Background Very few studies have been performed to understand the underlying neural substrates of adolescent major depressive disorder (MDD). Studies in depressed adults have demonstrated that the subgenual anterior cingulate cortex (sgACC) plays a pivotal role in depression and have revealed aberrant patterns of resting-state functional connectivity (RSFC). Here, we examine the RSFC of the sgACC in medication-naïve first-episode adolescents with MDD. Methods Twenty-three adolescents with MDD and 36 well-matched control subjects underwent functional magnetic resonance imaging to assess the RSFC of the sgACC. Results We observed elevated connectivity between the sgACC and the insula and between the sgACC and the amygdala in the MDD group compared with the control subjects. Decreased connectivity between the sgACC and the precuneus was also found in the MDD group relative to the control subjects. Within the MDD group, higher levels of depression significantly correlated with decreased connectivity between the sgACC and left precuneus. Increased rumination was significantly associated with reduced connectivity between sgACC and the middle and inferior frontal gyri in the MDD group. Conclusions Our study is the first to examine sgACC connectivity in medication-naïve first-episode adolescents with MDD compared with well-matched control participants. Our results suggest aberrant functional connectivity among the brain networks responsible for salience attribution, executive control, and the resting-state in the MDD group compared with the control participants. Our findings raise the possibility that therapeutic interventions that can restore the functional connectivity among these networks to that typical of healthy adolescents might be a fruitful avenue for future research.

Objective While substantial literature has reported regional cerebral blood flow (rCBF) abnormalities in adults with depression, these studies commonly necessitated the injection of radioisotopes into subjects. The recent development of arterial spin labeling (ASL), however, allows for noninvasive measurements of rCBF. Currently, no published ASL studies have examined cerebral perfusion in adolescents with depression. Thus, the aim of the present study was to examine baseline cerebral perfusion in adolescent depression using a newly developed ASL technique: pseudocontinuous arterial spin labeling (PCASL). Method 25 medication-naive adolescents (ages 13–17 years) diagnosed with major depressive disorder (MDD) and 26 well-matched controls underwent functional magnetic resonance imaging. Baseline rCBF was measured via a novel PCASL method that optimizes tagging efficiency. Results Voxel-based whole brain analyses revealed significant frontal, limbic, paralimbic, and cingulate hypoperfusion in the group with depression (p<0.05, corrected). Hyperperfusion was also observed within the subcallosal cingulate, putamen, and fusiform gyrus (p<0.05, corrected). Similarly, region-of-interest analyses revealed amygdalar and insular hypoperfusion in the group with depression, as well as hyperperfusion in the putamen and superior insula (p<0.05, corrected). Conclusions Adolescents with depression and healthy adolescents appear to differ on rCBF in executive, affective, and motor networks. Dysfunction in these regions may contribute to the cognitive, emotional, and psychomotor symptoms commonly present in adolescent depression. These findings point to possible biomarkers for adolescent depression that could inform early interventions and treatments and establishes a methodology for using PCASL to noninvasively measure rCBF in clinical and healthy adolescent populations.

Purpose Evidence suggests that aberrant glutamatergic-signalling plays a role in numerous psychopathologies. To ascertain the mechanisms of neuropsychiatric illnesses and their treatment, accurate and reliable imaging techniques are required; proton magnetic resonance spectroscopy (1H-MRS) can non-invasively measure glutamatergic function. Until recently, overlapping glutamatergic signals (glutamate, glutamine, and glutathione) could not easily be separated. However, the advent of novel pulse sequences and higher field magnetic resonance imaging (MRI) allows more precise resolution of overlapping glutamatergic signals, although the question of signal reliability remains undetermined. Materials and Methods At 7 T MR, we acquired 1H-MRS data from the medial pregenual anterior cingulate cortex of healthy volunteers (N = 26) twice on two separate days. An adapted echo time optimised point resolved spectroscopy sequence, modified with the addition of a J-suppression pulse to attenuate N-acetyl-aspartate multiplet signals at 2.49 parts per million, was used to excite and acquire the spectra. In house software was used to model glutamate, glutamine, and glutathione, amongst other metabolites, referenced to creatine. Intraclass correlation coefficients (ICCs) were computed for within- and between-session measurements. Results Within-session measurements of glutamate, glutamine, and glutathione were on average reliable (ICCs ≥ 0.7). As anticipated, ICCs for between-session values of glutamate, glutamine, and glutathione were slightly lower but nevertheless reliable (ICC > 0.62). A negative correlation was observed between glutathione concentration and age (r(24) = −0.37; P < .05), and a gender effect was noted on glutamine and glutathione. Conclusion The adapted sequence provides good reliability to measure glutamate, glutamine and glutathione signals.

