The neurostructural consequences of glaucoma and their overlap with disorders exhibiting emotional dysregulations: a voxel-based meta-analysis and tripartite system model

Glaucoma is a neurodegenerative disorder characterized by progressive optic nerve damage and the most common cause for irreversible blindness. Emotional dysregulations are common in glaucoma patients, with high rates of generalized anxiety and depression. Glaucoma leads to pathological changes in the visual pathways of the brain, yet accumulating evidence suggests that the brain changes may reach beyond the visual system. To robustly determine brain morphological alterations in glaucoma and determine a potential overlap with changes observed in anxiety and depression we performed a pre-registered comparative meta-analysis of case control studies examining brain structural integrity in patients with glaucoma, and further determined whether the identified regions are nodes of distinct overarching large-scale networks and overlap with meta-analytic brain structural maps of generalized anxiety disorder (GAD) and major depressive disorder (MDD). Glaucoma patients exhibited robust reductions in gray matter volume in regions contributing to visual processing (lingual gyrus, thalamus), but volumetric reductions extended beyond systems involved in visual processing and also affected the left putamen and insula. Behavioral and functional network level decoding demonstrated distinct large-scale networks and involvement in visual, motivational or affective domains, respectively. Reductions in the insular region involved in pain and affective processes overlapped with alterations previously observed in GAD. Our findings may suggest a tripartite brain model of glaucoma, with changes in visual processing regions such as the lingual gyrus as well as additional alterations in putamen and insular regions meta-analytically associated with motivational or emotional functions, respectively. Together the findings indicate broad neuroanatomical alterations in glaucoma that extend beyond the visual system and may gate further pathological developments.