Brain cells and pain

Question 1

neuron classification: morphology

Answer 1

• The different types of neuron can be classified based on morphology
  
  • Classification in terms of number of neuronal processes (bits that stick out from the cell)
    
    • Bipolar neurons have one axon or dendrite going in and one axon going out.
    • Unipolar neurons have only one going in/out.
    • Multi-polar neurons neurons have lot of bits (e.g. dendrites) going in.
  • Classification in terms of length of the neuronal processes
  • For multipolar only
    
    • Golgi I neurons: long axons
      Golgi II neurons: shorter axons project locally

Question 2

what are neurons for?

Answer 2

• Three major purposes
  
  • Sensation – afferent neurons: to gather and send information from the senses such as touch, smell, sight etc.
  • Integration - interneurons: to process all information gathered, thus allowing us to take action.
  • Action – motor neurons: to send appropriate signals to effectors
    ○ Muscles (cardiac, smooth, and skeletal)
    Glands

Question 3

neuron classification: function

Answer 3

• Function classification based on whether conveying messages towards, within or away from the central nervous system
  
  • Towards: Sensory neurons (bipolar, unipolar)
    The sensory neurons we will look at are called nociceptors – they transmit information about tissue damage to the CNS, where the information is integrated by interneurons to create the sensation of pain.

Question 4

pain

Answer 4

• An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.
  
  • We have a clear definition of pain issued by the IASP. It indicates that pain has at least both sensory and emotional components – the emotional aspects is an inherent property. Some other sensations such as loud noises may also be unpleasant emotionally, but pain is different to a loud noise in that is it associated with the perception of actual or potential tissue damage.
    Note that, according to the definitions, pain can occur without evidence of actual tissue damage, for example many patients suffering chronic pain have no clear tissue damage, but the pain sensation still resembles that associated with tissue damage (e.g. tenderness, burning) that are inherently unpleasant, but are actually caused by the CNS rather than tissue damage.
    sensory and emotional aspects of pain are also associated with cognitive responses, whereby your attention is drawn to the pain, you form memories of the pain, and with that memory you can learn to expect pain in certain situations. It’s also possible to imagine pain and be hypnotised into feeling pain as more or less intense – something that is used therapeutically

Question 5

dimensions of pain

Answer 5

○ sensory: type of stimulus, intensity, location
○ affective: unpleasantness, emotions
cognitive: attention, memory, expectation, imagination

Question 6

sensory/integrative aspects: from receptors to spinal cord to the brain

Answer 6

ensory information is collected from nociceptors and streamed to CNS via peripheral nerves, containing many types of fibres. These consist of pseudo-unipolar neurons. I’ll describe these different types of fibres later.
- In the spinal cord, there are some neurons specialised for processing pain (“nociceptive-specific”) and others that process many types of sensation – these latter are called Wide Dynamic Range neurons and are essential to understanding pain perception. These are multi-polar interneurons, with a long axon, and are also sometimes referred to as projection neurons.
The first major relay station is brainstem nuclei, followed by the thalamus, and then via “third” multi-polar neurons to the cerebral cortex. In addition, there are descending multi-polar interneurons from the brain to the spinal cord that allow cognition to modulate spinal sensitivity to pain

Question 7

peripheral sensory neurons

Answer 7

• Contain receptors (either cellular, e.g. vision; or molecular, e.g. pain nociceptors)
  
  • Translate receptor codes to neural codes
  • Transmit information to CNS
  • LEFT: visual sensory neurons are attached to a receptor. Receptors are needed when information is complicated e.g. light captured in the eyes – light is complex to analyse so a neuron by itself would not be able to do that, it needs special receptors (rods and cones in the retina). The neuron translates this complicated information into a simpler neural code or “language” – yes and no, like binary in computers, but the temporal patterns can be complex bursts and we don’t know exactly how neurons code the information they are carrying.
  • RIGHT: nociceptors are not attached to a separate receptor. The neuron just needs to know if the tissue is damaged or not and the neuron can do this by itself. However, even though there is no additional cell that acts as a receptor, there are still chemical receptors – transmembrane proteins on the surface of the neuron that sense tissue damage and trigger action potentials.

