Pain, Predictive Coding, and the Placebo Effect Flashcards
Name two different models that have been proposed regarding perception by the brain. (2)
Passive reactionary process
Active anticipatory process
Describe the ‘passive reactionary process’ model of brain perception. (3)
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.
Describe the ‘active anticipatory process’ model of brain perception. (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.
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.
attention
motivation
reward
dopamine
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.
anticipate
filter out
optimise
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.
quickly
surprising
unpredictable
adapt
Describe what is meant by a generative model. (3)
The brain generates models of the world
and continually uses data input from sensory organs
to update, refine, and optimise these generative models.
Give another name for a surprising or unpredictable stimulus, when thinking of perception as a process of probabilistic inference and Bayesian information processing. (1)
Statistical irregularity
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 ……………………….
generative models
updated
sensory input
unexpected aspect
predict the future
surprised (by the unexpected)
prediction error
generative model
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)
Prediction error
What is meant by ‘probabilistic inference’? (3)
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.
Why does perception by the brain use probabilistic inference to predict the future? (2)
To optimise future motor commands
necessary to achieve a desired outcome.
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.
Neural networks
predict
regularities
recurring
predictions
the most (statistically) likely events
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)
Don’t know - this is the question that scientists are trying to answer.
When looking at a graph representing Bayesian probability and information processing, what are the curves called? (1)
Probability density functions
When looking at a graph representing Bayesian probability and information processing, what does the area under the curve always equal? (1)
1
When looking at a graph representing Bayesian probability and information processing, what is on the Y axis? (1)
Probability
When looking at a graph representing Bayesian probability and information processing, what are the three elements represented by the curves? (3)
Prior belief
Posterior belief
Likelihood
What is meant by ‘prior belief’? (1)
How we expect the world to behave in a given situation (the brain’s generative model).
What is meant by ‘likelihood’ in Bayesian information processing? (1)
The sensory stimuli being received, which will determine the likelihood of an event happening the way we think it will.
What is meant by ‘posterior belief’? (1)
The updated belief, based on the prior belief and the sensory stimuli (evidence; likelihood). The event that is perceived.
In Bayesian information processing, what is the difference between the likelihood and the prior belief called? (1)
Prediction error
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)
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.
Describe the precision of the prior expectation and the weighting of the posterior belief in a completely novel situation (in Bayesian information processing). (2)
Imprecise prior
Posterior weighted towards sensory input
Describe what is meant by the following sentence:
‘Our brains use probability (Bayesian inference) to predict the future.’
(2)
The brain integrates prior beliefs with incoming sensory information
to predict the future and decide how best to optimise our movements and act.
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 ………………………………
Bayes’
probability
predictions
senses
updated
old
new information
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)
This fence will not cause pain
The action potentials produced in nociceptive neurones that were not predicted
Some fences are electric
Describe the advantage for the brain of it sending down predictions and not having to process every bit of sensory information. (2)
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.
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 …………………………
prediction errors
the prior belief system
Describe the posterior belief in terms of probability of the hypothesis and the evidence. (1)
P (H/E)
(Probability that the hypothesis (prior) is true given the evidence).
When observing a string or sequence of evidence regarding a hypothesis, describe how the posterior and prior change while observing the evidence. (2)
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.
Describe how Bayesian computation in the brain is linked to learning. (3)
Bayesian computation facilitates learning
as the brain ensures our priors are as accurate as possible
by using new evidence to update our predictions.
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 …………………………..
byproduct
predict the future
update our beliefs about the world
predict the future
predictions
learning
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.
Bayesian probabilities
neural input
neural networks
probability distributions
population coding
In the context of Bayesian information processing and population coding, what do neuronal tuning curves represent? (1)
The response of that neurone to different stimuli.
Describe what is meant by the ‘free energy principle’ in the context of information processing. (5)
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.
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 …………………………..
generative models
neural signals
sensory organs
learning
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 ……………………………..
predict the future
continued survival
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.
prediction error
actions
predictions
The so-called ‘free energy principle’ posits that perception and action selection are governed by one overarching objective, which is…
(1)
To avoid surprises and minimise prediction errors
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 ………………………….
neural network activity
prediction errors
Briefly describe the two ways that the brain has of avoiding prediction errors under the free energy principle. (2)
Prediction fulfilled by choosing appropriate action.
Brain uses surprise as a teaching signal to adjust prior beliefs.
Describe how the brain may minimise prediction error by choosing appropriate actions. (2)
- 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
Describe how the brain may minimise prediction error by using surprise as a teaching tool to adjust prior beliefs. (3)
Learning or updating generative model
so that the current prediction error is explained away
and more accurate future predictions become possible.
