Marked Reductions in Visual Evoked Responses But Not γ-Aminobutyric Acid Concentrations or γ-Band Measures in Remitted Depression

doi:10.1016/j.biopsych.2012.09.032

Biological Psychiatry

Volume 73, Issue 7, 1 April 2013, Pages 691-698

https://doi.org/10.1016/j.biopsych.2012.09.032 Get rights and content

Abstract

Background

Magnetic resonance spectroscopy (MRS) studies have consistently demonstrated reduced cortical γ-aminobutyric acid (GABA) concentrations in individuals with major depression. However, evidence for a persistent deficit during remission, which would suggest that GABA dysfunction is a possible trait marker of depression, is equivocal. Although MRS measures total concentration of GABA, magneto-encephalography provides direct measures of neural activity, with cortical γ oscillations shaped by the activity of GABAergic inhibitory interneurons. In this study we investigated whether γ oscillations and GABA concentrations would differ in individuals with remitted depression (RD) compared with never depressed control subjects (ND).

Methods

Thirty-seven healthy, unmedicated female volunteers (n = 19 RD, and n = 18 ND) were recruited. The γ oscillation frequencies and amplitudes in the visual cortex, induced by simple grating stimuli, were quantified with time-frequency analyses. Distinct GABA/glutamate + glutamine MRS peaks were resolved from MEGA-PRESS difference spectra in prefrontal, occipital, and subcortical volumes.

Results

The RD and ND individuals did not differ in the frequency of subclinical depressive symptoms. The ND were slightly older (mean = 23 years vs. 21 years), but age did not correlate with dependent measures. There were no group differences in GABA levels or induced cortical γ measures, but RD individuals had markedly reduced M80 (C1) components of the pattern-onset evoked response (46% reduction, Cohen’s d = 1.01, p = .006).

Conclusions

Both MRS and magneto-encephalography measures of the GABA system are normal in RD. However, the early visual evoked response is a potential trait marker of the disorder.

Section snippets

Recruitment and Sample

Thirty-seven healthy female volunteers were recruited from the staff and student body of Cardiff University. The study was approved by the School of Psychology ethics committee of Cardiff University. All individuals gave their informed consent to participate. Inclusion criteria included female gender, age 18–35 years, normal or corrected-to-normal vision, and current good health. For the RD cohort (n = 19), a previous history of depression was determined with an adapted version of the Mini

Sample Characteristics, Illness History, and Depression Symptoms

The ND individuals were slightly older than the RD individuals [23 years (SD = 2.6) vs. 21 years (SD = 1.5), t(35) = 2.9, p = .006], but the small variance in age did not correlate with any of the dependent MEG and MRS measures.

The illness history of the RD individuals is shown in Table 1. Only one third had experienced more than one episode. Most had experienced melancholic depression, although less than one half had received antidepressant treatment. Most had a BADDS score of 60 or above,

Discussion

This is the first study to use IGF as a surrogate in vivo estimate of the action of GABA interneurons on cortical pyramidal cells in unmedicated RD, in combination with MRS measures of GABA concentration. It is also the first study to investigate GABA concentrations in RD in both cortical and subcortical regions.

Our main finding is that RD have normal IGF and MRS-GABA concentrations in the occipital cortex. Hence, two independent imaging measures support the conclusion that occipital GABA

References (61)

A. Alcaro et al.
Is subcortical-cortical midline activity in depression mediated by glutamate and GABA? A cross-species translational approach
Neurosci Biobehav Rev
(2010)
P.E. Croarkin et al.
Evidence for GABAergic inhibitory deficits in major depressive disorder
Neurosci Biobehav Rev
(2011)
Z. Bhagwagar et al.
Reduction in occipital cortex γ-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects
Biol Psychiatry
(2007)
G. Hasler et al.
Normal prefrontal γ-aminobutyric acid levels in remitted depressed subjects determined by proton magnetic resonance spectroscopy
Biol Psychiatry
(2005)
M.L. Phillips et al.
Neurobiology of emotion perception II: Implications for major psychiatric disorders
Biol Psychiatry
(2003)
G.J. Siegle et al.
Can’t shake that feeling: Event-related fMRI assessment of sustained amygdala activity in response to emotional information in depressed individuals
Biol Psychiatry
(2002)
L.M. Ward
Synchronous neural oscillations and cognitive processes
Trends Cogn Sci
(2003)
L.E. Ethridge et al.
Neural activations during auditory oddball processing discriminating schizophrenia and psychotic bipolar disorder
Biol Psychiatry
(2012)
A. Ozerdem et al.
Disturbance in long distance γ coherence in bipolar disorder
Prog Neuropsychopharmacol Biol Psychiatry
(2010)
T.Y. Liu et al.
Different patterns of abnormal γ oscillatory activity in unipolar and bipolar disorder patients during an implicit emotion task
Neuropsychologia
(2012)

R.C. Kessler et al.

