Higher pain processing

1. medial/ lateral pathways

   Annotations:

   • Kulkarni et al (2005) medial- affective-motivational lateral- senso-discriminative

Annotations:

•  How does the pain matrix function to  produce the sensation of pain?     ? pattern of activation within the pain matrix – flow and integration of information?   
• do specific areas of the pain matrix serve specialized sub functions & encode different aspects of the pain experience?   
• Def- a network of cortical areas through which pain is generated from nociception 
• Legrain et al 

1. Salience detection system

   Annotations:

   • New idea- based on the controversy

   Attachments:

   • Pain processing
   1. saliency for threat detection

      Annotations:

      •    While neural responses to nociceptive stimuli probably reflects detection of saliency, it doesn’t mean that these brain responses are not important for pain- potentially this system is useful for the detection of potential physical threats associated with pain, but not exclusively pain Therefore, the present interpretation of the salience detection system suggests that its activity underlies a crucial function for all sensory systems, including the nociceptive system, providing the ability to detect and to orient selectively attention to significant sensory events, in particular those that could represent a potential threat.   
      1. Pain is predominant?

         Annotations:

         • One could argue that, as compared to other sensory modalities, the nociceptive system could be more predominantly involved in the detection of salience
         1. high-threshold receptors
         2. Alodynia

            Annotations:

            • studies have shown that if a nociceptive stimulus is applied at a specific body location, it enhances the responses of wide dynamic range (WDR) neurons at the segmental level of the dorsal horn receiving inputs from that body location and concurrently inhibits the responses of WDR neurons originating from all other body locations. 
         3. not different mechanisms

            Annotations:

            • However, there is no reason to consider that the cortical processing of the inherently highly salient content of nociceptive input should involve different mechanisms or structures than those involved in the cortical processing of the salience content of non-nociceptive input.   
      2. Evidence
         1. Neuropsychological
            1. insular lesions

               Annotations:

               •    o   the patients were able to recognize nociceptive stimuli as painful, the stimuli did not elicit a feeling of unpleasantness, nor did they elicit withdrawal motor reactions or emotional facial expressions. >> patients also failed to react to viewing approaching objects such as threatening gestures against their body. 
            2. complex regional pain syndrome (CRPS)

               Annotations:

               • demonstrating neglect-like behaviors in the affected limbs, but they are not tied to the side of affected limb, but to the space where the affected limb normally resides >>   These observations show clearly that the deficits observed in CRPS patients are based on a spatial representation of the body that is independent of the somatotopic localization of the symptoms.   
   2. Salience
      1. What is it?

         Annotations:

         • the salience of a stimulus is determined by how much it contrasts, along one or more physical dimensions, from its surrounding 
         • Salience is also determined according to the past context and memories 
      2. Adaptive behaviour

         Annotations:

         • processing salient events in a sensory environment contributes to selecting new/different events which take priority  as they might have an adaptive role- e.g. to flight or flee from danger
      3. Detection

         Annotations:

         •    o   the detection of local contrasts along various physical dimensions o   the detection of transient variations in the flow of afferent energy o   the detection of a mismatch between the afferent sensory input and a memory template of recent past events   
         1. Why?
            1. Prioritising important stimuli
            2. improve the perception of important stimuli
            3. prompt action
      4. Salience stimuli

         Annotations:

         • factors contributing to salience of a stimuli
         1. Novelty

            Annotations:

            •  novel events are salient because they are completely new or because they deviate from the expectations built from recent past experiences.
         2. sharpness of stimuli onset

            Annotations:

            • suddenness of its appearance
         3. stimulus deviance

            Annotations:

            • not sure what this means
         4. stimulus intensity
   3. +
      1. Legrain et al labs
         1. novel stimulus

            Annotations:

            • stimulus novelty enhances the magnitude of nociceptive event-related magnetic fields( ERPs) and disrupts consecutively ongoing task performance  >>supports salience detection- salient sensory input is enhanced and receives more attention as compared to less salient sensory input          
      2. Previous experiments

         Annotations:

         • The differences in stimulus salience (i.e. ability to stand out relative to neighboring stimuli) could account for all the previous evidence (electrophysiology/ neuroimaging)   
         1. magnitude response
         2. innocuous stimuli
         3. Attention

