1) Pain: Definition and Neurobiological Basics of Pain
Article 1: Representation of Pain in the Brain (Chapter 7, McMahon)
Defining a Pain Network in the Brain
• Regions associated with pain include:
- S1, S2, anterior cingulate cortex (ACC), insular cortex (IC), prefrontal cortex
(PFC), thalamus, cerebellum
• Regions activated by pain receive either direct or indirect nociceptive
input:
- S1 and S2: receive noxious and innocuous somatosensory input from
somatosensory thalamus
- Cingulate cortex: input from medial thalamic nuclei and lateral thalamic
regions that contain nociceptive neurons
- IC: thalamocortical nociceptive input
- ACC: painful stimuli evoke potentials over the human anterior cingulate
gyrus
• Posterior cingulate cortex:
- Parts receiving spinothalamic–thalamocortical input are cingulate motor
areas with direct projections to the primary motor cortex
➔ Provide a direct route for controlling motor responses to painful stimuli
• Prefrontal cortical regions:
- Activated in a number of imaging studies of acute pain
• The most common subcortical pain-related activation takes place in the thalamus
and cerebellum
• Nuclei in the thalamus receives nociceptive input from the dorsal horn, and the
cerebellum has reciprocal spinal connectivity
- Striatum activated during pain
• PAG, nucleus accumbens and amygdala also observed to be active in pain
studies
- Nucleus accumbens/amygdala: activity is probably a reflection of
nociceptive transmission through spino-parabrachial-amygdala projections
- PAG: observed to be active in somatic and visceral pain (when brain stem
studied)
➔ Evidence that multiple ascending nociceptive pathways are engaged in
signalling the information integrated at the cortical level, in addition to
spinothalamic pathways
Brain Processing of the Multidimensionality of Pain
• Somatosensory cortices: important for perception of sensory features (location,
duration)
- Sensory-discriminative dimension of pain processing
• Limbic and paralimbic regions (ACC and IC): important for emotional and
motivational aspect
Iman Shadid 540667
, • Different studies show:
1) ACC → affective aspect of pain
- Study: demonstrated selective modulation of ACC pain-evoked activity
after hypnotic suggestion of changes in pain unpleasantness
➔ Also showed a significant correlation between ACC activity and
subjects’ ratings of pain unpleasantness
➔ Suggesting involvement of the ACC in the affective dimension of the
pain experience
2) IC → pain affect, pain perception: encodes subjective magnitude of pain
- Lesions: higher ratings of acute thermal pain, increased S1 activity in
absence of IC activity
➔ Increased transmission of nociceptive information to S1 and that
increased acute thermal pain sensitivity results
- Implicated in visceral sensory and motor integration, emotional
responses, and memory functions and is also consistently activated by
painful stimuli
- Most specific for pain perception:
➔ Posterior area encoding nociceptive stimulus properties
➔ Anterior region related to the subjective magnitude of pain
3) PFC → related to cognitive aspects of pain perception rather than pain
sensation/affect
- Highest activity when a stimulus just becomes painful, with lower
activation being associated with higher levels of pain
4) Cerebellum → modulation of visceral and somatic nociceptive responses
- Activity may be more important in the regulation of afferent nociceptive
activity than in the perception of pain
5) S1 and S2 → deficits in pain sensations when lesions involved
- Lesions: could not localise or describe the nature of a painful stimulus
➔ Poorly localised and ill-defined unpleasant feeling when presenting
with a noxious stimulus
Iman Shadid 540667
,How do we Distinguish Location and Quality of Pain?