Question 8

nociceptors are free nerve endings

Answer 8

Most frequently researched part of the body regarding pain is the skin. Most nociceptors are here. Pain has the function of informing about threat of integrity to body structure – the first thing when injured is damage to the skin as it surrounds all other tissues and organs. We lack nociceptors in brain (except meninges), bone, liver, kidney, lungs

Question 9

skin has different layers

Answer 9

○ Superficial – epidermis can be removed without bleeding. Contains no nociceptors.
Dermis contains nociceptors. Merkel and Meissner discs detect pressure. Ruffini bodies detect vibration.
○ Blue fibres are nociceptive. Free nerve endings in right in yellow and green. ½ mm depth into skin. Very primitive compared to these complex vibration and pressure sensors.
- Axon originates in DRG and cell extends to spinal cord, so it’s a very long neuron. Perhaps a metre.

Question 10

how is the presence of skin damage transmitted to the neuron

Answer 10

Coloured parts of figure on axon are molecular receptors – these are sensors. Polymodal – can detect many types of pain. Mechanical (pressure), chemical agents (e.g. capsaicin), heat/cold.
○ Molecular structures now understood – TRP.
○ Each is a protein composed of chain of amino acids.
○ Many thousands protrude the endings of the nerves.
○ Stimulus changes the receptor and causes a change in the conformation of the receptor.
○ This lets in Calcium ions to cause cell depolarisation and action potentials

Question 11

Capsaicin and TRP-V1

Answer 11

• E.g. capsaicin can cause this change in TRPv1 to cause Ca in-flow.
  
  • Once open, calcium ions to flow inwards. +ve charged. Causes action potential, but using Ca instead of Na. Ca is abundant outside and so flow inside due to concentration gradient. Causes depolarisation and action potential.
    Different types of TRP channels: most famous is TRPv1. Capsaicin activates this one. Also responds to mechanical pressure, heat and acid.

Question 12

labelled line theory of pain

Answer 12

• Core ideas:
  ○ Posits that specific neurons, or “lines,” are dedicated to transmitting specific types of sensory information (e.g. temperature, pressure, or a specific type of pain).
  ○ One-to-one mapping between the activated neuron and the perceived sensation
  
  • Caveats:
    ○ Many neurons are polymodal (that is, respond to more than one stimulus modality)
    ○ The theory ignores neuronal integration (“cross-talk”) in the spine/brain.
  • Noxious stimuli can be categorized as supra-threshold mechanical stimuli, like an impact, or chemical stimuli, often resulting from pathological processes such as inflammation. These stimuli act upon specialized ion channels to produce pain. The third type of stimulus that can produce pain is thermal energy, either high or low temperatures. These are the only three types of stimuli that can produce pain, so since nociceptors respond to mechanical, chemical, and thermal energies, we refer to them as polymodal receptors.
    Implications: one-to-one mapping between the activated neuron and the perceived sensation. If a “heat-pain” neuron is activated, you feel heat-related pain; if a “mechanical-pain” neuron is activated, you feel pressure-related pain. But this is only true if we ignore the more complex integrative processes in the CNS

Question 13

evidence supporting the labelled line theory: different peripheral nerve fibre types

Answer 13

• Different types of fibres (axons) associated with nociception and pain.
  
  • Fibres can be of 4 basic types:
  • A type (thicker) due to myelin sheath. Transmit faster.
  • A Beta: fast fibres needed to differentiate fine sensations with high fidelity.
  • A Delta: slower and transmit pain, but “first pain” (next slide).
    C type: no myelin sheath, thin and transmit slower “second pain” (next slide). Also transmit soft comforting sensations.

Question 14

evidence supporting the labelled line theory: first and second pain- C vs A delta

Answer 14

• A-delta fibers (First Pain)
  
  • “labelled line” for initial, sharp, and localized pain sensation.
  • myelinated, for faster signal transmission.
  • e.g. immediate sensation from chili peppers (sharp spiciness)
• C-fibers (Second Pain)
  
  • “labelled line” for dull, aching, more diffuse pain that follows the initial sharp pain.
  • unmyelinated, resulting in slower signal transmission.
    e.g. lingering, diffuse burn from spicy foods.