The glutamatergic modulator ketamine has striking and rapid antidepressant effects in major depressive disorder (MDD), but its mechanism of action remains unknown. Proton magnetic resonance spectroscopy (1H-MRS) is the only non-invasive method able to directly measure glutamate levels in vivo; in particular, glutamate and glutamine metabolite concentrations are separable by 1H-MRS at 7T. This double-blind, placebo-controlled, crossover study that included H-MRS scans at baseline and at 24 h post ketamine and post-placebo infusions sought to determine glutamate levels in the pregenual anterior cingulate (pgACC) of 20 medication-free MDD subjects and 17 healthy volunteers (HVs) 24 h post ketamine administration, and to evaluate any other measured metabolite changes, correlates, or predictors of antidepressant response. Metabolite levels were compared at three scan times (baseline, post-ketamine, and post-placebo) in HVs and MDD subjects at 7T using aH-MRS sequence specifically optimized for glutamate. No significant between-group differences in H-MRS-measured metabolites were observed at baseline. Antidepressant response was not predicted by baseline glutamate levels. Our results suggest that any infusion-induced increases in glutamate at the 24-h post ketamine time point were below the sensitivity of the current technique; that these increases may occur in different brain regions than the pgACC; or that subgroups of MDD subjects may exist that have a differential glutamate response to ketamine.

Major depressive disorder (MDD) is highly prevalent and associated with considerable morbidity, yet its pathophysiology remains only partially understood. While numerous studies have investigated the neurobiological correlates of MDD, most have used only a single neuroimaging modality. In particular, diffusion tensor imaging (DTI) studies have failed to yield uniform results. In this context, examining key tracts and using information from multiple neuroimaging modalities may better characterize potential abnormalities in the MDD brain. This study analyzed data from 30 participants with MDD and 26 healthy participants who underwent DTI, magnetic resonance spectroscopy (MRS), resting‐state functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG). Tracts connecting the subgenual anterior cingulate cortex (sgACC) and the left and right amygdala, as well as connections to the left and right hippocampus and thalamus, were examined as target areas. Reduced fractional anisotropy (FA) was observed in the studied tracts. Significant differences in the correlation between medial prefrontal glutamate concentrations and FA were also observed between MDD and healthy participants along tracts connecting the sgACC and right amygdala; healthy participants exhibited a strong correlation but MDD participants showed no such relationship. In the same tract, a correlation was observed between FA and subsequent antidepressant response to ketamine infusion in MDD participants. Exploratory models also suggested group differences in the relationship between DTI, fMRI, and MEG measures. This study is the first to combine MRS, DTI, fMRI, and MEG data to obtain multimodal indices of MDD and antidepressant response and may lay the foundation for similar future analyses.

Background This study sought to reproduce, in a larger sample, previous findings of a correlation between smaller raw 3-Tesla (3T) hippocampal volumes and improved antidepressant efficacy of ketamine in individuals with major depressive disorder (MDD). A secondary analysis stratified subjects according to functional BDNF rs6265 (val66met) genotype. Methods Unmedicated subjects with treatment-resistant MDD (n=55) underwent baseline structural 3T MRI. Data processing was conducted with FSL/FIRST and Freesurfer software. The amygdala, hippocampus, and thalamus were selected a priori for analysis. All subjects received a single 0.5mg/kg × 40-minute ketamine infusion. Pearson correlations were performed with subcortical volumes and percent change in MADRS score (from baseline to 230 minutes, 1 day, and 1 week post-infusion). Results Raw and corrected subcortical volumes did not correlate with antidepressant response at any timepoint. In val/val subjects (n=23), corrected left and right thalamic volume positively correlated with antidepressant response to ketamine at 230 minutes post-infusion but did not reach statistical significance. In met carriers (n=14), corrected left and right thalamic volume negatively correlated with antidepressant response to ketamine. Conclusion Baseline subcortical volumes implicated in MDD did not correlate with ketamine’s antidepressant efficacy. Baseline thalamic volume and BDNF genotype may be a combinatorial rapid antidepressant response biomarker.

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