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The bodily senses
From Ch. 22
“Principles of Neural Science”, 4th Ed.
Kandel et al
Bodily senses
• Bodily senses = somatic sensation
– Large variety of receptors
– Distributed throughout the body
• Sensory information
– Nerves transmit information from the
receptors by frequency modulation of
electrical signals (action potentials)
Dorsal root ganglion (DRG)
•
DRG contains the cell bodies of sensory
neurons
•
All somatosensory information from
limbs and trunk are transmitted via DRG
– Stimulus transmission from sensory
receptor to CNS
•
Primary afferent neuron has two
branches to
– Periphery
– Spinal cord
The sensory receptor
• Peripheral receptor
– Located at the terminal of the sensory neuron
– Molecular specialization that transforms one
type of energy into action potentials
– Special transducer molecules
Somatic receptor types
• Fiber classification
– Conduction velocity (skin) or fiber diameter (muscle)
– Myelinated or unmyelinated
• 4 major modalities (distinct system of receptors and pathways to the
brain)
– Discriminative touch (size, shape, texture, movement across skin)
– Proprioception (joint position)
– Nociceptors (tissue damage, inflammation, chemical irritation, pain, itch)
– Thermal receptors (warm, cold)
Somatic receptor types
1
2
3
4
Somatic receptor types
1
2
3
4
Somatic receptor types
1
2
3
4
Nerve endings and fiber types
• Nerve endings
– Bare nerve endings
• Thermal and painful (nociception) sensations
– Encapsulated nerve endings
• Touch and proprioception
• Deformation of receptive surface
• Large diameter myelinated axons (rapid conduction)
– Mechanoreceptors (touch, greatest density in glabrous skin [hairless],
finger tips, lips)
– Proprioceptors (joint position)
• Small diameter myelinated and unmyelinated (slow
conduction)
– Thermal receptors
– Nociceptors
Location of nerve endings
Mechanoreceptors
• Specialized organs surrounding the nerve endings
– Sensitive to displacement/ deformation
• 4 major types in glabrous skin
– Superficial location (located below skin ridges)
• Meissner corpuscle – in glabrous skin
– Rapidly adapting, fluid filled structure, sense deformation of small areas
• Merkel disk receptor - in glabrous skin and hairy skin
– Slowly adapting, sense sustained pressure, salient bumps, sharp edges
– Deep subcutaneous location (less numerous)
• Pacinian corpuscle
– Similar to Meissner corpuscle, rapid indentation, minute vibration,
frictional displacement, small irregularities (edges/ corners)
• Ruffini ending
– Slowly adapting, links folds in skin at the joints, sense stretch and
bending, shape of grasped objects, global properties of objects, wide
area of skin
Mechanoreceptors
• Deep receptors sense deformation of a wider skin area that extends
beyond the overlying ridges
• Nerve fibers to superficial layers branch off to several nearby sensory
receptors
• Nerve fibers in subcutaneous layers only innervate one receptor
• 4 types of mechanosensitivity
– Gentle touch of skin (well-localized)
– Vibration (frequency and amplitude)
– Texture (discrimination with fine spatial detail, two-point discrimination)
– Shape of objects grasped
Receptive field (RF)
Small, welllocalized
Large, central
zone with max
sensitivity
Directionspecific
stretch
•
Size and structure of RF vary
Receptive field (RF)
2-3 mm diameter
Fine spatial
differences
Small, welllocalized
10 mm diameter
10-25
receptors
Relative sensitivity to pressure
Large, central
zone with max
sensitivity
Directionspecific
stretch
coarse
spatial
differences
Central zone with large
continuous surface
Directly above receptor
•
Size and structure of RF vary
Receptor distribution
Most numerous
receptor types
Uniform distribution
Fine spatial
sensitivity
Best at finger tips
Finger tips are the most densely innervated region of the skin
300 mechanoreceptive nerve fibers per square centimeter
Two-point discrimination
• Two-point discrimination
– Min distance as which 2
stimuli can be resolved as
distinct
– Determine if one or more
points are stimulated
• Spatial resolution depends
on the RF size/ receptor
density
• Spatial resolution of stimuli
varies across the body
• Smallest receptive fields in
fingers, lips, and tounge
April 15, 2009
Vibration sense
• Vibration is coded by spike trains
– Each AP signals one sinusoidal cycle
