In vivo quantification of GABA by magnetic resonance spectroscopy and its applications in panic disorder and manganese neurotoxicity

Zaiyang Long, Purdue University

Abstract

Magnetic resonance spectroscopy (MRS) provides a non-invasive tool allowing us to directly detect brain metabolites in vivo. One of the growing research interests is focused on γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the human brain. Due to its low concentration and spectral overlapping with other larger resonances, the measurement has been proven to be complicated with standard single voxel MRS techniques. Among methods for reliably detecting GABA, the MEGA-PRESS technique has been most widely used. However the total signal resulting from this approach can be contaminated by macromolecules and homocarnosine. Various acquisition and quantification methods have been reported to minimize the contribution of macromolecules. However, the question as to which quantification method provides the best estimate of pure GABA remains elusive. Therefore, the research presented was designed to the optimize the fitting method using LCModel, and to apply this improved method to quantify in vivo GABA levels in panic disorder (PD) and manganese (Mn) neurotoxicity research. By introducing macromolecule resonances into the fitting model, optimizing fitting parameters and comparing results to an acquisition technique which eliminates co-editing of macromolecules, an optimal LCModel fitting method was found. This GABA MRS technique, together with short echo time MRS, was further used to explore family history effects on metabolic changes of Panic Disorder (PD). A significant decrease in GABA was detected in the anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC) in PD patients, which tends to be pronounced in patients with a PD family history. Overall, the results indicate that deficits in GABA levels in PD patients vary by brain regions and possibly by family history status. At the same time, the developed technique was used to explore the mechanism of manganese (Mn) neurotoxicity. Firstly, the relationship between occupational Mn exposure, changes in GABA, and motor deficits indicated by the Purdue Pegboard test was studied in Mn-exposed smelters. Increasing GABA in the thalamus of smelters was found to significantly correlate with the duration of exposure. Strong inverse correlations were found between an increase in GABA and decrease in scores of all the Purdue Pegboard tests. Thus, GABA may be a potential biomarker of Mn exposure and motor deficits in smelters. Secondly, metabolite levels including GABA, as well as T1 signal intensity index, a semi-quantitative indicator of Mn accumulation, were compared among different brain regions in Mn-exposed welders and smelters. Although smelters had higher Mn in the erythrocytes and urine than welders, welders showed more significant metabolic changes, especially in the frontal cortex. In addition, welders also showed significantly higher thalamic and hippocampal signal intensity indices. Overall, the frontal cortex appears particularly vulnerable to Mn exposure in terms of metabolite changes. The type of exposure seems to play an important role in the extent of Mn-induced toxic changes and should be carefully investigated in the future.

Degree

Ph.D.

Advisors

Dydak, Purdue University.

Subject Area

Neurosciences|Toxicology|Surgery|Health sciences

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