Pain processing and pain perception in the human brain: a neural signals approach
Lead Research Organisation:
University College London
Department Name: Institute of Cognitive Neuroscience
Abstract
Pain is an almost universal experience. Its importance for health, well-being and disease processes is undeniable. One can experience more or less pain, and measuring pain intensity is important in diagnosis, assessment and therapy. However, this measurement is surprisingly difficult, because pain levels depend on complex factors such as expectation, attention, and even personality. Moreover, robust, valid measures of pain intensity are elusive. Current methods, such as numerical pain rating scales, rely strongly on patients' verbal understanding - e.g., the phrase "worst pain imaginable" is generally used to define the top of the scale. Perhaps for these reasons, ratings show notoriously poor correlation with the energy of a noxious stimulus, and also with activation of putative 'pain centres' or 'pain networks' in the brain.
This project develops a novel approach to understanding pain perception. Using a state-of-the-art feedback-controlled laser stimulator, we expose the skin on the back of the hand of healthy volunteers to brief, quantified pulses of radiant heat, causing a sharp 'pinprick' pain. This reflects signals in a specific neurophysiological pain pathway ("A-delta pathway"). Participants are stimulated randomly with either of two energies, both above the individual's threshold to activate the A-delta pathway. They judge whether they experienced 'higher' or 'lower' intensity. We use standard methods to calculate two distinct aspects of pain perception: the SENSITIVITY with which a person's judgements track the actual stimulation energy, and their BIAS in preferring to respond 'higher', or 'lower', irrespective of actual stimulation energy. For example, someone who simply fears strong pain might judge ALL pain stimuli as 'higher' intensity: they would then show strong bias and low sensitivity.
We also record the brain activity evoked by laser stimulation, using EEG electrodes non-invasively placed on the scalp. By dividing the distribution of EEG amplitudes in two at different cutoff points, we can simulate how effective the EEG signal at that particular moment would be in classifying the higher and lower intensity stimuli. We will thus identify the components of the brain's response to noxious stimulation that best approximate the sensitivity and bias components of pain perception. This provides a novel, well-controlled, physiologically-specific, and fully objective method to search for the neural basis of pain perception. It does not require any subjective definition or instruction regarding what counts as 'pain', and merely requires participants to judge whether a stimulus is more or less intense. By testing a large sample of participants, we address individual differences between people in pain perception. We may identify psychological profiles associated with high and low pain bias, and with high and low pain sensitivity.
Two further large experiments leverage these important methodological developments. Experiment 2 aims to show how our method can be used to quantify and understand the potency of a popular analgesic drug (remifentanil). Double-blind infusions of drug or placebo are compared to address whether the drug influences bias or sensitivity, and which EEG components underlie this change.
Experiment 3 uses these new measurement approaches to investigate the basis of the well-known placebo effect - perhaps the most striking finding in pain research. Participants learn that a specific visual stimulus, presented before laser stimulation, predicts whether the next stimulus will be more or less intense. Again, we assess whether this predictive cue changes sensitivity or bias. We will identify the EEG components that are responsible for how the cue influences these two aspects of pain perception.
Overall, the results provide a novel and objective approach to pain perception, useful for future clinical studies of pain and analgesia.
This project develops a novel approach to understanding pain perception. Using a state-of-the-art feedback-controlled laser stimulator, we expose the skin on the back of the hand of healthy volunteers to brief, quantified pulses of radiant heat, causing a sharp 'pinprick' pain. This reflects signals in a specific neurophysiological pain pathway ("A-delta pathway"). Participants are stimulated randomly with either of two energies, both above the individual's threshold to activate the A-delta pathway. They judge whether they experienced 'higher' or 'lower' intensity. We use standard methods to calculate two distinct aspects of pain perception: the SENSITIVITY with which a person's judgements track the actual stimulation energy, and their BIAS in preferring to respond 'higher', or 'lower', irrespective of actual stimulation energy. For example, someone who simply fears strong pain might judge ALL pain stimuli as 'higher' intensity: they would then show strong bias and low sensitivity.
We also record the brain activity evoked by laser stimulation, using EEG electrodes non-invasively placed on the scalp. By dividing the distribution of EEG amplitudes in two at different cutoff points, we can simulate how effective the EEG signal at that particular moment would be in classifying the higher and lower intensity stimuli. We will thus identify the components of the brain's response to noxious stimulation that best approximate the sensitivity and bias components of pain perception. This provides a novel, well-controlled, physiologically-specific, and fully objective method to search for the neural basis of pain perception. It does not require any subjective definition or instruction regarding what counts as 'pain', and merely requires participants to judge whether a stimulus is more or less intense. By testing a large sample of participants, we address individual differences between people in pain perception. We may identify psychological profiles associated with high and low pain bias, and with high and low pain sensitivity.
