Investigating Fear System Myelination in PTSD Using In Vivo and Post Mortem Data

PROJECT SUMMARY/ABSTRACT This proposal will examine maladaptive gray matter (GM) myelination as a candidate mechanism underpinning two functional brain abnormalities well established in Posttraumatic Stress Disorder (PTSD): hyper- connectedness of the threat response network (TRN: defined as hippocampus (HIP), amygdala (AMYG), anterior insula (INS), and dorsal anterior cingulate cortex (dACC)), and disruption of the default mode network (DMN). Experience- and activity-dependent GM myelination have been observed in many brain regions and have broad relevance to psychiatric disorders. While experience-dependent myelination evolved to accelerate nerve conduction, myelination in GM has been shown to reduce synaptic density and synapse-based neuroplasticity in animal models. Our model proposes that excess GM myelination in the TRN in PTSD results in a hyperconnected salience network (SN; which includes AMYG, dACC, and INS but not HIP. See “Bridging Frameworks” section) and a poorly connected and hypoactive DMN. Given that myelin development and re- myelination in both cortical and subcortical GM are responsive to therapeutic agents, confirming our model could lead to novel targets for treatment of PTSD, a condition that has resisted pharmacotherapeutic intervention. Our proposed model yields a candidate mechanism underpinning the “synaptic disconnection” syndrome proposed by Krystal and colleagues to explain impaired functional brain connectivity in PTSD. It is also noteworthy that recent evidence suggests that DMN dysconnectivity in PTSD is not associated with the disruption of large frontal white matter tracks. As such, excess GM myelination in key structures may supply an explanation for this phenomenon. Using a combination of postmortem neuropathology in PTSD cases versus brain bank controls, and in vivo neuroimaging at 3T in a matched case control design, we will examine if PTSD is associated with increased myelin content and decreased synaptic and neurite density in the TRN structures. Finally, we will test if increased GM myelin and decreased neurite density in TRN account for increased resting state (RS) connectivity within the SN and decreased RS connectivity within the DMN in the same living subjects. Integration of postmortem neuropathology, afforded by the National PTSD Brain Bank, and in vivo neuroimaging will enable a highly novel but broadly testable exploration of GM myelination and its consequences in the human brain as modified by PTSD.