Sex and depression in the National Comorbidity Survey. I: Lifetime prevalence, chronicity and recurrence

J Affect Disord

(1993)

J. Vrba et al.

Signal processing in magnetoencephalography

Methods

(2001)

S.D. Muthukumaraswamy et al.

Spatiotemporal frequency tuning of BOLD and γ band MEG responses compared in primary visual cortex

Neuroimage

(2008)

Z. Bhagwagar et al.

Reduction in occipital cortex γ-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects

Biol Psychiatry

(2007)

E.C. Lalor et al.

Visual sensory processing deficits in schizophrenia: Is there anything to the magnocellular account?

Schizophr Res

(2012)

C. Normann et al.

Long-term plasticity of visually evoked potentials in humans is altered in major depression

Biol Psychiatry

(2007)

S.A. Sands et al.

Effect of antidepressants on GABA(B) receptor function and subunit expression in rat hippocampus

Biochem Pharmacol

(2004)

K.S. Kendler et al.

Stressful life events and previous episodes in the etiology of major depression in women: An evaluation of the “kindling” hypothesis

Am J Psychiatry

(2000)

M.H. Trivedi et al.

Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice

Am J Psychiatry

(2006)

A.J. Rush et al.

STAR*D: Revising conventional wisdom

CNS Drugs

(2009)

V. Krishnan et al.

The molecular neurobiology of depression

Nature

(2008)

A.V. Kalueff et al.

Role of GABA in anxiety and depression

Depress Anxiety

(2007)

B. Luscher et al.

The GABAergic deficit hypothesis of major depressive disorder

Mol Psychiatry

(2011)

G. Sanacora et al.

Reduced cortical γ-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy

Arch Gen Psychiatry

(1999)

G. Hasler et al.

Reduced prefrontal glutamate/glutamine and c-aminobutryric acid levels in major depression determined using proton magnetic resonance spectroscopy

Arch Gen Psychiatry

(2007)

G. Sanacora et al.

Increased cortical GABA concentrations in depressed patients receiving ECT

Am J Psychiatry

(2003)

G. Hasler et al.

Discovering imaging endophenotypes for major depression

Mol Psychiatry

(2011)

Z. Bhagwagar et al.

Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients

Int J Neuropsychopharmacol

(2008)

W.C. Drevets

Neuroimaging abnormalities in the amygdala in mood disorders

Ann N Y Acad Sci

(2003)

H.L. Urry et al.

Amygdala and ventromedial prefrontal cortex are inversely coupled during regulation of negative affect and predict the diurnal pattern of cortisol secretion among older adults

J Neurosci

(2006)