Two further large experiments leverage these important methodological developments. Experiment 2 aims to show how our method can be used to quantify and understand the potency of a popular analgesic drug (remifentanil). Double-blind infusions of drug or placebo are compared to address whether the drug influences bias or sensitivity, and which EEG components underlie this change.
Experiment 3 uses these new measurement approaches to investigate the basis of the well-known placebo effect - perhaps the most striking finding in pain research. Participants learn that a specific visual stimulus, presented before laser stimulation, predicts whether the next stimulus will be more or less intense. Again, we assess whether this predictive cue changes sensitivity or bias. We will identify the EEG components that are responsible for how the cue influences these two aspects of pain perception.
Overall, the results provide a novel and objective approach to pain perception, useful for future clinical studies of pain and analgesia.
Technical Summary
Evidence-based medicine requires rigorous methods to measure pain experience and its neural bases, yet these methods remain elusive. Noxious laser heat conveyed by the Adelta pathway provides a key experimental model of human pain.
We focus on perceived intensity of 'pinprick' laser pain, identified by reaction times as Adelta-mediated. Noxious stimuli are presented at two preselected levels within the Adelta range. Volunteers report each stimulus as 'higher' or 'lower' intensity. Signal detection measures of d' (sensitivity) and C (bias) provide key indices of pain processing WITHIN the Adelta pathway.
Different features of the EEG responses to nociceptive stimuli (e.g., N1, N2, P2 waves, gamma power) are extracted. Bisecting the amplitude distribution for each component is equivalent to a 'higher/lower' perceptual judgement, defining NEUROMETRIC d' and C. By varying cutoff values, we identify WHICH neural component best approximates perceptual sensitivity and bias. This produces a highly-controlled, pathway-specific model of pain intensity, able to distinguish bias from sensitivity at both perceptual and neural levels.
Experiments 2 and 3 put the method to work. Infusions of remifentanil, or saline are given under clinical supervision in Expt 2. We investigate whether analgesia involves changes in perceptual sensitivity or bias, and associated EEG neurometric changes. Experiment 3 extends the method to placebo and nocebo conditioning. Visual cues signal impending lower or higher intensity, while neutral cues have no predictive value. We assess whether placebo/nocebo cues change perceptual and neurometric sensitivity, relative to neutral cues, or rather change biases. Neural events after the cue but before the laser could also influence pain perception. We thus investigate the interesting hypotheses that reduced pain perception under placebo is based on DIFFERENT neural signals, and not simply reduced levels of 'normal' nociceptive signals.
We focus on perceived intensity of 'pinprick' laser pain, identified by reaction times as Adelta-mediated. Noxious stimuli are presented at two preselected levels within the Adelta range. Volunteers report each stimulus as 'higher' or 'lower' intensity. Signal detection measures of d' (sensitivity) and C (bias) provide key indices of pain processing WITHIN the Adelta pathway.
Different features of the EEG responses to nociceptive stimuli (e.g., N1, N2, P2 waves, gamma power) are extracted. Bisecting the amplitude distribution for each component is equivalent to a 'higher/lower' perceptual judgement, defining NEUROMETRIC d' and C. By varying cutoff values, we identify WHICH neural component best approximates perceptual sensitivity and bias. This produces a highly-controlled, pathway-specific model of pain intensity, able to distinguish bias from sensitivity at both perceptual and neural levels.
Experiments 2 and 3 put the method to work. Infusions of remifentanil, or saline are given under clinical supervision in Expt 2. We investigate whether analgesia involves changes in perceptual sensitivity or bias, and associated EEG neurometric changes. Experiment 3 extends the method to placebo and nocebo conditioning. Visual cues signal impending lower or higher intensity, while neutral cues have no predictive value. We assess whether placebo/nocebo cues change perceptual and neurometric sensitivity, relative to neutral cues, or rather change biases. Neural events after the cue but before the laser could also influence pain perception. We thus investigate the interesting hypotheses that reduced pain perception under placebo is based on DIFFERENT neural signals, and not simply reduced levels of 'normal' nociceptive signals.
Planned Impact
Impact and Exploitation:
Robust pain measurement protocols, and methods for establishing neurometric-perceptual equivalence may interest pharmaceutical and other life-science companies. Potential commercial exploitation will be discussed with UCL Business PLC (Dr Abigail Watts), and UCL's dedicated Translational Research Office (https://www.ucl.ac.uk/translational-research/). The suggest relevant industrial contacts, and provide appropriate dedicated funding streams for pump-priming of translational work with qualified partners.
