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Reduced Anterior Cingulate Cortex Glutamatergic Concentrations in Childhood Major Depression

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ABSTRACT

Objective

To examine in vivo glutamatergic neurochemical alterations in the anterior cingulate cortex of children with major depressive disorder (MDD).

Method

Single-voxel proton magnetic resonance spectroscopic (1H-MRS) examinations of the anterior cingulate cortex were conducted in 13 psychotropic-naïve children and adolescents with MDD and 13 age- and sex-matched healthy children and adolescents. Ten of the 13 MDD patient–control pairs also had a 1H-MRS examination of occipital cortex.

Results

Anterior cingulate glutamatergic (Glx) concentrations were significantly lower (19% decrease) in MDD patients versus controls (9.27 ± 0.43 versus 11.47 ± 0.26, respectively, p = .000). Reduced anterior cingulate Glx in MDD patients was associated with increased severity of functional impairment. These results remained comparably significant after controlling for age and anterior cingulate volume. Occipital cortex Glx did not differ between MDD patients and controls.

Conclusions

These preliminary findings provide new evidence of localized functional neurochemical marker alterations in Glx in anterior cingulate cortex in pediatric MDD. Altered anterior cingulate Glx neurotransmission may be involved in the pathogenesis of MDD.

Section snippets

Subjects

This research investigation was approved by the Wayne State University Human Investigation Committee. All legal guardians provided written informed consent and all children gave written assent before initiating studies and after having understood all issues involved in participation in the study protocol. Thirteen psychotropic drug-naïve, right-hand-dominant child and adolescent outpatients with MDD and 13 healthy comparison subjects matched for age, gender, weight, height, handedness, and

RESULTS

A significant decrease (19%) in Glx was observed in the anterior cingulate cortex (t24 = 4.01, p = .000; F1,22 = 16.50, p = .001) but not in the occipital cortex (t18 = 0.97, p = .344; F1,17 = 0.99, p = .333) in MDD patients versus controls (Fig. 3, Table 2). Reduced anterior cingulate Glx in MDD patients was inversely correlated with increased functional impairment as measured by the CGI-S (r = −0.66, p = .021) but was not correlated with depressive symptom score as measured by the CDRS-R or

Clinical Implications

To our knowledge, this is the first neuroimaging study of children with MDD demonstrating localized decreased anterior cingulate Glx concentrations. These findings replicate and extend the findings of Auer et al. (2000) and Pfleiderer et al. (2003) in studies that demonstrated reduced anterior cingulate Glx concentrations in severely depressed unipolar adults. Our study provides important new data about disturbances in anterior cingulate Glx neurotransmission without the potential confounds of

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      These findings suggest that ACC dysfunction may be involved in the pathophysiology of MDD. Previous studies have shown the difference in neuro-metabolites in the ACC between MDD patients and healthy control subjects (Mirza et al., 2004; Gabbay et al., 2017; Hasler et al., 2007; Güleş et al., 2020; Chen et al., 2014). Glutamate (Glu), glutamine (Gln), γ-aminobutyric acid (GABA), N-acetyl-aspartate (NAA), choline (Cho) and Myo-inositol (MI) were the most commonly examined neuro-metabolites in MDD patients with 1H-MRS studies (Lener et al., 2017; Drago et al., 2018; Tosun et al., 2020).

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    This work was supported in part by the State of Michigan Joe F. Young Sr. Psychiatric Research and Training Program, grants from NIMH (MH65122, MH59299, MH02037), NARSAD, and the Miriam L. Hamburger Endowed Chair at Children's Hospital of Michigan and Wayne State University.

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