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MEDIAL FRONTAL CORTEX GAMMA-AMINOBUTYRIC ACID CONCENTRATIONS IN PSYCHOSIS SPECTRUM AND MOOD DISORDERS: A META-ANALYSIS OF PROTON MAGNETIC RESONANCE SPECTROSCOPY STUDIES

      ABSTRACT

      Background

      Abnormalities of gamma-aminobutyric acid-ergic (GABAegic) systems may play a role in schizophrenia and mood disorders. Magnetic resonance spectroscopy allows for non-invasive in-vivo quantification of GABA; however, studies of GABA in schizophrenia have yielded inconsistent findings. This may stem from grouping together disparate voxels from functionally heterogeneous regions.

      Methods

      We searched PubMed for magnetic resonance spectroscopy studies of medial frontal cortex (MFC) GABA in patients with schizophrenia, bipolar disorder, depression, and individuals meeting ultra-high risk for psychosis criteria. Voxel placements were classified as rostral-, rostral-mid-, mid-, or posterior MFC, and meta-analyses conducted for each group, for each sub-region.

      Results

      Of 341 screened articles, 23 studies of schizophrenia, 6 studies of bipolar disorder, 20 studies of depression and 7 studies of ultra-high risk met inclusion criteria. Meta-analysis revealed lower mid- (SMD = -0.28, 95% confidence interval [CI] = -0.48 to -0.07, p < .01) and posterior (SMD = -0.29, 95% CI = -0.49 to -0.09, p <.01) MFC GABA in schizophrenia and increased rostral MFC GABA in bipolar disorder (SMD = 0.76, 95% CI = 0.25 to 1.25, p < .01). In depression, reduced rostral MFC GABA (SMD = -0.36, 95% CI = -0.64 to -0.08, p = .01) did not survive correction for multiple comparisons. We found no evidence for GABA differences in ultra-high risk individuals.

      Conclusions

      While limited by small numbers of published studies, these results substantiate the relevance GABA in the pathophysiology of psychosis spectrum and mood disorders and underline the importance of voxel placement.

      Keywords

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      REFERENCES

        • Lewis D.A.
        • Hashimoto T.
        • Volk D.W.
        Cortical inhibitory neurons and schizophrenia.
        Nature Reviews Neuroscience. 2005, April; 6 (Nature Publishing Group): 312-324
        • Hashimoto T.
        • Volk D.W.
        • Eggan S.M.
        • Mirnics K.
        • Pierri J.N.
        • Sun Z.
        • et al.
        Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia.
        J Neurosci. 2003; 23: 6315-6326
        • Volk D.W.
        • Austin M.C.
        • Pierri J.N.
        • Sampson A.R.
        • Lewis D.A.
        Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical γ-aminobutyric acid neurons in subjects with schizophrenia.
        Arch Gen Psychiatry. 2000; 57: 237-245
        • Akbarian S.
        • Kim J.J.
        • Potkin S.G.
        • Hagman J.O.
        • Tafazzoli A.
        • Bunney W.E.
        • Jones E.G.
        Gene Expression for Glutamic Acid Decarboxylase is Reduced without Loss of Neurons in Prefrontal Cortex of Schizophrenics.
        Arch Gen Psychiatry. 1995; 52: 258-266
        • Thompson M.
        • Weickert C.S.
        • Wyatt E.
        • Webster M.J.
        Decreased glutamic acid decarboxylase67 mRNA expression in multiple brain areas of patients with schizophrenia and mood disorders.
        J Psychiatr Res. 2009; 43: 970-977
        • Guidotti A.
        • Auta J.
        • Davis J.M.
        • Gerevini V.D.
        • Dwivedi Y.
        • Grayson D.R.
        • et al.
        Decrease in Reelin and Glutamic Acid Decarboxylase67 (GAD67) Expression in Schizophrenia and Bipolar Disorder: A Postmortem Brain Study.
        Arch Gen Psychiatry. 2000; 57: 1061-1069
      1. Torrey EF, Barci BM, Webster MJ, Bartko JJ, Meador-Woodruff JH, Knable MB (2005): Neurochemical markers for schizophrenia, bipolar disorder, and major depression in postmortem brains. 57: 252–260.

      2. Woo TUW, Kim AM, Viscidi E (2008): Disease-specific alterations in glutamatergic neurotransmission on inhibitory interneurons in the prefrontal cortex in schizophrenia. 1218: 267–277.

