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 on the origins of plasticity and cellular substrates for diverse psychosocial and environmental influences on pain. 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.

Mechanistic Insights

These ensembles provide adaptive flexibility to context and introspective bodily states, and serve as convergent substrates for divergent influences, such as:

• Past experience of pain
• Fear memory
• Expectation

Research Methodology

Using cutting-edge in vivo methods, we aim to:

1. Identify neocortical pain ensembles that delineate pain from other sensory percepts, valence states, and cognitive functions, and 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 and delineate 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, and its dysfunction in chronic pain.
3. Study the potential of reversing plasticity of neuronal ensembles by non-invasive neurostimulation and behavioral approaches for achieving pain relief.