In this study, we propose a novel approach for reconstructing brainstem fiber trajectories, and relating their connectivity levels to combat-related chronic pain.

Evaluation of brainstem pathways using diffusion tensor MRI (DTI) and tractography may provide insights into clinical diseases associated with brainstem circuit dysfunctions. However, identification of these tracts has been elusive, with relatively few in vivo studies to date.

In this approach, we first performed manual DTI tractography of nine brainstem fibers to confirm the precision of tractographic results with existing anatomical knowledge. Next, we defined region-of-interest (ROI) pairs representing each brainstem fiber’s termini in a brain template in the standardized space using a high-quality computational image registration pipeline. These ROI pairs could be transferred onto individual DTI space and allowed for automated brainstem tractography and extraction of brainstem fibers’ connectivity measures. Lastly, we examined the relationships between each fiber’s connectivity level with chronic pain in 17 veterans.

This novel, automated brainstem tractographic approach has shown to render results comparable to the precisions of manual tractography, and is feasible for analyzing clinical DTI data by measuring fractional anisotropy (FA) in each brainstem tract. Significant correlations between reduced FA and increased pain levels, including ‘pain right now’ and ‘worst pain in last months,’ were detected in two brainstem tracts – the dorsal and medial longitudinal fasciculi – which are known to be involved in pain control circuits.

This study provides in vivo anatomical evidence that human brainstem connections are organized into discrete circuits. The results suggest usefulness of diffusion tensor tractography and quantitative analyses of brainstem tracts in examining chronic pain syndromes. Further investigations of the DTI connectivity in brainstem circuits may provide important insights regarding healthy vs. dysfunctional brainstem function in the context of pain.