Alterations of cerebral functional connectivity associated with persistent pain – PINCH

Functional ultrasound imaging (fUS) imaging is a unique neuroimaging approach, developed and validated in collaboration with us by the team of Dr Mickael Tanter (Institut Langevin, ESPCI, Paris). Using a relatively small setup, our teams previously showed that it allows imaging and measurement of cerebral blood flow in anaesthetized 16–18 and freely moving rodents 19 with an excellent spatial (100 ?m) and temporal resolution (1 ms). Using this technique, we are currently studying whole brain maps of haemodynamic responses to several types of innocuous stimuli in anaesthetized animals.
We have also shown that we can measure functional connectivity using this technique, with high reproducibility 16 and propose to use it further to decipher the nature of brain areas altered in chronic pain conditions and their link with other pathologies.
In an article in preparation (Rahal et al., 2020), the current consortium studied using fUS imaging the alteration of resting state networks in short- versus long-term inflammatory pain in rats. The study was performed in anesthetized animals using 5 imaging planes. Using matrix analysis, we observed a strong decreased resting state connectivity in the somato-motor network. The changes were restricted to this network. These results illustrate for the first time that it is indeed possible to image changes in functional connectivity networks under anesthesia in animal models of persistent pain. Also, it illustrates that our consortium has the necessary expertise in signal and statistical analysis to perform such analysis.

Using a first set-up of imaging, in freely moving animals, we have identified brain areas involved in the sensory coding of cold and warm temperatures. Results show contrasted results when the animals are exposed to cold (15°C), neutral (25°C) or warm (32°C) temperature (applied on the floor).
In order i) to circumvent the problem of motions artefacts and ii) image entire networks on multiple planes (which is very difficult in only one 2D plane of imaging), we have developed a new set-up of imaging in head fixed animals. We also developed a thorough algorithm dedicated for the signal processing of these experiments. It is particularly designed to threshold motion artefacts and the noise created and removes these noisy parts in the acquisitions. Our first results show that we can image several networks in healthy mice.

The originality of our project is i) to perform neuroimaging with outstanding spatial and temporal resolutions and in a large field of view, in non-anesthetized animals, ii) to bridge the understanding of brain alteration in chronic pain states in animal models and human pathologies and finally iii) to propose and demonstrate in a preclinical setting a unique strategy for future personalized treatments of chronic pain based on functional connectivity monitoring.

Only oral presentations in international meetings so far.

1. Therapeutic Ultrasound - Winter School - Les Houches France, March 2019

2. Workshop on Functional Ultrasound of the Brain – Cargese, France, 27 October - 02 November 2019

Chronic pain diseases affect 30% of the European population. Unfortunately, only 50% of patients receive appropriate alleviation, due to a lack of treatment specificity and efficacy, as a result of a current poor understanding of the underlying mechanisms. The project ‘PINCH’ is a transdisciplinary and innovative project, based on an integrated approach whose aim is to provide highly relevant information on the brain’s function during the experience of acute pain (in healthy animals) and aberrant hypersensitivity (in neuropathic animals). Using a highly innovative neuroimaging technique (fUS) in freely moving animals pioneered by the partners of this consortium, this project will determine selective biomarkers of acute/neuropathic pain, i.e. decipher the brain areas and brain networks differentially activated during the multiple components of acute or chronic pain. In addition, we will determine the specific alterations of brain networks concomitant with the emergence of either anxiety or depression. Finally, the last part of this project, proposes a general framework for the optimized and personalized treatment of chronic pain based on functional connectivity monitoring. In this proof-of-concept study, we propose to use individual analysis of functional connectivity assessed by ultrasound for a personalized pain relief strategy. Such approach is key for a future clinical transfer in chronic pain patients.