Major depressive disorder (MDD) is a leading cause of distress, disability, and suicides. As per the latest WHO report, MDD affects more than 260 million people worldwide. Despite decades of research, the underlying etiology of depression is not fully understood. Glutamate and γ-aminobutyric acid (GABA) are the major excitatory and inhibitory neurotransmitters, respectively, in the matured central nervous system. Imbalance in the levels of these neurotransmitters has been implicated in different neurological and psychiatric disorders including MDD.1H nuclear magnetic resonance (NMR) spectroscopy is a powerful non-invasive method to study neurometabolites homeostasisin vivo. Additionally,13C-NMR spectroscopy together with an intravenous administration of non-radioactive13C-labeled glucose or acetate provides a measure of neural functions. In this review, we provide an overview of NMR-based measurements of glutamate and GABA homeostasis, neurometabolic activity, and neurotransmitter cycling in MDD. Finally, we highlight the impact of recent advancements in treatment strategies against a depressive disorder that target glutamate and GABA pathways in the brain.

Purpose: To explore the presence of new resonances beyond 9.4 ppm from the human brain, down-field proton MRS was performed in vivo in the human brain on 6 healthy volunteers at 7 T. Methods:To maximize the SNR, a large voxel was placed within the brain to cover the maximal area in such a way that sinus cavities were avoided. A spectrally selective 90 • E-BURP pulse with an excitation bandwidth of 2 ppm was used to probe the spectral chemical shift range between 9.1 and 10.5 ppm. The E-BURP pulse was integrated with PRESS spatial localization to obtain non-water-suppressed proton MR spectra from the desired spectral region. Results:In the down-field proton MRS obtained from all of the volunteers scanned, we identified a new peak consistently resonating at 10.1 ppm. Protons associated with this resonance are in cross-relaxation with the bulk water, as demonstrated by the water saturation and deuterium exchange experiments. Conclusion:Based on the chemical shift, this new peak was identified as the indole (-NH) proton of l-tryptophan (l-TRP) and was further confirmed from phantom experiments on l-TRP. These promising preliminary results potentially pave the way to investigate the role of cerebral metabolism of l-TRP in healthy and disease conditions. K E Y W O R D S1 H MRS, brain, down-field spectroscopy, NAD + , spectral excitation INTRODUCTIONRecently published studies on the in vivo detection of nicotinamide adenosine dinucleotide (NAD + ) in the 1 H-NMR spectrum by de Graff et al 1,2 has re-ignited a lot of interest in determining the characteristics of the down-field proton MRS (DF 1 H MRS) found at chemical shifts > 4.7 ppm. 3-5 A challenge of DF 1 H MRS is that many of the metabolite peaks that resonate in this region are either in direct chemical exchange or have significant cross-relaxation with water. [6][7][8] Consequently,

Alzheimer’s disease (AD) is a very common neurodegenerative disorder. Although a majority of the AD cases are sporadic, most of the studies are conducted using transgenic models. Intracerebroventricular (ICV) administered streptozotocin (STZ) animals have been used to explore mechanisms in sporadic AD. In this study, we have investigated memory and neurometabolism of ICV-STZ-administered C57BL6/J mice. The neuronal and astroglial metabolic activity was measured in 1H-[13C]-NMR spectrum of cortical and hippocampal tissue extracts of mice infused with [1,6-13C2]glucose and [2-13C]acetate, respectively. STZ-administered mice exhibited reduced (p = 0.00002) recognition index for memory. The levels of creatine, GABA, glutamate and NAA were reduced (p ≤ 0.04), while that of myo-inositol was increased (p < 0.05) in STZ-treated mice. There was a significant (p ≤ 0.014) reduction in aspartate-C3, glutamate-C4/C3, GABA-C2 and glutamine-C4 labeling from [1,6-13C2]glucose. This resulted in decreased rate of glucose oxidation in the cerebral cortex (0.64 ± 0.05 vs. 0.77 ± 0.05 µmol/g/min, p = 0.0008) and hippocampus (0.60 ± 0.04 vs. 0.73 ± 0.07 µmol/g/min, p = 0.001) of STZ-treated mice, due to similar reductions of glucose oxidation in glutamatergic and GABAergic neurons. Additionally, reduced glutamine-C4 labeling points towards compromised synaptic neurotransmission in STZ-treated mice. These data suggest that the ICV-STZ model exhibits neurometabolic deficits typically observed in AD, and its utility in understanding the mechanism of sporadic AD.

