Pain, Predictive Coding, and the Placebo Effect

Question 1

Name two different models that have been proposed regarding perception by the brain. (2)

Answer 1

Passive reactionary process

Active anticipatory process

Question 2

Describe the ‘passive reactionary process’ model of brain perception. (3)

Answer 2

The brain passively absorbs sensory input,

processes this information in some way,

and then reacts by controlling motor and autonomic responses to these ‘passively experienced’ sensory stimuli.

Question 3

Describe the ‘active anticipatory process’ model of brain perception. (3)

Answer 3

Based on the intended goal of a person’s actions (movement),

the brain actively searches for and anticipates the information that it expects to be present in that particular environmental setting.

The end goal, and a person’s motivation to action that outcome, will influence how the brain perceives and reacts to constantly changing environmental and sensory stimuli.

Question 4

Fill the gaps relating to perception by the brain. (4)

The active anticipatory process model of perception incorporates the activity of neural systems that regulate …………………….., ………………………, and …………………. pathways.
These pathways are partly driven by the neurotransmitter ……………………….
The pathways are necessary to achieve a desired outcome.

Answer 4

attention

motivation

reward

dopamine

Question 5

Fill the gaps relating to perception by the brain. (3)

The goal of the brain is to ……………………. the information that will be given, …………………. unwanted stimuli, and ……………….. the action that it will take.

Answer 5

anticipate

filter out

optimise

Question 6

Fill the gaps relating to perception by the brain. (4)

The methods that the brain uses to process sensory information may have evolved to ………………. identify and focus on events and stimuli in the outside world that are …………………….. or …………………….. and to ……………… to them accordingly.

Answer 6

quickly

surprising

unpredictable

adapt

Question 7

Describe what is meant by a generative model. (3)

Answer 7

The brain generates models of the world

and continually uses data input from sensory organs

to update, refine, and optimise these generative models.

Question 8

Give another name for a surprising or unpredictable stimulus, when thinking of perception as a process of probabilistic inference and Bayesian information processing. (1)

Answer 8

Statistical irregularity

Question 9

Fill the gaps relating to perception by the brain. (8)

The brain has an idea of what the world should look like. It makes ………………………. based on the probabilities and patterns of events occurring in the world, and these models are constantly being ……………………. as the brain is exposed to more …………………..
This means that in unfamiliar situations, the brain can immediately focus in on the ………………………..
The constant updating of models means that the brain can more accurately ……………………… and not be ……………………………

When the brain encounters something that it did not expect and did not predict, a ………………………….. is sent to the brain. This signal then helps to update the ……………………….

Answer 9

generative models

updated

sensory input

unexpected aspect

predict the future

surprised (by the unexpected)

prediction error

generative model

Question 10

The brain is constantly trying to predict future sensory input. What is the signal called which is sent to the brain when we encounter something that was not predicted? (1)

Answer 10

Prediction error

Question 11

What is meant by ‘probabilistic inference’? (3)

Answer 11

The process of calculating the probability of a certain event happening

depending on prior and current evidence.

The evidence is constantly being updated based on new sensory stimuli and experiences.

Question 12

Why does perception by the brain use probabilistic inference to predict the future? (2)

Answer 12

To optimise future motor commands

necessary to achieve a desired outcome.

Question 13

Fill the gaps relating to probabilistic inference and perception by the brain. (6)

Perception is a process of probabilistic inference. ………………….. in the brain need to compute and ……………………. the expected statistical …………………….. (otherwise known as ……………………. patterns) of the outside world.
Thus, the brain applies a probabilistic model to generate …………………….. about future events.
The brain may then generate motor commands based on ………………………………… to occur.

Answer 13

Neural networks

predict

regularities

recurring

predictions

the most (statistically) likely events

Question 14

Is perception a true reflection of reality, or a mixture of reality and what we determine to be the most ‘statistically plausible’ event given our prior experiences in similar situations? (1)

Answer 14

Don’t know - this is the question that scientists are trying to answer.

Question 15

When looking at a graph representing Bayesian probability and information processing, what are the curves called? (1)

Answer 15

Probability density functions

Question 16

When looking at a graph representing Bayesian probability and information processing, what does the area under the curve always equal? (1)

Answer 16

1

Question 17

When looking at a graph representing Bayesian probability and information processing, what is on the Y axis? (1)

Answer 17

Probability

Question 18

When looking at a graph representing Bayesian probability and information processing, what are the three elements represented by the curves? (3)

Answer 18

Prior belief

Posterior belief

Likelihood

Question 19

What is meant by ‘prior belief’? (1)

Answer 19

How we expect the world to behave in a given situation (the brain’s generative model).

