Prefrontal cortical GABA abnormalities are associated with reduced hippocampal volume in major depressive disorder
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Hippocampal volume reduction has been related to treatment-resistant depression (TRD) and is hypothesized to reflect impaired amino-acid neurotransmission. To better understand the role of amino acid neurotransmission in hippocampal volume deficits, and subsequent resistance to treatment, this study investigated the relationship between hippocampal volumes and GABA levels in the anterior cingulate cortex (ACC), previously associated with TRD. Thirty-three medication-free major depressive disorder (MDD; 14 TRD and 19 non-TRD) and 26 healthy controls (HC) subjects were studied. Participants underwent high-resolution magnetic resonance imaging (MRI) to estimate hippocampal volume and proton MR spectroscopy ((1)H MRS) to measure ACC GABA levels. MDD patients, with known ACC GABA levels, were divided into two groups: MDD Low GABA and MDD High GABA. We found a significant reduction in hippocampal volume in the MDD Low GABA group compared to MDD High GABA (p<0.001) and HC (p=0.01). The relationship between hippocampal volume and cortical GABA was population (i.e. MDD group) and region specific (i.e. prefrontal cortex). Comparing TRD, non-TRD and HC groups, there was a main effect of group on hippocampal volume (p=0.04), which post hoc analysis revealed as smaller hippocampal volume in TRD subjects than in non-TRD (p=0.05) and HC groups (p=0.03). No hippocampal volume differences between non-TRD and HC groups. The data provides insight into the role of prefrontal neurochemical deficits in the limbic structural abnormalities observed in MDD. In addition, it replicates the relationship between TRD and smaller hippocampal volumes.
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Several human magnetic resonance spectroscopy studies report lower medial prefrontal cortex GABA levels in major depressive disorder.
“Several human MRS studies have reported lower mPFC GABA levels in MDD (139–141).”
From The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology (2019) · cites this paper as [139]
Lower medial prefrontal cortex GABA levels in major depressive disorder have been linked to smaller hippocampal volumes and to treatment resistance.
“Reduced mPFC GABA levels in MDD have been associated with smaller hippocampal volumes (139) and treatment resistance (142,143).”
From The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology (2019) · cites this paper as [139]
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“For example, the HPC and mPFC exhibit increased synchrony in anxiogenic environments (Adhikari et al., 2010; Schoenfeld et al., 2014; Abdallah et al., 2015).”
BackgroundAbdallah, C. G., Sanacora, G., Duman, R. S., & Krystal, J. H. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.05.010 · Cited by 219 · see citing works
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Self-citation
- Authors
- Abdallah, C. G., Jackowski, A., Sato, J. R., Mao, X., Kang, G., Cheema, R., Coplan, J. D., Mathew, S. J., & Shungu, D. C.
- Affiliations
- Yale University (US)
- Universidade Federal de São Paulo (BR)
- Universidade Federal do ABC (BR)
- Cornell University (US)
- SUNY Downstate Health Sciences University (US)
- Michael E. DeBakey VA Medical Center (US)
- Corresponding author
- Abdallah, Chadi G.
- ORCID
- Venue
- European Neuropsychopharmacology
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 25
- Issue
- 8
- Pages
- 1082-1090
- ISSN
- 0924-977X (ISSN-L)
- PMC
- PMC4526377
- OpenAlex
- W1560836719
- Cited by
- 67
- References
- 50
- Citations by year
- 2026: 8 · 2025: 2 · 2024: 4 · 2023: 6 · 2022: 3 · 2021: 4 · 2020: 8 · 2019: 10 · 2018: 10 · 2017: 6 · 2016: 5 · 2015: 1
- FWCI
- 5.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- European Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01-MH07895 (DCS), K23-MH-069656, MO1-RR-00071 (SJM))
- CFIDS Association of America, Inc (DCS)
- Weill Cornell Medical College New Faculty Development Funds (DCS)
- NIDA (T32 DA022975)
- Clinical Neurosciences Division of the VA National Center for Posttraumatic Stress Disorder, the Brain & Behavior Research Foundation (NARSAD New Investigator Award—Vital Projects Fund Inc. Investigator) (NIMH K23 MH-101498 (CGA))
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- major depressive disorder, treatment-resistant depression, hippocampal volume, GABA, anterior cingulate cortex, prefrontal cortex, amino acid neurotransmission, 1H NMR
- MeSH terms
- Adult, Major Depressive Disorder, Female, gamma-Aminobutyric Acid, Gyrus Cinguli, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Organ Size, Prefrontal Cortex, Proton Magnetic Resonance Spectroscopy
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