• Differentiating types of pain:
- S1 cortex identifies locus of pain affecting the skin (cutaneous)
- IC also participates in localization
- Different types of pain → different primary loci of activation within the IC,
S1, motor cortex, and PFC
• Laterality of pain representation:
- Many nociceptive pathways are bilateral, but the spinothalamic pathway is
mainly contralateral
- Bilateral activity in S2 and IC
- Contralateral activity in S1 and ACC
• Distinct Brain Responses to Nociception and to Subjective Perceived Pain:
- Pain may also consist of a ventral, in this case intensity-coding, stream
terminating in the IC and a dorsal, spatial localization stream
• Temporal sequence of Cortical Activity during Pain Perception:
- Earliest pain-induced brain activity originates in the vicinity of S2
➔ Tactile stimuli activate this region only after processing in S1
➔ Adjacent dorsal IC is activated slightly but significantly later than the
operculum
- Neither cold nor painful cold produced detectable activation of S1
➔ The results suggest different processing of cold, painful cold, and touch
in the human brain
- First pain (S1) signals threat and provides sensory information for
withdrawal, second pain (ACC) attracts longer lasting attention and
motivates behavioural responses
➔ Both pains activate S2
- There’s a well-organized temporal sequence of brain activity that transforms
noxious stimulus to pain perception
➔ Parts of the ACC and amygdala responded in a predictive pattern:
▪ The thalamus, basal ganglia, part of the IC, and the
supplementary motor region were activated next
▪ And the perception-related part of the IC was activated last,
together with the higher cognitive frontal and parietal regions
Iman Shadid 540667
, Brain’s Role in Modulating Pain
• Opiates in the brain:
- μ- opioid receptors are involved in regulation of the experience of pain,
including areas in descending inhibition (PAG, thalamus, amygdala) and
areas involved in complex and integrative aspects of pain such as
assessment of stimulus salience, as well as affective and integrative
aspects of the pain experience (ventral BG, IC, ACC, PFC)
• Dopamine and pain:
- Dopamine plays a role in pain modulation
➔ Also for pleasure, motivation, and motor control
- Increased dopaminergic activity attenuates nocifensive (behaviours
associated with protection against insult and injury) behaviour in animals
➔ Deactivation of dopaminergic structures leads to hyperalgesia (an
increased sensitivity to feeling pain and an extreme response to pain) in
animals
- Healthy individuals release dopamine in the striatum in response to pain
➔ One role of striatal dopamine is pain regulation
➔ Some chronic pain states may be associated with altered dopaminergic
neurotransmission
Mechanisms Underlying Psychological Modulation of Pain
• Attention and distraction:
- Performing a distracting task modulates pain-evoked activity in the thalamus
and other cortical regions like S1, ACC and IC
➔ Other regions, including PAG, parts of the ACC, and the orbitofrontal
cortex (within the PFC), are activated when subjects perform distracting
tasks, thus suggesting that these regions may be involved in the
modulatory circuitry related to attention
- Changes in pain related to attentional state reflect change in cortical
processing (S2-IC, ACC), and decrease in ascending afferent input from
spinal cord (because of activation of descending inhibitory controls)
➔ Cognitive modulation of pain by attention involves early sensory
processing in S2–IC and later processing in the ACC
• Effect of emotional state on pain-evoked activity:
- Negative emotional states alter pain perception
➔ e.g. produced by looking at emotional faces, listening to unpleasant
music, or smelling unpleasant odours
➔ Largest effect on pain unpleasantness rather than the sensory-
discriminative components of the sensation
- Emotional states alter pain-evoked cortical activation
➔ Most commonly in regions associated with the affective component of
pain processing, particularly the ACC and IC
Iman Shadid 540667
Article 1: Representation of Pain in the Brain (Chapter 7, McMahon)
Defining a Pain Network in the Brain
• Regions associated with pain include:
- S1, S2, anterior cingulate cortex (ACC), insular cortex (IC), prefrontal cortex
(PFC), thalamus, cerebellum
• Regions activated by pain receive either direct or indirect nociceptive
input:
- S1 and S2: receive noxious and innocuous somatosensory input from
somatosensory thalamus
- Cingulate cortex: input from medial thalamic nuclei and lateral thalamic
regions that contain nociceptive neurons
- IC: thalamocortical nociceptive input
- ACC: painful stimuli evoke potentials over the human anterior cingulate
gyrus
• Posterior cingulate cortex:
- Parts receiving spinothalamic–thalamocortical input are cingulate motor
areas with direct projections to the primary motor cortex
➔ Provide a direct route for controlling motor responses to painful stimuli
• Prefrontal cortical regions:
- Activated in a number of imaging studies of acute pain
• The most common subcortical pain-related activation takes place in the thalamus
and cerebellum
• Nuclei in the thalamus receives nociceptive input from the dorsal horn, and the
cerebellum has reciprocal spinal connectivity
- Striatum activated during pain
• PAG, nucleus accumbens and amygdala also observed to be active in pain
studies
- Nucleus accumbens/amygdala: activity is probably a reflection of
nociceptive transmission through spino-parabrachial-amygdala projections
- PAG: observed to be active in somatic and visceral pain (when brain stem
studied)
➔ Evidence that multiple ascending nociceptive pathways are engaged in
signalling the information integrated at the cortical level, in addition to
spinothalamic pathways
Brain Processing of the Multidimensionality of Pain
• Somatosensory cortices: important for perception of sensory features (location,
duration)
- Sensory-discriminative dimension of pain processing
• Limbic and paralimbic regions (ACC and IC): important for emotional and
motivational aspect
Iman Shadid 540667
, • Different studies show:
1) ACC → affective aspect of pain
- Study: demonstrated selective modulation of ACC pain-evoked activity
after hypnotic suggestion of changes in pain unpleasantness
➔ Also showed a significant correlation between ACC activity and
subjects’ ratings of pain unpleasantness
➔ Suggesting involvement of the ACC in the affective dimension of the
pain experience
2) IC → pain affect, pain perception: encodes subjective magnitude of pain
- Lesions: higher ratings of acute thermal pain, increased S1 activity in
absence of IC activity
➔ Increased transmission of nociceptive information to S1 and that
increased acute thermal pain sensitivity results
- Implicated in visceral sensory and motor integration, emotional
responses, and memory functions and is also consistently activated by
painful stimuli
- Most specific for pain perception:
➔ Posterior area encoding nociceptive stimulus properties
➔ Anterior region related to the subjective magnitude of pain
3) PFC → related to cognitive aspects of pain perception rather than pain
sensation/affect
- Highest activity when a stimulus just becomes painful, with lower
activation being associated with higher levels of pain
4) Cerebellum → modulation of visceral and somatic nociceptive responses
- Activity may be more important in the regulation of afferent nociceptive
activity than in the perception of pain
5) S1 and S2 → deficits in pain sensations when lesions involved
- Lesions: could not localise or describe the nature of a painful stimulus
➔ Poorly localised and ill-defined unpleasant feeling when presenting
with a noxious stimulus
Iman Shadid 540667
,How do we Distinguish Location and Quality of Pain?