Question 20

What is meant by ‘likelihood’ in Bayesian information processing? (1)

Answer 20

The sensory stimuli being received, which will determine the likelihood of an event happening the way we think it will.

Question 21

What is meant by ‘posterior belief’? (1)

Answer 21

The updated belief, based on the prior belief and the sensory stimuli (evidence; likelihood). The event that is perceived.

Question 22

In Bayesian information processing, what is the difference between the likelihood and the prior belief called? (1)

Answer 22

Prediction error

Question 23

Describe what is meant by ‘precision’ in Bayesian information processing, and how this is shown on the graph. (2)

How does the precision affect the posterior belief? (1)

Answer 23

How accurate the prior or sensory information is.

More precise = taller curve and less precise = flatter and more spread out curve

The posterior belief will be weighted towards either the prior or sensory stimuli depending on which is more precise.

Question 24

Describe the precision of the prior expectation and the weighting of the posterior belief in a completely novel situation (in Bayesian information processing). (2)

Answer 24

Imprecise prior

Posterior weighted towards sensory input

Question 25

Describe what is meant by the following sentence:

‘Our brains use probability (Bayesian inference) to predict the future.’

(2)

Answer 25

The brain integrates prior beliefs with incoming sensory information

to predict the future and decide how best to optimise our movements and act.

Question 26

Fill the gaps relating to information processing by the brain. (7)

The probabilistic model that the brain uses is thought to adhere to ……………………. theorem.

The Bayesian brain can be conceptualised as a ………………….. machine that constantly makes ……………………… about the world and then updates them based on information that it receives from the …………………….

The theorem permits the brain to compute an ………………… probability that something is true, based on the ………………….. probability of something being true with the addition of ………………………………

Answer 26

Bayes’

probability

predictions

senses

updated

old

new information

Question 27

In an example of Bayesian information processing in the brain, a person touches a normal-looking fence, but it is actually electric.

What was the prior belief? (1)

What was the prediction error? (1)

What is the likely posterior belief? (1)

Answer 27

This fence will not cause pain

The action potentials produced in nociceptive neurones that were not predicted

Some fences are electric

Question 28

Describe the advantage for the brain of it sending down predictions and not having to process every bit of sensory information. (2)

Answer 28

Processing all information would require too much energy

so by processing only the information that it did not predict, the brain is more energy efficient and can save energy for the future.

Question 29

Fill the gaps relating to Bayesian information processing. (2)

Bayesian learning allows us to minimise the ……………………….. that reach the brain.
Any of these signals that do reach the brain will help to update …………………………

Answer 29

prediction errors

the prior belief system

Question 30

Describe the posterior belief in terms of probability of the hypothesis and the evidence. (1)

Answer 30

P (H/E)

(Probability that the hypothesis (prior) is true given the evidence).

Question 31

When observing a string or sequence of evidence regarding a hypothesis, describe how the posterior and prior change while observing the evidence. (2)

Answer 31

For every new piece of evidence, the old posterior becomes the new prior.

Therefore, the prior (our model of the world) changes with each step.

Question 32

Describe how Bayesian computation in the brain is linked to learning. (3)

Answer 32

Bayesian computation facilitates learning

as the brain ensures our priors are as accurate as possible

by using new evidence to update our predictions.

Question 33

Fill the gaps relating to Bayesian computation in the brain. (6)

Our memory may actually be a ………………… of the brain trying to ……………………..
Our accounts of past experiences may exist in our memory as a byproduct of using them to …………………………….

The brain is always trying to ……………………………….. and be one step ahead. If we encounter something we have never seen before, we have to update our ……………………………. for next time. This is a form of …………………………..

Answer 33

byproduct

predict the future

update our beliefs about the world

predict the future

predictions

learning

Question 34

Fill the gaps relating to Bayesian information processing in the brain. (5)

The brain is thought to be capable of computing …………………………. and making precise predictions with the help of ………………….. that it receives.

Through the coordinated firing of ……………….., the brain represents sensory information in the form of ……………………………

This relates to ………………………., where a group of neurones is activated and produces a neural code. The brain then has to predict the exact sensory input that has caused the particular firing pattern that it receives.

Answer 34

Bayesian probabilities

neural input

neural networks

probability distributions

population coding

Question 35

In the context of Bayesian information processing and population coding, what do neuronal tuning curves represent? (1)

Answer 35

The response of that neurone to different stimuli.

