Dissociable Neural Responses to Conditioned Social Threats are Modulated by Spatial Proximity in PTSD and MDD

Abstract

The brains response to potential threats is shaped by the egocentric spatiotemporal distance to the threat. While distal threats recruit evaluative, cognitive-fear networks for strategic planning, proximal threats engage evolutionarily conserved reactive-fear circuitry to mount immediate defensive responses. Understanding this dual neural architecture is clinically relevant, as the spatial proximity to a traumatic event predicts subsequent psychiatric symptom severity and recovery. Despite the well-characterized disruptions to threat circuitry in posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), how these networks respond to threats at distinct spatial distances has yet to be investigated in these disorders. Utilizing 3D virtual reality technology, we implemented a spatially-modulated fear conditioning paradigm by presenting human avatars at proximal (peripersonal) and distal (extrapersonal) distances, paired with shock, to trauma-exposed participants (n = 50) during functional MRI (fMRI). We modeled associations between PTSD and MDD symptom severity and task-evoked hemodynamic responses within cognitive-fear and reactive-fear threat networks. Our results support a transdiagnostic disruption of thalamic responses to proximal threats, driven by heightened activation to the safety stimulus and stronger deactivation to the threat stimulus. MDD showed a disorder-specific effect of disrupted activity across cognitive-fear and social cognition regions in response to proximal social threats, and illness severity-by-proximity effects across motor regions. PTSD symptom severity was uniquely associated with hyperactivity of the amygdala to distal threats. Transdiagnostic disruption of connectivity between the dorsal precuneus and several subcortical structures followed a disorder-specific gradient across the anterior-posterior axis. While thalamic disruptions to threats represent a shared transdiagnostic effect, PTSD and MDD are distinguished by differences in amygdala hyperactivation and cognitive-fear network hypoactivation, respectively.