# Brain networks activated when aggravating baseline chronic pain of an individual with new daily persistent headache: a case study

## TL;DR

This case study explores brain activity in a person with chronic headache pain, identifying specific brain regions and connections involved in pain aggravation.

## Contribution

The study reveals a novel brain circuit model for neuropathic pain perception and potential targets for personalized neuromodulation therapies.

## Key findings

- Five brain regions showed increased activity when chronic headache pain was aggravated.
- A cortical circuit involving the IPL, insula, cerebellum, and PAG was identified.
- Negative effect paths emerged on high-pain days, revealing dynamic circuit behavior.

## Abstract

In this study we examined neuronal mechanisms associated with chronic headache pain by recruiting a participant diagnosed with New Daily Persistent Headache (NDPH), who had the reliable characteristic that his baseline chronic pain could be immediately and consistently modulated (partially relieved or aggravated) by applying deep pressure to specific locations along his face and head. We sought to map brain regions responsive to modulations of his baseline pain using functional magnetic resonance imaging (fMRI). We constructed customized MRI-compatible 3D-printed face masks and skull plates affixed with syringe plungers that could apply and remove deep pressure to discrete craniofacial locations. Using On/Off block paradigms, we collected fMRI data across nine sessions while pressing on locations that either increased, decreased, or had no effect on his chronic pain. Although displacement artifacts precluded use of relief point data, we did reveal five brain regions that showed significantly increased responses when stimulating locations that aggravated his baseline headache pain, including the right anterior insula, bilateral inferior parietal lobule (IPL) foci, plus bilateral cerebellar regions (lobule VIIIb). Using structural vector autoregression (Granger causality), resting-state functional connectivity MRI analyses of the above somatosensory-related aggravated pain network further revealed effective connectivity (positive effect paths) from the left IPL to the right anterior insula, and these two regions had positive effect paths to the right IPL. This cortical circuit was coupled with the cerebellar foci plus the participant’s anatomically derived periaqueductal gray (PAG) region. Moreover, on days when the participant had greater degrees of baseline chronic headache pain the right IPL and PAG exhibited negative effect paths on the left IPL and left cerebellum, respectively, thereby revealing additional psychophysiological attributes of this circuit. Together, these results not only identified candidate targets for patient-customized neuromodulation therapies but also revealed a novel testable circuit model regarding potential mechanisms underlying one form of neuropathic pain perception.