Question 36

Describe what is meant by the ‘free energy principle’ in the context of information processing. (5)

Answer 36

The free energy principle is a theoretical framework

that considers the brain to be a prediction machine

that uses information from previous experiences (memory)

to predict future events (intelligence)

in order to reduce surprise or uncertainty about the outside world.

Question 37

Fill the gaps relating to information processing in the brain. (4)

The brain continuously updates its prior beliefs (also known as ………………………………..) about the outside world based on the ………………… it receives from the ………………………
This is a form of …………………………..

Answer 37

generative models

neural signals

sensory organs

learning

Question 38

Fill the gaps relating to information processing by the brain. (2)

Learning and memory have evolved to more precisely ………………………., which from an evolutionary perspective, is beneficial and necessary for the organism’s ……………………………..

Answer 38

predict the future

continued survival

Question 39

Fill the gaps relating to the free energy principle. (3)

The free energy principle focusses on the brain’s ability to minimise …………………… and optimise its ……………….. by constantly updating its ……………………… about the future.

Answer 39

prediction error

actions

predictions

Question 40

The so-called ‘free energy principle’ posits that perception and action selection are governed by one overarching objective, which is…

(1)

Answer 40

To avoid surprises and minimise prediction errors

Question 41

Fill the gaps relating to the Bayesian brain. (2)

The Bayesian brain attempts to maintain homeostasis at a ‘set point’ of ………………………….. that remains free of ………………………….

Answer 41

neural network activity

prediction errors

Question 42

Briefly describe the two ways that the brain has of avoiding prediction errors under the free energy principle. (2)

Answer 42

Prediction fulfilled by choosing appropriate action.

Brain uses surprise as a teaching signal to adjust prior beliefs.

Question 43

Describe how the brain may minimise prediction error by choosing appropriate actions. (2)

Answer 43

• Moving the sensory organs (eyes, limbs, body) to parts of the environment where the sensory inputs better match the predictions
• Eg. keeping eyes on road while driving to avoid surprises

Question 44

Describe how the brain may minimise prediction error by using surprise as a teaching tool to adjust prior beliefs. (3)

Answer 44

Learning or updating generative model

so that the current prediction error is explained away

and more accurate future predictions become possible.

Question 45

Describe what is meant by ‘predictive coding’. (3)

Answer 45

Instead of the brain computing all of the neural information that is present in the sensory data it receives from sensory organs

it may be preferable to only represent the prediction error

which is the difference between what the brain predicts will happen and what actually happens.

Question 46

Define ‘prediction error’ and give a formula for it. (2)

Answer 46

The difference (or maybe ratio) between the sensory input and the predicted signal (i.e. the prior belief).

Prediction error = input - prediction

Question 47

Fill the gaps relating to predictive coding. (3)

One reason the brain may use predictive coding schemes is that, if the prediction is correct, very little ……………….. is wasted and costly spikes (i.e. …………………………….) are kept to a minimum, thus improving the ……………………… of the brain.

Answer 47

energy

energy intensive action potentials

computational efficiency

Question 48

By what cellular mechanism does the brain send out predictions? (1)

Answer 48

Action potentials

Question 49

Describe how predictions from the brain interact with pain pathways. (4)

Answer 49

• Predictions from higher centres activate endogenous pain modulatory systems
• Which release 5HT and NA onto the spinal cord interneurones
• The interneurones can then release GABA and enkephalins
• To inhibit activity of second order neurones and prevent a large number of nociceptive action potentials going to the brain

Question 50

Give a name for the nociceptive signals in the pain pathway that travel up to the brain because they have not been predicted and inhibited. (1)

Answer 50

Prediction errors

Question 51

What happens in the pain processing pathway if the brain did not make a prediction about pain? (2)

Answer 51

• No descending control
• Lots of action potentials (prediction errors) reach the brain regarding pain

Question 52

Describe a hypothesis relating to spontaneous brain activity and predictive coding. (1)

Answer 52

Spontaneous activity measured in the brain may actually be the brain making predictions and sending the predictions down to the spinal cord.

Question 53

What is the role of ascending feed-forward neural pathways in the context of predictive coding? (1)

Answer 53

Carry stimulus-related information from the outside world.

Question 54

Fill the gaps relating to predictive coding. (9)

Long-range feedback connections from ………………….. and local laterally-projecting interneurones populations provide natural ……………………………. for processing external sensory input.

The brain is thought to control ……………………… (predictions) that cancel out the expected ……………………. sensory input, and the difference between these neural signals, represented as changes in the …………………………. of primary projection neurones, is called the ……………………..

The errors (EPSPs) sum together at the …………….. to generate ……………….. that encode (or amplify) only the ……………………… signals for the brain to process using Bayesian methods.

