A wave
• associated with atrial contraction
• C wave
• associated with ventricular contraction
• bulging of AV valves and tugging on atrial muscle
• V wave
• associated with atrial filling

138
Function of Valves

• Open with a forward pressure gradient
• e.g. when LV pressure gt the aortic pressure the
  aortic valve is open
• Close with a backward pressure gradient
• e.g. when aortic pressure gt LV pressure the
  aortic valve is closed

139
Heart Valves

• AV valves
• Mitral Tricupid
• Thin filmy
• Chorda tendineae act as check lines to prevent
  prolapse
• papillary muscles-increase tension on chorda t.
• Semilunar valves
• Aortic Pulmonic
• stronger construction

140
Valvular dysfunction

• Valve not opening fully
• stenotic
• Valve not closing fully
• insufficient/regurgitant/leaky
• Creates vibrational noise
• aka murmurs

141
Law of Laplace

• Wall tension (pressure)(radius)/2
• At a given operating pressure as ventricular
  radius ? , developed wall tension ?.
• ? tension ? ? force of ventricular contraction
• two ventricles operating at the same pressure but
  with different chamber radii
• the larger chamber will have to generate more
  wall tension, consuming more energy oxygen
• Batista resection
• How does this law explain how capillaries can
  withstand high intravascular pressure?

142
Control of Heart Pumping

• Intrinsic properties of cardiac muscle cells
• Frank-Starling Law of the Heart
• Within physiologic limits the heart will pump all
  the blood that returns to it without allowing
  excessive damming of blood in veins
• heterometric homeometric autoregulation
• direct stretch on the SA node

143
Mechanism of Frank-Starling

• Increased venous return causes increased stretch
  of cardiac muscle fibers. (Intrinsic effects)
• increased cross-bridge formation
• increased calcium influx
• both increases force of contraction
• increased stretch on SA node
• increases heart rate

144
Heterometric autoregulation

• Within limits as cardiac fibers are stretched the
  force of contraction is increased
• more cross bridge formation as actin overlap is
  removed
• more Ca influx into cell associated with the
  increased stretch

145
Homeometric autoregulation

• Ability to increase strength of contraction
  independent of a length change

146
Extrinsic Influences on heart

• Autonomic nervous system
• Hormonal influences
• Ionic influences
• Temperature influences

147
Control of Heart by ANS

• Sympathetic innervation-
• heart rate
• strength of contraction
• conduction velocity
• Parasympathetic innervation
• - heart rate
• - strength of contraction
• - conduction velocity

148
Interaction of ANS

• SNS effects and Parasympathetic effects blocked
  using propranolol (beta blocker) atropine
  (muscarinic blocker) respectively.
• HR will increase
• Strength of contraction decreases
• From the previous results it can be concluded
  that under resting conditions
• Parasympathetic NS exerts a dominate inhibitory
  influence on heart rate
• Sympathetic NS exerts a dominate stimulatory
  influence on strength of contraction

149
Cardioacclerator reflex

• Stretch on right atrial wall stretch receptors
  which in turn send signals to medulla oblongata
  SNS outflow to heart
• AKA Bainbridge reflex
• Helps prevents damning of blood in the heart
  central veins

150
Major Hormonal Influences

• Thyroid hormones
• inotropic
• chronotropic
• also causes an increase in CO by ? BMR

151
Ionic influences

• Effect of elevated KECF
• dilation and flaccidity of cardiac muscle at
  concentrations 2-3 X normal (8-12 meq/l)
• decreases resting membrane potential
• Effect of elevated Ca ECF
• spastic contraction

152
Effect of body temperature

• Elevated body temperature
• HR increases about 10 beats for every degree F
  elevation in body temperature
• Contractile strength will increase temporarily
  but prolonged fever can decrease contractile
  strength due to exhaustion of metabolic systems
• Decreased body temperature
• decreased HR and strength

153
Terminology

• Chronotropic ( increases) (- decreases)
• Anything that affects heart rate
• Dromotropic
• Anything that affects conduction velocity
• Inotropic
• Anything that affects strength of contraction
• eg. Caffeine would be a chronotropic agent
  (increases heart rate)

154
EKG

• Measures potential difference across the surface
  of the myocardium with respect to time
• lead-pair of electrodes
• axis of lead-line connecting leads
• transition line-line perpendicular to axis of lead

155
Rate

• Paper speed- 25 mm/sec 1 mm .04 sec.
• Normal rate ranges usually between 60-80 bps
• Greater than 100 tachycardia
• Less than 50 bradycardia

156
Electrocardiography

• P wave-atrial depolarization
• QRS complex-ventricular depolarization
• T wave-ventricular repolarization

157
Leads

• A pair of recording electrodes
• electrode is active
• - electrode is reference
• The direction of the deflection ( or -) is based
  on what the active electrode sees relative to the
  reference electrode
• Routine EKG consists of 12 leads
• 6 frontal plane leads
• 6 chest leads (horizontal)

158
Type of Deflection
159
Analysis of EKG

• Rate
• Rhythm Intervals
• Axis
• Hypertrophy
• Infarction

160
Rhythm Intervals

• PR interval
• time from SA node to entering the ventricle
• includes the AV nodal delay
• 1st degree AV block
• PR interval greater than .2 sec.
• less than .10 sec. inadequate delay-possible
  accessory conduction pathway from atria to
  ventricle
• Prolonged QT interval
• increased incidence of sudden cardiac death
• Sinus arrhythmia
• longest shortest RR vary by gt .16 sec
• heart rate variability

161
Rhythm Intervals (cont.)

• QRS complex
• duration .06-.08 sec.
• Prolonged gt .12 sec.
• Associated with ventricular hypertrophy or
  conduction block in purkinje system

162
Axis

• Mean electrical axis (MEA)
• average direction of ventricular depolarization
• the ventricle depolarizes from base to apex
  from endocardium to epicardium (A.D.I.O.)
• vector analysis using 2 frontal plane leads
• if QRS of lead I AvF is positive MEA is normal.
• normal axis between -30 105 degrees
• axis deviation
• conduction block hypertrophy shift axis to the
  side of the problem. i.e. Left bundle branch
  block creating a left axis deviation

163
Hypertrophy

• Hypertrophy of one ventricle relative to the
  other can be associated with anything that
  creates an abnormally high work load on that
  chamber.
• e.g. Systemic hypertension increasing work load
  on the left ventricle
• prolonged QRS complex (gt .12 sec)