        • Karolewicz B.
        • MacIag D.
        • O’Dwyer G.
        • Stockmeier C.A.
        • Feyissa A.M.
        • Rajkowska G.
        Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression.
        Int J Neuropsychopharmacol. 2010; 13: 411-420
        • Petty F.
        Plasma concentrations of γ-aminobutyric acid (GABA) and mood disorders: A blood test for manic depressive disease?.
        Clinical Chemistry. 1994; 40 40: 296-302
        • Petty F.
        • Kramer G.L.
        • Fulton M.
        • Davis L.
        • Rush A.J.
        Stability of plasma GABA at four-year follow-up in patients with primary unipolar depression.
        Biol Psychiatry. 1995; 37: 806-810
        • Gold B.I.
        • Bowers M.B.
        • Roth R.H.
        • Sweeney D.W.
        GABA levels in CSF of patients with psychiatric disorders.
        Am J Psychiatry. 1980; 137: 362-364
        • Gerner R.H.
        • Hare T.A.
        CSF GABA in normal subjects and patients with depression, schizophrenia, mania, and anorexia nervosa.
        Am J Psychiatry. 1981; 138: 1098-1101
        • Kasa K.
        • Otsuki S.
        • Yamamoto M.
        • Sato M.
        • Kuroda H.
        • Ogawa N.
        Cerebrospinal fluid γ-aminobutyric acid and homovanillic acid in depressive disorders.
        Biol Psychiatry. 1982; 17: 877-883
        • Fee C.
        • Banasr M.
        • Sibille E.
        Somatostatin-Positive Gamma-Aminobutyric Acid Interneuron Deficits in Depression: Cortical Microcircuit and Therapeutic Perspectives.
        Biological Psychiatry. 2017, October 15; 82 (Elsevier): 549-559
        • Mescher M.
        • Tannus A.
        • O’Neil Johnson M.
        • Garwood M.
        Solvent suppression using selective echo dephasing.
        J Magn Reson - Ser A. 1996; 123: 226-229
        • Mescher M.
        • Merkle H.
        • Kirsch J.
        • Garwood M.
        • Gruetter R.
        Simultaneous in vivo spectral editing and water suppression.
        NMR Biomed. 1998; 11: 266-272
        • Öngür D.
        • Prescot A.P.
        • McCarthy J.
        • Cohen B.M.
        • Renshaw P.F.
        Elevated gamma-aminobutyric acid levels in chronic schizophrenia.
        Biol Psychiatry. 2010; 68: 667-670
        • Kegeles L.S.
        • Mao X.
        • Stanford A.D.
        • Girgis R.
        • Ojeil N.
        • Xu X.
        • et al.
        Elevated prefrontal cortex γ-aminobutyric acid and glutamate-glutamine levels in schizophrenia measured in vivo with proton magnetic resonance spectroscopy.
        Arch Gen Psychiatry. 2012; 69: 449-459
        • Rowland L.M.
        • Kontson K.
        • West J.
        • Edden R.A.
        • Zhu H.
        • Wijtenburg S.A.
        • et al.
        In vivo measurements of glutamate, GABA, and NAAG in schizophrenia.
        Schizophr Bull. 2013; 39: 1096-1104
        • Kelemen O.
        • Kiss I.
        • Benedek G.
        • Kéri S.
        Perceptual and cognitive effects of antipsychotics in first-episode schizophrenia: The potential impact of GABA concentration in the visual cortex.
        Prog Neuro-Psychopharmacology Biol Psychiatry. 2013; 47: 13-19
        • Tayoshi S.
        • Nakataki M.
        • Sumitani S.
        • Taniguchi K.
        • Shibuya-Tayoshi S.
        • Numata S.
        • et al.
        GABA concentration in schizophrenia patients and the effects of antipsychotic medication: A proton magnetic resonance spectroscopy study.
        Schizophr Res. 2010; 117: 83-91
        • Kumar V.
        • Vajawat B.
        • Rao N.P.
        Frontal GABA in schizophrenia: A meta-analysis of 1H-MRS studies.
        World J Biol Psychiatry. 2021; 22: 1-13
        • Nakahara T.
        • Tsugawa S.
        • Noda Y.
        • Ueno F.
        • Honda S.
        • Kinjo M.
        • et al.
        Glutamatergic and GABAergic metabolite levels in schizophrenia-spectrum disorders: a meta-analysis of 1H-magnetic resonance spectroscopy studies.
        Molecular Psychiatry. 2021; https://doi.org/10.1038/s41380-021-01297-6
        • Schür R.R.
        • Draisma L.W.
        • Wijnen J.P.
        • Boks M.P.
        • Koevoets M.G.J.C.
        • Joëls M.
        • et al.
        Brain GABA levels across psychiatric disorders: A systematic literature review and meta-analysis of 1H-MRS studies.
        Human Brain Mapping. 2016, September 1; 37 (John Wiley and Sons Inc.): 3337-3352
        • Sydnor V.J.
        • Roalf D.R.
        A meta-analysis of ultra-high field glutamate, glutamine, GABA and glutathione 1HMRS in psychosis: Implications for studies of psychosis risk.
        Schizophr Res. 2020; 226: 61-69
        • Egerton A.
        • Modinos G.
        • Ferrera D.
        • McGuire P.
        Neuroimaging studies of GABA in schizophrenia: A systematic review with meta-analysis.
        Translational Psychiatry. 2017; 7https://doi.org/10.1038/tp.2017.124
        • Bhagwagar Z.
        • Wylezinska M.
        • Jezzard P.
        • Evans J.
        • Boorman E.
        • Matthews P.M.
        • Cowen P.J.
        Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients.
        Int J Neuropsychopharmacol. 2008; 11: 255-260
      3. Song XM, Hu XW, Li Z, Gao Y, Ju X, Liu DY, et al. (2021): Reduction of higher-order occipital GABA and impaired visual perception in acute major depressive disorder. Mol Psychiatry 2021 2611 26: 6747–6755.

