1. Somatosensory and Pain
Saygin, AP

2. Somatosensation
Is complex… Touch, Pressure, Vibration Temperature, Pain Proprioception (sense of movement, position, force)

3. Sensory Axons
Faster vs. Slower

4. Pain pathways (rat model) Both ascending and descending
The spinoparabrachial pathway (blue line) originates from superficial dorsal horn of spinal cord and projects to affective areas of the brain. The spinothalamic pathway (red line) originates from the deep dorsal horn and projects to areas of the cortex concerned with sensory discrimination and affect.
Hip = Hippocampus
PAG = Periaqueductal gray
PB = Parabrachial area
RVM = Rostroventral medial medulla
VMH = Ventral medial nucleus of hypothalamus

5. Somatosensory cortex
Insula
Anterior cingulate cortex (ACC)
Sensory and affective (pain is unpleasant)

6. Neuropathy
(Peripheral) neuropathy: Damage to nerves due to injury or illness
Weakness, autonomic changes, and sensory changes
Twitches, loss of fine motor control
Loss of sensation, pain, pins and needles and other paresthesias
Impaired balance, posture
Mononeuropathy: Usually injury, compression.
Mononeuritis multiplex: loss of function of individual peripheral nerves. Diabetes, infections (e.g. lyme disease, HIV), amyloidosis, immune diseases like rheumatoid arthtritis and SLE
Polyneuropathy: Cells in different parts of the body are affected, without regardless of nerve through which they pass. Distal axonopathy, demyelinating diseases, diabetes.
Autonomic neuropathy: e.g., cardio, urinary, GI systems

7. Diabetic neuropathy
Neuropathy is the most common complication in diabetes
Can affect all peripheral nerves: pain, motor, sensory and autonomic
Nerves are supplied by small blood vessels
Diabetes leads to microvascular injuries to the vessels. Can start with vasoconstriction and lead to neuronal ischemia.
Usually longer nerves affected first – starts at the toes.

8. Pain
Of pain, you could wish only one thing: that it should stop. Nothing in the world was so bad as physical pain. In the face of pain, there are no heroes, no heroes, he thought over and over as he writhed on the floor, clutching uselessly at this disabled left arm. (George Orwell, 1984)

9. Pain and Brain Where is the pain? Is the pain “all in your head”?
Pain arises from neural processing at multiple levels…
Pain inhibition can also be high level
Endorphins
Hypnosis, placebo

10. Nociceptive pain
Pain has a cause. Something external is making you hurt and it will stop. That’s “good pain”. An unpleasant, subjective, sensory and emotional experience which is associated with actual or potential tissue damage…

11. Neuropathic pain
Neuropathic pain: BAD PAIN… Nerves can generate pain by firing abnormally and this pain sometimes doesn't go away.

12. Neuropathic pain
Neuropathic pain: BAD PAIN… Nerves can generate pain by firing abnormally and this pain sometimes doesn't go away. Phantom pain is a kind of neuropathic pain which has attracted a lot of attention - but many other millions of people are affected by neuropathic pain who don’t have phantom limbs. See Flor et al Nature Reviews Neuroscience 7, for review of phantom pain

13. Phantom Limbs Feels like limb is still there
Might move or be paralyzed
Pain is common
How do you treat a nonexistent limb’s pain?
Prior Treatment
Surgery, Further amputation
More modern: Treatments for neuropathic pain in general

14. Pain disorders when the limb is still present
Neuropathic pain
First talked about during the civil war by Mitchell - causalgia
Gunshot wound pain never ending in some soldiers

16. Pain disorders when the limb is still present
Causalgia is now called Complex Regional Pain Syndrome (also Reflex Sympathetic Dystrophy)
Focal pain in limb (usually hands or feet) - can spread.
Usually after trauma, injury, surgery but can happen with no cause “will just not heal and stop hurting”
Pain is usually sharp, burning. Can have sweating, bruising, swelling.
Reduced tolerance for pain (hyperalgesia). Touch sensation will usually turn to pain (allodynia). Sort of like when you have a sunburn.

17. Causes of neuropathic pain
Peripheral nerve injury
Nerve compression, trauma, amputation, diabetes,…
Dorsal root ganglia in the spinal cord
Compression, inflammation
Spinal cord, brainstem, thalamus, cortex
Infarction, tumors, trauma

19. How is neuropathic pain treated?
NSAIDs, Opioid painkillers
However, neuropathic pain usually only partially responds to opioid painkillers
Some success with anticonvulsant (epilepsy) and antidepressant medication. Guesses why?
Nerve blocks and ablations
Surgery usually doesn’t work. Amputation usually doesn’t work.
Capsaicin at periphery
THC
Severe cases - Morphine pumps. Spinal cord stimulators, cortical stimulators.

20. Why do some people develop chronic neuropathic pain?
Noone knows right now… Genetic factors, immune factors, neurotoxins are all probably factors
But here are some things we know about neuropathic pain:
The nervous system is very adaptive…
Not always a good thing

21. Changes in the nervous system due to long-term pain
Peripheral sensitization Spinal mechanisms, LTP Higher-up changes in CNS (Central sensitization or centralization)

22. Peripheral Sensitization
Prolonged pain stimulus changes the sensitivity of peripheral neurons - literally making them fire at lower thresholds.

23. Spinal changes Axonal sprouting in spinal cord
For example, normally C-fibers and A-delta fibers connect to different laminae - after peripheral nerve injury, axons will grow into each others’ layers.
Perhaps explains why normally non-painful mechanical stimulation or touch sensation becomes painful in patients (allodynia)
These people were initially thought to have “psychogenic pain” - but in animal models we now understand pain mechanisms better

24. Spinal neurons also increase sensitivity
The mechanism was not very clear until now. Pain neurotransmission in spinal cord is complex - many neurotransmitter types, temporal summation…

25. LTP in the spinal cord
Anyone remember Long term potentiation (LTP) from your memory classes?

26. LTP in the spinal cord
Anyone remember Long term potentiation (LTP) from your memory classes? High frequency stimulation of a synapse  An enduring facilitation of synaptic transmission Important for learning and memory

27. LTP in the spinal cord
Evidence of pain stimulus causing LTP in spinal dorsal root ganglia
One implication is also - in prolonged pain, this stimulus may sometimes act as input which can sensitize the spinal neurons and make them “learn”
Of course we don’t want neurons to learn pain but understanding mechanisms is important

28. Central Sensitization
“Centralization” Primary and secondary somatosensory, insular, anterior cingulate, and prefrontal cortices (S1, S2, IC, ACC, PFC) and thalamus. MEG study found shrinkage of the extension of the cortical hand representation for the CRPS affected side correlated with pain intensity (Maihofner et al 2003). Differences in affective pain-related areas such as the anterior cingulate (Hsieh et al., 1995) Research is being done on activating the pain inhibitory pathway (esp. periacqueductal gray) in pain conditions Cognitive/Affective component of chronic pain

29. Depression
Depression and Pain

30. Readings
Required: Optional: Apkarian et al. for more on brain and pain, and Sandkuhler on central sensitization and LTP