            Annotations:

            •    o   Attention studies- the more background noise, the more difficult it is to detect the nociceptive stimuli>> reduced magnitude of ERPs >> the magnitude of the elicited brain responses does not depend only on the absolute intensity of the nociceptive stimulus, but also on the contrast between its intensity and the intensity of the surrounding input, and, hence, its salience   
   4. assists attentional systems in threat detection

      Annotations:

      • detection of salience could be used as a mechanism to assist attentional systems in localizing the stimuli that are the most susceptible to signal an important change, such as a threat, occurring in the proximal space surrounding the body
      1. Electrophysiology

         Annotations:

         •  o   Electrophysiology in primates frontal/ parietal lobes- found neurons that response to multimodal threats occurring in the space proximal to the body and that participate to defensive behaviours   
         1. Frontal/ parietal
            1. processing of sensory input

               Annotations:

               • Other functions-   ·         selectively biasing the cortical processing of incoming sensory inputs according to their salience and their relevance  
            2. coordination of perception and action

               Annotations:

               • Other functions
            3. Map sensory info

               Annotations:

               • specific parieto-frontal networks -  map sensory information according to specific representation frames for the purpose of particular actions (e.g., retinal space for saccades, peripersonal space for grasping, extrapersonal space for reaching) 
               • The frame that maps multimodal events in the space surrounding the body is conceptualized by the notion of peripersonal space, i.e., a representation of the body and environment within grasp
      2. hypothesis

         Annotations:

         • the salience detection system represents mechanisms by which attentional systems are informed about changes in the representations of the body. 
         1. Pain matrix- what is it really?

            Annotations:

            •    >> what has been previously labeled as the “pain matrix” would no longer constitute a sensory-specific cortical network, but, instead, it would constitute an action-specific cortical network representing the activity by which the individual is able to identify and responds adequately to an immediate threat.   
            1. Part of a threat detection system
2. Brain regions
   1. Somatosensory (S1, S2)
      1. S2
         1. Noxious stimuli

            Annotations:

            • using implanted intracerebral electrodes in epileptic patients stimulation of S2 elicits report of pain   
         2. Magnitude-intesity

            Annotations:

            • Magnitude of the response in the area correlates with the intensity of pain perception
            • using fMRI/ PET
      2. S1
   2. Anterior cingulate (ACC)
      1. Magnitude-intesity
   3. amygdala
   4. Prefrontal
   5. Insula
      3. innocuous stimuli

         Annotations:

         • EEG/ fMRI studies-  These brain areas responded to tactile, auditory and visual stimuli 
      4. lesions

         Annotations:

         •    o   the patients were able to recognize nociceptive stimuli as painful, the stimuli did not elicit a feeling of unpleasantness, nor did they elicit withdrawal motor reactions or emotional facial expressions. >> patients also failed to react to viewing approaching objects such as threatening gestures against their body. 
3. +

   Annotations:

   • evidence for the pain matrix
   1. noxious stimuli

      Annotations:

      •   Cortical structures constituting the pain matrix are activated by nociceptive stimuli   
   2. magnitude response- intensity of pain

      Annotations:

      •    §Magnitude of the response in the pain matrix correlates with the intensity of pain perception (self report)   
      1. PET/ fMRI

         Annotations:

         •   >> show that magnitude of the hemodynamic responses in SI, SII, the insula and the anterior cingulate cortex can reliably predict the amount of pain perceived Correlation between intensity of stimuli and amplitude of responses   
      2. EEG/ MEG

         Annotations:

         • magnetic fields (ERFs) elicited by nociceptive stimuli, and originating from operculo-insular, post-central and cingulate areas, i.e., from brain regions belonging to the “pain matrix, may correlate with the physical intensity of the stimuli, and, even more, with the perceived intensity of pain 
   3. Experimental manipulations

      Annotations:

      •   Experimental manipulations modulate different aspects of the pain experience modulate activity within the pain matrix (e.g. analgesia administration, placebo effects)   
      1. Attention

         Annotations:

         • distracting subjects’ attention away from the nociceptive stimulus may result concomitantly in a decrease of pain rating and a decrease of the magnitude of the elicited brain  responses 
      2. Drugs
   4. Stimulation

      Annotations:

      • Stimulation of discrete areas of the pain matrix can cause the sensation of pain   
4. -

   Annotations:

   • Evidence against the pain matrix
   1. NS neurons

      Annotations:

      •    NS neurons (neurons responding to high intensity stimuli) are sparsely distributed in the pain matrix   
   2. Is nociception a modality?