        • Price R.B.
        • Shungu D.C.
        • Mao X.
        • Nestadt P.
        • Kelly C.
        • Collins K.A.
        • et al.
        Amino Acid Neurotransmitters Assessed by Proton Magnetic Resonance Spectroscopy: Relationship to Treatment Resistance in Major Depressive Disorder.
        Biol Psychiatry. 2009; 65: 792-800
        • Abdallah C.G.
        • Jiang L.
        • De Feyter H.M.
        • Fasula M.
        • Krystal J.H.
        • Rothman D.L.
        • et al.
        Glutamate Metabolism in Major Depressive Disorder.
        Am J Psychiatry. 2014; 171: 1320
        • Walter M.
        • Henning A.
        • Grimm S.
        • Schulte R.F.
        • Beck J.
        • Dydak U.
        • et al.
        The relationship between aberrant neuronal activation in the pregenual anterior cingulate, altered glutamatergic metabolism, and anhedonia in major depression.
        Arch Gen Psychiatry. 2009; 66: 478-486
        • Shaw A.
        • Brealy J.
        • Richardson H.
        • Muthukumaraswamy S.D.
        • Edden R.A.
        • John Evans C.
        • et al.
        Marked Reductions in Visual Evoked Responses But Not γ-Aminobutyric Acid Concentrations or γ-Band Measures in Remitted Depression.
        Biol Psychiatry. 2013; 73: 691-698
        • Boy F.
        • Evans C.J.
        • Edden R.A.E.
        • Singh K.D.
        • Husain M.
        • Sumner P.
        Individual differences in subconscious motor control predicted by GABA concentration in SMA.
        Curr Biol. 2010; 20: 1779-1785
        • Grachev I.D.
        • Vania Apkarian A.
        Aging alters regional multichemical profile of the human brain: An in vivo 1H-MRS study of young versus middle-aged subjects.
        J Neurochem. 2001; 76: 582-593
        • Greenhouse I.
        • Noah S.
        • Maddock R.J.
        • Ivry R.B.
        Individual differences in GABA content are reliable but are not uniform across the human cortex.
        Neuroimage. 2016; 139: 1-7
        • de la Vega A.
        • Chang L.J.
        • Banich M.T.
        • Wager T.D.
        • Yarkoni T.
        Large-Scale Meta-Analysis of Human Medial Frontal Cortex Reveals Tripartite Functional Organization.
        J Neurosci. 2016; 36: 6553-6562
        • Taylor S.F.
        • Tso I.F.
        GABA abnormalities in schizophrenia: A methodological review of in vivo studies.
        Schizophrenia Research. 2015, September 1; 167 (Elsevier B.V.): 84-90
        • Romeo B.
        • Choucha W.
        • Fossati P.
        • Rotge J.Y.
        Meta-analysis of central and peripheral γ-aminobutyric acid levels in patients with unipolar and bipolar depression.
        J Psychiatry Neurosci. 2018; 43: 58-66
        • Scotti-Muzzi E.
        • Umla-Runge K.
        • Soeiro-de-Souza M.G.
        Anterior cingulate cortex neurometabolites in bipolar disorder are influenced by mood state and medication: A meta-analysis of 1H-MRS studies.
        European Neuropsychopharmacology. 2021; 47: 62-73
        • Godfrey K.E.M.
        • Gardner A.C.
        • Kwon S.
        • Chea W.
        • Muthukumaraswamy S.D.
        Differences in excitatory and inhibitory neurotransmitter levels between depressed patients and healthy controls: A systematic review and meta-analysis.
