Altered anterior cingulate glutamatergic metabolism in depressed adolescents with current suicidal ideation

Abstract

The anterior cingulate cortex (ACC) is involved in emotion regulation and salience processing. Prior research has implicated ACC dysfunction in suicidal ideation (SI) and suicidal behavior. This study aimed to quantify ACC glutamatergic concentrations and to examine relationships with SI in a sample of healthy and depressed adolescents. Forty adolescents underwent clinical evaluation and proton magnetic resonance spectroscopy (1 H-MRS) at 3 T, utilizing a 2-dimensional J-averaged PRESS sequence sampling a medial pregenual ACC voxel. Cerebrospinal fluidcorrected ACC metabolite concentrations were compared between healthy control (HC, n = 16), depressed without SI (Dep/SI−, n = 13), and depressed with SI (Dep/SI+, n = 11) youth using general linear models covarying for age, sex, and psychotropic medication use. Relationships between ACC metabolites and continuous measures of SI were examined using multiple linear regressions. ROC analysis was used to determine the ability of glutamate+glutamine (Glx) and the N-acetylaspartate (NAA)/Glx ratio to discriminate Dep/SI− and Dep/SI+ adolescents. Dep/SI+ adolescents had higher Glx than Dep/SI− participants (p adj = 0.012) and had lower NAA/Glx than both Dep/SI− (p adj = 0.002) and HC adolescents (p adj = 0.039). There were significant relationships between SI intensity and Glx (p FDR = 0.026), SI severity and NAA/Glx (p FDR = 0.012), and SI intensity and NAA/Glx (p FDR = 0.004). ACC Glx and NAA/Glx discriminated Dep/SI− from Dep/SI+ participants. Uncoupled NAA−glutamatergic metabolism in the ACC may play a role in suicidal ideation and behavior. Longitudinal studies are needed to establish whether aberrant glutamatergic metabolism corresponds to acute or chronic suicide risk. Glutamatergic biomarkers may be promising targets for novel risk assessment and interventional strategies for suicidal ideation and behavior.

Higher Levels of Pro-inflammatory Cytokines Are Associated With Higher Levels of Glutamate in the Anterior Cingulate Cortex in Depressed Adolescents

“…We focused on the dorsal division of the ACC based on findings of previous studies that abnormalities in this region may be a neurodevelopmentally sensitive marker of adolescent depression (28), in contrast to the rostral (pregenual) or medial ACC (22). Studies focused on the rostral and medial ACC in depressed adolescents, however, have found evidence of higher Glx (sum of glutamate and glutamine, a precursor to glutamate and GABA) in depressed adolescents with suicidal ideation than in healthy controls (53), as well as reductions in the ratio of glutamine to glutamate (Gln/Glu) in response to treatment-related symptom improvement (54). Although these studies examined Glx and Gln/Glu rather than solely Glu, their data are nonetheless consistent with our findings that higher levels of Glu may contribute to depressive symptomatology.…”

Glutamate and GABA Homeostasis and Neurometabolism in Major Depressive Disorder

“…Glutamate level was reported to be decreased together with myo-inositol (a glial marker) and NAA in ACC of depressed subjects ( 120 , 126 ). Reduced levels of Glx and glutamine have also been reported in the hippocampus of unipolar MDD subjects ( 121 ).…”

“…Although the physiological role of NAA in neural function is unclear, it is typically associated with neuronal integrity and mitochondrial health ( 158 ). Reduced level of NAA is reported in different brain regions of depressed subjects, including PFC ( 112 , 113 ), ACC ( 120 , 126 ), right frontal and parietal lobe ( 108 ), and in the hippocampus ( 122 , 159 ) ( Tables 1 , 2 ). A lower level of NAA has also been seen in the hippocampus ( 122 ), nucleus accumbens ( 110 ) and PFC ( 112 , 116 ) of rodent models of depression.…”

Understanding complex functional wiring patterns in major depressive disorder through brain functional connectome

“…Interestingly, previous studies also reported some protein and metabolite biomarkers for suicidal behaviors in the brain regions with functional connectome alternations and the peripheral blood [ 88 – 92 ]. These proteins, neurotransmitters, and metabolites are primarily related to neurogenesis, neurometabolism, synaptic plasticity, and immune-inflammatory processes (Fig.…”