Reward Decision Network Disconnection in Poststroke Apathy: A Prospective Multimodality Imaging Study

Apathy is a common neuropsychiatric symptom following stroke, characterized by reduced goal-directed behavior. The reward decision network (RDN), which plays a crucial role in regulating goal-directed behaviors, is closely associated with apathy. However, the relationship between poststroke apathy (PSA) and RDN dysfunction remains unclear due to apathy heterogeneity, the confounding effect of depression and individual variability in lesion impacts. This study aims to dissect the heterogeneity of PSA and explore the link between lesion-induced RDN damage and PSA. We prospectively recruited 207 patients with acute ischemic infarction and 60 demographically matched healthy controls. Participants underwent neuroimaging and longitudinal neuropsychiatric assessments. To characterize PSA heterogeneity, we employed multivariate analysis and clustering algorithms based on whole-brain functional connectivity and clinical assessments to classify patients into different PSA biotypes. We embedded each patient's lesion into a structural connectome atlas to obtain white matter (WM) disconnection maps. On this basis, WM disconnection scores were calculated for each brain region to quantify lesion-induced WM damage. We employed the XGBoost model to predict PSA biotypes based on WM disconnection scores, comparing the performance of models focusing on RDN-specific versus whole-brain WM disconnection. Additionally, we explored WM damage patterns across different biotypes by comparing disconnection scores in critical brain regions. We identified four PSA biotypes with unique clinical trajectories and neurobiological underpinnings. Biotype 4 was characterized by persistent apathy with depressive symptoms. Biotype 2 showed persistent apathy. Biotype 3 was non-apathetic. Biotype 1 exhibited delayed-onset apathy. The XGBoost models, when focused on the RDN-specific WM disconnection, performed significantly better in predicting PSA biotypes compared to the whole-brain WM disconnection model (t(164.66) = 8.871, p < 0.001). Analysis of WM disconnection patterns revealed that Biotype 4 exhibited more extensive RDN damage in crucial regions, Biotype 1 had a unique pattern of damage in the anterior cingulate cortex (t(61) = 1.874, p = 0.032), and Biotype 2 had a unique pattern of damage in the orbitofrontal cortex (t(53)= 1.827, p = 0.036). This study dissected PSA heterogeneity and demonstrated that RDN damage is a critical factor in PSA variability. We found that lesion-induced WM disconnections in anterior cingulate cortex and orbitofrontal cortex can lead to delayed-onset and persistent apathy, respectively. Furthermore, our findings revealed that apathy not only has distinct pathogenic mechanisms, but also shares neurobiological substrates with depression.