        Journal of Psychiatric Research. 2018; 105: 33-44
        • Wenneberg C.
        • Glenthøj B.Y.
        • Hjorthøj C.
        • Buchardt Zingenberg F.J.
        • Glenthøj L.B.
        • Rostrup E.
        • et al.
        Cerebral glutamate and GABA levels in high-risk of psychosis states: A focused review and meta-analysis of 1H-MRS studies.
        Schizophrenia Research. 2020; 215: 38-48
        • Conn V.S.
        • Valentine J.C.
        • Cooper H.M.
        • Rantz M.J.
        • VS C.
        • JC V.
        • et al.
        Grey literature in meta-analyses.
        Nursing Research. 2003; 52 (Nurs Res): 256-261
        • Viechtbauer W.
        Conducting meta-analyses in R with the metafor.
        J Stat Softw. 2010; 36: 1-48
        • Huedo-Medina T.B.
        • Sánchez-Meca J.
        • Marín-Martínez F.
        • Botella J.
        Assessing heterogeneity in meta-analysis: Q statistic or I 2 Index?.
        Psychol Methods. 2006; 11: 193-206
        • Eggers H.C.
        • Lipa P.
        • Buschbeck B.
        Sensitive test for models of bose-einstein correlations.
        Phys Rev Lett. 1997; 79: 197-200
        • Cen H.
        • Xu J.
        • Yang Z.
        • Mei L.
        • Chen T.
        • Zhuo K.
        • et al.
        Neurochemical and brain functional changes in the ventromedial prefrontal cortex of first-episode psychosis patients: A combined functional magnetic resonance imaging—proton magnetic resonance spectroscopy study.
        Aust N Z J Psychiatry. 2020; 54: 519-527
        • Chen T.
        • Wang Y.
        • Zhang J.
        • Wang Z.
        • Xu J.
        • Li Y.
        • et al.
        Abnormal Concentration of GABA and Glutamate in The Prefrontal Cortex in Schizophrenia.-An in Vivo 1H-MRS Study.
        Shanghai Arch Psychiatry. 2017; 29: 277-286
        • Chiu P.W.
        • Lui S.S.Y.
        • Hung K.S.Y.
        • Chan R.C.K.
        • Chan Q.
        • Sham P.C.
        • et al.
        In vivo gamma-aminobutyric acid and glutamate levels in people with first-episode schizophrenia: A proton magnetic resonance spectroscopy study.
        Schizophr Res. 2018; 193: 295-303
        • de la Fuente-Sandoval C.
        • Reyes-Madrigal F.
        • Mao X.
        • León-Ortiz P.
        • Rodríguez-Mayoral O.
        • Jung-Cook H.
        • et al.
        Prefrontal and Striatal Gamma-Aminobutyric Acid Levels and the Effect of Antipsychotic Treatment in First-Episode Psychosis Patients.
        Biol Psychiatry. 2018; 83: 475-483
        • Ragland J.D.
        • Maddock R.J.
        • Hurtado M.Y.
        • Tanase C.
        • Lesh T.A.
        • Niendam T.A.
        • et al.
        Disrupted GABAergic facilitation of working memory performance in people with schizophrenia.
        NeuroImage Clin. 2020; 25https://doi.org/10.1016/j.nicl.2019.102127
      4. Wang JJ, Wang JJ, Tang Y, Zhang T, Cui H, Xu L, et al. (2016): Reduced γ-Aminobutyric Acid and Glutamate+Glutamine Levels in Drug-Naïve Patients with First-Episode Schizophrenia but Not in Those at Ultrahigh Risk. Neural Plast 2016. https://doi.org/10.1155/2016/3915703

