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Novel neurophysiological techniques to quantify pain and stratify patients

Periodic Reporting for period 4 - PAINSTRAT (Novel neurophysiological techniques to quantify pain and stratify patients)

Reporting period: 2020-05-01 to 2021-10-31

The PAINSTRAT project falls into the field of the neuroscience of pain. It has two main objectives. The first objective consists in identifying which activities of the human brain are related to the perception of pain. The second objective is to discover if these brain activities can tell us whether an individual is more or less at risk of developing chronic pain. Achieving these objectives strongly depends on a better understanding of the brain activity recorded during pain in health and disease.

These objectives are challenging. The main hurdle is that the brain activity that specifically gives rise to painful sensations remain elusive. 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? Addressing this question constitutes the foundation of the PAINSTRAT project.

The question addressed by PAINSTRAT is important for a basic understanding of brain function, but it also has obvious implications for the society. Sadly, remarkably little has changed in respect to the diagnosis and treatment of pain compared to 15 years ago, at least in terms of available analgesic drugs. The result is that pain, and particularly chronic pain, remains poorly treated for a substantial proportion of the 20% of Europeans that experience it, and it is a critical and ubiquitous problem in modern healthcare, alone costing the EU at least the staggering figure of €250
In the first half of the PAINSTRAT project we have tackled the issue of identifying the brain correlates of painful percepts and understanding the functional significance of the brain responses elicited by painful stimuli. In a number of scientific publications we have 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. We have suggested concrete methods to ensure researchers use appropriate experimental methods and thereby draw accurate conclusions from their results. For example, we have shown that 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.

We clearly demonstrated the problem of specificity of the brain activity commonly recorded during the perception of painful stimuli in one fMRI brain scanning experiment conducted on 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.

Given that, as described in the previous section, brain responses elicited by short lasting stimuli largely reflect the unspecific detection of novel salient events, to identify pain-specific neural activities we devised two different approaches.

A first approach consists in recording brain activity in response to painful and non-painful stimuli that are precisely 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. We 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 two independent experiments, we observed that multivariate pattern analysis can isolate neural features that allow distinguishing the responses triggered (1) by saliency-matched painful vs. non-painful stimuli, and (2) by high vs. low saliency stimuli independently of whether they elicit pain. These results indicate that the neural activity within the so-called “pain matrix” 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 approach consists in the use of experimental paradigms in which painful percepts are obtained in response to slow-rising, tonic stimuli oscillating at very slow frequencies (e.g. 0.1 Hz), while the activity from the human brain and spinal cord is recorded with electrophysiology. This approach, which minimises the “polluting” effect of stimulus novelty on the recorded brain activity, has allowed us to identify a feature of brain activity (consisting in an increase of power and phase-locking at the same frequency of the stimulus) that are 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. It is also important to highlight that slow fluctuations of painful percepts reflect more closely pain observed in chronic pain conditions.
The progress described in the previous paragraph (which is a non-exhaustive description of the several activities conducted by the PAINSTRAT team – see the detailed description of the 19 scientific publications in the project achievements section) is clearly beyond the state-of-the-art, given that the identification of the specific measures outlined earlier had not been achieved (e.g. the true neural entrainment of brain activity, specifically observed during slowly-oscillating painful percepts, or the identification of patterns of brain activity specifically related to painful percepts following the presentation of transient and saliency-matched noxious and non-noxious somatosensory stimuli). The activities of the PAINSTRAT team in the second half of the project are expected to consolidate these results, and test whether the identified features can be informative about the likelihood that an individual is more or less at risk of developing chronic pain.