Week 2-Brain cells

Question 1

How can different types of neurons be classified?

Answer 1

-By morphology (structure)

-Classified based off the number of neuronal processes (bits that stick out of the cell) AND the length of them (for multipolar only e.g.,Golgi I long axons and Golgi II have short axons)

Unipolar=only have one going in/out
Bipolar= have one axon or dendrite going in and one axon going out
Multipolar= have lots of bits e.g., dendrites going in

Question 2

Explain the 3 major purposes of the neuron

Answer 2

1.Sensation-afferent (enter) neurons: gather and sends information from the senses/environment and sends to different systems.

2.Integration-interneurons: Processes all information, gathered allowing us to take action + integrates sensory and cognitive information in the CNS as mediators

3.Action-motor neurons: Sends appropriate signals to effectors e.g., muscles and glands

Question 3

How do we classify neurons based off their function?

Answer 3

-Towards are sensory neurons (bipolar + unipolar)

-Within are interneurons (multipolar short OR long)

-Away are motor neurons (multipolar long)

Question 4

What are nociceptors?

Answer 4

Sensory neurons which transmit information about tissue damage to the CNS, where the information is then integrated by the interneurons to create the sensation of pain

Question 5

What is the International Association for the Study of Pain’s (2020) definition of pain?

Answer 5

An unpleasant sensory and emotional experience associated with, or resembling that associated with actual or potential tissue damage

Question 6

What are the 3 dimensions of pain?

Answer 6

1.Sensory: type of stimulus, intensity and location

2.Affective: unpleasantness and emotions

3.Cognitive: attention, memory, expectation and imagination

Question 7

Who proposed the earliest idea of pain?

Answer 7

Descartes (pain has a connection to the soul) HOWEVER believed the pineal gland (the soul) processed pain which we know now not to be true

Question 8

What does the sensation of pain cause and how does this occur?

Answer 8

An automatic withdrawal reflex (motor neurons)

1.Interneurons in the spinal cord are activated where the information from many nociceptors and other sensory neurons is initially integrated.

2.This integration involves multipolar neurons with short axons. These interneurons trigger motor neurons to stimulate the muscles, resulting in a withdrawal reflex.

(Since this is a reflex it doesn’t require the brain or any cognitive integration, only integration within the spinal cord.)

Question 9

How is sensory information transmitted to the brain via the spinal cord?

Answer 9

1.Sensory information collected from nociceptors and streamed to the CNS via peripheral nerves consisting of pseudo-unipolar neurons (fibres)

2.Pain specialised neurons in the spinal cord and wide-dynamic range neurons aka WDR (process many types of sensations) are essential to understanding pain perception

3.First major relay station is brainstem nuclei then the thalamus and then via “third” multipolar neurons to the cerebral cortex

4.There are descending multi-polar interneurons from the brain to the spinal cord that allows cognition to modulate spinal sensitivity to pain

Question 10

What are Wide-Dynamic Range neurons?

Answer 10

Multipolar interneurons with a long axon sometimes referred to as projection neurons

Question 11

What are periphery sensory neurons?

Answer 11

-Neurons containing receptors either cellular e.g., vision OR molecular e.g., pain nociceptors

-Translates receptor codes to neural codes

-Transmits information to the CNS

Question 12

What is the structure and function of visual sensory neurons?

Answer 12

S: Attached to a receptor which is needed when information is complicated (e.g., light captured in the eyes needs special receptors e.g., rods and cones as neurons can’t analyse that by themselves)

F: Neuron translates this complicated information into a simpler neural code or language (yes/no) BUT the temporal patterns can be complex bursts and we don’t know exactly how neurons code the info they’re carrying

Question 13

What is the structure of pain nociceptors?

Answer 13

-Not attached to a separate receptor (needs to know if the tissue is damaged or not which the neuron can do by itself)

-There are chemical receptors: transmembrane proteins on the surface of the neuron that senses tissue damage and triggers action potentials

Question 14

What do peripheral nociceptors do?

