Altered habenular connectivity in chronic low back pain: An fMRI and machine learning study

The habenula has been implicated in the pathogenesis of pain and analgesia, while evidence concerning its function in chronic low back pain (cLBP) is sparse. This study aims to investigate the resting-state functional connectivity (rsFC) and effective connectivity of the habenula in 52 patients with cLBP and 52 healthy controls (HCs) and assess the feasibility of distinguishing cLBP from HCs based on connectivity by machine learning methods. Our results indicated significantly enhanced rsFC of the habenula-left superior frontal cortex (SFC), habenula-right thalamus, and habenula-bilateral insular pathways as well as decreased rsFC of the habenula-pons pathway in cLBP patients compared to HCs. Dynamic causal modelling revealed significantly enhanced effective connectivity from the right thalamus to right habenula in cLBP patients compared with HCs. RsFC of the habenula-SFC was positively correlated with pain intensities and Hamilton Depression scores in the cLBP group. RsFC of the habenula-right insula was negatively correlated with pain duration in the cLBP group. Additionally, the combination of the rsFC of the habenula-SFC, habenula-thalamus, and habenula-pons pathways could reliably distinguish cLBP patients from HCs with an accuracy of 75.9% by support vector machine, which was validated in an independent cohort (N = 68, accuracy = 68.8%, p = .001). Linear regression and random forest could also distinguish cLBP and HCs in the independent cohort (accuracy = 73.9 and 55.9%, respectively). Overall, these findings provide evidence that cLBP may be associated with abnormal rsFC and effective connectivity of the habenula, and highlight the promise of machine learning in chronic pain discrimination.