• Differentiating types of pain:
- S1 cortex identifies locus of pain affecting the skin (cutaneous)
- IC also participates in localization
- Different types of pain → different primary loci of activation within the IC,
S1, motor cortex, and PFC
• Laterality of pain representation:
- Many nociceptive pathways are bilateral, but the spinothalamic pathway is
mainly contralateral
- Bilateral activity in S2 and IC
- Contralateral activity in S1 and ACC
• Distinct Brain Responses to Nociception and to Subjective Perceived Pain:
- Pain may also consist of a ventral, in this case intensity-coding, stream
terminating in the IC and a dorsal, spatial localization stream
• Temporal sequence of Cortical Activity during Pain Perception:
- Earliest pain-induced brain activity originates in the vicinity of S2
➔ Tactile stimuli activate this region only after processing in S1
➔ Adjacent dorsal IC is activated slightly but significantly later than the
operculum
- Neither cold nor painful cold produced detectable activation of S1
➔ The results suggest different processing of cold, painful cold, and touch
in the human brain
- First pain (S1) signals threat and provides sensory information for
withdrawal, second pain (ACC) attracts longer lasting attention and
motivates behavioural responses
➔ Both pains activate S2
- There’s a well-organized temporal sequence of brain activity that transforms
noxious stimulus to pain perception
➔ Parts of the ACC and amygdala responded in a predictive pattern:
▪ The thalamus, basal ganglia, part of the IC, and the
supplementary motor region were activated next
▪ And the perception-related part of the IC was activated last,
together with the higher cognitive frontal and parietal regions
Iman Shadid 540667
, Brain’s Role in Modulating Pain
• Opiates in the brain:
- μ- opioid receptors are involved in regulation of the experience of pain,
including areas in descending inhibition (PAG, thalamus, amygdala) and
areas involved in complex and integrative aspects of pain such as
assessment of stimulus salience, as well as affective and integrative
aspects of the pain experience (ventral BG, IC, ACC, PFC)
• Dopamine and pain:
- Dopamine plays a role in pain modulation
➔ Also for pleasure, motivation, and motor control
- Increased dopaminergic activity attenuates nocifensive (behaviours
associated with protection against insult and injury) behaviour in animals
➔ Deactivation of dopaminergic structures leads to hyperalgesia (an
increased sensitivity to feeling pain and an extreme response to pain) in
animals
- Healthy individuals release dopamine in the striatum in response to pain
➔ One role of striatal dopamine is pain regulation
➔ Some chronic pain states may be associated with altered dopaminergic
neurotransmission
Mechanisms Underlying Psychological Modulation of Pain
• Attention and distraction:
- Performing a distracting task modulates pain-evoked activity in the thalamus
and other cortical regions like S1, ACC and IC
➔ Other regions, including PAG, parts of the ACC, and the orbitofrontal
cortex (within the PFC), are activated when subjects perform distracting
tasks, thus suggesting that these regions may be involved in the
modulatory circuitry related to attention
- Changes in pain related to attentional state reflect change in cortical
processing (S2-IC, ACC), and decrease in ascending afferent input from
spinal cord (because of activation of descending inhibitory controls)
➔ Cognitive modulation of pain by attention involves early sensory
processing in S2–IC and later processing in the ACC
• Effect of emotional state on pain-evoked activity:
- Negative emotional states alter pain perception
➔ e.g. produced by looking at emotional faces, listening to unpleasant
music, or smelling unpleasant odours
➔ Largest effect on pain unpleasantness rather than the sensory-
discriminative components of the sensation
- Emotional states alter pain-evoked cortical activation
➔ Most commonly in regions associated with the affective component of
pain processing, particularly the ACC and IC
Iman Shadid 540667
