Medial prefrontal cortex neurotransmitter abnormalities in posttraumatic stress disorder with and without comorbidity to major depression

Abstract

Posttraumatic stress disorder (PTSD) is a chronic psychiatric condition that follows exposure to a traumatic stressor. Though previous in vivo proton (¹H) MRS) research conducted at 4 T or lower has identified alterations in glutamate metabolism associated with PTSD predisposition and/or progression, no prior investigations have been conducted at higher field strength. In addition, earlier studies have not extensively addressed the impact of psychiatric comorbidities such as major depressive disorder (MDD) on PTSD-associated ¹H-MRS-visible brain metabolite abnormalities. Here we employ 7 T ¹H MRS to examine concentrations of glutamate, glutamine, GABA, and glutathione in the medial prefrontal cortex (mPFC) of PTSD patients with MDD (PTSD+_MDD+; N = 6) or without MDD (PTSD+_MDD-; N = 5), as well as trauma-unmatched controls without PTSD but with MDD (PTSD-_MDD+; N = 9) or without MDD (PTSD-_MDD-; N = 18). Participants with PTSD demonstrated decreased ratios of GABA to glutamine relative to healthy PTSD-_MDD- controls but no single-metabolite abnormalities. When comorbid MDD was considered, however, MDD but not PTSD diagnosis was significantly associated with increased mPFC glutamine concentration and decreased glutamate:glutamine ratio. In addition, all participants with PTSD and/or MDD collectively demonstrated decreased glutathione relative to healthy PTSD-_MDD- controls. Despite limited findings in single metabolites, patterns of abnormality in prefrontal metabolite concentrations among individuals with PTSD and/or MDD enabled supervised classification to separate them from healthy controls with 80+% sensitivity and specificity, with glutathione, glutamine, and myoinositol consistently among the most informative metabolites for this classification. Our findings indicate that MDD can be an important factor in mPFC glutamate metabolism abnormalities observed using ¹H MRS in cohorts with PTSD.

Keywords: GABA; glutamate; glutamine; in vivo proton MRS; major depressive disorder; medial prefrontal cortex; posttraumatic stress disorder; supervised machine learning.