– Vibration frequency is signalled by
the AP frequency
• Different receptors have different
sensitivity
– Merkel: 5-15 Hz
– Meissner: 20-50 Hz
– Pacinian: 60-400 Hz
• Detection depends on size of skin
indentation and frequency
Sensory threshold
April 15, 2009
– Detection threshold = tuning
threshold = Lowest stimulus intensity
that evokes one AP/ cycle
– Intensity of vibration depends on the
total number of nerve fibers activated
Adaption and threshold
• Slowly adapting (SA)
– Constant pressure
• Rapidly adapting (RA)
(1) Adapting at the beginning and end of stimulus
(2) Encode sense of motion of object
- Fires when position change (firing rate proportional to speed)
- Stops firing when object is at rest
• AP/ sec depends on indentation force
• Sensory threshold
– The minimum stimulus intensity generating an AP
– RA’s have lowest touch threshold
– Pacinian corpuscles are the most sensitive mechanoreceptor
Shape and size
• P= F/a
• At constant force (F), the
smaller area (a) stimulated
results in bigger pressure (P)
=> higher firing rate
• Strong initial response
• Firing rate is proportional to the
curvature of each probe
Constant force
April 15, 2009
Spatial characteristics
• Texture, size, and shape are
signalled by population of receptors
Smaller
Receptive field diameter
Bigger
Higher
Spatial resolution
Lower
• Periodic firing of groups of receptors
signal the spatial characteristic
– Active and inactive receptors
contribution
• The individual receptor is only
stimulated by a part of the pattern
• The spatial resolution depends on
receptor density and type of receptor
• Natural stimuli rarely activates a
single receptor alone
April 15, 2009
Example: lifting an object
• Lifting and object
– Grasp, force increase, object lifted, vertical gravitational pull,
force decrease, release
• Grasp and release
– Meissner c. : contact/ release; increased grasp force
– Pacinian c. : transient pressure at start/ stop
• Grip force
– Merkel disks: continous firing/ proportional with force
• Gravitational pull
– Ruffini endings: slowly adapting, sense stretch
Somatic receptor types
1
2
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4
Thermal receptors
4 thermal sensations: cold, cool, warm, hot
•
Constant temperature
– Adaption
– Tonic discharge/ steady
rate
Peak sensitivity
•
Body temperature
– Continuously low rate
– Cold fibers more active
Adaption
Silenced
•
Most sensitive to changes in
temp than constant temp
•
Warm fibers:
– Range, 29-49 deg
– Peak/ preferred, 45 deg
•
Encoding of temperature
involves comparing the relative
activity of different populations
Cold fibers:
– Range 5-40 deg
– Peak/ preferred, 25 deg
Somatic receptor types
1
2
3
4
Nociceptors
•
Information about stimuli that can damage
tissue are conveyed by nociceptors
•
Chemicals are released from traumatized
tissue
Mechanical nociceptor
– E.g. Substance P, histamine, and bradykinin
•
2 overall types:
– Nociceptive specific
– Wide dynamic range neurons
•
3 classes of nociceptors
– Mechnical: pinch, punctate, squeeze
– Thermal: above 45 deg or below 5 deg
Polymodal: mechanical, thermal, chemical
Somatic receptor types
1
2
3
4
Proprioception: sense of position and movement of one’s own limbs wo. Vision
(1) static limb position, (2) limb movement (kinesthesia); in muscle and joints
April 15, 2009
Afferent fibers
Different size and conduction velocity of axons
Compound AP =
sum of all activated
nerves
Spike amplitude is
proportional to fiber
diameter
-Large fibers conduct faster than small/ thin fibers
because the internal resistance to current flow is low
and nodes of Ranvier are spaced further apart
- Myelination sheets increase conduction velocity
April 15, 2009
Innervations of dorsal roots
Dermatomes
Important for location
of spinal injury
Distinct ascending pathways
•
Dorsal column-medial lemniscal
system
–
–
–
–
•
Anterolateral system
–
–
–
–
Contralateral
April 15, 2009
Touch and proprioception from limbs and
trunk
Somtatotopically organized from spinal to
cortical level
Ascends ipsilateral side
Cross over to contralateral side in medulla
Spinal lamina I, IV, V, VII, VII
Pain and temperature from limbs and trunks
Cross over to contralateral side in spinal cord
Somtatotopically organized from spinal to
cortical level
The perception of pain
From Ch. 24
“Principles of Neural Science”, 4th Ed.
