The potential of 1H-MRS in CNS drug development

Abstract

Rationale Proton magnetic resonance spectroscopy (1 H-MRS) is a cross-species neuroimaging technique that can measure concentrations of several brain metabolites, including glutamate and GABA. This non-invasive method has promise in developing centrally acting drugs, as it can be performed repeatedly within-subjects and be used to translate findings from the preclinical to clinical laboratory using the same imaging biomarker. Objectives This review focuses on the utility of single-voxel 1 H-MRS in developing novel glutamatergic or GABAergic drugs for the treatment of psychiatric disorders and includes research performed in rodent models, healthy volunteers and patient cohorts. Results Overall, these studies indicate that 1 H-MRS is able to detect the predicted pharmacological effects of glutamatergic or GABAergic drugs on voxel glutamate or GABA concentrations, although there is a shortage of studies examining dose-related effects. Clinical studies have applied 1 H-MRS to better understand drug therapeutic mechanisms, including the glutamatergic effects of ketamine in depression and of acamprosate in alcohol dependence. There is an emerging interest in identifying patient subgroups with 'high' or 'low' brain regional 1 H-MRS glutamate levels for more targeted drug development, which may require ancillary biomarkers to improve the accuracy of subgroup discrimination. Conclusions Considerations for future research include the sensitivity of single-voxel 1 H-MRS in detecting drug effects, inter-site measurement reliability and the interpretation of drug-induced changes in 1 H-MRS metabolites relative to the known pharmacological molecular mechanisms. Ongoing technological development, in single-voxel 1 H-MRS and in related complementary techniques, will further support applications within CNS drug discovery.

Glyceryl trinitrate in first-episode psychosis unmedicated with antipsychotics: A randomised controlled pilot study

“…Future studies of novel medicines should assess the drugs bioavailability in the brain through neuroimaging studies. Furthermore, novel medicines with glutamatergic targets should select patients with elevated brain glutamate levels, as determined by 1H-MRS scans (Egerton, 2019).…”

A study on the correlation of the asymmetric regulation between the periaqueductal gray and the bilateral trigeminal nucleus caudalis in migraine male rats

“…Proton magnetic resonance spectroscopy ( 1 H-MRS) is one of the methods for noninvasive quantitative analysis of metabolism, biochemical changes and compounds in human organs and tissues. Many metabolites such as N-acetyl aspartate (NAA), lactate (Lac), creatine (Cr) and glutamate (Glu) can be detected simultaneously [ 13 ]. In recent years, MRS has been used to study the changes of brain metabolites and neurotransmitters in migraine patients [ 14 – 16 ].…”

Quantifying GABA in Addiction: A Review of Proton Magnetic Resonance Spectroscopy Studies

“…As a result, addiction, which has endured significant stigma throughout various periods in history, has started to gain its ground as a complex, chronic, relapsing brain disorder-characterized by the “compulsion to seek and take the substance, loss of control in limiting intake, and the emergence of negative affective states (e.g., mood changes, anxiety, irritability)” [ 1 , 2 ]. Much like chronic relapsing diseases such as hypertension, asthma, and diabetes, understanding underlying mechanisms of addiction is essential in providing effective and personalized treatment plans for affected individuals [ 3 , 4 ]. In recent decades, the focus of addiction research has gradually shifted towards understanding neurobiological and neurochemical changes that accompany chronic substance exposure leading to the development of addiction and addictive behaviors in humans [ 2 , 5 ].…”

“…Since then, applications of MRS in addiction research have significantly expanded. While mostly used in research settings, there is increasing evidence that it can also provide useful information for diagnostics and monitoring treatment efficacies [ 3 , 23 , 47 , 54 ]. Given that MRS, specifically 1 H-MRS, uses the same standard radio-frequency coils developed for the acquisition of clinical and diagnostic MR images, MRS is more affordable and readily accessible than brain imaging tools such as PET or SPECT [ 55 ].…”