        • Xia M.
        • Wang J.
        • Sheng J.
        • Tang Y.
        • Li C.
        • Lim K.
        • et al.
        Effect of Electroconvulsive Therapy on Medial Prefrontal γ-Aminobutyric Acid among Schizophrenia Patients: A Proton Magnetic Resonance Spectroscopy Study.
        J ECT. 2018; 34: 227-232
        • Yang Z.
        • Zhu Y.
        • Song Z.
        • Mei L.
        • Zhang J.
        • Chen T.
        • et al.
        Comparison of the density of gamma-aminobutyric acid in the ventromedial prefrontal cortex of patients with first-episode psychosis and healthy controls.
        Shanghai Arch Psychiatry. 2015; 27: 341-347
        • Marsman A.
        • Mandl R.C.W.
        • Klomp D.W.J.
        • Bohlken M.M.
        • Boer V.O.
        • Andreychenko A.
        • et al.
        GABA and glutamate in schizophrenia: A 7 T 1H-MRS study.
        NeuroImage Clin. 2014; 6: 398-407
        • Bojesen K.B.
        • Ebdrup B.H.
        • Jessen K.
        • Sigvard A.
        • Tangmose K.
        • Edden R.A.E.
        • et al.
        Treatment response after 6 and 26 weeks is related to baseline glutamate and GABA levels in antipsychotic-naïve patients with psychosis.
        Psychol Med. 2020; 50: 2182-2193
        • Brandt A.S.
        • Unschuld P.G.
        • Pradhan S.
        • Lim I.A.L.
        • Churchill G.
        • Harris A.D.
        • et al.
        Age-related changes in anterior cingulate cortex glutamate in schizophrenia: A 1H MRS Study at 7 Tesla.
        Schizophr Res. 2016; 172: 101-105
        • Goto N.
        • Yoshimura R.
        • Moriya J.
        • Kakeda S.
        • Ueda N.
        • Ikenouchi-Sugita A.
        • et al.
        Reduction of brain γ-aminobutyric acid (GABA) concentrations in early-stage schizophrenia patients: 3T Proton MRS study.
        Schizophrenia Research. 2009; 112: 192-193
        • Reid M.A.
        • Salibi N.
        • White D.M.
        • Gawne T.J.
        • Denney T.S.
        • Lahti A.C.
        7T Proton Magnetic Resonance Spectroscopy of the Anterior Cingulate Cortex in First-Episode Schizophrenia.
        Schizophr Bull. 2019; 45: 180-189
        • Rowland L.M.
        • Krause B.W.
        • Wijtenburg S.A.
        • McMahon R.P.
        • Chiappelli J.
        • Nugent K.L.
        • et al.
        Medial frontal GABA is lower in older schizophrenia: A MEGA-PRESS with macromolecule suppression study.
        Mol Psychiatry. 2016; 21: 198-204
        • Wijtenburg S.A.
        • Wang M.
        • Korenic S.A.
        • Chen S.
        • Barker P.B.
        • Rowland L.M.
        Metabolite Alterations in Adults With Schizophrenia, First Degree Relatives, and Healthy Controls: A Multi-Region 7T MRS Study.
        Front Psychiatry. 2021; 12https://doi.org/10.3389/fpsyt.2021.656459
        • Hjelmervik H.
        • Craven A.R.
        • Sinceviciute I.
        • Johnsen E.
        • Kompus K.
        • Bless J.J.
        • et al.
        Intra-Regional Glu-GABA vs Inter-Regional Glu-Glu Imbalance: A 1H-MRS Study of the Neurochemistry of Auditory Verbal Hallucinations in Schizophrenia.
        Schizophr Bull. 2020; 46: 633-642
        • Marenco S.
        • Meyer C.
        • Kuo S.
        • Van Der Veen J.W.
        • Shen J.
        • DeJong K.
        • et al.
        Prefrontal GABA levels measured with magnetic resonance spectroscopy in patients with psychosis and unaffected siblings.
        American Journal of Psychiatry. 2016; 173 173: 527-534
      5. Simmonite M, Taylor SF (2021): GABA concentrations in first episode psychosis and attenuated psychosis syndrome. Manuscr Prep.

