Periodic Reporting for period 5 - PAINSTRAT (Novel neurophysiological techniques to quantify pain and stratify patients)
Reporting period: 2021-11-01 to 2022-12-31
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.
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.