Antidepressant mechanisms of ketamine: a review of actions with relevance to treatment-resistance and neuroprogression.

Concurrent with recent insights into the neuroprogressive nature of depression, ketamine shows promise in interfering with several neuroprogressive factors, and has been suggested to reverse neuropathological patterns seen in depression. These insights come at a time of great need for novel approaches, as prevalence is rising and current treatment options remain inadequate for a large number of people. The rapidly growing literature on ketamine's antidepressant potential has yielded multiple proposed mechanisms of action, many of which have implications for recently elucidated aspects of depressive pathology. This review aims to provide the reader with an understanding of neuroprogressive aspects of depressive pathology and how ketamine is suggested to act on it. Literature was identified through PubMed and Google Scholar, and the reference lists of retrieved articles. When reviewing the evidence of depressive pathology, a picture emerges of four elements interacting with each other to facilitate progressive worsening, namely stress, inflammation, neurotoxicity and neurodegeneration. Ketamine acts on all of these levels of pathology, with rapid and potent reductions of depressive symptoms. Converging evidence suggests that ketamine works to increase stress resilience and reverse stress-induced dysfunction, modulate systemic inflammation and neuroinflammation, attenuate neurotoxic processes and glial dysfunction, and facilitate synaptogenesis rather than neurodegeneration. Still, much remains to be revealed about ketamine's antidepressant mechanisms of action, and research is lacking on the durability of effect. The findings discussed herein calls for more longitudinal approaches when determining efficacy and its relation to neuroprogressive factors, and could provide relevant considerations for clinical implementation.

MEGA-PRESS and PRESS measure oxidation of glutathione in a phantom.

PURPOSE: Investigate the possibility of measuring changes in glutathione (GSH) concentration using the MRS PRESS and MEGA-PRESS sequences by tracking the natural oxidation of GSH, and to examine the accuracy of the two methods. METHODS: 122 GSH edited MEGA-PRESS and PRESS acquisitions were acquired on a "braino" based phantom +3.0 mM GSH during a period of 11 days. All spectra were analyzed in LCModel. (The MEGA-PRESS data were first preprocessed in Matlab). Degradation curves were modeled. A one year follow-up on the same phantom and measurements from a similar phantom without GSH and one pure GSH phantom were also included. RESULTS: Both MEGA-PRESS and PRESS showed degradation of the measured GSH signal. Modeling the exponential decay of the GSH signal in MEGA-PRESS and PRESS gave for t = 0; 2.9 i.u. for MEGA-PRESS and 2.3 i.u. for PRESS. As t increased, the GSH concentration converged to zero for MEGA-PRESS but not for PRESS (0.7 i.u.). GSH for the one year follow up were 0.0 i.u. for MEGA-PRESS and 0.6 i.u. for PRESS. Similar phantom without GSH yielded 0.0 i.u. for both MEGA-PRESS and PRESS. CONCLUSION: It is possible to measure changes in GSH concentration in a phantom using both PRESS and MEGA-PRESS techniques, however the PRESS spectrum appears to include oxidized GSH (GSSG). In addition, GSH edited MEGA-PRESS measurement gives more precise values at lower GSH concentrations.

Current Practice and New Developments in the Use of In Vivo Magnetic Resonance Spectroscopy for the Assessment of Key Metabolites Implicated in the Pathophysiology of Schizophrenia.

Magnetic Resonance Spectroscopy (MRS) has become a valuable tool for investigating the biochemical bases of both normal processes in the healthy brain and elucidating the pathophysiology of neuropsychiatric disorders. As a rapidly advancing field, new developments in pulse sequence design have seen new possibilities arise in terms of what can be done with in vivo spectroscopy. While the applications of MRS are numerous, this review has been confined to the use of single voxel spectroscopy in the assessment of five key metabolites and their roles in schizophrenia: N-acetylaspartate (NAA), glutamate (Glu) and glutamine (Gln), γ-aminobutyric acid (GABA) and glutathione (GSH). This article will briefly cover the roles they play in schizophrenia, review current methods being used in their assessment and highlight new approaches that may potentially overcome some of the limitations current methods pose.

No Effects of Anodal tDCS on Local GABA and Glx Levels in the Left Posterior Superior Temporal Gyrus.

A number of studies investigating the biological effects of transcranial direct current stimulation (tDCS) using magnetic resonance spectroscopy (MRS) have found that it may affect local levels of γ-aminobutyric acid (GABA), glutamate and glutamine (commonly measured together as "Glx" in spectroscopy), and N-acetyl aspartate (NAA), however, these effects depend largely on the stimulation parameters used and the cortical area targeted. Given that different cortical areas may respond to stimulation in different ways, the purpose of this experiment was to assess the as yet unexplored biological effects of tDCS in the posterior superior temporal gyrus (pSTG), an area that has attracted some attention as a potential target for the treatment of auditory verbal hallucinations in schizophrenia patients. Biochemical changes were monitored using continuous, online MRS at a field strength of 3 Tesla. Performing intrascanner stimulation, with continuous spectroscopy before, during and after stimulation, permitted the assessment of acute effects of tDCS that would otherwise be lost when simply comparing pre- and post-stimulation differences. Twenty healthy participants underwent a repeated-measures experiment in which they received both active anodal and sham intrascanner stimulation in a stratified, randomized, double-blind experiment. No significant changes in GABA, Glx, or NAA levels were observed as a result of anodal stimulation, or between active and sham stimulation, suggesting that a single session of anodal tDCS to the pSTG may be less effective than in other cortical areas that have been similarly investigated.

Within- and between-session reproducibility of GABA measurements with MR spectroscopy.

PURPOSE: The reproducibility of the MEGA-PRESS (MEshcher-GArwood Point RESolved Spectroscopy) MR spectroscopy sequence for the measurement of gamma- aminobutyric acid (GABA) is addressed, focusing on optimizing the number of repetitions at two voxel locations in the human brain and associated possibilities in analysis tools. MATERIALS AND METHODS: Two 20-min MEGA-PRESS acquisitions were run (echo time = 68 ms, repetition time = 1800 ms, repetitions = 328): one from a 21 mL volume in the anterior cingulate cortex (ACC) and one from a 22 mL volume in the left Broca's area in 21 healthy male volunteers (age 32 years ± 6[SD]). Subjects were scanned twice with identical protocols, 1 week apart. Data were acquired on a 3 Tesla GE Discovery 750 scanner using a 32-channel head coil. Spectroscopy data were partitioned into shorter epochs, numerically equivalent to scans of progressively increasing duration, and compared both within and between sessions. Three different analysis schemes were applied: (1) Vendor prototype preprocessor, with quantification by LCModel. (2) Pure Gannet pipeline. (3) Preprocessing with Gannet, and quantification with LCModel. The coefficient of variation (CV) were calculated as a measure of reproducibility. RESULTS: Increasing the number of repetitions showed improvements for within- and between-session reproducibility up to around 218 repetitions. (CV ranging from 4 to 14%). Gannet combined with LCModel approach proved the best method. (CV = 4-5%). Measurements from the ACC area had higher CVs than the Broca area. (CV = 6-14% versus 4-7%). CONCLUSION: Measurement in the Broca area yields better reproducibility than the ACC. With appropriate acquisition times and preprocessing tools, measurements from the ACC area are also reliable. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:421-430.