Microglial Remodeling Links Chronic Pain to Depression, With Xiao Xiao, PhD

In an interview with HCPLive, Xiao Xiao, PhD, from Fudan University, described findings from a study showing that microglia-mediated changes in the hippocampus could drive the shift from persistent pain to depression. The results point to a critical window for earlier intervention.

Chronic pain is a known risk factor for depression, yet the underlying mechanisms have been unclear. The study, led by Ming Ding and Shitong Xiang at Fudan University, combined longitudinal human neuroimaging with rodent models to reveal a biphasic pattern of hippocampal change. Early in chronic pain, hippocampal volume increases alongside preserved or improved cognitive performance. Over time, this adaptive phase gives way to hippocampal atrophy, cognitive decline, and depression- and anxiety-like behaviors.

Xiao noted that the transition from pain to depression reflects a dynamic and potentially modifiable process.

“Timing is critical,” Xiao said. “Traditionally, psychiatric or [behavioral] interventions are often introduced once the patients meet the clear diagnostic criteria for depression. Our work supports a more proactive approach. These high-risk patients could be identified earlier and supported.”

She emphasized that this does not imply all patients with chronic pain need early intervention. Those showing persistent pain or changes in mood or cognition may benefit from timely behavioral support. Intervening during this transitional phase, when neural systems may still be reversible, could mitigate progression to comorbid depression.

The study identifies the dentate gyrus as a key hub in chronic pain. Early, increased activity of adult-born neurons promotes adaptive plasticity. With ongoing nociceptive input, microglial activation drives maladaptive remodeling, disrupting network balance and promoting affective pathology.

In animal models, experimental modulation of microglia prevented depression-like behaviors while preserving cognitive function, suggesting an advantage over interventions targeting neurons alone. Microglia thus emerge as a potential therapeutic target, though not yet clinically applicable.

Currently, no therapies specifically target microglial activation in this context. Xiao noted that agents like minocycline, which cross the blood-brain barrier and have anti-inflammatory effects, have shown promise in preclinical studies by inhibiting microglial activation. However, these approaches remain experimental, and their effectiveness in preventing depression in chronic pain has not been confirmed in clinical trials.

The study also highlights variability in patient trajectories. Progression to depression appears influenced by pain duration and severity, baseline mental health, stress sensitivity, coping strategies, and social context. These factors may converge on hippocampal pathways to determine whether adaptive plasticity persists or fails.

Xiao highlighted the need for longitudinal studies in chronic pain populations to clarify timing and predictors of this transition. Developing integrated models combining clinical, behavioral, and biological data could help identify patients most likely to benefit from early intervention. Future research may explore targeted therapies, including noninvasive neuromodulation such as focused ultrasound directed at hippocampal structures.

“…our study… highlights microglia as [an] important component of this process,” Xiao said. “This is not [yet an]... actionable target in clinical practice.”

Check out the first part of our interview with Xiao here.

References

Ding M, Xiang S, Zhang Y, et al. From chronic pain to depression: Neurogenesis-driven microglial remodeling in the hippocampal dentate gyrus. Science. 2026;391(6791):eaee6177. doi:10.1126/science.aee6177