Question 15

nociceptive pathway in the spinal cord

Answer 15

• Spinothalamic tract transmits pain to the brain. This is after crossing the spinal cord from right to left. On the left is the dorsal column.
  
  • 10 zones (laminas) have been identified in the spinal cord grey matter, which contain different types of interneurons.
  • DRG contains the cell bodies of the peripheral neurons. Here we can see where the neurons, that contribute the axons providing free nerve endings, originate.
  • There are many types of interneuron in the spinal cord. Two of these types are SG neurons and WDR neurons. Each is associated with different theories about how pain is encoded in the spinal cord.

Question 16

spinal interneurons and theories of pain

Answer 16

• Labelled lines theory / specificity theory:
  ○ Specialised nociceptive neurons for pain vs. non-pain inputs (mirroring that in periphery)
  Issues: does not account for many pain phenomena
  
  • Population coding theory:
    ○ Co-activation of a number of unspecialised neurons (e.g. Wide-Dynamic Range, WDR) result in pain.
    Accounts for spatial summation of pain
  • Combinatorial coding theory:
    ○ Central sensitisation: A-beta activation (normally for touch) results in pain.
    ○ Gate-control: Different neuronal fibre types (e.g. A-beta touch and A-delta pain fibres) can interfere to reduce pain.
    Lateral inhibition: Cross-talk inhibition can refine spatial localisation of pain

Question 17

population coding theory of pain

Answer 17

• Population coding theory: If WDR neurons respond to both noxious AND non-noxious inputs, how can they mediate pain sensations specifically? It is thought to be the number of WDR neurons activated that are important, and the number activated can increase as their receptive fields increase
  
  • Co-activation of a number of unspecialised neurons (e.g. Wide-Dynamic Range, WDR) result in pain.
  • The recruitment of larger numbers of WDR neurons is associated with increasing intensities of pain.
  • Wide Dynamic Range (WDR) interneurons:
    ○ WDR neurons are so-called because they respond to BOTH noxious (nociceptive) and non-noxious (e.g. touch) inputs.
    ○ The relationship between WDR neurons and pain may be due to that fact that WDR neurons have large receptive fields
    WDR neurons also selectively expand their receptive fields in response to nociceptive inputs.

Question 18

spinal integration: population coding

Answer 18

• WDR neurons respond to both noxious and non-noxious stimuli – so how do they encode pain specifically? By population coding.
• WDR neurons have large receptive fields (provides a mechanism for spatial summation of pain)
• Increasingly intense noxious inputs increase the size of the receptive fields, which means more WDR neurons are activated by more intense stimuli (green to yellow to red in the figure)
• Hence, noxious stimulus intensity can be encoded by progressive recruitment of increasing numbers of WDR neurons
• WDR neurons receptive fields are large - frequently encompassing an entire limb or body quadrant. In other words, if you stimulate one place on a limb and then stimulate again at another place, there are some neurons that will respond to both stimulations, despite the different spatial locations. Due to these large receptive fields, they overlap and thus if you stimulate two sites at the same time, you get spatial summation of pain – it feels more intense than stimulating one site only.
  Accordingly, a weak noxious stimulus would recruit a relatively small portion of the population of spinal WDR neurons, but progressively intense noxious stimuli activate progressively larger portions of the WDR population. Thus, while single WDR neurons cannot provide sufficient information to distinguish a noxious from an innocuous stimulus, populations of these neurons acting in concert can provide sufficient information to support this distinction.

Question 19

evidence supporting population coding: WDR population coding

Answer 19

• Greater area of activation in spinal cord with increasing stimulus intensity:
  “Progressive increases in noxious stimulus intensity applied to the distal hindpaw produced progressive increases in spinal cord activation… Low stimulus intensities (45°C) activated the segment L4 … as noxious stimulus intensities increased (49°C), activation extended from L2 to L5… innocuous brushing produced minimal recruitment of activation, restricted to L4.”

