1. From Ch. 22 “Principles of Neural Science”, 4th Ed. Kandel et al
The bodily senses
From Ch. 22
“Principles of Neural Science”, 4th Ed.
Kandel et al

2. Bodily senses Bodily senses = somatic sensation Sensory information
Large variety of receptors
Distributed throughout the body
Sensory information
Nerves transmit information from the receptors by frequency modulation of electrical signals (action potentials)

3. 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

4. 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

5. 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)

6. Somatic receptor types1 2 3 4

7. Somatic receptor types1 2 3 4

8. Somatic receptor types1 2 3 4

9. Nerve endings and fiber types
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

10. Location of nerve endings

11. 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

12. 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

13. Receptive field (RF) Size and structure of RF vary
Large, central zone with max sensitivity
Small, well- localized
Direction- specific stretch
Size and structure of RF vary

14. Receptive field (RF) Size and structure of RF vary
Large, central zone with max sensitivity
Small, well- localized
Direction- specific stretch
2-3 mm diameter
10 mm diameter
Relative sensitivity to pressure
Central zone with large continuous surface
Directly above receptor
10-25 receptors
Fine spatial differences
coarse spatial differences
Size and structure of RF vary

15. Receptor distribution
Most numerous receptor types
Fine spatial sensitivity
Best at finger tips
Uniform distribution
Finger tips are the most densely innervated region of the skin
300 mechanoreceptive nerve fibers per square centimeter

16. 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

17. 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: Hz
Pacinian: Hz
Detection depends on size of skin indentation and frequency
Detection threshold = tuning threshold = Lowest stimulus intensity that evokes one AP/ cycle
Intensity of vibration depends on the total number of nerve fibers activated
Sensory threshold
April 15, 2009

18. 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

19. Shape and size
Constant force
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
April 15, 2009

20. Spatial characteristics
Smaller Receptive field diameter Bigger
Higher Spatial resolution Lower
Texture, size, and shape are signalled by population of receptors
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

21. 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

22. Somatic receptor types1 2 3 4

23. Thermal receptors 4 thermal sensations: cold, cool, warm, hot
Constant temperature
Adaption
Tonic discharge/ steady rate
Body temperature
Continuously low rate
Cold fibers more active
Most sensitive to changes in temp than constant temp
Warm fibers:
Range, deg
Peak/ preferred, 45 deg
Cold fibers:
Range 5-40 deg
Peak/ preferred, 25 deg
Peak sensitivity
Adaption
Silenced
Encoding of temperature involves comparing the relative activity of different populations

24. Somatic receptor types1 2 3 4

25. Mechanical nociceptor
Nociceptors
Information about stimuli that can damage tissue are conveyed by nociceptors
Chemicals are released from traumatized tissue
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
Mechanical nociceptor

26. Somatic receptor types1 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

27. Afferent fibers Different size and conduction velocity of axons
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
Compound AP = sum of all activated nerves
Spike amplitude is proportional to fiber diameter
April 15, 2009

28. Innervations of dorsal roots
Dermatomes
Important for location of spinal injury

29. 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
Anterolateral system
Spinal lamina I, IV, V, VII, VII
Pain and temperature from limbs and trunks
Cross over to contralateral side in spinal cord
Contralateral
April 15, 2009

30. From Ch. 24 “Principles of Neural Science”, 4th Ed. Kandel et al
The perception of pain
From Ch. 24
“Principles of Neural Science”, 4th Ed.
Kandel et al

31. 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

32. Mechanical nociceptor
Nociceptors
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
Mechanical nociceptor
April 29, 2009

33. Somatic receptor types1 2 3 4
April 29, 2009

34. Afferent fibers Different size and conduction velocity of axons
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
Compound AP = sum of all activated nerves
Spike amplitude is proportional to fiber diameter
April 29, 2009

35. Nociceptive afferents
DRG
Spinal dorsal horn
Compound Action Potential
First pain: Sharp and pricking, faster A-delta fibers
Second pain, burning and dull, slower C-fibers
Blocking each nerve blocks the sensation
April 15, 2009

36. Spinal dorsal horn neurons
2 overall types of interneurons:
Nociceptive specific: responds exclusively to noxious stimuli
Wide dynamic range neurons: graded response to non-noxious and noxious stimuli
Lamina I and II
Direct input from mainly A-delta and C fibers.
NS and WDR interneurons
Lamina III and IV
Direct input from A-beta. Nonnoxious input. Topographically organised receptive field
Lamina V
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-alpha (nonnoxious) from joints and muscle
Lamina VII and VIII
Respond to noxious input. Polysynaptic. Bilateral response
April 29, 2009

37. Neurotransmitters Fast synaptic potentials Slow 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

38. Peripheral activation and sensitization
April 29, 2009

39. 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

40. Chronic pain Spontaneous ongoing pain Referred pain Hyperalgesia
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

41. 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

42. Hyperalgesia Peripheral sensitization: Central sensitization:
Increased nociceptor sensitivity
Increased spontaneous activity
Central sensitization:
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
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

43. 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
Niddam et al. 2008
PTS
CTR
P<0.001
IMES stimulus-response curves
April 29, 2009

44. 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

45. 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

46. 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
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
April 29, 2009

47. 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

48. Neuroimaging of acute pain
Cutaneous pain
Muscle pain
Visceral pain
Insula
Amygdala
ACC
PCC
Vermis
Thalamus
PPC
PFC
Chen et al.
Tooth pain
Lin et al. (preliminary)
Lu et al., 2004
Niddam et al., 2002

49. 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
Spinothalamic pathway
Spinal lamina I, V-VII
Pain and temperature from limbs and trunks
Cross over to contralateral side in spinal cord
Contralateral
April 29, 2009

50. Ascending pathways 5 major ascending pathways Thalamic nuclei
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

51. Ascending pathways
April 29, 2009

52. Pain pathways in the brain
Ascending pathways and cortical/ sub-cortical connectivity
Spino-bulbo-spinal loop (pain facilitation)
Apkarian et al. 2005
Millan 2002
Pain components (variable expression):
Sensory-discriminative, affective-motivational
Cognitive, Motor
April 29, 2009

53. Pain and the brain: pathways
Stress and the reward/ motivation system
Dopamine based mesolimbic system modulates mainly tonic pain
Hypothalamus
Amygdala
Hippocampus
Ventral tegmental area Dopoaminergic nucleus
Ventral striatum/ Nucleus accumbens
Ventral pallidum
MDm thalamus
Pain modulation
Anterior cingulate
April 29, 2009

54. Motivation and emotions
Borsook 2007, EJP

55. Pain modulation: large fibers
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 afferent (non-nociceptive)
Small-diameter afferent (nociceptive)
Inhibitory interneurons (spontaneously active)
Projection neurons
Large-diameter fibers
Excites interneuron and decrease pain transmission/ Closes the pain-gate
Small-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
Pin prick, pinch, ice cold produces burning pain
The gate control hypothesis
April 29, 2009

56. Pain modulation: opiods
Direct stimulation of PAG produces analgesia
Inhibits firing of nociceptive neurons in lamina I and V
Descending pathway recruited: PAG excites rostroventral medulla/ nucleus raphe magnus (5HT)
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
Other regions not involved in pain also contains opioid receptor
Minimize diffusion by local administration can avoid side effects e.g. in cerebrospinal fluid
April 29, 2009