Periodic Reporting for period 2 - PainPersist (Psychobiological mechanisms of pain persistence)
Reporting period: 2022-07-01 to 2023-12-31
What is the problem/issue being addressed?
The project PainPersist addresses the problem of chronification of pain. Pain is an important acute warning signal that allows the organism to act when appropriate, to avoid tissue damage. However, pain can become persistent and develop into a chronic state. When this is the case, it is no longer an adequate warning signal and can cause high degrees of suffering for the individuals affected. When pain becomes chronic and no longer serves as an adequate warning signal, it has a strong negative impact on both those affected as well as their environment.
Why is it important for society?
Affecting more than 15 % of adults in the general population, chronic pain is one of the major physical and mental health care problems of society. Beside the high level of individual suffering, the costs of chronic pain for society as a whole is high. Due to the chronic characteristics of the illness, costs stretch over long timespans and can cause additional societal costs for treatment of further conditions, caused by chronic pain e.g. anxiety, stress, depression, or obesity.
What are the overall objectives?
Since the late 1970’s the awareness that psychological processes play a key role in the development of persistent pain has increased, and psychological treatments of chronic pain have proved beneficial. Along these lines, the core objective of this project is to better understand which psychological processes may be key in shaping the very early trajectory from acute to persistent pain. Practically, our core objective is to perform long-term pain experiments in a well-controlled setting and explicitly test the potential of psychological interventions to prevent adverse pain trajectories. In a number of preparatory work packages, we perform experiments to improve the measurement of brain activation and to test several potential interventions.
The project PainPersist addresses the problem of chronification of pain. Pain is an important acute warning signal that allows the organism to act when appropriate, to avoid tissue damage. However, pain can become persistent and develop into a chronic state. When this is the case, it is no longer an adequate warning signal and can cause high degrees of suffering for the individuals affected. When pain becomes chronic and no longer serves as an adequate warning signal, it has a strong negative impact on both those affected as well as their environment.
Why is it important for society?
Affecting more than 15 % of adults in the general population, chronic pain is one of the major physical and mental health care problems of society. Beside the high level of individual suffering, the costs of chronic pain for society as a whole is high. Due to the chronic characteristics of the illness, costs stretch over long timespans and can cause additional societal costs for treatment of further conditions, caused by chronic pain e.g. anxiety, stress, depression, or obesity.
What are the overall objectives?
Since the late 1970’s the awareness that psychological processes play a key role in the development of persistent pain has increased, and psychological treatments of chronic pain have proved beneficial. Along these lines, the core objective of this project is to better understand which psychological processes may be key in shaping the very early trajectory from acute to persistent pain. Practically, our core objective is to perform long-term pain experiments in a well-controlled setting and explicitly test the potential of psychological interventions to prevent adverse pain trajectories. In a number of preparatory work packages, we perform experiments to improve the measurement of brain activation and to test several potential interventions.
As part of our preparatory work packages, we are currently working on 8 experiments:
WP1.1.
With the aim of detecting the effects of several neurotransmitters in our other experiments, we are working to improve magnetic resonance spectroscopy (MRS). To this end we adopt numerous changes to the pulse sequences which are used in MRS. First steps towards an improvement of the signal to noise ratio (SNR) have been achieved.
WP1.3.
Units of the human cortex can be classified into separate specific layers. Detecting layer specific signals is usually done using magnetic resonance imaging (MRI) which can achieve a very high magnetic field during measurements, such as 7 Tesla. In this experiment we will compare the SNR from measurements using both 7 and 3 Tesla strength MRI. We have measured our paradigm with 7 Tesla strength. We are in the process of preparing the data collection on 3 Tesla.
WP1.4.
In order to detect changes in pain intensity as objectively as possible, we are developing a mobile device, which gives out a combined measure of psychophysiological signals, deliberately excluding subjective ratings given by our participants. At this point in time all necessary technical equipment and infrastructure has been installed. We have developed a deep learning analysis pipeline and are about to start the collection of pilot data.
WP2.1.
To investigate basal mechanisms of the hypothesis that expectations can induce selective attention towards signs of symptom improvement, we performed an experiment, where participants received sequences of slowly increasing (up-slopes) and sequences of slowly decreasing (down-slopes) pain-stimulation. The results of our analysis show that the pain-intensity was rated as lower during up-slopes when simultaneously performing a high attention task. Pain-intensity was also rated as lower during down-slopes, when simultaneously performing a low attention task. Skin conductance level tracked the up- and down-slopes and was modulated by the load of the cognitive task.
WP2.4.
Conditioned Pain Modulation (CPM) is a paradigm which is used to investigate how a painful stimulus can modulate the perceived pain from another painful stimulus. We performed an experiment in which our participants perceived pressure pain stimuli on both upper arms simultaneously, with a constant tonic conditioning pressure and a repeatedly occurring phasic test pressure. Pain ratings to the phasic test pain stimuli showed behavioral CPM developing over time. In the fMRI data we found effects of the paradigm in several brain regions, such as the right parietal operculum, posterior insula, as well as in bilateral primary somatosensory cortices.
WP2.5.
Generalization has been implicated as a core contributor to persistent pain, suggesting that imprecise encoding of an originally painful stimulus can lead to more generalization of subsequent pain. We are currently establishing a paradigm with which we will investigate the role of latent causes in pain perception. This can teach us about how encoding of painful stimuli might generalize to and influence the perception of new stimuli. In this paradigm participants will be trained to associate specific visual stimuli with low or high pain, resulting in two latent causes of pain. The degree of similarity between a new incoming stimulus and the previously learned causes will influence the perceived level of pain.