Describe what is meant by ‘predictive coding’. (3)
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.
Define ‘prediction error’ and give a formula for it. (2)
The difference (or maybe ratio) between the sensory input and the predicted signal (i.e. the prior belief).
Prediction error = input - prediction
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.
energy
energy intensive action potentials
computational efficiency
By what cellular mechanism does the brain send out predictions? (1)
Action potentials
Describe how predictions from the brain interact with pain pathways. (4)
- 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
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)
Prediction errors
What happens in the pain processing pathway if the brain did not make a prediction about pain? (2)
- No descending control
- Lots of action potentials (prediction errors) reach the brain regarding pain
Describe a hypothesis relating to spontaneous brain activity and predictive coding. (1)
Spontaneous activity measured in the brain may actually be the brain making predictions and sending the predictions down to the spinal cord.
What is the role of ascending feed-forward neural pathways in the context of predictive coding? (1)
Carry stimulus-related information from the outside world.
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.
higher cognitive centres
neuroanatomical check points
inhibitory signals
excitatory
membrane potential
prediction error
soma
action potentials
surprising
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 ………………………….
glutamate
serotonin
noradrenaline
GABA
enkephalins
prediction error
neuronal ensemble
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 …………………….
internal model
sensory input
prediction
prediction error
representation
learning
What is meant by an ‘overfitted’ generative model? (1)
A model that is too specific based on individual experiences, and may not apply to other situations.
What is the benefit of having a generalisable generative model rather than an overfitted generative model? (2)
More applicable to lots of different situations.
Can extrapolate to unknown situations.
What is the accuracy in Bayesian models? (1)
Difference between prior and posterior beliefs.
Give two drawbacks of the predictive coding hypothesis of brain information processing. (2)
- 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
Give two drawbacks of the Bayesian inference hypothesis of brain information processing. (2)
- 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
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 ……………………
higher
lower
sensory pathway
salience
sensory input
What is the functional unit of the spinal cord ad brain that captures, processes, transforms, transmits, and stores information? (1)
Nobody really knows, however it could be neuronal ensembles
How are neuronal ensembles formed? (1)
Through Hebbian plasticity mechanisms (LTP and LTD)
Describe how Hebbian plasticity leads to formation of neuronal ensembles. (2)
Synapses between co-active neurones are strengthened
by repeated exposure to the same stimulus.
What receptor does morphine bind to? (1)
Mu opioid receptor
Which G protein is coupled to the MOR? (1)
Gi
Describe the downstream effects of activating the mu opioid receptor on the presynaptic membrane. (5)
Inhibition of adenylyl cyclase
Reduced ATP being converted to cAMP
Reduced PKA activation
Reduced calcium influx into cells
Reduced neurotransmitter release
Describe the downstream effects of activating the mu opioid receptor on the postsynaptic membrane. (3)
Enhanced K currents
Hyperpolarisation of neurone
Reduced neuronal firing
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.
False - they are found pre and postsynaptically in the dorsal horn, and also in higher brain centres such as the RVM and PAG
Name two serotonin/noradrenaline reuptake inhibitors which could potentially used to alleviate pain. (2)
What are these drug typically used for? (1)
Duloxetine
Venlafaxine
These drugs are typically used as antidepressants.
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.
Opioid
SNRIs
serotonin
noradrenaline
descending pathway
interneurones
GABA
endogenous opioids
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.
True
What is a placebo? (2)
A drug, device, or other treatment that is physically and pharmacologically inert.
They do not have any direct therapeutic effects on the body.
Briefly describe how the context of a situation may contribute to the placebo effect. (4)
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.
Give four types (and examples) of external context cues that can influence the placebo effect. (4)
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)
Give five types of internal context cues that can influence the placebo effect. (5)
Expectations of the outcome
Emotions
Meaning schema
Explicit memories
Pre-cognitive associations
What is the nocebo effect? (1)
Give an example. (1)
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.
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)
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
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)
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.
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)
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.
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)
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.
What is the general, societal consequence of the placebo effect in clinical trials? (1)
Makes it difficult to get some drugs approved, as clinical trails show confusing results.
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)
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)
What is the ‘pain matrix’? (1)
The brain regions which are activated and contribute to the conscious perception of pain.
