Uncovering the cortical cellular basis of specificity and chronicity of pain

Introduction

Chronic pain remains a fundamental unsolved puzzle in biology and an unmet global challenge in clinical practice. Progress is limited by major gaps in knowledge on neural substrates, owing to overwhelming redundancy of implicated regions and pathways with several pain-unrelated sensory, cognitive, and emotional functions.

Challenges in Understanding Pain

There is also a lack of understanding of the origins of plasticity and cellular substrates for diverse psychosocial and environmental influences on pain.

Proposed Mechanism

Here we propose that neocortical neuronal ensembles, i.e., discrete cohorts of co-active neurons intermingled within seemingly redundant pathways, represent a mechanistic correlate for imparting specificity to pain perception. These ensembles also provide adaptive flexibility to context and introspective bodily states, serving as convergent substrates for divergent influences, such as:

1. Past experience of pain
2. Fear memory
3. Expectation

Methodology

Using cutting-edge in vivo methods, we aim to achieve the following objectives:

1. Identify neocortical pain ensembles that delineate pain from other sensory percepts, valence states, and cognitive functions. We will determine their composition, connectivity, coordinated activity in local and across distant networks, and functional relevance to pain.

2. Study their dynamic plasticity over the transition from acute to chronic pain. This includes delineating bottom-up (peripheral-spinal) and top-down (brain intrinsic) influences, with a focus on studying the role of the salience network in channeling context, expectation, and fear memory, as well as its dysfunction in chronic pain.

3. Investigate the potential of reversing plasticity of neuronal ensembles by non-invasive neurostimulation and behavioral approaches for achieving pain relief.

Conclusion

Through this comprehensive approach, we aim to enhance the understanding of chronic pain and explore innovative avenues for treatment.