        • De La Fuente-Sandoval C.
        • Reyes-Madrigal F.
        • Mao X.
        • León-Ortiz P.
        • Rodríguez-Mayoral O.
        • Solís-Vivanco R.
        • et al.
        Cortico-striatal GABAergic and glutamatergic dysregulations in subjects at ultra-high risk for psychosis investigated with proton magnetic resonance spectroscopy.
        Int J Neuropsychopharmacol. 2015; 19: 1-10
        • Menschikov P.E.
        • Semenova N.A.
        • Ublinskiy M.V.
        • Akhadov T.A.
        • Keshishyan R.A.
        • Lebedeva I.S.
        • et al.
        1H-MRS and MEGA-PRESS pulse sequence in the study of balance of inhibitory and excitatory neurotransmitters in the human brain of ultra-high risk of schizophrenia patients.
        Dokl Biochem Biophys. 2016; 468: 168-172
        • Wenneberg C.
        • Glenthøj B.Y.
        • Glenthøj L.B.
        • Fagerlund B.
        • Krakauer K.
        • Kristensen T.D.
        • et al.
        Baseline measures of cerebral glutamate and GABA levels in individuals at ultrahigh risk for psychosis: Implications for clinical outcome after 12 months.
        Eur Psychiatry. 2020; 63https://doi.org/10.1192/j.eurpsy.2020.77
        • Da Silva T.
        • Hafizi S.
        • Rusjan P.M.
        • Houle S.
        • Wilson A.A.
        • Prce I.
        • et al.
        GABA levels and TSPO expression in people at clinical high risk for psychosis and healthy volunteers: A PET-MRS study.
        J Psychiatry Neurosci. 2019; 44: 111-119
        • Modinos G.
        • Şimşek F.
        • Azis M.
        • Bossong M.
        • Bonoldi I.
        • Samson C.
        • et al.
        Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis.
        Neuropsychopharmacology. 2018; 43: 2652-2659
        • Brennan B.P.
        • Admon R.
        • Perriello C.
        • LaFlamme E.M.
        • Athey A.J.
        • Pizzagalli D.A.
        • et al.
        Acute change in anterior cingulate cortex GABA, but not glutamine/glutamate, mediates antidepressant response to citalopram.
        Psychiatry Res - Neuroimaging. 2017; 269: 9-16
        • Gabbay V.
        • Mao X.
        • Klein R.G.
        • Ely B.A.
        • Babb J.S.
        • Panzer A.M.
        • et al.
        Anterior cingulate cortex γ-aminobutyric acid in depressed adolescents: Relationship to anhedonia.
        Arch Gen Psychiatry. 2012; 69: 139-149
        • Hasler G.
        • Neumeister A.
        • Van Der Veen J.W.
        • Tumonis T.
        • Bain E.E.
        • Shen J.
        • et al.
        Normal prefrontal gamma-aminobutyric acid levels in remitted depressed subjects determined by proton magnetic resonance spectroscopy.
        Biol Psychiatry. 2005; 58: 969-973
        • Hasler G.
        • Van Der Veen J.W.
        • Tumonis T.
        • Meyers N.
        • Shen J.
        • Drevets W.C.
        Reduced prefrontal glutamate/glutamine and γ-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy.
        Arch Gen Psychiatry. 2007; 64: 193-200
        • Ironside M.
        • Moser A.D.
        • Holsen L.M.
        • Zuo C.S.
        • Du F.
        • Perlo S.
        • et al.
        Reductions in rostral anterior cingulate GABA are associated with stress circuitry in females with major depression: a multimodal imaging investigation.
        Neuropsychopharmacology. 2021; 46: 2188-2196
        • Kantrowitz J.T.
        • Dong Z.
        • Milak M.S.
        • Rashid R.
        • Kegeles L.S.
        • Javitt D.C.
        • et al.
        Ventromedial prefrontal cortex/anterior cingulate cortex Glx, glutamate, and GABA levels in medication-free major depressive disorder.
        Transl Psychiatry. 2021; 11https://doi.org/10.1038/s41398-021-01541-1
      6. Wang Z, Zhang A, Zhao B, Gan J, Wang G, Gao F, et al. (2016): GABA+ levels in postmenopausal women with mild-to-moderate depression A preliminary study. Med (United States) 95. https://doi.org/10.1097/MD.0000000000004918