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)
- Somatosensory cortex
- Insular cortex
- Prefrontal cortex
- Anterior cingulate cortex
- Thalamus
- Periaqueductal grey
- Cerebellum
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)
- Basal ganglia
- Parabrachial complex
- Posterior cingulate
- Amygdala
- Hypothalamus
- Supplementary motor area
Which brain area may be involved in producing the nocebo response? (1)
Hippocampus
Which brain regions may be involved in generating the ‘pain experience’? (12)
- 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
Which brain regions may be involved in the cognitive modulation of pain via the descending pain modulatory system? (7)
- Prefrontal cortex (dlPFC, vlPFC)
- Rostral anterior cingulate cortex
- Thalamus
- Hypothalamus
- Amygdala
- PAG
- RVM
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.
intensity
pain matrix
networks
multisensory integration
emotional processing
cognition
attention
people
contexts
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.
True
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 …………………
salience
conscious awareness
the functional significance of a stimulus
(Bayesian) surprise
salience
chronic pain
True or false? Explain your answer if necessary. (1)
Prediction errors are maximised and amplified at each synapse in the ascending pain pathway.
False - prediction errors are minimised via descending predictions
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.
interneurone
excitatory EPSPs
action potentials
gate
salient
Name the ‘model’ that the brain uses to predict what will happen in certain situations. (1)
Generative models
What is the missing word/s? (1)
The brain generates …………………………, which is thought to actually be predictions about the future.
spontaneous activity
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.
True
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 ……………………………
noradrenaline
serotonin
GABA
enkephalin
dorsal horn
Describe the hypothesis behind how placebo hypoalgesia works. (4)
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.
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).
Positive expectations
PFC
PAG
Which molecules/neurotransmitters signal the top-down predictions of a generative model about pain? (1)
Opioids
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.
top-down predictions
generative model
thalamus
somatosensory cortex
ACC
PFC
PAG
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)
Prefrontal cortex
- Alzheimer’s disease
- Following repetitive transcranial magnetic stimulation
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.
white matter pathways
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.
higher cortical neural networks
prediction errors
pain
Describe how positive prior experiences with pharmacological treatments or specific doctors may affect the placebo response. (3)
- 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
The posterior probability is the statistically optimal combination of the …………………… and …………………….. (2)
prior belief
incoming sensory data
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.
True
What is placebo hypoalgesia conditioning? (3)
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.
How does the placebo hypoalgesic effect change over time after conditioning? (1)
Why? (1)
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.
A study investigated the effects of repeated placebo hypoalgesia conditioning trials on the placebo effect.
Describe and explain the findings of this study. (3)
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.
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).
sensory evidence
top-down prediction
incoming sensory signal
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
- 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
Describe how manipulating attention alters the perceived intensity and unpleasantness of pain. (2)
Decreased attention:
- decreased intensity
- no effect on unpleasantness
Describe how altering mood alters the perceived intensity and unpleasantness of pain. (2)
Bad mood:
- no effect on intensity
- pain perceived as more unpleasant
Name four brain regions which are activated in placebo hypoalgesia. (4)
- Anterior cingulate cortex
- Prefrontal cortex
- Periaqueductal grey
- Rostral ventral medulla
State a piece of ‘evidence’ supporting the fact that volunteers in clinical trials for analgesia form a specific model for different contexts. (1)
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.
How do opioid antagonists affect placebo hypoalgesia? (1)
Partially block placebo hypoalgesia
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 ………………………….
endogenous opioids
pain reduction
analgesics
Name seven brain areas involved in releasing opioids during placebo analgesia. (7)
- PFC (dl and vl)
- ACC (medial and rostral)
- orbitofrontal cortex
- Nucleus accumbens
- Insula
- Amygdala
- PAG
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)
Dopamine
- Nucleus accumbens
- Ventral putamen
Name a neurotransmitter which MAY be involved in the nocebo effect. (1)
Cholecystokinin
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.
more
higher
heightened neuroimmune interactions
What is the DPMS? (1)
Name six brain regions involved in the DPMS. (6)
Descending pain modulatory system
- dlPFC
- ACC
- Insula
- Hypothalamus
- Amygdala
- PAG
Name the primary DPMS output structure. (1)
PAG
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.
lower
similar
less
How does DPMS response to moderate pain change with age in males and females? (2)
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)
Suggest two potential reasons for sex differences in pain responses. (2)
- Different neuroimmune interactions
- Different DPMS activity
A systematic review looked at sex differences in the placebo and nocebo effect.
Which sex responded more strongly to placebo and nocebo treatment? (2)
MALES responded more strongly to placebo treatment.
FEMALES responded more strongly to nocebo treatment.
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)
Verbal
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)
Conditioning procedures