Kandel et al
Somatic sensations
• Somatic sensation = bodily sensation
– Pain is a submodality of somatic sensation
– Pain and nociception (conscious vs. peripheral)
• Pain sensation is the most salient sensation
–
–
–
–
–
Pricking
Burning
Aching
Stinging
Soreness
• Pain is a warning of actual or potential injury and damage
• Pain depends on the psychological state
– The same stimulus can result in different responses under similar
conditions and in different individuals
Nociceptors
Mechanical nociceptor
•
Information about stimuli that can damage
tissue are conveyed by nociceptors
•
Chemicals are released from traumatized
tissue
– E.g. Substance P, histamine, and bradykinin
•
3 classes of nociceptors
– Mechnical: pinch, punctate, squeeze
– Thermal: above 45 deg or below 5 deg
Polymodal: mechanical, thermal, chemical
April 29, 2009
Somatic receptor types
1
2
3
4
April 29, 2009
Afferent fibers
Different size and conduction velocity of axons
Compound AP =
sum of all activated
nerves
Spike amplitude is
proportional to fiber
diameter
-Large fibers conduct faster than small/ thin fibers
because the internal resistance to current flow is low
and nodes of Ranvier are spaced further apart
- Myelination sheets increase conduction velocity
April 29, 2009
Nociceptive afferents
Compound Action Potential
DRG
Spinal dorsal horn
First pain: Sharp and pricking, faster A-delta fibers
Second pain, burning and dull, slower C-fibers
April 15, 2009
Blocking each nerve blocks the sensation
Spinal dorsal horn neurons
•
2 overall types of interneurons:
–
–
•
Lamina I and II
–
–
•
Direct input from A-beta and A-delta. Direct/ indirect from C-fibers. Convergence of visceral
afferents. WDR interneurons projecting to brain stem and thalamus.
Lamina VI
–
•
Direct input from A-beta. Nonnoxious input. Topographically organised receptive field
Lamina V
–
•
Direct input from mainly A-delta and C fibers.
NS and WDR interneurons
Lamina III and IV
–
•
Nociceptive specific: responds exclusively to noxious stimuli
Wide dynamic range neurons: graded response to non-noxious and noxious stimuli
Direct input from A-alpha (nonnoxious) from joints and muscle
Lamina VII and VIII
–
Respond to noxious input. Polysynaptic. Bilateral response
April 29, 2009
Neurotransmitters
• Fast synaptic potentials
– Glutamate (amino acid)
– Efficient reuptake of amino acids
– Range: postsynaptic neurons in vicinity
• Slow synaptic potentials
– Neuropeptides e.g. Substance P
– No reuptake mechanisms
– Range: diffusion, many neurons, unlocalized nature of pain
• Neuropeptides
– Released and increased in persistent pain conditions
– Enhances and prolong the actions of glutamate
– Application of substance P produces signs of inflammation e.g. heat,
redness, and swelling
April 29, 2009
Peripheral activation and
sensitization
April 29, 2009
Chronic pain
• Chronic pain appears to serve no useful purpose
– Abnormal pain states
– Nociceptive and neuropathic
• Nociceptive pain
– Direct activation of nociceptors
– Tissue damage or inflammation
• Neuropathic pain
– Direct injury to the nerves
– Peripheral or central
– Burning or electrical sensation
April 29, 2009
Chronic pain
•
Spontaneous ongoing pain
– Pain of variable intensity and duration
– Spontaneous discharges in periphery and centrally
•
Referred pain
– Pain in a location distant from the source. Could be explained by viscero-somatic
convergence in lamina V
•
Hyperalgesia
– Increased pain sensitivity
•
Allodynia
– Non-painful input becomes painful e.g. touch on sun burned skin
•
Allodynia and hyperalgesia only exist during stimulation
•
Alterations in biochemical properties and excitability of dorsal horn neurons
can induce spontaneous pain, hyperalgesia and allodynia
April 29, 2009
Referred pain
• Signals from muscles and viscera
can be felt as pain elsewhere
• Example: myocardial infarction and
angina can be felt in chest and left
arm
• Mechanism: convergence of
afferents muscle/ viscera afferents
and somatic afferents.
