1. Physiology of the
nervous system
Prof. Vajira Weerasinghe
Professor of Physiology, Faculty of Medicine
University of Peradeniya & Consultant Neurophysiologist,
Teaching Hospital, Peradeniya
www.slideshare.net/vajira54
3. Topics
• Action potential
• Nerve impulse transmission
• Neuromuscular junction
• Muscle contraction
• Degeneration and regeneration of nerves
• Autonomic nerve systems
• Neurotransmission
• Physiology of sensory nervous system
• Physiology of motor function
• Physiology of pain and consciousness
• CSF composition, formation and drainage
4. Excitable tissues
• Excitable tissues have more
negative RMP
( - 70 mV to - 90 mV)
excitable Non-excitable
Red cell
GIT
neuron
muscle
• Non-excitable tissues
have less negative RMP
-53 mV epithelial cells
-8.4 mV RBC
-20 to -30 mV fibroblasts
-58 mV adipocytes
5. Resting Membrane Potential
• This depends on following factors
• Ionic distribution across the membrane
• Membrane permeability
• Other factors
• Na+
/K+
pump
7. Flow of Potassium
• Potassium concentration intracellular is more
• Membrane is freely permeable to K+
• There is an efflux of K+
K+
K+K+
K+
K+ K+
K+
K+
K+
K+
8. Flow of Potassium
• Entry of positive ions in to the extracellular fluid
creates positivity outside and negativity inside
K+
K+K+
K+
K+ K+
K+
K+
K+
K+
9. Flow of Potassium
• Outside positivity resists efflux of K+
• (since K+
is a positive ion)
• At a certain voltage an equilibrium is reached
and K+
efflux stops
K+
K+K+
K+
K+ K+
K+
K+
K+
K+
10. Ionic channels
• Leaky channels (leak channels)
– Allow free flow of ions
– K+ channels (large number)
– Na+ channels (fewer in number)
– Therefore membrane is more permeable to K+
11. Na/K pump
• Active transport system for Na+-K+
exchange using energy
• It is an electrogenic pump since 3 Na+
efflux coupled with 2 K+ influx
• Net effect of causing negative charge
inside the membrane
3 Na+
2 K+
ATP ADP
12. Factors contributing to RMP
• One of the main factors is K+ efflux (Nernst Potential:
-90mV)
• Contribution of Na+ influx is little (Nernst Potential:
+60mV)
• Na+/K+ pump causes more negativity inside the
membrane
• Negatively charged protein ions remaining inside the
membrane contributes to the negativity
• Net result: -70 to -90 mV inside
13. Action Potential (A.P.)
• When an impulse is
generated
– Inside becomes positive
– Causes depolarisation
– Nerve impulses are
transmitted as AP
Depolarisation
Repolarisation
-70
+30
RMP
Hyperpolarisation
14. • Sub-threshold stimulus No action potential
• Threshold stimulus Action potential is
triggered
• Supra-threshold stimulus Action potential is
triggered
• Strength of the stimulus above the threshold is coded
as the frequency of action potentials
15. Physiological basis of AP
• When the threshold level is reached
– Voltage-gated Na+ channels open up
– Since Na+ conc outside is more than the inside
– Na+ influx will occur
– Positive ion coming inside increases the positivity of the
membrane potential and causes depolarisation
-70
+30
outside
inside
Na+
Voltage-gated Na+ channel
16. Physiological basis of AP
– When membrane potential reaches +30, Na+
channels are inactivated
– Then Voltage-gated K+ channels open up
– K+ efflux occurs
– Positive ion leaving the inside causes more negativity inside
the membrane
– Repolarisation occurs
-70
+30
outside
inside
At +30
K+
17. Hyperpolarisation
• When reaching the
Resting level rate
slows down
• Can go beyond the
resting level
– Hyperpolarisation
• (membrane becoming
more negative)
-70
+30
18. Role of Na+/K+ pump
• Since Na+ has come in and K+ has gone out
• Membrane has become negative
• But ionic distribution has become unequal
• Na+/K+ pump restores Na+ and K+ conc slowly
– By pumping 3 Na+ ions outward and 2+ K ions
inward
19. Propagation of AP
• When one area is depolarised