Answer 54

higher cognitive centres

neuroanatomical check points

inhibitory signals

excitatory

membrane potential

prediction error

soma

action potentials

surprising

Question 55

Fill the gaps relating to predictive coding in the spinal cord. (7)

Primary afferent fibres bring in ……………………… to depolarise second order neurones.
Descending pathways release ……………….. and ……………… onto interneurones.
Interneurones release …………………. and …………………… onto second order neurones.
These signals will partly cancel each other out, so only the ……………………. is transmitted to the brain.

The neurones that modify the dorsal horn response (e.g. second order neurones, interneurones) are together called the ………………………….

Answer 55

glutamate

serotonin

noradrenaline

GABA

enkephalins

prediction error

neuronal ensemble

Question 56

Fill the gaps relating to generative models. (6)

Predictions are made on the basis of an …………………….. of the world.
The brain essentially uses ……………….. to predict the underlying causes of that input.
The better this internal model fits the world, the better the ………………… that can be made, and the lower the ……………………..
Minimising prediction error, therefore, drives a neural circuit to improve its …………………….. of the world.
In other words, minimisation of prediction errors drives …………………….

Answer 56

internal model

sensory input

prediction

prediction error

representation

learning

Question 57

What is meant by an ‘overfitted’ generative model? (1)

Answer 57

A model that is too specific based on individual experiences, and may not apply to other situations.

Question 58

What is the benefit of having a generalisable generative model rather than an overfitted generative model? (2)

Answer 58

More applicable to lots of different situations.

Can extrapolate to unknown situations.

Question 59

What is the accuracy in Bayesian models? (1)

Answer 59

Difference between prior and posterior beliefs.

Question 60

Give two drawbacks of the predictive coding hypothesis of brain information processing. (2)

Answer 60

• Does not explain how predictions (prior expectations) are computed in the brain
• Does not explain how prediction errors should ultimately be used by the brain to update its prior knowledge

Question 61

Give two drawbacks of the Bayesian inference hypothesis of brain information processing. (2)

Answer 61

• Does not specify the underlying neurophysiological mechanisms that regulate probabilistic programming in the brain
• Does not specify how similar sensory situations might be represented and differentiated in higher cognitive centres at the level of neural network activity

Question 62

Fill the gaps relating to predictive coding and Bayesian inference. (5)

Predictive coding describes the differences in neuronal activity between ………………… and …………………. populations of neurons in the …………………, whereas Bayesian inference describes the end-result of computing the ………………… of prediction errors generated by ……………………

Answer 62

higher

lower

sensory pathway

salience

sensory input

Question 63

What is the functional unit of the spinal cord ad brain that captures, processes, transforms, transmits, and stores information? (1)

Answer 63

Nobody really knows, however it could be neuronal ensembles

Question 64

How are neuronal ensembles formed? (1)

Answer 64

Through Hebbian plasticity mechanisms (LTP and LTD)

Question 65

Describe how Hebbian plasticity leads to formation of neuronal ensembles. (2)

Answer 65

Synapses between co-active neurones are strengthened

by repeated exposure to the same stimulus.

Question 66

What receptor does morphine bind to? (1)

Answer 66

Mu opioid receptor

Question 67

Which G protein is coupled to the MOR? (1)

Answer 67

Gi

Question 68

Describe the downstream effects of activating the mu opioid receptor on the presynaptic membrane. (5)

Answer 68

Inhibition of adenylyl cyclase

Reduced ATP being converted to cAMP

Reduced PKA activation

Reduced calcium influx into cells

Reduced neurotransmitter release

Question 69

Describe the downstream effects of activating the mu opioid receptor on the postsynaptic membrane. (3)

Answer 69

Enhanced K currents

Hyperpolarisation of neurone

Reduced neuronal firing

Question 70

True or false? Explain your answer if necessary. (1)

Mu opioid receptors are restricted to the rostral ventral medulla, and are not found in other areas of the pain pathway.

Answer 70

False - they are found pre and postsynaptically in the dorsal horn, and also in higher brain centres such as the RVM and PAG

Question 71

Name two serotonin/noradrenaline reuptake inhibitors which could potentially used to alleviate pain. (2)

What are these drug typically used for? (1)

Answer 71

Duloxetine

Venlafaxine

These drugs are typically used as antidepressants.

Question 72

Fill the gaps relating to pain treatment. (8)

…………………. drugs, although very good, don’t work that well for all types of pain. In neuropathic pain, we can use other agents like ………………….. to prevent reuptake of ……………………. and ………………… at the level of the ………………………

Therefore, if we enhance the actions of these neurotransmitters, we can activate ………………… to release more …………………. and ……………………. to inhibit nociceptive signals from being carried to the brain.

