Glutamatergic Deficiencies in Major Depression are Related to Impaired Functional Responses and Brain Activity at Rest

Background: Recent studies support the involvement of glutamatergic mechanisms in major depression. Functional and MRS studies converge in specific impairments in anterior cingulate cortex (ACC). Patiens show weaker negative BOLD responses and smaller glutamate levels and post mortem findings revealed glial decline and reduced expression of enzymes mediating glial reuptake of glutamate (Glu) and it’s conversion to glutamine (Gln). We therefore investigated the dependence of BOLD responses in ACC on glutamatergic metabolite levels. Methods: We used combined MRS and fMRI at rest and during tasks on a 3 Tesla Scanner. A total of 30 MDD Patients was compared to a matched sample of healthy controls. Clinical assessments were complemented by psychological measurements of emotional reactivity to visual and auditory stimuli. At rest, we measured metabolite levels in different parts of the ACC with a MRS sequence optimized for Glu/Gln separation and resting state fMRI was recorded for 10 minutes. Results: Pregenual ACC in MDD was characterized by weaker negative BOLD responses when compared to healthy controls. Positive task induced BOLD responses in dorsal ACC were not reduced in amplitude. BOLD fluctuations at rest and during task were accompanied by reduced levels of glutamate and glutamine. Subjects BOLD responses in the pregenual ACC correlated strongest with glu levels in patients while such association could not be established for healthy controls. In contrast correlations of fMRI/MRS signals in dorsal ACC were comparable for patients and controls. Conclusions: We demonstrated a direct interdependence of glutamatergic and functional deficits in MDD