      Annotations:

      •    at a cortical level nociception may not be represented as a distinct sensory modality?   
   3. Innocuous stimuli

      Annotations:

      •    when NS specific neurons are identified they often respond to high intensity stimuli of other modalities e.g. auditory stimuli
      1. EEG/ fMRI

         Annotations:

         •    o   EEG and fMRI studies- nociceptive, tactile, auditory and visual stimuli can elicit spatially indistinguishable responses in the insula, the anterior cingulate cortex and the largest part of SII o   >> thus indicating that the bulk of the brain responses to nociceptive stimuli reflects multimodal neural activity (i.e., activity that can be triggered by any kind of stimulus independently of sensory modality)   
         •    o   the only fraction of the brain responses elicited by nociceptive stimuli that was not explained by multimodal neural activity, located in SI and a small portion of SII, could be explained by somatosensory-specific activity that was not nociceptive-specific (i.e., activity that can be triggered by both nociceptive and tactile somatosensory stimuli).   
      2. Novel information

         Annotations:

         • Pain related brain areas also responded to stimuli carrying novel information
   4. Magnitude-repsonse

      Annotations:

      • The magnitude of the responses in that network may be dissociated from the subjective intensity of pain as well as from the physical intensity of the nociceptive stimulus 
      1. Iannettie et al (2008)

         Annotations:

         •  o   delivered trains of three identical nociceptive laser pulses with a constant 1-second inter-stimulus interval, using four different stimulus intensities. o   Following the first stimulus of the train, the magnitude of the elicited ERPs was strongly related to the perceived intensity of pain, and both were related to the actual intensity of the nociceptive stimulus. o   In contrast, following the second and third stimuli, the relationship between the magnitude of ERPs and the magnitude of perceived pain intensity was markedly disrupted. >> stimulus repetition decreased significantly the magnitude of nociceptive ERPs, but did not affect the perception of pain intensity
      2. Clark et al (2008)

         Annotations:

         •    o   presented nociceptive laser stimuli cued by a visual signal preceding the nociceptive stimulus with a variable time delay. Duration of the delay could be predicted or not predicted by the participants. They observed that the perceived intensity of pain and the magnitude of the elicited ERPs were affected differently by the delay separating the visual cue and the nociceptive stimulus. Longer duration delays led to an increased intensity of perception. In contrast, the magnitude of ERPs did not depend on the duration of the delay, but on whether or not this delay was predictable, being larger when the delay was unpredictable.   
      3. Mouraux and Plaghki (2007)

         Annotations:

         •   o EEG-   delivered nociceptive stimuli either alone or shortly after an innocuous somatosensory stimulus. o   >> The intensity of perception induced by the nociceptive stimuli was not different between the two conditions. o   In contrast, the nociceptive stimuli presented after a tactile stimulus elicited ERPs of reduced magnitude relatively to the ERPs elicited by single nociceptive stimuli.   
      4. - neural activity and pain

         Annotations:

         •    >>  These different examples all show that the neural activity recorded in the so-called “pain matrix” cannot be considered as a direct correlate of the conscious perception of a somatosensory stimulus as painful.   
      5. Impaired attention
         1. Tiede et al. (2011)

            Annotations:

            • showed that sleep deprivation attenuates the magnitude of ERPs evoked by nociceptive stimuli but tends to amplify the perception of pain. In this study, sleep deprivation suppressed the modulator effect of attention on pain ratings, but did not suppress its effect on ERP amplitude
         2. Bastuji et al. (2008)

            Annotations:

            •    delivered short series of nociceptive stimuli to healthy sleeping subjects, using an intensity that was clearly perceived and qualified as painful when awake. >> 70% of the stimuli did not produce any arousal reaction, and only 11% of the stimuli triggered an electromyographic response. o   In contrast, nociceptive stimuli elicited reproducible ERPs, albeit of reduced magnitude, both during stage 2 and paradoxical sleep.   
5. Legrain et al (2011)