• A potential difference exists between that site
and the adjacent membrane
• A current flow is initiated
• Current flow through this local circuit is
completed by extra cellular fluid
20. Propagation of AP
• This local current flow will cause opening of
voltage-gated Na+ channel in the adjacent
membrane
• Na+ influx will occur
• Membrane is depolarised
21. Propagation of AP
• Then the previous area become repolarised
• This process continue to work
• Resulting in propagation of AP
30. AP propagation along myelinated
nerves
• Na+ channels are conc
around nodes
• Therefore depolarisation
mainly occurs at nodes
31. Distribution of Na+ channels
• Number of Na+ channels per
square micrometer of membrane
in mammalian neurons
50 to 75 in the cell body
350 – 500 in the initial
segment
< 25 on the surface
of myelin
2000 – 12,000 at the nodes of
Ranvier
20 – 75 at the axon
terminal
32. AP propagation along myelinated
nerves
• Local current will flow from one node to another
• Thus propagation of action potential and therefore nerve
conduction through myelinated fibres is faster than
unmyelinated fibre
– Conduction velocity of thick myelinated A alpha fibres is
about 70-100 m/s whereas in unmyelinated fibres it is about
1-2 m/s
33.
34.
35. Skeletal muscle
• Skeletal muscle is supplied by
somatic nerve
• When there is a signal to the
muscle it contracts and relaxes
• Thus there are two events in the
skeletal muscle
– Electrical - action potential
– Mechanical - contraction
37. Skeletal muscle
• Electrical event in a skeletal muscle membrane
is exactly similar to nerve action potential
• Same duration = 1 msec
• Same voltage difference = from -70 to +30 mV
38. Effect of serum hypocalcaemia
• Concentration of calcium in ECF has a
profound effect on voltage level at which Na+
channels activated
• Hypocalcaemia causes hyperexcitability of the
membrane
• When there is a deficit of Ca2+ (50% below
normal) sodium channels open (activated) by a
small increase in the membrane potential from
its normal level
– Ca2+ ions binds to the Na+ channel and alters the
voltage sensor
39. Effect of serum hypocalcaemia
• Therefore membrane becomes hyperexcitable
• Sometimes discharging spontaneously
repetitively
–tetany occurs
• This is the reason for hypocalcaemia causing
tetany
41. Presynaptic terminal (terminal knob,
boutons, end-feet or synaptic knobs)
♦ Terminal has synaptic vesicles and mitochondria
♦ Mitochondria (ATP) are present inside the presynaptic
terminal
Vesicles containing neurotransmitter (Ach)
42. Presynaptic terminal (terminal knob,
boutons, end-feet or synaptic knobs)
♦ Presynaptic membrane contain voltage-gated Ca2+
channels
♦ The quantity of neurotransmitter released is proportional to
the number of Ca2+
entering the terminal
♦ Ca2+
ions binds to the protein molecules on the inner surface
of the synaptic membrane called release sites
♦ Neurotransmitter binds to these sites and exocytosis occur
44. • Postsynaptic membrane contain nicotinic
acetylcholine receptor
Ach
Na+
•This receptor contains several
sub units (2 alpha, beta, delta
& epsilon)
•Ach binds to alpha subunit
•Na+ channel opens up
•Na+ influx occurs
45. NMJ blocking
• Useful in general anaesthesia to facilitate
inserting tubes
• Muscle paralysis is useful in performing surgery
46. Neuromuscular blocking agents
• Non-depolarising type (competitive)
– Act by competing with Ach for the Ach receptors
– Binds to Ach receptors and blocks
– Prevent Ach from attaching to its receptors
– No depolarisation
– Late onset, prolonged action
– 70–80% of receptors should be occupied to produce an effect
– To produce complete block, at least 92% of receptors must be occupied
– Ach can compete & the effect overcomes by an excess Ach
– Anticholinesterases can reverse the action
– eg.
