Novel neurophysiological techniques to quantify pain and stratify patients

Periodic Reporting for period 5 - PAINSTRAT (Novel neurophysiological techniques to quantify pain and stratify patients)

Okres sprawozdawczy: 2021-11-01 do 2022-12-31

The PAINSTRAT project started in 01/01/2016 and ended in 31/12/2022. Throughout these years it made fundamental contributions into the field of the neuroscience of pain. Its overarching aim has been understanding the functional significance of the large activity elicited in the human brain by painful stimuli. This understanding is crucial to identify the components of this large neural activity that are more specifically related to pain, and do not depend on factors that are related but not specific to pain, such as novelty, saliency, and behavioural relevance. The identification of such more specific components not only would lead to better physiological understanding, but also have clinical relevance to measure pain and its consequences in clinical conditions.
Reaching these objectives is challenging. The main hurdle is that the brain activity that specifically gives rise to painful sensations remained elusive so far. Indeed, most of the brain activity measured in awake humans using brain scanning techniques does not reflect pain perception per se, but the unspecific detection of novel salient events, irrespective of the sensory modality of the stimulus. Thus a fundamental question remains unaddressed: does the brain activity sampled by these techniques when an individual experiences pain correspond to the neuronal activity causing the emergence of the painful percept? This question is the foundation of the PAINSTRAT project.
The results achieved by PAINSTRAT are important for basic understanding of brain function, but also have obvious implications for the society. Mostly because of the lack of a specific pain biomarker, little has changed in respect to the diagnosis and treatment of pain compared to 20 years ago, and clinical pain remains poorly treated, and a critical and ubiquitous problem in modern healthcare.

Throughout the lifespan of the PAINSTRAT project, the team has performed both theoretical and empirical work, and thereby tackled the issue of identifying the brain correlates of painful percepts and understanding the functional significance of the brain responses elicited by painful stimuli. The outcome of PAINSTRAT work has been reported in 44 publications in leading scientific journals. In these publications the team has dissected the difficulties and pitfalls in the extremely widely use of brain imaging techniques, as well as of some advanced approaches to analyse brain imaging data, to identify a real neural ‘pain signature’, and thus derive a way to predict perceived pain from brain activity would have enormous basic and clinical implications. The team has suggested concrete methods to ensure researchers use appropriate experimental methods and thereby draw accurate conclusions from their results. It has also clarified, for example, how a brain measure that in some instances correlates with the perception of pain can still demonstrate good utility because it is able to identify clinically-meaningful groups of patients with a high sensitivity and specificity. However, this does not necessarily imply that the same brain measure reflects directly the mechanisms that give rise to a given clinical pain condition, as the patterns of neural activation that allow discrimination between conditions might be entirely epiphenomenal. This work has clear clinical relevance, and has obtained significant attention and a high number of citations already during the lifespan of the project.
In several publications the team demonstrated the issue of specificity of the brain activity commonly recorded during the perception of painful stimuli. One of the studies worth highlighting was conducted using fMRI brain scanning in a rare group of individuals who cannot feel pain. These individuals have a genetic abnormality of peripheral nerves sensing noxious stimuli, resulting in pain insensitivity through an impaired peripheral afferent input that leaves tactile percepts fully intact. This allowed complete experimental disambiguation of sensory responses and painful sensations. In response to identical noxious stimuli, we found that pain-free participants showed normal activation of brain regions commonly activated by painful stimuli in healthy controls.
Following the work demonstrating that the brain responses elicited by short lasting stimuli largely reflect the unspecific detection of novel and behaviourally-relevant salient events rather than pain per se, to identify pain-specific neural activities the team went on devising a number of approaches that can summarized as exploiting two main strategies.
A first strategy consisted in recording brain activity in response to painful and non-painful stimuli that are exquisitely matched with respect to their novelty and saliency content, to test whether pain-selective information can be isolated in the fMRI responses elicited by painful stimuli. The team analysed the data with an approach (called multivariate pattern analysis) that is more sensitive than conventional univariate approaches in detecting differences across conditions in the fMRI signals. In a number of independent experiments, w observed that multivariate pattern analysis can isolate neural features that allow distinguishing the responses triggered by saliency-matched painful vs. non-painful stimuli. These results indicate that the neural activity initially considered to reflect pain perception in fact reflects both the quality and the saliency content of the eliciting stimuli, highlighting the functional heterogeneity of this brain response. Importantly, the neural features distinguishing the painful quality of the percept and the saliency content are spatially distributed and cannot be ascribed to a specific brain structure.
A second strategy capitalised on empirical work, also conducted during the PAINSTRAT project, dissecting the stimulus features that determine the supramodal nature of the brain response. This has allowed the PAINSTRAT team to devise experimental paradigms in which painful percepts are obtained in response to stimuli that do not entail those features that maximize non-pain-specific responses, such as sudden increases of stimulus intensity. Thus, by using, for example, slow-rising, tonic stimuli oscillating at very slow frequencies (e.g. 0.1 Hz), while the activity from the human brain and spinal cord was recorded with electrophysiology, the team was able to minimise the “polluting” effect of stimulus novelty on the recorded brain activity, and thereby identify a precise feature of brain activity (consisting in an increase of power and phase-locking at the same frequency of the stimulus) that is specifically related to painful percepts. Remarkably, the magnitude of this brain activity relates to the individual variability of pain ratings, and it is thus a promising candidate to reflect a true correlate of the brain activity giving rise to painful percepts, and it will be used to study the cortical activity underlying the perception of sustained pain in both healthy participants and patients with chronic pain. Importantly, the slow fluctuations of painful percepts tracked by this identified type of neural activity, reflect more closely pain observed in chronic pain conditions.

The non-exhaustive description of PAINSTRAT achievements in the previous paragraph is clearly beyond the state-of-the-art, given that the identification of the specific measures outlined earlier had not been achieved previously.

PAINSTRAT

Periodic Reporting for period 5 - PAINSTRAT (Novel neurophysiological techniques to quantify pain and stratify patients)

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