• Convergence on the same
projection neurons in the dorsal
horn
• The brain cannot tell the difference
April 29, 2009
Hyperalgesia
•
Peripheral sensitization:
–
–
•
Central sensitization:
–
–
–
–
–
–
•
Increased spontaneous activity
Hyperexcitability of spinal dorsal horn neurons
Wind-up: progressive increased response = amplification (depends on glutamate acting on
NMDA receptors)
Prolonged after-discharges to afferent input
Expansion of peripheral receptive fields of central neurons
Can be induced by repetitive firing of nociceptive afferents
Primary hyperalgesia
–
–
•
Increased nociceptor sensitivity
Increased spontaneous activity
Hyperalgesia in damaged area (within 5-10mm)
Peripheral sensitization
Secondary hyperalgesia:
–
–
Hyperalgesia in surrounding undamaged tissue (10-20mm).
Peripheral and central sensitization
April 29, 2009
Clinical hyperalgesia
Myofascial pain patients (PTS) vs. normal controls (CTR)
Myofascial trigger points are hyperalgesic contractures in the muscle
Pressure pain thresholds
P<0.001
800
600
400
200
IMES stimulus-response curves
6
Pain Intensity
Pressure [kPa]
1000
PTS
5
CTR
4
P<0.001
3
2
0
CTR
PTS
6
10
14
Stimulus Intensity [mA]
Niddam et al. 2008
April 29, 2009
Pain and the brain
• Pain is a subjective conscious experience. Pain does not
exist without the brain
• CNS inhibitory or facilitatory mechanisms are remarkable
efficient in decreasing or amplifying the pain experience
• Changes in CNS contributes to chronic pain
(reorganization: biochemical, atrophy, functions)
• A better understanding of endogenous pain modulatory
systems may lead to new mechanism-based therapies
and drug targets
April 29, 2009
Pain and the brain: modulation
• Factors that can influence the pain experience
– Top-down brain processes
•
•
•
•
•
Memories (previous experience)
Emotion
Cognition (attention/ distraction)
Mood (depression, anxiety)
Context (stress, anticipation/ expectation, placebo)
– Endogenous pain control systems
– Other factors
• Genes
• Pathological factors (structure, transmitters, receptors, transporters
etc.)
• Age, gender
April 29, 2009
Acute vs. chronic pain
• Acute pain characteristics
– Activation of peripheral receptors under normal conditions
– Sensation of pain closely related to the duration of the stimulus
• Chronic pain characteristics
– Spontaneous ongoing pain
• Peripheral sensitization (spontaneous resting activity and hyperexcitable receptors)
• Central sensitization (prolonged peripheral input)
– Lowered pain threshold (Hyperalgesia)
– Non-nociceptive input becomes painful (allodynia)
– Functional and structural changes in PNS and CNS
•
•
•
•
•
April 29, 2009
Segmental expansion of receptive fields
De novo synthesis of membrane proteins
Spouting of spinal terminals of afferent fibers
Formation of new synaptic contacts
Altered balance in descending influences
Acute vs. chronic pain
• It is important to differentiate between:
– Acute and chronic pain states
• Different time horizons engage different emotional coping strategies
• Chronic pain becomes maladaptive and is highly co-morbid with
mood and anxiety disorders
• Chronic pain induces CNS changes
– Ongoing spontaneous chronic pain vs. perturbations
of chronic pain (allodynia/ hyperalgesia)
• Passive vs. active coping => medial vs. lateral brain regions?
April 29, 2009
Neuroimaging of acute pain
Cutaneous pain
Muscle pain
Visceral pain
PFC
PFC
ACC
PFC
ACC
PCC
PPC
PPC
Insula
PCC
PCC
Chen et al.
