Relationships Between GABA Levels and Functional Connectivity Are Disrupted in Adolescent Major Depressive Disorder
Vilma Gabbay, MD, MS; Benjamin Ely, BS; Chuqing Kang; Barbara J. Coffey, MD, MS; F. Xavier Castellanos, MD; Dikoma C. Shungu, PhD; and Michael Milham, MD, PhD
From the New York University Child Study Center, New York (Drs Castellanos, Coffey, and Gabbay, Mr Ely, and Ms Kang), the Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York (Drs Castellanos, Coffey, Gabbay, and Milham); Weill Cornell Medical College, New York, New York (Dr Shungu); and the Child Mind Institute, New York, New York (Dr Milham).
This poster presentation was supported by NIH (AT002395, AT004576, MH077072, MH077072-03S1, MH075895), Chrissy Rossi National Alliance for Research on Schizophrenia and Depression Award, and Leon Levy and Anita Saltz Foundations.
Background: Adolescent major depression (MDD) is a significant public health concern associated with functional and structural abnormalities in the striatum1 and anterior cingulate cortex (ACC).2 We recently demonstrated that ACC levels of gamma-aminobutyric acid (GABA) are decreased in adolescents with MDD.2 Here, we extend these findings by examining the relationship between ACC GABA levels and striatal functional connectivity (FC) in adolescents with MDD and healthy controls (HC). We hypothesized that the ACC GABAergic system modulates fronto-striatal FC, and that this modulation is disrupted in adolescents with MDD.
Methods: Patient population consisted of 18 MDD and 15 HC subjects, ages 12-19. Subjects diagnosed with MDD via the K-SADS-PL had episode duration ≥ 6 weeks and CDRS-R scores ≥ 40. All subjects were psychotropic medication-free for > 3 months. FC Measurements by fMRI for 6 bilateral striatal seeds were obtained on a 3.0 T scanner by acquiring 197 contiguous echo planar imaging functional volumes (TR = 2s, 39 slices) during rest with eyes open. A high-resolution T1-weighted 3D anatomical image was also acquired using a magnetization prepared gradient echo sequence for spatial normalization and localization.
In Vivo GABA Measurements by 1H MRS were acquired from a single 2.5x2.5x3.0 cm3 ACC voxel using a GE 3.0T “EXCITE” MR system and an 8-channel phased-array head coil via the standard J-editing difference method. Rank-based ANCOVA compared the MDD and HC groups while adjusting for age, handedness, sex, and ethnicity.
Results: In the combined group of MDD and HC subjects, fronto-striatal FC was inversely correlated with ACC GABA concentrations (R2 = 0.28, Fig. 1A). In keeping with our hypothesis, this correlation was much stronger for the HC group (R2 = 0.78, Fig. 1B) than for the MDD group (R2 = 0.15, Fig. 1C).
Conclusions: Our findings are in line with previously published reports of ACC and striatal metabolic and functional abnormalities in MDD, and are potentially consistent with the ACC GABAergic system modulating fronto-striatal FC. These findings suggest that FC and GABA levels could serve as objective imaging biomarkers of MDD as well as targets for treatment and response monitoring.
To understand the alterations in fronto-striatal FC and ACC GABA levels associated with adolescent MDD
To understand how combining distinct research modalities can lead to novel discoveries in neuropsychiatric investigations
1. Forbes EE, Hariri AR, Martin SL, et al. Altered striatal activation predicting real-world positive affect in adolescent major depressive disorder. Am J Psychiatry. 2009;166(1):64–73. PubMed
2. Gabbay V, Mao X, Klein RG, et al. Anterior cingulate cortex γ-aminobutyric acid in depressed adolescents: relationship to anhedonia. Arch Gen Psychiatry. 2012;69(2):139–149. PubMed