Targeting the posterior thalamic hub: hemispheric-specific encoding of pain-depression comorbidity after hemorrhagic...

Post-stroke pain (PSP) and post-stroke depression (PSD) frequently co-occur after thalamic hemorrhage and may mutually exacerbate one another, with persistent pain contributing to affective dysfunction and depression altering sensory processing. Because current symptom-specific treatments often provide limited benefit, identifying shared neural mechanisms underlying PSP-PSD comorbidity may offer a more clinically relevant framework for developing targeted circuit-based therapies.

Twelve patients with isolated anterior or posterior thalamic hemorrhage underwent parallel multimodal assessments, including standardized pain, mood, anxiety, and cognitive evaluations together with structural MRI, diffusion tensor imaging, and resting-state functional MRI to characterize lesion topography and thalamocortical connectivity. Guided by the clinical findings, we subsequently established nucleus-specific murine models of thalamic hemorrhage using stereotactic collagenase injection. Mice underwent sequential behavioral phenotyping, fiber photometry recording, and viral tracing analyses to investigate the circuit mechanisms underlying pain-depression comorbidity.

In patients, posterior thalamic hemorrhage was the exclusive locus for PSP-PSD comorbidity and exhibited severe disruption of thalamocortical functional connectivity, with right-sided lesions having the most profound effect. In mice, focal hemorrhage confined to the posterior thalamic nucleus (PO), but not adjacent parafascicular or ventral posterolateral nuclei, recapitulated both mechanical hyperalgesia and delayed depression-like behaviors. In the murine model, we uncovered a striking hemispheric specialization: left PO lesions induced anhedonia, while right PO lesions led to behavioral despair. PO neurons became hyperexcitable to pain after hemorrhage, a state amplified with PSD onset. Viral tracing revealed lateralized PO projections to somatosensory cortices.

The posterior thalamic nucleus represents a lateralized thalamocortical substrate for post-stroke pain-depression comorbidity after hemorrhagic stroke. These findings support the potential value of lesion-topography-based prognostic stratification and circuit-guided neuromodulation strategies targeting both sensory and affective symptoms. A major limitation of this study is the relatively small but carefully phenotyped clinical cohort, which warrants validation in larger longitudinal studies.