The nuclear Overhauser effect (NOE) quantification from the steady-state NOE imaging suffers from multiple confounding non-NOE-specific sources, including direct saturation, magnetization transfer, and relevant chemical exchange species, and is affected by B 0 and B 1 + inhomogeneities. The B 0 -dependent and B 1 + -dependent data needed for deconvolving these confounding effects would increase the scan time substantially, leading to other issues such as patient tolerability. Here, we demonstrate the feasibility of brain lipid mapping using an easily implementable transient NOE (tNOE) approach.Methods: This 7T study used a frequency-selective inversion pulse at a range of frequency offsets between 1.0 and 5.0 parts per million (ppm) and −5.0 and −1.0 ppm relative to bulk water peak. This was followed by a fixed/variable mixing time and then a single-shot 2D turbo FLASH readout. The feasibility of tNOE measurements is demonstrated on bovine serum albumin phantoms and healthy human brains. Results:The tNOE measurements from bovine serum albumin phantoms were found to be independent of physiological pH variations. Both bovine serum albumin phantoms and human brains showed broad tNOE contributions centered at approximately −3.5 ppm relative to water peak, with presumably aliphatic moieties in lipids and proteins being the dominant contributors. Less prominent tNOE contributions of approximately +2.5 ppm relative to water, presumably from aromatic moieties, were also detected. These aromatic signals were free from any CEST signals. Conclusion:In this study, we have demonstrated the feasibility of tNOE in human brain at 7 T. This method is more scan-time efficient than steady-state NOE and provides NOE measurement with minimal confounders.

To monitor the metabolic turnover of β-hydroxybutyrate (BHB) oxidation using 2 H-MRS in conjunction with intravenous administration of 2 H labeled BHB.Methods: Nine-month-old mice were infused with [3,4,4,4]-2 H 4 -BHB (d 4 -BHB; 3.11 g/kg) through the tail vein using a bolus variable infusion rate for a period of 90 min. The labeling of downstream cerebral metabolites from the oxidative metabolism of d 4 -BHB was monitored using 2 H-MRS spectra acquired with a home-built 2 H surface coil on a 9.4T preclinical MR scanner with a temporal resolution of 6.25 min. An exponential model was fit to the BHB and glutamate/glutamine (Glx) turnover curves to determine rate constants of metabolite turnover and to aid in the visualization of metabolite time courses.Results: Deuterium label was incorporated into Glx from BHB metabolism through the tricarboxylic acid (TCA) cycle, with an increase in the level of [4,4]-2 H 2 -Glx (d 2 -Glx) over time and reaching a quasi-steady state concentration of ∼0.6 ± 0.1 mM following 30 min of infusion. Complete oxidative metabolic breakdown of d 4 -BHB also resulted in the formation of semi-heavy water (HDO), with a four-fold (10.1 to ∼42.1 ± 7.3 mM) linear (R 2 = 0.998) increase in its concentration by the end of infusion. The rate constant of Glx turnover from d 4 -BHB metabolism was determined to be 0.034 ± 0.004 min −1 . Conclusion: 2 H-MRS can be used to monitor the cerebral metabolism of BHB with its deuterated form by measuring the downstream labeling of Glx. The integration of 2 H-MRS with deuterated BHB substrate provides an alternative and clinically promising MRS tool to detect neurometabolic fluxes in healthy and disease conditions. K E Y W O R D S2 H-MRS, brain, d 4 -BHB, ketone bodies, metabolism, TCA