        • Zhang Z.
        • Fan Q.
        • Bai Y.
        • Wang Z.
        • Zhang H.
        • Xiao Z.
        Brain gamma-aminobutyric acid (GABA) concentration of the prefrontal lobe in unmedicated patients with Obsessivecompulsive disorder: a research of magnetic resonance spectroscopy.
        Shanghai Arch Psychiatry. 2016; 28: 263-270
        • Deligiannidis K.M.
        • Fales C.L.
        • Kroll-Desrosiers A.R.
        • Shaffer S.A.
        • Villamarin V.
        • Tan Y.
        • et al.
        Resting-state functional connectivity, cortical GABA, and neuroactive steroids in peripartum and peripartum depressed women: a functional magnetic resonance imaging and spectroscopy study.
        Neuropsychopharmacology. 2019; 44: 546-554
        • Draganov M.
        • Vives-Gilabert Y.
        • de Diego-Adeliño J.
        • Vicent-Gil M.
        • Puigdemont D.
        • Portella M.J.
        Glutamatergic and GABA-ergic abnormalities in First-episode depression. A 1-year follow-up 1H-MR spectroscopic study.
        J Affect Disord. 2020; 266: 572-577
        • Knudsen M.K.
        • Near J.
        • Blicher A.B.
        • Videbech P.
        • JU Blicher
        Magnetic resonance (MR) spectroscopic measurement of γ-aminobutyric acid (GABA) in major depression before and after electroconvulsive therapy.
        Acta Neuropsychiatr. 2019; 31: 17-26
        • Baeken C.
        • Lefaucheur J.P.
        • Van Schuerbeek P.
        The impact of accelerated high frequency rTMS on brain neurochemicals in treatment-resistant depression: Insights from 1H MR spectroscopy.
        Clin Neurophysiol. 2017; 128: 1664-1672
        • Persson J.
        • Wall A.
        • Weis J.
        • Gingnell M.
        • Antoni G.
        • Lubberink M.
        • Bodén R.
        Inhibitory and excitatory neurotransmitter systems in depressed and healthy: A positron emission tomography and magnetic resonance spectroscopy study.
        Psychiatry Res - Neuroimaging. 2021; 315https://doi.org/10.1016/j.pscychresns.2021.111327
        • Smith G.S.
        • Oeltzschner G.
        • Gould N.F.
        • Leoutsakos J.M.S.
        • Nassery N.
        • Joo J.H.
        • et al.
        Neurotransmitters and Neurometabolites in Late-Life Depression: A Preliminary Magnetic Resonance Spectroscopy Study at 7T.
        J Affect Disord. 2021; 279: 417-425
        • Benson K.L.
        • Bottary R.
        • Schoerning L.
        • Baer L.
        • Gonenc A.
        • Eric Jensen J.
        • Winkelman J.W.
        1H MRS Measurement of Cortical GABA and Glutamate in Primary Insomnia and Major Depressive Disorder: Relationship to Sleep Quality and Depression Severity.
        J Affect Disord. 2020; 274: 624-631
        • Brady R.O.
        • Mccarthy J.M.
        • Prescot A.P.
        • Jensen J.E.
        • Cooper A.J.
        • Cohen B.M.
        • et al.
        Brain gamma-aminobutyric acid (GABA) abnormalities in bipolar disorder.
        Bipolar Disord. 2013; 15: 434-439
        • Godlewska B.R.
        • Yip S.W.
        • Near J.
        • Goodwin G.M.
        • Cowen P.J.
        Cortical glutathione levels in young people with bipolar disorder: A pilot study using magnetic resonance spectroscopy.
        Psychopharmacology (Berl). 2014; 231: 327-332
        • Wang P.W.
        • Sailasuta N.
        • Chandler R.A.
        • Ketter T.A.
        Magnetic resonance spectroscopic measurement of cerebral gamma-aminobutyric acid concentrations in patients with bipolar disorders.
        Acta Neuropsychiatr. 2006; 18: 120-126
        • Huber R.S.
        • Kondo D.G.
        • Shi X.F.
        • Prescot A.P.
        • Clark E.
        • Renshaw P.F.
        • Yurgelun-Todd D.A.
        Relationship of executive functioning deficits to N-acetyl aspartate (NAA) and gamma-aminobutyric acid (GABA) in youth with bipolar disorder.
        J Affect Disord. 2018; 225: 71-78
        • Prisciandaro J.J.
        • Tolliver B.K.
        • Prescot A.P.
        • Brenner H.M.
        • Renshaw P.F.
        • Brown T.R.
        • Anton R.F.
        Unique prefrontal GABA and glutamate disturbances in co-occurring bipolar disorder and alcohol dependence.
        Transl Psychiatry. 2017; 7https://doi.org/10.1038/tp.2017.141
        • Soeiro-de-Souza M.G.
        • Henning A.
        • Machado-Vieira R.
        • Moreno R.A.
        • Pastorello B.F.
        • da Costa Leite C.
        • et al.
        Anterior cingulate Glutamate-Glutamine cycle metabolites are altered in euthymic bipolar I disorder.
        Eur Neuropsychopharmacol. 2015; 25: 2221-2229
        • Pomarol-Clotet E.
        • Canales-Rodríguez E.J.
        • Salvador R.
        • Sarró S.
        • Gomar J.J.
        • Vila F.
        • et al.
        Medial prefrontal cortex pathology in schizophrenia as revealed by convergent findings from multimodal imaging.
        Mol Psychiatry. 2010; 15: 823-830
      7. Ridderinkhof KR, Ullsperger M, Crone EA, Nieuwenhuis S (2004, October 15): The role of the medial frontal cortex in cognitive control. Science, vol. 306. Science, pp 443–447.