Answer 72

Opioid

SNRIs

serotonin

noradrenaline

descending pathway

interneurones

GABA

endogenous opioids

Question 73

True or false? Explain your answer if necessary. (1)

There is compelling evidence that neural responses in sensory cortical areas, and thus perception, are influenced just as much by predictions and expectations about stimuli as they are by the actual stimuli themselves.

Answer 73

True

Question 74

What is a placebo? (2)

Answer 74

A drug, device, or other treatment that is physically and pharmacologically inert.

They do not have any direct therapeutic effects on the body.

Question 75

Briefly describe how the context of a situation may contribute to the placebo effect. (4)

Answer 75

All treatments are delivered in a context

which includes social and physical cues, verbal suggestions, and treatment history.

This context is actively interpreted by the brain and can elicit expectations, memories and emotions

which in turn can influence health-related outcomes in the brain and body.

Question 76

Give four types (and examples) of external context cues that can influence the placebo effect. (4)

Answer 76

Verbal suggestions (this will make you feel better)

Place cues (eg. doctor’s office or hospital)

Social cues (body language, voice tone, white coat)

Treatment cues (syringe, needle, tablet)

Question 77

Give five types of internal context cues that can influence the placebo effect. (5)

Answer 77

Expectations of the outcome

Emotions

Meaning schema

Explicit memories

Pre-cognitive associations

Question 78

What is the nocebo effect? (1)

Give an example. (1)

Answer 78

A patient has a negative expectation and then feels that negative result even if it is not ‘present’.

They may feel more pain or side effects of a drug if that is what they are expecting.

Question 79

Describe the possible scenarios when a person in a clinical trial is testing a new drug, in terms of the prior predictions that they can make. (3)

Answer 79

The person doesn’t know what is happening at all so they cannot make a prediction

The person knows they may or may not be getting a drug, so their prediction is inaccurate

The person knows exactly what they are taking – they can accurately predict the outcome

Question 80

Describe the posterior (outcome) of Bayesian information processing relating to the prior and evidence (observation) in an analgesic clinical trial scenario where the person doesn’t know what is happening at all. (3)

Answer 80

The person cannot make a prediction (the prior is very imprecise)

Therefore they experience a painful stimulus that closely matches the true/intended pain rating of the actual stimulus

so the posterior is completely determined by the observation/evidence.

Question 81

Describe the posterior (outcome) of Bayesian information processing relating to the prior and evidence (observation) in an analgesic clinical trial scenario where the person knows they may or may not be getting an analgesic drug. (3)

Answer 81

The prior expectation is imprecise (the person is not sure if they are getting a drug)

so they experience a painful stimulus that is similar to the true/intended pain rating of the actual stimulus

so the posterior is heavily weighted towards the observation/evidence.

Question 82

Describe the posterior (outcome) of Bayesian information processing relating to the prior and evidence (observation) in an analgesic clinical trial scenario where the person knows exactly what they are taking. (3)

Answer 82

The prior expectation is more precise due to the subject being told that they will receive an analgesic drug

So they experience a painful stimulus that closely matches their prior expectation of the pain

so the posterior shifts towards the prior.

Question 83

What is the general, societal consequence of the placebo effect in clinical trials? (1)

Answer 83

Makes it difficult to get some drugs approved, as clinical trails show confusing results.

Question 84

A study tested the analgesia efficacy of opioid infusions based on patients’ prior expectations (they tested the placebo effect). They gave opioids while applying repeated painful thermal stimuli.

Describe the analgesic efficacy in the following situations:

a) patient unaware of opioid infusion (no expectancy)

b) patient aware of opioid infusion (positive expectancy)

c) patient told that opioid infusion has stopped (negative expectation)

What is the name of each of these effects? (6)

Answer 84

a) analgesics show some efficacy (drug effect)

b) analgesics show significantly higher levels of efficacy (placebo effect)

c) analgesics show significantly reduced effect (nocebo effect)

Question 85

What is the ‘pain matrix’? (1)

Answer 85

The brain regions which are activated and contribute to the conscious perception of pain.

Question 86

Noxious stimuli elicit neural activation and connectivity patterns within and between numerous brain areas.

Name 7 brain areas which are consistently activated in response to a noxious stimulus. (7)

Answer 86

• Somatosensory cortex
• Insular cortex
• Prefrontal cortex
• Anterior cingulate cortex
• Thalamus
• Periaqueductal grey
• Cerebellum

Question 87

Noxious stimuli elicit neural activation and connectivity patterns within and between numerous brain areas.

