Dissociable Thalamocortical Circuit Disruptions During Contextual Fear Renewal in PTSD

Post-traumatic stress disorder (PTSD) is marked by impaired contextual modulation of fear, leaving patients vulnerable to symptom return after extinction-based therapy. The thalamus is theorized to coordinate hippocampal-prefrontal circuits during contextual updating. Yet, its role in PTSD remains uncharacterized. We examined the contribution of the medial mediodorsal thalamus (MDm) to extinction-recall and fear renewal and its association with symptom severity.

425 participants completed threat renewal and 524 extinction-recall paradigms during fMRI (threat renewal: 189 healthy controls, HC; 129 trauma-exposed HC, TEHC; 107 PTSD extinction-recall: 280 HC; 132 TEHC; 112 PTSD). Analyses examined MDm activation and connectivity with canonical fear-regions; lateral mediodorsal thalamus (MDl) and anterior pulvinar served as control regions. Structural equation modeling characterized the covariance linking thalamocortical connectivity to diagnostic group.

During fear renewal but not extinction-recall, a Time × Group interaction emerged in MDm functional connectivity: PTSD participants showed reduced MDm connectivity with hippocampus and sgACC relative to control groups during early but not late fear renewal. Parallel reductions emerged in anterior pulvinar-vmPFC connectivity. MDl, showed no group differences. Structural equation modeling indicated that thalamo-hippocampal connectivity covaried with group via both MDm-sgACC and anterior pulvinar-vmPFC connectivity. MDm-dACC connectivity scaled with PTSD severity, independent of MDl and anterior pulvinar.

State-specific reductions in MDm-hippocampal-cingulate and pulvinar-vmPFC connectivity during early fear renewal in PTSD highlight parallel thalamocortical alterations during flexible contextual threat updating. These alterations, along with the selective MDm-dACC association with symptom severity, nominate MDm-centered circuit as a hypothesis-generating focus for future mechanistic neuromodulation studies.