Answer 14

-Detect noxious (painful) stimuli and inflammation

-Passes this information to spinal interneurons

Question 15

What are the 4 main features of peripheral nociceptors?

Answer 15

1.Free nerve endings penetrate the dermis

2.Molecular receptors detect temperature, chemicals and mechanical pressure

3.Action potentials pass this information on to spinal interneurons

4.Different fibres/axon types

Question 16

Name 2 theories relevant to peripheral nociceptors

Answer 16

1.Labelled line theory

2.First and second pain

Question 17

True or false: We lack nociceptors in the brain (except meninges), bone, liver, kidney, and lungs.

Answer 17

True

Question 18

What are the different layers of the skin?

Answer 18

1.Superficial- epidermis can be removed without bleeding contains no nociceptors

2.Dermis- contains nociceptors. Merkl and Meissner discs detect pressure. Ruffini bodies detect vibration

Question 19

Where is the pain?

Answer 19

-Blue fibres are nociceptive

-Free nerve endings are 1/2mm depth into the skin

-Axon originate in DRG and cell extends to the spinal cord so it’s a very long neuron (potentially a metre)

Question 20

How is the presence of skin damage transmitted to the neuron?

Answer 20

Molecular receptors are sensors and are polymodal (can detect several types of pain e.g., mechanical (pressure), chemical agents (e.g., capsaicin) and heat/cold)

Question 21

What are these molecular receptors on the free nerve endings?

Answer 21

-Each is a protein composed of an amino acid chain

-Many thousands protrude the nerve endings

-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 22

How do Capsaicin and TRP-V1 cause a spicy sensation?

Answer 22

1.Capsaicin can cause this change in TRPv1 to cause Ca in-flow.

2.Once open, calcium ions flow inwards. +ve charged. Causes action potential, but using Ca instead of Na. Ca is abundant outside and so flows inside due to the concentration gradient. Causes depolarisation and action potential.

3.Different types of TRP channels: most famous is TRPv1. Capsaicin activates this one. Also responds to mechanical pressure, heat and acid.

4.Capsaicin will bind to receptor and allow pore to open causing membrane potential or will generate heat

Question 23

What are the core ideas of the Labelled line theory of pain?

Answer 23

-Specific neurons or “lines” are dedicated to transmitting specific types of sensory information e.g., temperature, pressure or a specific type of pain

-1-to-1 mapping between the activated neuron and the perceived sensation

Question 24

What are the 3 types of stimulus in the Labelled line theory of pain?

Answer 24

1.Innocuous mechanical forces

2.Noxious stimuli: can be categorised 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.

3.Moderate temperature changes

Question 25

What are the limitations of the Labelled line theory of pain?

Answer 25

-Many neurons are polymodal (respond to more than one pain stimulus modality e.g., nociceptors respond to mechanical, chemical, and thermal energies)

-Theory ignores neuronal integration (“cross-talk” aka crossing over) in the spine and brain ALSO 1-to-1 mapping is only fully true if we ignore the complex integrative processes in the CNS (just suggests one area is focused on one stimuli which isn’t the case)

Question 26

How do different peripheral nerve fibre types support the Labelled line theory of pain?

Answer 26

-A type (thicker) due to myelin sheath transmit faster

-A Beta: fast fibres need to differentiate fine sensations with high fidelity

-A Delta: slower and transmits pain but “first pain”

-C type: no myelin sheath, thin and transmit slower “second pain” ALSO transmits soft comforting sensations

Question 27

How does first and second pain support the Labelled line theory of pain?

Answer 27

-Laser stimulus is used to stimulate the skin as it’s easy to control and selectively activate receptors

First pain: A-delta fibers
-Sharp pricking, localised and brief sensation e.g., immediate sensation from chilli peppers
-This is due to faster transmission achieved by myelination

Second pain: C-fibers
-Dull, aching, burning prolonged pain sensation following initial sharp sensation e.g., lingering burn from spice
-This is due to a slower signal transmission as it is unmyelinated

Question 28

Name 4 functions on what spinal interneurons do

Answer 28

1.Integration of sensory information from the periphery

2.Modulation of pain sensitivity

3.Initiates automatic withdrawal reflexes

4.Passes (modulated) information to the brain

Question 29

What are the 2 main features of the spinal interneurons?