• Curare
• Atracurium
• Tubocurarine
47. Neuromuscular blocking agents
• Depolarising type (non-competitive)
– Act like Ach, but resistant to AchE action
– Bind to motor end plate and once depolarises
– Persistent depolarisation leads to a block
• Due to inactivation of Na channels
– Two phases
• Phase I – depolarisation phase – fasciculations
• Phase II – paralysis phase
– Ach cannot compete
– Quick action start within 30 sec, recover within 3 min and is
complete within 12–15 min
– Anticholinesterases cannot reverse the action
– eg.
• Succinylcholine
• Ach in large doses
• Nicotine
48. Anticholinesterases
• AchE inhibitors
– Inhibit AchE so that Ach accumulates and causes
depolarising block
• Reversible
– Competitive inhibitors of AChE
– Block can be overcome by curare
• physostigmine, neostigmine, edrophonium
• Irreversible
– Binds to AChE irreversibly
• , insecticides, nerve gases
49. NMJ disorders
• Myasthenia gravis
– Antibodies to Ach receptors
– Post synaptic disorder
• Lambert Eaton Syndrome (myasthenic syndrome)
– Presynaptic disorder (antibodies against Ca channels)
• Botulism
– Presynaptic disorder
– Binds to the presynatic region and prevent release of Ach
50. Differences between sympathetic andDifferences between sympathetic and
parasympathetic nervous systemsparasympathetic nervous systems
Ach (N)
Ach (N) Ach (M)
Nor
Sympathetic
Parasympathetic
Adre
51. Neurotransmitters and ReceptorsNeurotransmitters and Receptors
► Acetylcholine (ACh) and norepinephrine (NE) are theAcetylcholine (ACh) and norepinephrine (NE) are the
two major neurotransmitters of the ANStwo major neurotransmitters of the ANS
► ACh is released by all preganglionic axons and allACh is released by all preganglionic axons and all
parasympathetic postganglionic axonsparasympathetic postganglionic axons
► Cholinergic fibersCholinergic fibers – ACh-releasing fibers– ACh-releasing fibers
► Adrenergic fibersAdrenergic fibers – sympathetic postganglionic– sympathetic postganglionic
axons that release NEaxons that release NE
► Neurotransmitter effects can be excitatory or inhibitoryNeurotransmitter effects can be excitatory or inhibitory
depending upon the receptor typedepending upon the receptor type
52. Nicotinic Receptors (cholinergic)Nicotinic Receptors (cholinergic)
►Nicotinic receptors are found on:Nicotinic receptors are found on:
Motor end plates (somatic targets)Motor end plates (somatic targets)
All ganglionic neurons of both sympatheticAll ganglionic neurons of both sympathetic
and parasympathetic divisionsand parasympathetic divisions
The hormone-producing cells of theThe hormone-producing cells of the
adrenal medullaadrenal medulla
►The effect of ACh binding to nicotinicThe effect of ACh binding to nicotinic
receptors isreceptors is always stimulatoryalways stimulatory
53. Muscarinic ReceptorsMuscarinic Receptors
(cholinergic)(cholinergic)
►Muscarinic receptors occur on all effectorMuscarinic receptors occur on all effector
cells stimulated by postganglioniccells stimulated by postganglionic
cholinergic fiberscholinergic fibers
►The effect of ACh binding:The effect of ACh binding:
Can be either inhibitory or excitatoryCan be either inhibitory or excitatory
Depends on the receptor typeDepends on the receptor type of theof the
target organtarget organ
54. Adrenergic ReceptorsAdrenergic Receptors
► The two types of adrenergic receptors are alphaThe two types of adrenergic receptors are alpha
and betaand beta
► Each type has two or three subclassesEach type has two or three subclasses
((αα11,, αα22,, ββ11,, ββ22 ,, ββ33))
► Effects of NE binding to:Effects of NE binding to:
αα receptors is generally stimulatoryreceptors is generally stimulatory
ββ receptors is generally inhibitoryreceptors is generally inhibitory
► A notable exception – NE binding toA notable exception – NE binding to ββ receptors ofreceptors of
the heart is stimulatorythe heart is stimulatory
55. Alpha ReceptorsAlpha Receptors
► Alpha 1: adrenergic receptors located onAlpha 1: adrenergic receptors located on
postsynaptic effector cells.postsynaptic effector cells.