Question 20

evidence supporting population coding: WDR receptive fields

Answer 20

• “Dynamic expansion of receptive fields of nociceptive neurons may represent a key factor for neuron recruitment. Relatively brief (20s) barrages of C-fiber input can evoke nearly 400% increases in receptive field sizes of nociceptive neurons in the rat dorsal horn, a portion of which project supraspinally.”
• The image shows the receptive field of a single dorsal horn neuron, which initially responds only to sensory stimulation of the toes, but increases its receptive field in response to higher intensity (painful) direct stimulation of C-fibres.
• The receptive fields are first mapped using non-painful stimuli – stimulating each part of the toes and foot and working out which neurons in the spine respond. Then there is a conditioning stimulus that is painful. Following the C-fibre conditioning stimulus the receptive fields of 28 of 48 dorsal horn neurons increased in size from 217±32mm2 before conditioning to 880± 157 mm2 at peak expansion, for a period of 42 ± 6 mins.

Question 21

spatial summation

Answer 21

• Large receptive fields of WDR neurons support spatial summation, since:
  
  • the same neuron can respond to stimuli at 2 different locations.
  • this means a greater likelihood of a WDR neuron reaching the threshold for generating action potentials
• Can occur even when stimuli are separated by ~40 cm in humans.
• But, maximal at 5- and 10-cm separation distances (smaller distances summate less – due to lateral inhibition)
• One of the phenomena explained by WDR neurons having large receptive fields is spatial summation of pain: pain feels worse when it covers a larger area of the skin.
• Spatial summation only occurs within a limb, not across limbs – in fact, pain in one limb can inhibit pain in another limb (“heterotopic conditioned pain modulation”).
  But there is no current evidence supporting the propriospinal interconnections idea specifically.

Question 22

combinatorial coding theory of spinal interneurons

Answer 22

• Central sensitisation: A-beta activation (normally for touch) results in pain due to spinal “cross-talk”
• Gate-control: Different neuronal fibre types (e.g. A-beta touch and A-delta pain fibres) can interfere to reduce pain.
• Lateral inhibition: Cross-talk inhibition can refine spatial localisation of pain.

Question 23

spinal integration: sensitisation to touch

Answer 23

• Injecting capsaicin into the skin causes increased sensitivity to pain.
• In the “primary zone” of application:
  
  • Peripheral sensitisation
  • Activates nerve endings (e.g. C-nociceptors)
  • Even light pressure and harmless heat causes pain.
• In the “secondary zone”
  
  • Central sensitisation
  • Light touch now causes pain, similar to certain neuropathic chronic pain conditions
    Affects the spinal cord neurons, making the central nervous system more sensitive.

Question 24

spinal integration

Answer 24

• Gate Control Theory of Pain: This is a theory regarding how the brain perceives pain from a particular point. According to this theory, non-painful inputs from a particular part of the body close the “gates” to a painful input, which invokes the feeling of a dulled pain from the affected part.
• Gate Control Theory of Pain: Role for Substantia Gelatinosa (SG) interneurons
  
  • Non-painful sensory inputs close the “gates” to a painful input, reducing the pain.
  • Substantia gelatinosa (SG) neurons of the dorsal horn are inhibitory.
  • C-fibres (responsible for pain) inhibit SG neurons
  • Ab-fibres (responsible for touch) excite SG neurons.
    Hence, the SG acts as a gate and determine whether pain is encoded within WDR neurons that eventually transmit information to the brain.

Question 25

spinal integration: lateral inhibition

Answer 25

• Spatial perception is “sharpened” due to an inhibitory integration process
• Also explains the nonlinearity of spatial summation of pain, i.e. stimuli that are close together summate less than those further apart (up to about 20cm)
• Another integrative phenomenon has an opposing effect, by causing inhibition in the spinal cord, called lateral inhibition. Doesn’t have implications for intensity coding of pain but is relevant to how we can discriminate pain location.
• If you consider than the population coding mechanisms on the previous slides result from the large receptive fields of WDR neurons, this means that similar neurons are being activated regardless of which part of the skin is producing the signals. So how it is then possible to discriminate where in the body the stimulus is come from?
• In fact, we know that people are able to report better spatial discrimination than appears possible by the distribution of sensory receptors in the skin – there appear to be fewer sensory receptors than would allow such good spatial discrimination ability. localization of single point noxious thermal stimuli is accomplished with errors as small as approximately 1cm, which exceeds that which would be predicted by the receptive field sizes (1.7cm diameter) of C polymodal nociceptive afferents, and accordingly, would likely require additional processing centrally
• This is due to lateral inhibition, in which the most strongly activated neuron in the spinal cord acts to inhibit those surrounding it, so that a spatially more precise signal is sent to the brain.

