Reduced Prefrontal Glutamate/Glutamine and γ-Aminobutyric Acid Levels in Major Depression Determined Using Proton Magnetic Resonance Spectroscopy

Abstract

Context: Increasing evidence indicates that major depressive disorder (MDD) is associated with altered function of the major excitatory and inhibitory neurotransmitters glutamate and ␥-aminobutyric acid (GABA), respectively. A recently developed magnetic resonance spectroscopy method allows for reliable measurement of glutamate/glutamine (Glx) and GABA concentrations in prefrontal brain regions that have been implicated in the pathophysiologic mechanisms of MDD by studies using other neuroimaging and postmortem techniques.Objective: To measure Glx and GABA levels in 2 regions of the prefrontal brain tissue in unmedicated adults with MDD.Design: Cross-sectional study for association.Setting: Psychiatric outpatient clinic.Participants: Twenty unmedicated, depressed patients with MDD and 20 age-and sex-matched controls.Intervention: Participants underwent scanning using a 3-T whole-body scanner with a transmit-receive head coil, providing a homogeneous radiofrequency field and the capability of obtaining spectroscopic measurements in a dorsomedial/dorsal anterolateral prefrontal region of interest (ROI) and a ventromedial prefrontal ROI. Main Outcome Measures:Glx and GABA levels derived from magnetic resonance spectroscopy signals.Results: Depressed patients had reduced Glx levels in both ROIs. The GABA levels were reduced in the dorsomedial/dorsal anterolateral prefrontal ROI. Levels of GABA and Glx were positively correlated in both ROIs. Conclusions:For the first time, GABA and Glx concentrations were compared between unmedicated depressed adults and controls in prefrontal ROIs. The abnormal reductions in Glx and GABA concentrations found in the MDD sample were compatible with findings from postmortem histopathologic studies, indicating that glial cell density is reduced in the same areas in MDD.

Investigation of Cortical Glutamate–Glutamine and γ-Aminobutyric Acid in Obsessive–Compulsive Disorder by Proton Magnetic Resonance Spectroscopy

“…Although Hasler et al (2009) found no differences in MPFC GABA in unmedicated subjects with panic disorder or in unmedicated patients with major depressive disorder (MDD, Hasler et al, 2007), Kegeles et al (2012) found increased GABA levels in the MPFC of unmedicated patients with schizophrenia using identical methodology to ours. In more dorsal voxels, decreases in GABA levels were found in unmedicated patients with MDD (Hasler et al, 2007) and in recovered, medication-free patients with a history of MDD (Bhagwagar et al, 2008). Of note, when the four patients in our OCD sample with a history of MDD were removed, decreases in MPFC GABA levels were even more robust in OCD patients compared with controls (F 1,39 ¼ 8.079, p ¼ 0.007).…”

“…One is that there are Glx reductions both in pediatric and adult OCD samples, but our larger voxel diluted a more localized Glx signal difference. However, use of this larger voxel did not prevent detection of significant MPFC Glx findings in other diagnostic groups using similar methods (Hasler et al, 2007;Kegeles et al, 2012). Another possibility is that there are reduced Glx levels in pediatric but not adult OCD patients in this brain region, suggesting that the pathophysiology of pediatric and adult OCD might differ.…”

“…(Geramita et al, 2011;Kegeles et al, 2006) due to their high structural, chemical and magnetic similarities with GABA. This pulse sequence been used in other patient populations to separate Glx from GABA (Hasler et al, 2007;Kegeles et al, 2012). The Glx signal is sufficiently strong that the partially edited measurement has high reliability (Hasler et al, 2007;Kegeles et al, 2006Kegeles et al, , 2012, comparable to that of GABA itself.…”

Global brain atrophy and metabolic dysfunction in LGI1 encephalitis: A prospective multimodal MRI study

“…A trend of lower concentration was seen in the GM voxel, but significance was lost after correcting for multiple comparisons. Since decreased glutamine/glutamate ratios were similarly observed in patients with depression and mood disorders [35,36], this may suggest the need for increased vigilance for affective disturbances in patients following LGI1 encephalitis. Considering structural MRI data indicating global atrophy, we expected a significant tNAA difference between the LGI1 patients and control subjects.…”

Chronic psychosocial stress in mice leads to changes in brain functional connectivity and metabolite levels comparable to human depression

“…In fact, FC within the DMN is increased by stress (Soares et al, 2013) and in depression (Grimm et al, 2009;Whitfield-Gabrieli and Ford, 2012). In addition to these analyses of the changes in brain function underlying depression, region-specific metabolic changes as derived from MRS have been reported for depressed patients (Hasler et al, 2007). These metabolic changes could be related to altered neuronal and glial function (Harrison, 2002;Rajkowska and Stockmeier, 2013;Yuksel and Ongur, 2010).…”