Sympathetic Shift and Insular Alteration: Unravelling the Link Between Anxiety and Heart Rate Variability in Parkinson's Disease

Abstract Background Anxiety and autonomic dysfunction are frequent non‐motor symptoms of Parkinson's disease (PD). Their relationship, as well as the neural mechanisms underlying this relationship, remain unexplored. Objectives We aimed to investigate the relationship between cardiovascular functions and anxiety in PD and the structural neural changes underlying this putative interaction. We also investigated the effect of dopaminergic medications on such a relationship. Methods Fifty PD patients (27 with anxiety, PD_Anx; 23 without anxiety, PD_noAnx) and 16 age‐ and gender‐matched healthy controls (HC) were included. Blood pressure (BP), heart rate, and heart rate variability (HRV) were assessed at rest and in response to an orthostatic challenge, both ON and OFF dopaminergic medications. Voxel‐based morphometry was used to examine grey matter volume in brain areas linked to autonomic regulation and anxiety, including the amygdala, insula, cingulate cortex, hypothalamus, and putamen. Results PD_Anx patients showed significantly lower HRV compared with both PD_noAnx patients and HC ( P < 0.05), indicating increased sympathetic activity. Both PD groups had higher BP OFF medication compared with HC ( P < 0.001, P < 0.005, respectively); there was no difference between PD_Anx and PD_noAnx ( P = 0.31). Structural brain analyses showed that anxiety altered the relationship between HRV and left insula volume, with a positive correlation in PD_noAnx patients and a reversed relationship in PD_Anx patients. Conclusions Anxiety in PD is associated with a shift toward sympathetic predominance, which correlates with structural changes in the insula. Insular alteration may predispose PD patients to heightened sympathetic outflow and anxiety. Changes in HRV may be interpreted as a functional indicator of anxious states in PD. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.