WP3.1.
In a further experiment we have tested whether pain relief is related to actual control or the perceived level of control. Since in most studies, controllability and predictability effects on pain processing are confounded we introduced a new experimental paradigm with the aim of disentangling these effects. During the experiment, which partly took place during fMRI, painful stimuli were either (1) controllable and predictable, (2) uncontrollable and predictable, or (3) uncontrollable and unpredictable. Participants rated individual heat pain stimuli applied to their forearm using a visual analogue scale. Our analyses indicate relevant pairwise interaction effects of controllability, predictability, and intensity on pain intensity ratings. Preliminary fMRI analyses suggest that there is an effect of controllability and predictability on attention and salience related brain network activation during expectation of painful stimuli and during the stimulation.
WP3.5.
As a preparation for potential exercise-induced analgesic effects in chronic pain we performed an experiment where aerobic exercise was performed outside of the scanner, followed by an fMRI session during which thermal and pressure pain was applied while placed in the scanner. Following each pain application, the participants rated the perceived intensity on a visual analog scale. Furthermore, pharmacological underpinnings in the opioid system of such an effect were investigated by the means of giving participants an individual dose of Naloxone, a medicine which reduces the effects of opioids. Our analyses of the collected data are ongoing.
WP1.1.
With the aim of detecting the effects of several neurotransmitters in our other experiments, we are working to improve magnetic resonance spectroscopy (MRS). To this end we adopt numerous changes to the pulse sequences which are used in MRS. First steps towards an improvement of the signal to noise ratio (SNR) have been achieved.
WP1.3.
Units of the human cortex can be classified into separate specific layers. Detecting layer specific signals is usually done using magnetic resonance imaging (MRI) which can achieve a very high magnetic field during measurements, such as 7 Tesla. In this experiment we will compare the SNR from measurements using both 7 and 3 Tesla strength MRI. We have measured our paradigm with 7 Tesla strength. We are in the process of preparing the data collection on 3 Tesla.
WP1.4.
In order to detect changes in pain intensity as objectively as possible, we are developing a mobile device, which gives out a combined measure of psychophysiological signals, deliberately excluding subjective ratings given by our participants. At this point in time all necessary technical equipment and infrastructure has been installed. We have developed a deep learning analysis pipeline and are about to start the collection of pilot data.
WP2.1.
To investigate basal mechanisms of the hypothesis that expectations can induce selective attention towards signs of symptom improvement, we performed an experiment, where participants received sequences of slowly increasing (up-slopes) and sequences of slowly decreasing (down-slopes) pain-stimulation. The results of our analysis show that the pain-intensity was rated as lower during up-slopes when simultaneously performing a high attention task. Pain-intensity was also rated as lower during down-slopes, when simultaneously performing a low attention task. Skin conductance level tracked the up- and down-slopes and was modulated by the load of the cognitive task.
WP2.4.
Conditioned Pain Modulation (CPM) is a paradigm which is used to investigate how a painful stimulus can modulate the perceived pain from another painful stimulus. We performed an experiment in which our participants perceived pressure pain stimuli on both upper arms simultaneously, with a constant tonic conditioning pressure and a repeatedly occurring phasic test pressure. Pain ratings to the phasic test pain stimuli showed behavioral CPM developing over time. In the fMRI data we found effects of the paradigm in several brain regions, such as the right parietal operculum, posterior insula, as well as in bilateral primary somatosensory cortices.
WP2.5.
Generalization has been implicated as a core contributor to persistent pain, suggesting that imprecise encoding of an originally painful stimulus can lead to more generalization of subsequent pain. We are currently establishing a paradigm with which we will investigate the role of latent causes in pain perception. This can teach us about how encoding of painful stimuli might generalize to and influence the perception of new stimuli. In this paradigm participants will be trained to associate specific visual stimuli with low or high pain, resulting in two latent causes of pain. The degree of similarity between a new incoming stimulus and the previously learned causes will influence the perceived level of pain.
WP3.1.
In a further experiment we have tested whether pain relief is related to actual control or the perceived level of control. Since in most studies, controllability and predictability effects on pain processing are confounded we introduced a new experimental paradigm with the aim of disentangling these effects. During the experiment, which partly took place during fMRI, painful stimuli were either (1) controllable and predictable, (2) uncontrollable and predictable, or (3) uncontrollable and unpredictable. Participants rated individual heat pain stimuli applied to their forearm using a visual analogue scale. Our analyses indicate relevant pairwise interaction effects of controllability, predictability, and intensity on pain intensity ratings. Preliminary fMRI analyses suggest that there is an effect of controllability and predictability on attention and salience related brain network activation during expectation of painful stimuli and during the stimulation.
WP3.5.
As a preparation for potential exercise-induced analgesic effects in chronic pain we performed an experiment where aerobic exercise was performed outside of the scanner, followed by an fMRI session during which thermal and pressure pain was applied while placed in the scanner. Following each pain application, the participants rated the perceived intensity on a visual analog scale. Furthermore, pharmacological underpinnings in the opioid system of such an effect were investigated by the means of giving participants an individual dose of Naloxone, a medicine which reduces the effects of opioids. Our analyses of the collected data are ongoing.
We expect to make contributions to the field, in accordance with our hypotheses as described in the individual work packages.
We expect to publish the results of our work in peer-reviewed scientific journals. We also expect to present our results on scientific congresses relevant to our field.
We expect to publish the results of our work in peer-reviewed scientific journals. We also expect to present our results on scientific congresses relevant to our field.