Dissemination:
A long-term dissemination target of our work is chronic pain. Experimental pain provides a rigorous scientific model of pain perception and its underlying neural mechanisms, but our results will have increased societal and economic impact if they can be translated to the chronic pain state, which is a complex and costly concern in the NHS. After completion of experiment 1, we will make contact with experts in central chronic pain, with a view to developing an additional, future proposal for further project funding. One particular focus might be experimental pain testing on unaffected body parts of chronic pain patients, versus healthy controls, in order to identify changes in sensitivity and bias caused by chronic pain. A preliminary interest in collaboration has been expressed by Dr S Chong.
Wider audiences:
The dissemination of our research outcomes to general public will include a number of channels, such as giving talks in Café Scientifiques (events organised by The Royal Society), participating in educational activities (e.g. teaching in primary schools) and interviews in major UK and international media (e.g. BBC TV and radio, newspapers, etc). Both PIs have a track record in these avenues of disseminating results to the general public (e.g., TED talks, BBC TV and radio coverage; please see "Pathways to impact" for details). The dissemination of results to the general public is facilitated by Dr Harry Dayantis of the UCL media relations team.
Robust pain measurement protocols, and methods for establishing neurometric-perceptual equivalence may interest pharmaceutical and other life-science companies. Potential commercial exploitation will be discussed with UCL Business PLC (Dr Abigail Watts), and UCL's dedicated Translational Research Office (https://www.ucl.ac.uk/translational-research/). The suggest relevant industrial contacts, and provide appropriate dedicated funding streams for pump-priming of translational work with qualified partners.
Dissemination:
A long-term dissemination target of our work is chronic pain. Experimental pain provides a rigorous scientific model of pain perception and its underlying neural mechanisms, but our results will have increased societal and economic impact if they can be translated to the chronic pain state, which is a complex and costly concern in the NHS. After completion of experiment 1, we will make contact with experts in central chronic pain, with a view to developing an additional, future proposal for further project funding. One particular focus might be experimental pain testing on unaffected body parts of chronic pain patients, versus healthy controls, in order to identify changes in sensitivity and bias caused by chronic pain. A preliminary interest in collaboration has been expressed by Dr S Chong.
Wider audiences:
The dissemination of our research outcomes to general public will include a number of channels, such as giving talks in Café Scientifiques (events organised by The Royal Society), participating in educational activities (e.g. teaching in primary schools) and interviews in major UK and international media (e.g. BBC TV and radio, newspapers, etc). Both PIs have a track record in these avenues of disseminating results to the general public (e.g., TED talks, BBC TV and radio coverage; please see "Pathways to impact" for details). The dissemination of results to the general public is facilitated by Dr Harry Dayantis of the UCL media relations team.
Publications
Borhani K
(2017)
"Lacking warmth": Alexithymia trait is related to warm-specific thermal somatosensory processing.
in Biological psychology
Fardo F
(2018)
A mechanism for spatial perception on human skin.
in Cognition
Borhani K
(2017)
Choosing, Doing, and Controlling: Implicit Sense of Agency Over Somatosensory Events.
in Psychological science
Dupin L
(2019)
Dynamic Displacement Vector Interacts with Tactile Localization.
in Current biology : CB
Ferrè ER
(2018)
Ineffectiveness of tactile gating shows cortical basis of nociceptive signaling in the Thermal Grill Illusion.
in Scientific reports
Beck B
(2019)
Metacognition across sensory modalities: Vision, warmth, and nociceptive pain.
in Cognition
Beck B
(2019)
No temporal contrast enhancement of simple decreases in noxious heat.
in Journal of neurophysiology
Fardo F
(2018)
Organization of the Thermal Grill Illusion by Spinal Segments.
in Annals of neurology
Cataldo A
(2019)
Thermonociceptive interaction: interchannel pain modulation occurs before intrachannel convergence of warmth.
in Journal of neurophysiology
Mancini F
(2015)
Touch inhibits subcortical and cortical nociceptive responses.