Name 6 brain areas which are less consistently activated and show more context-dependent activation in response to a noxious stimulus. (6)

Answer 87

• Basal ganglia
• Parabrachial complex
• Posterior cingulate
• Amygdala
• Hypothalamus
• Supplementary motor area

Question 88

Which brain area may be involved in producing the nocebo response? (1)

Answer 88

Hippocampus

Question 89

Which brain regions may be involved in generating the ‘pain experience’? (12)

Answer 89

• Somatosensory cortex (S1)
• Thalamus
• Insula
• PAG
• RVM
• Amygdala
• Hypothalamus
• Nucleus accumbens
• Orbitofrontal cortex
• Prefrontal cortex (dlPFC, vlPFC, vmPFC)
• medial anterior cingulate cortex
• rostral anterior cingulate cortex

Question 90

Which brain regions may be involved in the cognitive modulation of pain via the descending pain modulatory system? (7)

Answer 90

• Prefrontal cortex (dlPFC, vlPFC)
• Rostral anterior cingulate cortex
• Thalamus
• Hypothalamus
• Amygdala
• PAG
• RVM

Question 91

Fill the gaps relating to pain. (9)

Earlier studies demonstrated a relatively consistent noxious stimuli–evoked response in some structures that correlated with the perceived ……………. of pain, leading to the hypothesis of a specific network for pain perception, known as the ……………………

More recent evidence has refuted this hypothesis by challenging the notion that pain can be uniquely associated with a specific pattern of activated brain regions.

Instead, pain perception seems to engage brain regions that coalesce into ………………… associated with ………………………, ………………………., ………………….., & …………………..

The brain areas activated can be different in different ………………… and ………………… Pain is very individual and subjective.

Answer 91

intensity

pain matrix

networks

multisensory integration

emotional processing

cognition

attention

people

contexts

Question 92

True or false? Explain your answer if necessary. (1)

The ‘pain matrix’ is not pain specific, but may actually code for the salience of sensory stimuli.

Answer 92

True

Question 93

Fill the gaps relating to the pain matrix. (6)

The ‘pain matrix’ is not pain-specific but should be considered a sensory modality that codes for the ……………….. of sensory stimuli, i.e., a neural network essential for bringing sensory signals to ……………………….

If we define salience as ……………………………, only stimuli which are behaviourally-relevant and substantially affect the observer’s beliefs or intentions (i.e. important) result in ……………………., i.e. are different from the predictions.

It may be possible for people to train themselves to not pay attention to pain, and reduce the ………………. of the information.

Abnormal assignment of salience to nociceptive input may contribute to the formation of …………………

Answer 93

salience

conscious awareness

the functional significance of a stimulus

(Bayesian) surprise

salience

chronic pain

Question 94

True or false? Explain your answer if necessary. (1)

Prediction errors are maximised and amplified at each synapse in the ascending pain pathway.

Answer 94

False - prediction errors are minimised via descending predictions

Question 95

Fill the gaps relating to predictive coding and pain perception. (5)

The predictive coding framework suggests that the classical descending pathways may modulate local ……………………… subpopulations to cancel out any ………………………. in feed-forward projection neurons, except those that are ‘surprising’ which are coded as ………………………….. and allowed to pass on to the next “……………………” in the pain pathway, until only the most ………………….. ‘prediction errors’ are allowed to reach the higher cognitive centres of perception in the brain.

Answer 95

interneurone

excitatory EPSPs

action potentials

gate

salient

Question 96

Name the ‘model’ that the brain uses to predict what will happen in certain situations. (1)

Answer 96

Generative models

Question 97

What is the missing word/s? (1)

The brain generates …………………………, which is thought to actually be predictions about the future.

Answer 97

spontaneous activity

Question 98

True or false? Explain your answer if necessary. (1)

Higher brain centres send predictions down through the sensory processing hierarchy to prevent too many action potentials (prediction errors) getting up to the brain.

Answer 98

True

Question 99

Fill the gaps relating to predictive coding and pain perception. (5)

The descending pathways release ……………………. and …………………… onto inhibitory interneurones (containing ……………………… and ………………………) to cancel out the activity in the ……………………………

Answer 99

noradrenaline

serotonin

GABA

enkephalin

dorsal horn

Question 100

Describe the hypothesis behind how placebo hypoalgesia works. (4)

Answer 100

Placebo hypoalgesia recruits an opioidergic system of descending pain control

the activation of which leads to inhibition of nociceptive processing at the level of the spinal cord

and thus reduces neural responses in pain-responsive brain regions, as well as the experience of pain.