Smooth muscles of blood vessels: ConstrictionSmooth muscles of blood vessels: Constriction
► Arteriolar constrictionArteriolar constriction
Bladder sphincterBladder sphincter
PenisPenis
UterusUterus
Pupillary muscles of irisPupillary muscles of iris
► Alpha 2Alpha 2
Same as the Alpha 1 but are located in the presynapticSame as the Alpha 1 but are located in the presynaptic
nerve terminalsnerve terminals
56. Adrenergic ReceptorAdrenergic Receptor
►Beta 1Beta 1
►CardiovascularCardiovascular
Cardiac muscle: increased contractilityCardiac muscle: increased contractility
increased force of contractionincreased force of contraction
Atrioventricular node: increased heart rateAtrioventricular node: increased heart rate
Sinoatrial node: increase in heart rateSinoatrial node: increase in heart rate
►EndocrineEndocrine
PancreasPancreas
57. Adrenergic ReceptorAdrenergic Receptor
►Beta 2Beta 2
►CardiovascularCardiovascular
Dilation of blood vesselsDilation of blood vessels
►EndocrineEndocrine
►Uterine relaxationUterine relaxation
►Respiratory: dilation of bronchial musclesRespiratory: dilation of bronchial muscles
58. HeartHeart
►Direct stimulation of receptorsDirect stimulation of receptors
Alpha 1 –Alpha 1 –
►Vasoconstriction of blood vessels which increasesVasoconstriction of blood vessels which increases
blood pressureblood pressure
►Pressor or vasopressor effect to maintain bloodPressor or vasopressor effect to maintain blood
pressurepressure
Beta 1Beta 1
►Increased force of myocardial contractionIncreased force of myocardial contraction
►Increased speed of electrical conduction in the heart.Increased speed of electrical conduction in the heart.
63. What happens inside a
receptor?