        • Taylor S.F.
        • Liberzon I.
        Neural correlates of emotion regulation in psychopathology.
        Trends Cogn Sci. 2007; 11: 413-418
      8. Waugh C, Lemus M, … IG-C and A, 2014 U (n.d.): The role of the medial frontal cortex in the maintenance of emotional states. academic.oup.com. Retrieved February 1, 2022, from https://academic.oup.com/scan/article-abstract/9/12/2001/1619973

        • Luu P.
        • Flaisch T.
        • Tucker D.M.
        Medial frontal cortex in action monitoring.
        J Neurosci. 2000; 20: 464-469
        • Rushworth M.F.S.
        • Walton M.E.
        • Kennerley S.W.
        • Bannerman D.M.
        Action sets and decisions in the medial frontal cortex.
        Trends in Cognitive Sciences. 2004; 8: 410-417
        • Woo T.U.W.
        • Walsh J.P.
        • Benes F.M.
        Density of Glutamic Acid Decarboxylase 67 Messenger RNA–ContainingNeurons That Express the N-Methyl-D-AspartateReceptor Subunit NR2A in the Anterior Cingulate Cortex in Schizophreniaand Bipolar Disorder.
        Arch Gen Psychiatry. 2004; 61: 649-657
        • Barch D.M.
        • Ceaser A.
        Cognition in schizophrenia: Core psychological and neural mechanisms.
        Trends in Cognitive Sciences. 2012, January 1; 16 (Elsevier Current Trends): 27-34
        • Minzenberg M.J.
        • Laird A.R.
        • Thelen S.
        • Carter C.S.
        • Glahn D.C.
        Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia.
        Arch Gen Psychiatry. 2009; 66: 811-822
        • Petty F.
        • Sherman A.D.
        Plasma GABA levels in psychiatric illness.
        J Affect Disord. 1984; 6: 131-138
        • Petty F.
        • Schlesser M.A.
        Plasma GABA in affective illness: A preliminary investigation.
        J Affect Disord. 1981; 3: 339-343
        • Perrine S.A.
        • Ghoddoussi F.
        • Michaels M.S.
        • Sheikh I.S.
        • McKelvey G.
        • Galloway M.P.
        Ketamine reverses stress-induced depression-like behavior and increased GABA levels in the anterior cingulate: An 11.7T 1H-MRS study in rats.
        Prog Neuro-Psychopharmacology Biol Psychiatry. 2014; 51: 9-15
        • Rodriguez C.I.
        • Kegeles L.S.
        • Levinson A.
        • Ogden R.T.
        • Mao X.
        • Milak M.S.
        • et al.
        In vivo effects of ketamine on glutamate-glutamine and gamma-aminobutyric acid in obsessive-compulsive disorder: Proof of concept.
        Psychiatry Res - Neuroimaging. 2015; 233: 141-147
        • Button K.S.
        • Ioannidis J.P.A.
        • Mokrysz C.
        • Nosek B.A.
        • Flint J.
        • Robinson E.S.J.
        • Munafò M.R.
        Power failure: Why small sample size undermines the reliability of neuroscience.
        Nat Rev Neurosci. 2013; 14: 365-376