This is mediated by the combination of top-down prior expectations (or predictions of pain relief) and bottom-up sensory signals.

Question 101

Fill the gaps relating to placebo hypoalgesia. (3)

…………………………… about a drug may enhance the analgesic effects of active drugs, or can make it seem like an inactive drug is working. This is due to predictions from the ……………….. (brain region) which sends descending signals via the ……………. (brain region).

Answer 101

Positive expectations

PFC

PAG

Question 102

Which molecules/neurotransmitters signal the top-down predictions of a generative model about pain? (1)

Answer 102

Opioids

Question 103

Fill the gaps relating to placebo hypoalgesia. (7)

In addition to a direct analgesic effect (exerted on synaptic terminals of nociceptive afferents in the dorsal horn, for example), opioids play an additional role by signalling the ………………………… of a ………………………., i.e., by representing the ‘precision’ of the top-down predictions (or the precision-weighted prediction errors) in the PAG-RVM-spinal cord system.

The brain is able to do this because the pain signals reach the …………………… and activate cortical regions such as the ………………………., attention centres in the brain such as the …………………….., and the ‘pain’ is then in the forefront of the mind, which activates the ………………………. This brain region then starts signalling to the ………………….. to release natural opioids to limit the prediction errors being sent to the brain.

Answer 103

top-down predictions

generative model

thalamus

somatosensory cortex

ACC

PFC

PAG

Question 104

Dysregulation of which key brain region may lead to a loss of placebo hypoalgesic effects? (1)

Name two situations/conditions in which dysregulation of this brain region may occur. (2)

Answer 104

Prefrontal cortex

• Alzheimer’s disease
• Following repetitive transcranial magnetic stimulation

Question 105

What is the missing word/words? (1)

The structural integrity of ………………………………. from the PFC to lower brain areas (eg. PAG) has been shown to be related to placebo hypoalgesia.

Answer 105

white matter pathways

Question 106

Fill the gaps relating to placebo hypoalgesia. (3)

Data suggest that if there is a dysregulation in the …………………………….. that send predictions downwards, this may lead to exacerbated ………………………… and thus the incoming sensory signals will be assigned a higher weighting when the brain perceives the magnitude of the external stimulus, i.e., a higher level of ………………….. may be perceived.

Answer 106

higher cortical neural networks

prediction errors

pain

Question 107

Describe how positive prior experiences with pharmacological treatments or specific doctors may affect the placebo response. (3)

Answer 107

• The person may generate predictions about the potential success of future therapies
• So they will have a stronger (more precise) prior belief that the drug will work
• And the posterior belief will be weighted towards the prior belief

Question 108

The posterior probability is the statistically optimal combination of the …………………… and …………………….. (2)

Answer 108

prior belief

incoming sensory data

Question 109

True or false? Explain your answer if necessary. (1)

The placebo effect is based on expectation and prior experience, because the predictive coding framework suggests that expectations (predictions) are the consequences of prior experience.

Answer 109

True

Question 110

What is placebo hypoalgesia conditioning? (3)

Answer 110

Pairing an analgesic treatment with a sensory cue (eg. skin patch)

will update the internal model

because an expectation of hypoalgesia is formed with the sensory cue.

Question 111

How does the placebo hypoalgesic effect change over time after conditioning? (1)

Why? (1)

Answer 111

Effects can be reduced after about 4-7 days

which may be due to a reduction in cue-related memory strength encoded by the hippocampus.

Question 112

A study investigated the effects of repeated placebo hypoalgesia conditioning trials on the placebo effect.

Describe and explain the findings of this study. (3)

Answer 112

Four conditioning trials lead to stronger placebo effects compared to a single conditioning trial.

This a type of reinforcement learning.

The group of participants receiving four trials form a more precise prior expectation (memory trace) and thus show a stronger placebo hypoalgesic effect.

Question 113

Fill the gaps relating to placebo hypoalgesia. (3)

Expectations can bias perception, but ………………………. can also update expectations.

The placebo hypoalgesic effect may be caused by an “enhanced” …………………… (i.e. increased gain in the neural signal) that effectively “cancels out” more of the ……………………………… than usual (i.e. allows less prediction errors to pass up the ascending pathways).