• TRANSDUCTION
• Stimulus energy is converted to action
potentials
• Inside the nervous system signals are always
action potentials
• Language of the nervous system contains only
1 word: action potentials
• At the brain opposite happens in
order to feel the sensation
• PERCEPTION
64. Two ascending pathways
• Dorsal column - medial lemniscus
pathway
fast pathway
• Spinothalamic pathway
slow pathway
These two pathways come together at the level of thalamus
69. Abnormalities
• Sensory loss
• Anaesthesia
• absence of sensation
• Paraesthesia
• abnormal sensation
• Hemianaesthesia
• Loss of sensation of one half of the body
• Astereognosis
70. Localisation of the abnormality
• Peripheral nerve
• part of a limb is affected
• Roots
• dermatomal pattern of sensory loss
• spinal cord
• a sensory level
• internal capsule
• one half of the body
71. What is a reflex?
Stimulus
Effector organ
Response
Central
connections
Efferent nerve
Afferent nerveReceptor
72. Stretch reflex
• This is a basic reflex present in the spinal cord
• Stimulus: muscle stretch
• Response: contraction of the muscle
• Receptors: stretch receptors located in the muscle
spindle
• Importance of stretch reflex
• Detects muscle length and changes in muscle length
73. Ia afferent nerve
α motor neuron
one
synapse
muscle
stretchmuscle
contraction γ Motor neuron
76. alpha motor neuron
• this is also called the final common
pathway
• Contraction of the muscle occurs
through this whether
• voluntary contraction through corticospinal
tract
or
• involuntary contraction through gamma
motor neuron - stretch reflex - Ia afferent
77. • Lower motor neuron lesion causes
• flaccid paralysis
• Upper motor neuron lesion causes
• spastic paralysis
79. Upper motor neuron
lesion
• muscle weakness
• spastic paralysis
• increased muscle tone (hypertonia)
• reflexes: exaggerated
• Babinski sign: positive
• superficial abdominal reflexes:
absent
• muscle wasting is very rare
80. Cerebellum
• Centre of motor coordination
• Cerebellar disorders cause incoordination or ataxia
• Functions of cerebellum
• Planning of movements
• Timing & sequencing of movements
• Particularly during rapid movments such as during walking, running
• From the peripheral feedback & motor cortical impulses, cerebellum
calculates when does a movement should begin and stop
81. Features of cerebellar disorders• ataxia
• incoordination of movements
• ataxic gait
• broad based gait
• leaning towards side of the lesion
• dysmetria
• cannot plan movements
• past pointing & overshoot
• decomposition of movements
• intentional tremor
• dysdiadochokinesis
• unable to perform rapidly alternating movements
• dysarthria
• slurring of speech
• dysphagia
• swallowing difficulty
• nystagmus
• oscillatory movements of the eye
• hypotonia
• reduction in tone
• due to excitatory influence on gamma motor neurons by cerebellum (through vestibulospinal tracts)
• decreased reflexes
• head tremor
• head tilt
82. Basal ganglia
• These are a set of deep nuclei located in and around the basal
part of the brain
• Caudate nucleus
• Putamen
• Globus pallidus
• Substantia nigra
• Subthalamic nuclei
• Basal ganglia disorders
• Parkinsonism
• Athetosis
• Chorea
• Hemiballismus
83. Parkinsonism
• due to destruction of dopamine secreting pathways
from substantia nigra to caudate and putamen.
• also called paralysis agitans
• first described by Dr. James Parkinson in 1817.
Clinical features:
• Rigidity of all the muscles
• Akinesia (bradykinesia): very slow movements,
sluggish to initiate
• Resting tremor
• Normal muscle power
84. • expressionless face
• flexed posture
• soft, rapid, indistinct speech
• slow to start walking
• rapid, small steps, tendency to run
• reduced arm swinging
• impaired balance on turning
• resting tremor (4-6 Hz) (pill-rolling tremor)
• diminishes on action
• cogwheel rigidity
• lead pipe rigidity
• impaired fine movements
• impaired repetitive movements
85. maintenance of posture
• mainly to maintain the static posture
• necessary for the stability of
movements
• involve a set of reflexes
• integrated at spinal cord, brain stem
and cortical level
89. What is pain?
• There is an International definition of pain
formulated by the IASP (International
Association for the study of pain)
• Pain is an unpleasant sensory and
emotional experience associated with
actual or potential tissue damage, or
described in terms of such damage
IASP – International Association for the Study of Pain 2011
91. • Transduction
– Process of converting noxious stimulus to action
potentials
• Perception
– Central processing of nociceptive impulses in order
to interpret pain
92. Dual nature of pain
fast and slow pain
• fast pain
– acute
– pricking type
– well localised
– short duration
– Aδ fibres are involved