Answer 29

1.Can be excitatory or inhibitory neurons (can both increase and decrease pain)

2.WDR neurons respond to pain and non-painful (e.g., touch) sensations

Question 30

What are the 2 main relevant theories and phenomena for spinal interneurons?

Answer 30

1.Population coding theory: More pain results from more neurons being active (WDR), from expansion of receptive fields and from spatial summation

2.Combinatorial coding theory: Cross-talk between different neurons modulates pain (increases or decreases) + Central sensitisation, lateral inhibition and gate-control

Question 31

What’s the Labelled lines theory / specificity theory in relation to spinal interneurons?

Answer 31

-Specialised nociceptive receptors for pain vs non-pain inputs (mirroring that in periphery)

Issues: does not account for many pain phenomena

Question 32

What’s the population coding theory in relation to spinal interneurons?

Answer 32

-Co-activation of a number of unspecialised neurons (e.g., WDR) results in pain

-Accounts for spatial summation of pain

-This theory would posit that the overall experience of spiciness is a result of the combined activity of both A-delta and C-fibers, along with other neurons involved in pain perception. This allows for a more nuanced experience and can account for individual differences.

Question 33

What’s the Combinatorial coding theory in relation to spinal interneurons?

Answer 33

1.Central sensitisation: A-beta activation (normally for touch) results in pain

2.Gate-control: Different neuronal fibre types (e.g., A-beta touch and A-delta pain fibres) can interfere to reduce pain

3.Lateral inhibition: Cross-talk inhibition can refine spatial localisation of pain

Question 34

What’s the nociceptive pathway in the spinal cord?

Answer 34

-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.

-There are many types of interneurons 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.

-The WDR interneurons are quite long (can potentially reach the brain)

Question 35

Why do WDR have their name and what is their relationship to pain?

Answer 35

-Because they respond to noxious (nociceptive) and non-noxious (e.g., touch) inputs

-The relationship may be due to the fact that WDR neurons have large receptive fields

-WDR neurons also selectively expand their receptive fields in response to nociceptive inputs

Question 36

How do WDR neurons encode pain specifically? (Coghill, 2020)

Answer 36

BY POPULATION CODING:
-WDR neurons have large receptive fields (provide a mechanism for spatial summation of pain)

-Increasingly intense noxious inputs increase the size of the receptive fields (Also, receptive fields increase with more intense pain stimuli. E.g. Injections of capsaicin have been shown to dramatically expand reflex receptive fields: Biurrun Manresa, J.A. et al. (2014)) which means more WDR neurons are activated by more intense stimuli

-Hence noxious stimulus intensity can be encoded by progressive recruitment of increasing numbers of WDR neurons (that are activated)

Question 37

What are receptive fields?

Answer 37

An area of the limb that WDR neurons are receptive to

Question 38

What’s Coghill et al’s (1993) evidence for WDR population coding?

Answer 38

Greater area of activation in the 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.”

lower temperature=milder pain and vice versa

Question 39

What’s Cook et al’s (1987) evidence for receptive fields?

Answer 39

“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.”

-It will increase 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 40

How do large receptive fields of WDR neurons support spatial summation? Quevedo, A.S. and Coghill, R.C. (2009)

Answer 40

-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

-This can occur even when stimuli are separated by ~40cm in humans

-But maximal at ~5-10cm separation distances (smaller distances summate less due to lateral inhibition)

Question 41

What occurs in the primary zone and secondary zone of spinal integration?