Question 26

pain pathways

Answer 26

• 1st neuron – the sensory nociceptor.
• 2nd neuron (interneuron): crosses the spinal cord and ascends all the way to the thalamus. Also very long. So left stimulation results in right thalamus activation. Note that this description is simplified – as shown in the previous slides, there are several spinal neurons activated and sending information to the brain.
• 3rd neuron (interneuron): from the thalamus to the rest of the cortex. Many of these, going to different cortical areas. Results in a distributed and degenerate pain system.
  This is an over-simplified description, since there are also many intermediate interneurons in the spinal cord between the 1st and 2nd neuron.

Question 27

pain neuromatrix theory

Answer 27

• Subjective pain is generated by a neural network (the “neuromatrix“)
• The neuromatrix integrates sensory, emotional, and cognitive inputs/processes
• Accounts for the multidimensional experience of pain
• Once in the brain the third neurons from the thalamus activate multiple areas in parallel. These cortical regions are also highly interconnected. They include somatosensory regions such as SI and SII, the posterior insula, mid-cingulate cortex, and amygdala. Thalamus acts as a relay station.
• Some brain areas are targeted by other tracts (i.e. they bypass the thalamus), for example leading to activation of the amygdala via the PBN. Hence, pain can be processed subconsciously by a faster route, to cause fight/flight, even before the pain is felt consciously. Hence there are 3 ways to respond to pain (a) spinal reflex (b) subconscious fear-driven response (c) conscious deliberation.
• The prefrontal cortex is activated a bit later, so the conscious part is delayed.
  All these brain regions are important for modulating descending controls via the brainstem – specifically the PAG, which can send descending projections to cause inhibition of the spinal cord.

Question 28

attention modulates spatial summation

Answer 28

“When participants were instructed to provide one overall rating of two noxious stimuli (typically used in studies of spatial summation), substantial spatial summation of pain was detected. However, when participants were instructed to divide their attention and provide separate ratings of each of the simultaneous stimuli, spatial summation of pain was abolished.”

Question 29

attention modulates spinal nociception

Answer 29

• Neuronal responses to painful stimulation in the dorsal horn were significantly reduced under high working memory load (“2-back” task) compared to low working memory load (“1-back” task).
• Reductions of spinal responses correlated with the “distraction from pain” effect: reduced pain perception by distraction.
• Likely to involve both opioidergic and nonopioidergic mechanisms – an opioid antagonist did not completely block the anti-nociceptive effect of distraction.
  Regions of the anterior cingulate cortex (ACC) have direct projections to laminae V–VII (including WDR neurons) - may provide attentional information to spinal neurons.

Question 30

descending nociceptive control is opioid mediated

Answer 30

• We know that the prefrontal-PAG circuit is controlled by endogenous opioids – the brain’s internal pain-killers.
• PAG is in the midbrain, while the RVM and DLPT are located slightly below in the medulla. These 3 regions create one complex system. PAG is like a computer, it calculates how much anti-nociception will be provided by considering all the information it is receiving from higher brain regions; RVM & DLPT are the executors – they acting send the signal down to the spinal cord.
• Right: Major inputs to PAG: amygdala (fear region), hypothalamus (emotional control), insula, ACC. PAG then sends signals to the spinal cord, but there are no direct fibres, so it does this through the RVM or DLPT. These have neurons that go to the spinal cord dorsal horn and stop the pain there.
• The way the rest of the brain “talks” to the PAG is via neuronal connections in which endogenous opioids (EO) are the mediators – therefore called the EO system – and is has pain-killing effects.
• How do we know it can stop pain? Electrical stimulation of any 3 of these brainstem regions (in animals) completely suppresses pain.
  How do we know opioids are involved? If morphine is injected (which binds to opioid receptors) into any of the 3 structures, pain is completed blocked.