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Abnormalities of GABAergic (gamma-aminobutyric acidergic) systems may play a role in schizophrenia and mood disorders. Magnetic resonance spectroscopy allows for noninvasive 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.
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A number of studies have used MRS to investigate GABA and glutamate within the occipital cortex in MDD. Results have, however, been inconsistent, with some studies finding metabolite reductions (Bhagwagar et al., 2007; Sanacora et al., 2004, 1999) but others finding no difference between patients and controls (Price et al., 2009; Shaw et al., 2013). This inconsistency points to a need for additional studies targeting this region, along with a synthesis of existing results through a meta-analysis of occipital cortex MRS studies in MDD.
The neurotransmitters GABA and glutamate have been suggested to play a role in Major Depressive Disorder (MDD) through an imbalance between cortical inhibition and excitation. This effect has been highlighted in higher brain areas, such as the prefrontal cortex, but has also been posited in basic sensory cortices. Based on this, magnetic resonance spectroscopy (MRS) was used to investigate potential changes to GABA+ and glutamate+glutamine (Glx) concentrations within the occipital cortex in MDD patients (n = 25) and healthy controls (n = 25). No difference in occipital GABA+ or Glx concentrations, nor in the GABA+/Glx ratio, was found between groups. An analysis of an extended MDD patient and unmatched control dataset (n = 90) found no correlation between metabolite concentrations and depressive symptoms. These results were integrated with prior studies through metabolite-specific meta-analyses, revealing no difference in occipital GABA and Glx concentrations between patients and controls. An effect of publication year on GABA group differences was found, suggesting that previously reported results may have been artifacts of measurement accuracy. Taken together, our results suggest that, contrary to some prior reports, MRS measurements of occipital GABA and Glx do not differ between MDD patients and controls.
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Disruptions in GABAergic signaling in major depressive disorder (MDD) are well-established across multiple peripheral and central methods of investigation. A host of gene expression changes in MDD subjects reflect deficits in GABAergic signaling. Mounting evidence suggests that these may be more distal manifestations of disruptions in the microcircuitry of the cortex and changes in the excitation-inhibition balance of this microcircuitry. Somatostatin (SST) neurons, a major interneuron subtype, are compromised in MDD patients and preclinical rodent models of stress. Indeed, SST neurons are selectively vulnerable to stress and show a host of transcriptomic change suggestive of impaired function. SST deficits are highly relevant to brain function, and many potential treatment targets present themselves in identifying these neurons as a key pathological feature of MDD.
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Based on full-text review, a further 39 studies were excluded for the following reasons: 16 were review articles rather than individual studies (Bustillo, 2013; Kalueff and Nutt, 2007; Kendell et al., 2005; Lee et al., 2014; Lener et al., 2017; Leung and Xue, 2003; Luscher and Fuchs, 2015; Luscher et al., 2011; Moore and Galloway, 2002; Nikolaus et al., 2014; Northoff and Sibille, 2014a; Northoff and Sibille, 2014; Prakash and Sumant, 2000; Quattrocki et al., 2000; Quinones and Kaddurah-Daouk, 2009; Uzunova et al., 2006); 12 did not include MRS techniques (Bosch et al., 2012; Kasa et al., 1982; Küçükibrahimoğlu et al., 2009; Levinson et al., 2010; Pabba and Sibille, 2016; Petty, 1994; Petty et al., 1995a; Petty et al., 1992; Petty and Schlesser, 1981; Preuss et al., 2013; Werner and Covenas, 2011; Wu et al., 2016); seven had no healthy control group (Milak et al., 2016; Salvadore et al., 2012; Sanacora et al., 2006; Sanacora et al., 2003; Sanacora et al., 2002; Streeter et al., 2017; Valentine et al., 2011); one was a letter to the editor (Jha and Sachdeva, 2016); one did not meet MDD diagnostic criteria (Taylor et al., 2011); one had missing data (Murrough et al., 2010); and due to inability to access the full text, one article that passed the initial abstract screening was excluded from this review (Bajbouj, 2011). A total of 38 studies were included in the analysis (Abdallah et al., 2017; Abdallah et al., 2014; Auer et al., 2000; Bhagwagar et al., 2007; Bhagwagar et al., 2008; Binesh et al., 2004; Block et al., 2009; Caetano et al., 2005; Epperson et al., 2006; Gabbay et al., 2017; Gabbay et al., 2012; Godlewska et al., 2017; Godlewska et al., 2015; Hasler et al., 2005; Hasler et al., 2007; Jollant et al., 2016; Kugaya et al., 2003; Li et al., 2016; McEwen et al., 2012; Merkl et al., 2011; Michael et al., 2003; Milne et al., 2009; Mirza et al., 2004; Nery et al., 2009; Pfleiderer et al., 2003; Portella et al., 2011; Price et al., 2009; Rosa et al., 2017; Rosenberg et al., 2005; Sanacora et al., 2004; Sanacora et al., 1999; Shaw et al., 2013; Taylor et al., 2009; Taylor et al., 2017; Venkatraman et al., 2009; Walter et al., 2009; Wang et al., 2016; Zhang et al., 2016), with a study population of 798 patients diagnosed with MDD, and 769 healthy controls. ( Table 1).
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Archival ReportMarked Reductions in Visual Evoked Responses But Not γ-Aminobutyric Acid Concentrations or γ-Band Measures in Remitted Depression

Abstract

Background

Methods

Results

Conclusions

Section snippets

Recruitment and Sample

Sample Characteristics, Illness History, and Depression Symptoms

Discussion

Neurosci Biobehav Rev

Neurosci Biobehav Rev

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Trends Cogn Sci

Biol Psychiatry

Prog Neuropsychopharmacol Biol Psychiatry

Neuropsychologia

J Affect Disord

Methods

Neuroimage

Biol Psychiatry

Schizophr Res

Biol Psychiatry

Biochem Pharmacol

Stressful life events and previous episodes in the etiology of major depression in women: An evaluation of the “kindling” hypothesis

Am J Psychiatry

Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice

Am J Psychiatry

STAR*D: Revising conventional wisdom

CNS Drugs

The molecular neurobiology of depression

Nature

Role of GABA in anxiety and depression

Depress Anxiety

The GABAergic deficit hypothesis of major depressive disorder

Mol Psychiatry

Reduced cortical γ-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy

Arch Gen Psychiatry

Reduced prefrontal glutamate/glutamine and c-aminobutryric acid levels in major depression determined using proton magnetic resonance spectroscopy

Arch Gen Psychiatry

Increased cortical GABA concentrations in depressed patients receiving ECT

Am J Psychiatry

Discovering imaging endophenotypes for major depression

Mol Psychiatry

Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients

Int J Neuropsychopharmacol

Neuroimaging abnormalities in the amygdala in mood disorders

Ann N Y Acad Sci

Amygdala and ventromedial prefrontal cortex are inversely coupled during regulation of negative affect and predict the diurnal pattern of cortisol secretion among older adults

J Neurosci

Archival Report
Marked Reductions in Visual Evoked Responses But Not γ-Aminobutyric Acid Concentrations or γ-Band Measures in Remitted Depression