– fast conduction 20 m/s
– somatic pain
• slow pain
– chronic
– throbbing type
– poorly localised
– long duration
– unmyelinated C fibres are
involved
– slow conduction 1-2 m/s
– visceral pain
94. Descending pain modulatory system
• several lines of experimental
evidence show the presence of
descending pain modulatory system
– discovery of morphine receptors
– they were known to be present in the brain
stem areas
– discovery of endogenous opioid
peptides
• eg. Endorphines, enkephalins, dynorphin
95. Gate control theory
• This explains how pain can be relieved very quickly by
a neural mechanism
• First described by P.D. Wall & Melzack (1965)
• “There is an interaction between pain fibres and touch
fibre input at the spinal cord level in the form of a
‘gating mechanism’
96. Gate control theory
central control
transmission
cell
touch
Aβ fibre
when C fibre is stimulated, gate will be opened & pain is felt
pain
C & Aδ
fibres
pain is felt
+
gate is
opened
97. Gate control theory
central control
transmission
cell
when Aβ & C fibres are stimulated together, gate will be closed
& pain is not felt
pain is
not felt
touch
Aβ fibre
pain
C & Aδ
fibres
+ -
gate is
closed
98. Consciousness
• Consciousness is the state of being awake and aware of one's
surroundings
• Assessed by observing a patient's alertness and
responsiveness, and can been seen as a continuum of states
ranging from
– alert
– oriented to time and place
– communicative
– disorientation
– delirium
– loss of any meaningful communication
– loss of movement in response to painful stimulation
• Glasgow Coma Scale (GCS) clinically measures the degree of
consciousness
99. Sleep
• A natural periodic state of rest for the
mind and body, in which the eyes usually
close and there is a decrease in bodily
movement and responsiveness to
external stimuli
• Whether it is a state of unconsciousness
is questionable
• coma is an unconscious state from which the person
cannot be aroused
• In general anaesthesia a patient is deliberately put into a state of
unconsciousness under the action of centrally acting drugs
100. Arousal & Reticular Activating System
• Keeping in conscious, alert, awake state. Is a
function of RAS.
• In parallel with the ascending somatosensory
tracts through thalamus to cortex.
• There is a more diffuse ascending system
consisting mostly of the ascending reticular
formation and diffuse nuclei of the thalamus.
• This RAS is necessary to maintain a general
level of excitability in the cortex.
102. CSF
• Cerebral blood flow: 750 ml/min (15% of cardiac output)
• volume of CSF
– 150 ml
• rate of production
– 500 ml/day
• formed
– mainly in the choroid plexuses of the ventricles
– small amounts in the ventricles, arachnoid membranes &
perivascular spaces
103. formation
• choroid plexus projects into
– horn of lateral ventricle
– posterior portion of 3rd ventricle
– roof of the 4th ventricle
• Mechanism:
– active transport of Na through the epithelial
cells, Cl follows passively
– osmotic outflow of water
– glucose moves in to CSF
– K and HCO3 moved out of CSF
104.
105. composition
• similar to plasma
– CSF Plasma
– Na 147 (similar) 150 mmol/l
– K 2.9 (less) 4.6 mmol/l
– HCO3 25 24.8 mmol/l
– Cl 113 (more) 99 mmol/l
– Pco2 50 40 mmHg
– pH 7.33 7.4
– osmolality 289 (similar) 289 mosm
– protein 20 (less) 6000 mg/dl
– glucose 64 (less) 100 mg/dl
– urea 12 (less) 15 mg/dl
• some substances do not pass into CSF
106. blood brain barrier
• tight junctions between capillary endothelial cells &
epithelial cells in the choroid prevent some
substances entering CSF
• small molecules & lipid soluble substances pass
through easily
• blood-brain barrier exists between blood & brain
tissue
• blood-CSF barrier is present in choroid
• these barriers are
– highly permeable to water, CO2, O2, lipid soluble
substances (such as alcohol), most anaesthetics,
– slightly permeable to electrolytes
– impermeable to proteins, large organic molecules
– drugs (variable)
107. blood brain barrier
• CO2 & O2 crosses easily
• H+ & HCO3- slow penetration
• glucose
– passive: slow penetration
– active transport system by glucose transporter GLUT
• Na-K-Cl transporter
• transporters for other substances
108. blood brain barrier
– No blood brain barrier in the hypothalamus &
posterior pituitary
• substances diffuses easily
• these areas contain chemoreceptors for various
substances to detect changes in conc
109. brain metabolism
– brain metabolism is 15% of total metabolism of
the body (although brain mass is 2% of total
body mass)
– therefore brain has an increased metabolic rate
– this is due to increased activity of neurons (AP)
– requires oxygen
– brain is not capable of anaerobic metabolism
– energy supply is by glucose
– glucose entry is not controlled by insulin