Question 31

descending control as predictive coding

Answer 31

• Predictive coding is the dominant theory of CNS sensory encoding.
• CNS processing is bi-directional.
• Descending information codes for predictions about sensory inputs.
• Ascending information codes for prediction errors, i.e. the discrepancy between predictions and actual input.
• This allows for more efficient sensory encoding in the CNS.
• Actions are also related to predictions (preceding sensory input) and prediction errors (after sensory input)

Question 32

sensory adaptation as neural integration

Answer 32

• Sensory adaptation: changes in context
  
  • Exposure to bright sunlight: pupils will constrict and photoreceptors will become less sensitive, protecting you from becoming overwhelmed
  • Eating fruit after chocolate cake and being woefully underwhelmed
  • Jumping into a cold swimming pool may feel unpleasantly cold initially and then warm later
    Coming home from a long trip and thinking that your house smells different

Question 33

adaptation: peripheral vs central

Answer 33

• Peripheral adaptation reduces the amount of information that reaches the CNS.
  ○ the level of receptor activity changes. The receptor responds strongly at first but then gradually declines. E.g. change in retina, inner ear muscles.
  
  • Central adaptation at the subconscious level further changes the amount of detail that arrives at the cerebral cortex.
    along sensory pathways inside the CNS. Generally involves the inhibition of neurons (e.g. lateral inhibition) along a sensory pathway. E.g. spinal cord, brainstem, but also sensory cortex.

Question 34

central adaptation

Answer 34

• A gradual decrease in the neuronal response of the sensory system, over time, in response to a constant stimulus
  E.g. Somatosensory Evoked Potentials (SEPs) decrease during sensory adaptation.

Question 35

why does central adaptation occur?

Answer 35

• Sharpening/priming: enhancing discrimination. Exposure to a complex stimulus can increase the ability to discriminate its features over time, despite decreased neural responses, via memory of previous stimulus.
  
  • Maintaining perceptual constancy: invariant percepts despite varying contexts. E.g. “colour constancy” – brain uses context to decide on object colours.
  • Highlighting novelty:
    ○ detecting and responding to novel events is crucial for survival in a rapidly changing environment
    ○ frees up our attention and resources to attend to other stimuli in the environment around us
    Efficient coding: e.g., predictive coding, so that neural resources are not wasted on the expected properties of the stimulus and can instead be devoted to signalling only the unexpected

Question 36

predictive coding

Answer 36

• As a compression tool (for efficiency)
  Linear predictive coding (LPC) used since 1950s for compression of audio speech patterns for efficient transmission at low bit rate.
  
  • As a general mechanism of perception
    ○ Proposed by Rao and Ballard (1999) – efficiency is important for the brain to minimise energy expenditure (already 20% of body total).
    Accounts for some properties of extraclassical receptive fields in the dorsal visual stream, e.g. sharpening
• Predictive coding is the dominant theory of CNS sensory encoding.
• CNS processing is bi-directional.
• Descending information codes for predictions about sensory inputs.
• Ascending information codes for prediction errors, i.e. the discrepancy between predictions and actual input.
• This allows for more efficient sensory encoding in the CNS.
  Actions are also related to predictions (preceding sensory input) and prediction errors (after sensory input)

Question 37

predictive coding: integration over time

Answer 37

• This is more efficient because the brain doesn’t need to respond much by the time of the third S1 stimulus as it’s well predicted. This could be the basis of neuronal adaptation. But when S2 happens, unexpectedly, the brain needs to expend more energy to process that. Potentially, if the change from S1 to S2 is predictable, then brain can also learn that and minimise prediction error. I.e. PC can learn the temporal structure of the environment to minimise prediction error. The predictions can be probabilistic – e.g. after this series of stimuli, it might predict S1 with a 75% chance.
• Each PC level could be different layers within a cortical column, or there could be more macroscopic PC schemes that operate across cortical regions. The function of the PC scheme may differ in each case.
• Dominant model for how cognition influences perception
• Feedback pathways convey predictions, and feedforward pathways in the brain convey prediction errors (discrepancies between data and predictions).
  Predictions that are made by higher stages of neural processing are conveyed via feedback connections to lower stages, where they are subtracted from incoming signals.

Question 38

complex regional pain syndrome

Answer 38

• CRPS has variable signs and symptoms.
• Pathophysiology is complex and maybe variable between patients.
  A range of biomarkers are needed to support patient stratification and improve