Answer 41

Primary:
-Peripheral sensitisation
-Activate nerve endings e.g., C-nociceptors
-Even light pressure and harmless heat cause pain

Secondary:
-Central sensitisation
-Light touch now causes pain, similar to certain chronic neuropathic conditions
-Affects the spinal cord neurons, making the CNS more sensitive

Question 42

How can the idea of general touch e.g., brushing cause painful sensations? (Baron, 2000)

Answer 42

1.Becomes more sensitive to heat as a result of capsaicin and once sensitised, anything mildly painful e.g., a needle, starts to hurt more.

2.AB fibres change normal pathway and cross as a result

Question 43

What is the Role for Substantia Gelatinosa (SG) interneurons in gate-control theory?

Answer 43

-Non-painful sensory inputs close the “gates” to a painful input, reducing the pain

-SG neurons of the dorsal horn are inhibitory

-C-fibres (responsible for pain) inhibit the SG neurons

-Ab fibres (responsible for touch) excite SG neurons

-Hence the SG acts as a gate and determines whether pain is encoded within WDR neurons that eventually transmit information to the brain

-SG fibre are causing inhibition of both A and C fibre input

-More WDR activated=greater sensation of pain

Question 44

How is it that people can discriminate the location of a painful stimulus so accurately?

Answer 44

-Due to lateral inhibition

-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)

-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 45

Why does rubbing an injury relieve pain?

Answer 45

Gate-control

Question 46

What do brain interneurons do?

Answer 46

-Receive ascending input from the spine

-Integrate spinal input with existing sensory, affective and cognitive information in the brain - important for the multidimensional perception of pain

-Initiate deliberative motor responses and behaviours

-Modulate spinal nociception (including the extent of the spinal reflex) depending on cognitive and emotional context

Question 47

What are the main features of brain interneurons?

Answer 47

-Different anatomical regions have different functions (e.g., sensory, affective, cognitive)

-Both short (local processing) and long (e.g., descending modulation) axon types

-Multiple neurotransmitters (e.g., NMDA, GABA, opioid and serotonin)

Question 48

What are the main 4 relevant theories and phenomena for brain interneurons?

Answer 48

1.Pain neuromatrix theory

2.Descending modulation

3.Central sensitisation (similar to spinal mechanisms)

4.Predictive coding theory

Question 49

What are the pain pathways in the brains interneurons?

Answer 49

The spinothalamic tract (anterolateral system)

3rd neuron: thalamus (ventrolbasal complex) —> cerebral cortex
-Many of these, going to different cortical areas. Results in a distributed and degenerate pain system.

2nd neuron: grey-matter –> thalamus crossing in anterior part of spinal cord
-Also very long. So left stimulation results in right thalamus activation. This is simplified – there are several spinal neurons activated and sending information to the brain.

1st neuron: spinal ganglion –> grey matter of the spinal cord
-the sensory nociceptor

Question 50

What is the pain neuromatrix theory in the brains interneurons?

Answer 50

-Subjective pain is generated by a neural network (“the neuromatrix”)

-The neuromatrix integrates sensory, affective and cognitive inputs and processes

-It 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.

-The prefrontal cortex is activated a bit later.

-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 51

What did Quevedo, A.S. and Coghill, R.C. (2007) say in relation to attention-modulating spatial summation in the brains interneurons?

Answer 51

“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.”

-Simple attentional instruction can modulate pain

Question 52

How does attention modulate spinal nociception according to Sprenger et al. (2012)?

Answer 52

-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 53

What happens when descending nociceptive control is opioid-mediated? (Tracey& Mantyh
(Neuron, 2007))

Answer 53

-How much analgesia to apply? Periaqueductal gray matter (PAG)

-Execution: Rostroventromedial medulla (RVM), dorsolateral pontine tegmentum (DLPT)

Evidence:
-Electrical stimulation of PAG/RVM causes suppression of behavioural response to pain (Reynolds, 1969)

-Microinjections of morphine – μ-opioid receptor agonist has the same antinociceptive effect

-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 54

What is descending control as predictive coding?

Answer 54

-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)