Attachments:

• Pain processing

1. Lateral?- Senso-discriminative

   Annotations:

   •    Where does it hurt? Stimulus localization How much does it hurt?   Intensity   Quality discrimination   Heat ? Pressure?   
2. Medial- Affective-motivational

   Annotations:

   •    Pain unpleasantness “I don’t like it”  Stimulus related attention Drive to stop the stimulus     
   •    Virtually all PET studies show activation of the ACC associated with pain unpleasantness Functionallyheterogeneous brain area that has been associated with integration of effect,cognition, social behaviour. Still debated whether there is a specific pain area in theACC  
3. Kulkarni et al (2005)

   Annotations:

   •    Methods- PET in human volunteers, using a CO2 laser as nociceptive stimuli (selectively activates A-delta, C-fibres without contamination by touch). Measure the cerebral responses to noxious and innocuous laser stimuli Results- ·         Attention to location increased responses in the contralateral (right) primary somatosensory and inferior parietal cortices >> This result implies that these components of the lateral pain system are concerned mainly with the localization of pain ·         attention to unpleasantness increased responses in bilateral perigenual cingulate and orbitofrontal cortices, contralateral (right) amygdala, ipsilateral (left) hypothalamus, posterior insula, M1 and frontal pole>> These areas comprise key components of the medial pain and neuroendocrine systems and the results suggest that they have a role in the affective response to pain   >>  Our results indicate the importance of attentional effects on the pattern of nociceptive processing in the brain. They also provide the first clear demonstration, within a single experiment, of a major division of function within the neural pain matrix.   

1. Trout
   1. Nociceptive fibres

      Annotations:

      •    A delta and c fibers in the trigeminal nerve were confirmed   
   2. electrophysiological responses to noxious stimuli

      Annotations:

      • mechanical pressure and thermal stimuli – nociceptors were identified and classified similar to the way that nociceptors are classified in mammals 
   3. Behavioural responses

      Annotations:

      •    motivation to feed after application of acetic acid to the lips of trout – using motivational state as a measure of the animal’s affective state or mood -   

1. Response to noxious stimuli

   Annotations:

   •    Hermit crabs will leave their shell when an electric shock is given to the belly inside the shell – when it is sufficiently severe.   
   •    Only crabs that were shocked evacuated their shell – indicating the aversive nature of the stimulus . Fewer crabs evacuated from a preferred species of shell indicating a motivational trade off –   
   •    Most crabs that were shocked were more likely to approach a new shell when offered - / approached it more quickly and made less investigative attempts   
2. Can experience pain

   Annotations:

   • most probably

Annotations:

• shows whether difference brain centres that are associated with pain are connected study projections

1. LIMITATIONS
   1. indirect pathways?
   2. function can't be inverstigated

Annotations:

•    identify cortical areas that receive information from the spinothalamic tract – functional properties that are known to be distinct for primary nociceptive afferents– e.g high threshold intensity encoding in the nociceptive range, sensitization following injury as a correlate of primary hyperalgesia.   

1. noxious stimuli

   Annotations:

   • Response of structures to noxious stimuli
2. direct or indirect connectivity?

   Annotations:

   •    1.functional criteria that are independent of whether connections are direct or indirect   

Annotations:

•    1.single cell electrophysiological recording from cortical structures & study of coding properties  

1. Voltage changes

   Annotations:

   • Measure voltage changes generated mainly by synchronized  post-synaptic activity occurring in cortical pyramidal cells Parallel arrangement of the pyramidal cells allows summation of current flow generated by EPSPs and IPSPs: voltage changes are measurable at the scalp surface   

1. EEG
   1. Good temporal resolution

      Annotations:

      • Good temporal resolution of cerebral activity related to a stimulus
   2. Originate?

      Annotations:

      •   Where do these electrical signals originate from? 
   3. Poor spatial resolution
   4. Direct

      Annotations:

      • direct measure of neural activity
2. fMRI
   1. Indirect
3. MEG

   Annotations:

   • Allows improved source localisation of electrical activity of the brain in response to noxious stimuli   
   1. Direct
4. PET
   1. Indirect