in Pain
Description | Contribution to EU Meaningful and Ethical Communication project |
Geographic Reach | Europe |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | I put forward a position paper on the importance of subjectivity, autonomy and sentience in the concept of the individual agent that underpins functional democratic societies. |
URL | https://knowledge4policy.ec.europa.eu/projects-activities/meaningful-ethical-communications_en |
Description | Grindley Grant for Conference Attendance |
Amount | £473 (GBP) |
Organisation | Experimental Psychology Society (EPS) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2016 |
End | 11/2016 |
Description | JSPS Conference Fund |
Amount | ¥4,000,000 (JPY) |
Funding ID | Not known |
Organisation | Japan Society for the Promotion of Science (JSPS) |
Sector | Public |
Country | Japan |
Start | 09/2016 |
End | 09/2016 |
Description | Travel Grant |
Amount | £750 (GBP) |
Organisation | Guarantors of Brain |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2016 |
End | 11/2016 |
Title | Signal detection measures of pain perception |
Description | Measuring pain levels is a scientific challenge of high applied importance. Most current approaches suffer from a number of biases. We have developed a method which clearly distinguishes true perceptual sensitivity from bias: this measure has been applied in a number of studies of high applied relevance, including quantifying placebo effects, and quantifying effects of anaesthetics and analgesics. |
Type Of Material | Physiological assessment or outcome measure |
Year Produced | 2018 |
Provided To Others? | No |
Impact | Following peer-reviewed application, this research method could attract interest from pharma, as a means of quantifying efficacy of analgesics |
Title | Calculation of neurometric d' |
Description | We developed this data analysis technique as an extension of signal detection theory to the analysis of electrophysiological data. It allows one to directly compare a human participant's ability to make a perceptual discrimination judgment (i.e., discriminating higher and lower levels of nociceptive stimulus intensity) with the potential for a neural marker recorded from the participant's brain to discriminate the same stimulus property. |
Type Of Material | Data analysis technique |
Provided To Others? | No |
Impact | This technique offers a way of identifying and contrasting neural markers of perception across different sensory modalities and tasks. |
Title | Somatosensory-evoked potential dataset |
Description | Ongoing collection of a large dataset of electroencephalogram (EEG) data evoked by nociceptive radiant heat (laser) stimulation, and by non-nociceptive transcutaneous electrical stimulation of the superficial radial nerve (from about 60 adult human participants, so far). |
Type Of Material | Database/Collection of data |
Provided To Others? | No |
Impact | This dataset can be used to identify features of the laser-evoked EEG signal that vary consistently with either the physical energy of the stimulus (i.e., neural markers of low-level nociceptive processing), or with participants' perception of stimulus intensity (i.e., neural markers of pain intensity perception). The inclusion of non-nociceptive somatosensory-evoked potentials in the dataset will further allow the distinction of any EEG features that specifically encode the intensity of nociceptive stimulation, or perceived pain intensity, rather than stimulus intensity or salience in general. |
Description | IIT Rome |
Organisation | Italian Institute of Technology (Istituto Italiano di Tecnologia IIT) |
Department | Neuroscience and Brain Technologies IIT |
Country | Italy |
Sector | Academic/University |
PI Contribution | Collaboration with Prof G Iannetti, Italian Institute of Technology |
Collaborator Contribution | During the period of the grant, the co-investigator was asked to start a new laboratory in Rome. I have been collaborating with him on new projects, in addition to continuing the existing grant work. New collaborations focus on thermal sensations. |
Impact | Not yet. |
Start Year | 2019 |
Description | University of Toronto |
Organisation | University of Toronto |
Department | Faculty of Dentistry |
Country | Canada |
Sector | Academic/University |
PI Contribution | Agreed to collaborate on novel research into effects of anaesthetics on cortical representation in humans. Design of experiments complete, with visit to Toronto planned spring 2018. |
Collaborator Contribution | Contribution to experimental design, analysis and experimentation |
Impact | Too early to produce outputs |
Start Year | 2017 |
Description | Lecture to trainees at the European Summer School on Pain |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Patrick Haggard gave a lecture to trainees at the European Summer School on Pain. |
Year(s) Of Engagement Activity | 2017 |
Description | New Sensations from Old Receptors |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | This is an invited keynote lecture at EuroHaptics 2022, which is the premier industry/academia venue for engineers and researchers interested in human somatic sensation. It has high traction in the fields of perceptual robotics, augmented reality etc. etc. |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.eurohaptics2022.org/ |
Description | Presentation of research findings at the European Pain School |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | The post-doctoral researcher and research assistant presented research findings at an international summer school for the study of pain research (European Pain School, IASP). The audience consisted of around 35 colleagues from a range of disciplines within the pain research field (neurophysiologists, neuroscientists, physicians, psychologists). |
Year(s) Of Engagement Activity | 2017 |
Description | Presentation of research findings at the European Pain School |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | The post-doctoral researcher and research assistant presented research findings at an international summer school for the study of pain research (European Pain School, IASP). The audience consisted of around 35 colleagues from a range of disciplines within the pain research field (neurophysiologists, neuroscientists, physicians, psychologists). |
Year(s) Of Engagement Activity | 2017 |
Description | Tate Modern outreach |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Patrick Haggard participated in an outreach activity at Tate Modern art gallery, April 2017 |
Year(s) Of Engagement Activity | 2017 |
URL | https://philosophy.sas.ac.uk/events/event/8098 |
Description | UCL/LSE debating society on neuroscience and individual experience |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Undergraduate students |
Results and Impact | Patrick Haggard spoke at a UCL/LSE debating society on neuroscience and individual experience, Nov 2017 |
Year(s) Of Engagement Activity | 2017 |
URL | https://lsesu.tumblr.com/post/168498827488/lsesu-neuroscience-society-conference |