The Relationship Between Aberrant Neuronal Activation in the Pregenual Anterior Cingulate, Altered Glutamatergic Metabolism, and Anhedonia in Major Depression

Abstract

Aberrant neuronal activation patterns of the pgACC in anhedonic depression are related to deficits of glutamatergic metabolism.

Temporal Dynamics of Antidepressant Ketamine Effects on Glutamine Cycling Follow Regional Fingerprints of AMPA and NMDA Receptor Densities

“…Therefore, we were able to directly formulate a hypothesis on the regional specificity of receptor-related drug effects and their temporal profile incorporating mechanisms of homeostatic plasticity. The present data support our hypothesis that the pgACC had decreased glutamine/glutamate ratio in MDD (Walter et al, 2009;Yüksel and Öngür, 2010b), as well as high AMPA receptor densities, which resulted in an increase of glutamatergic ratios during antidepressant treatment (Brennan et al, 2010). In this view, the capacity of ketamine to reserve depressive symptoms on a similar timescale, ie, after 1-2 days, with efficacy dependent on AMPA-related mechanisms (Maeng et al, 2008).…”

“…In particular, in MDD patients, the pgACC is characterized by reduced glx (Auer et al, 2000;Yüksel and Öngür, 2010b), which is potentially reflective of a hypoglutamatergic state. Moreover, evidence from the direct measurements of glutamine concentrations further pointed toward an impaired neuron-glia interactions in the pgACC (Brennan et al, 2010;Walter et al, 2009). In addition, reduced levels of the astroglial glutamine synthetase have been found in the cingulate cortex of depression patients (Bernstein et al, 2015).…”

“…In addition, reduced levels of the astroglial glutamine synthetase have been found in the cingulate cortex of depression patients (Bernstein et al, 2015). Furthermore, an MRS study reported metabolic deficits in the pgACC, characterized in a subset of highly anhedonic MDD patients, predominantly showing reduced glutamine but not glutamate concentrations relative to the healthy volunteers or to the non-anhedonic patients (Walter et al, 2009). Given that such clinical phenomenology may predispose patients towards treatment resistance (Kautzky et al, 2015), a direct reversal of such a glutaminergic deficit was proposed as a putative mechanism of action of novel glutamatergic agents, especially those effective in treatmentresistant patients (Brennan et al, 2010;Walter et al, 2014).…”

Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission?

“…Grimm et al [48] found a reduced deactivation during a task study, reflected in smaller negative BOLD responses in a sample of severely depressed patients; this functional deficit was accompanied by decreased pACC glutamate and glutamine levels, which are correlated with the severity of clinical depressive symptoms [49][50][51]. Moreover, these glutamatergic deficits have been related to anhedonia and abnormal functional activations in the pACC in humans [52]. Our finding of relatively increased QUIN immunoreactivity, which is potentially associated with serotonin depletion due to changes in the kynurenine pathway, would thus be consistent with the relative hyperactivation in the sACC.…”

Functional and anatomical connectivity‐based parcellation of human cingulate cortex

“…The CC is implicated in a diverse array of functions, such as emotion (George et al., 1995; Kross, Davidson, Weber, & Ochsner, 2009; Liotti et al., 2000; Rogers et al., 2004; Rolls, Grabenhorst, & Parris, 2008; Walter et al., 2008, 2009), movement (Beckmann, Johansen‐Berg, & Rushworth, 2009; Paus, 2001; Picard & Strick, 1996, 2001), self‐relevant assessment (Kelley et al., 2002; Vogt, Vogt, & Laureys, 2006), cognition (Luo et al., 2007; Pourtois et al., 2010; Sohn, Albert, Jung, Carter, & Anderson, 2007; Ursu, Clark, Aizenstein, Stenger, & Carter, 2009), memory (Maguire, 2001), visuospatial orientation (Vogt et al., 2006), navigation, imagination, and planning for the future (Vann, Aggleton, & Maguire, 2009). …”