Answer 113

sensory evidence

top-down prediction

incoming sensory signal

Question 114

Describe the consequences of prior conditioning protocols in placebo hypoalgesia, where an expectation of placebo hypoalgesia was generated with a very low-intensity stimulus and subsequently, during the testing phase, a very high-intensity stimulus was used. (4)

i.e. the incoming sensory data is very different to the predictive model

Answer 114

• Volunteers might question the efficacy of the analgesic treatment
• They may generate a disbelief in the placebo treatment (update their priors)
• So the initial model of ‘this is an analgesic drug’ may be replaced by ‘pills do not work for this pain’
• Which would reduce the prediction error, but may lead to chronic pain if the patient has no faith in pharmacological treatments for their type of pain

Question 115

Describe how manipulating attention alters the perceived intensity and unpleasantness of pain. (2)

Answer 115

Decreased attention:

• decreased intensity
• no effect on unpleasantness

Question 116

Describe how altering mood alters the perceived intensity and unpleasantness of pain. (2)

Answer 116

Bad mood:

• no effect on intensity
• pain perceived as more unpleasant

Question 117

Name four brain regions which are activated in placebo hypoalgesia. (4)

Answer 117

• Anterior cingulate cortex
• Prefrontal cortex
• Periaqueductal grey
• Rostral ventral medulla

Question 118

State a piece of ‘evidence’ supporting the fact that volunteers in clinical trials for analgesia form a specific model for different contexts. (1)

Answer 118

It has been observed that although volunteers differ in their individual placebo effects for different contexts, they show stable responses when repeatedly tested in these contexts.

Question 119

How do opioid antagonists affect placebo hypoalgesia? (1)

Answer 119

Partially block placebo hypoalgesia

Question 120

Fill the gaps relating to placebo hypoalgesia. (3)

The common assumption is that placebo hypoalgesia is paralleled by a release of ………………………….. and that these are responsible for the perceived …………………………. by acting as endogenous ………………………….

Answer 120

endogenous opioids

pain reduction

analgesics

Question 121

Name seven brain areas involved in releasing opioids during placebo analgesia. (7)

Answer 121

• PFC (dl and vl)
• ACC (medial and rostral)
• orbitofrontal cortex
• Nucleus accumbens
• Insula
• Amygdala
• PAG

Question 122

Apart from opioids, name another neurotransmitter which may play a role in placebo analgesia. (1)

Name two brain areas which may release this neurotransmitter during placebo analgesia. (2)

Answer 122

Dopamine

• Nucleus accumbens
• Ventral putamen

Question 123

Name a neurotransmitter which MAY be involved in the nocebo effect. (1)

Answer 123

Cholecystokinin

Question 124

Fill the gaps relating to sex differences in pain responses. (3)

The majority of clinical, basic human, and rodent studies, report that females are ……………….. sensitive to pain.

The risk of developing chronic pain is …………………. in women.

This may be due to ……………………………….. in women, who also tend to be more susceptible to developing autoimmune diseases.

Answer 124

more

higher

heightened neuroimmune interactions

Question 125

What is the DPMS? (1)

Name six brain regions involved in the DPMS. (6)

Answer 125

Descending pain modulatory system

• dlPFC
• ACC
• Insula
• Hypothalamus
• Amygdala
• PAG

Question 126

Name the primary DPMS output structure. (1)

Answer 126

PAG

Question 127

Fill the gaps relating to a study by Failla et al (2024) on sex differences in pain responses. (3)

Failla et al. (2024) report that females had ……………….. thresholds for what they called ‘just noticeable pain’ (JNP), but ………………….. thresholds for “weak pain” (WP) and “moderate pain” (MP) compared to males.

Females also rated WP and MP percepts as …………………. unpleasant than males.

Answer 127

lower

similar

less

Question 128

How does DPMS response to moderate pain change with age in males and females? (2)

Answer 128

MALES:

• Increased DPMS response to moderate pain with increasing age

FEMALES:

• Decreased DPMS response to moderate pain with increasing age (in the right ACC and insula)

Question 129

Suggest two potential reasons for sex differences in pain responses. (2)

Answer 129

• Different neuroimmune interactions
• Different DPMS activity

Question 130

A systematic review looked at sex differences in the placebo and nocebo effect.

Which sex responded more strongly to placebo and nocebo treatment? (2)

Answer 130

MALES responded more strongly to placebo treatment.

FEMALES responded more strongly to nocebo treatment.

Question 131

A systematic review looked at sex differences in the placebo and nocebo effect.

They found that males responded with larger placebo effects induced by what kind of information/cue? (1)

Answer 131

Verbal

Question 132

A systematic review looked at sex differences in the placebo and nocebo effect.

They found that females responded with larger nocebo effects induced by what kind of information/cue? (1)

Answer 132

Conditioning procedures