Tooth pain
Insula
Thalamus
Insula
Vermis
Amygdala
Vermis
Lin et al. (preliminary)
Lu et al., 2004
Niddam et al., 2002
Distinct ascending pathways
•
Dorsal column-medial lemniscal
system
– Touch and proprioception from limbs
and trunk
– Somtatotopically organized from spinal
to cortical level
– Ascends ipsilateral side
– Cross over to contralateral side in
medulla
•
Contralateral
April 29, 2009
Spinothalamic pathway
– Spinal lamina I, V-VII
– Pain and temperature from limbs and
trunks
– Cross over to contralateral side in
spinal cord
– Somtatotopically organized from spinal
to cortical level
Ascending pathways
• 5 major ascending pathways
– Spinothalamic: axons of nociceptive specific and WDR neurons from laminae I
and V-VII; contralateral projection, ascends in anterolateral white matter
– Spinoreticular: neurons in laminae VII and VIII; anterolateral ascend
– Spinomesencephalic: neurons in laminae I and V; anterolateral ascend to PAG,
and spinoparabrachial tract to PB, amygdala; pain affect
– Cervicothalamic: arises from lateral cervical nucleus; laminae III and IV; some
projects via the dorsal column to cuneate and gracile nuclei (large fiber pathway)
– Spinohypothalamic: laminae I, V, VIII; autonomic control
• Thalamic nuclei
– Lateral nuclear group: spinothalamic tract, NS and WDR, laminae I and V, small
receptive fields, encoding location of injury
– Medial nuclear group: spinoreticulothalamic tract, laminae VII and VIII
April 29, 2009
Ascending pathways
April 29, 2009
Pain pathways in the brain
Ascending pathways and cortical/ sub-cortical
connectivity
Spino-bulbo-spinal loop
(pain facilitation)
Apkarian et al. 2005
Pain components (variable expression):
Sensory-discriminative, affective-motivational
Cognitive, Motor
April 29, 2009
Millan 2002
Pain and the brain: pathways
• Stress and the reward/ motivation system
Hypothalamus
Amygdala
Dopamine based mesolimbic
system modulates mainly
tonic pain
Hippocampus
Ventral
tegmental area
Dopoaminergic
nucleus
April 29, 2009
Ventral striatum/
Nucleus accumbens
Ventral pallidum
MDm thalamus
Pain
modulation
Anterior cingulate
Motivation and emotions
Borsook 2007, EJP
Pain modulation: large fibers
The gate control hypothesis
•
The balance of activity in small- and large-diameter
fibers is important in pain transmission/ determines
the pain intensity
•
The gate control theory involves 4 types of neurons in
the dorsal horn of the spinal cord
–
–
–
–
•
Large-diameter fibers
–
•
Inhibits interneuron and increases pain transmission/
Opens the pain-gate
Observation: in absence of conduction in A-ά/ A-β
fibers pain perception is abnormal
–
April 29, 2009
Excites interneuron and decrease pain transmission/
Closes the pain-gate
Small-diameter fibers
–
•
Large-diameter afferent (non-nociceptive)
Small-diameter afferent (nociceptive)
Inhibitory interneurons (spontaneously active)
Projection neurons
Pin prick, pinch, ice cold produces burning pain
Pain modulation: opiods
•
Direct stimulation of PAG produces analgesia
–
–
•
Moprhine (an opioid) induced analgesia via endogenous
opioid receptors in descending pathway
•
Opioid receptors
–
–
–
Types: -, δ-, κ-, nociceptin
Transmitters: enkephalins, β-endorphin, dynorphin
Location (mainly): PAG, ventral medulla, superficial dorsal horn
•
Stress-induced analgesia of escapable pain is mediated
via the endogenous opioid system
•
Side effects
–
–
April 29, 2009
Inhibits firing of nociceptive neurons in lamina I and V
Descending pathway recruited: PAG excites rostroventral medulla/
nucleus raphe magnus (5HT)
Other regions not involved in pain also contains opioid
receptor
Minimize diffusion by local administration can avoid side
effects e.g. in cerebrospinal fluid