Improved reproducibility of γ-aminobutyric acid measurement from short-echo-time proton MR spectroscopy by linewidth-matched basis sets in LCModel.

γ-Aminobutyric acid (GABA), as the primary inhibitory neurotransmitter, is extremely important for maintaining healthy brain function, and deviations from GABA homeostasis are related to various brain diseases. Short-echo-time (short-TE) proton MR spectroscopy (1 H-MRS) has been employed to measure GABA concentration from various human brain regions at high magnetic fields. The aim of this study was to investigate the effect of spectral linewidth on GABA quantification and explore the application of an optimized basis-set preparation approach using a spectral-linewidth-matched (LM) basis set in LCModel to improve the reproducibility of GABA quantification from short-TE 1 H-MRS. In contrast to the fixed-linewidth basis-set approach, the LM basis-set preparation approach, where all metabolite basis spectra were simulated with a linewidth 4 Hz narrower than that of water, showed a smaller standard deviation of estimated GABA concentration from synthetic spectra with varying linewidths and lineshapes. The test-retest reproducibility was assessed by the mean within-subject coefficient of variation, which improved from 19.2% to 12.0% in the thalamus, from 27.9% to 14.9% in the motor cortex, and from 9.7% to 2.8% in the medial prefrontal cortex using LM basis sets at 7 T. We conclude that spectral linewidth has a large effect on GABA quantification from short-TE 1 H-MRS data and that using LM basis sets in LCModel can improve the reproducibility of GABA quantification.

Fast in vivo assay of creatine kinase activity in the human brain by 31 P magnetic resonance fingerprinting.

A new and efficient magnetisation transfer 31 P magnetic resonance fingerprinting (MT-31 P-MRF) approach is introduced to measure the creatine kinase metabolic rate k CK between phosphocreatine (PCr) and adenosine triphosphate (ATP) in human brain. The MRF framework is extended to overcome challenges in conventional 31 P measurement methods in the human brain, enabling reduced acquisition time and specific absorption rate (SAR). To address the challenge of creating and matching large multiparametric dictionaries in an MRF scheme, a nested iteration interpolation method (NIIM) is introduced. As the number of parameters to estimate increases, the size of the dictionary grows exponentially. NIIM can reduce the computational load by breaking dictionary matching into subsolutions of linear computational order. MT-31 P-MRF combined with NIIM provides T 1 PCr , T 1 ATP and k CK estimates in good agreement with those obtained by the exchange kinetics by band inversion transfer (EBIT) method and literature values. Furthermore, the test-retest reproducibility results showed that MT-31 P-MRF achieves a similar or better coefficient of variation (<12%) for T 1 ATP and k CK measurements in 4 min 15 s, than EBIT with 17 min 4 s scan time, enabling a fourfold reduction in scan time. We conclude that MT-31 P-MRF in combination with NIIM is a fast, accurate, and reproducible approach for in vivo k CK assays in the human brain, which enables the potential to investigate energy metabolism in a clinical setting.

γ-aminobutyric acid measurement in the human brain at 7 T: Short echo-time or Mescher-Garwood editing.

The purposes of the current study were to introduce a Mescher-Garwood (MEGA) semi-adiabatic spin-echo full-intensity localization (MEGA-sSPECIAL) sequence with macromolecule (MM) subtraction and to compare the test-retest reproducibility of γ-aminobutyric acid (GABA) measurements at 7 T using the sSPECIAL and MEGA-sSPECIAL sequences. The MEGA-sSPECIAL editing scheme using asymmetric adiabatic and highly selective Gaussian pulses was used to compare its GABA measurement reproducibility with that of short echo-time (TE) sSPECIAL. Proton magnetic resonance spectra were acquired in the motor cortex (M1) and medial prefrontal cortex (mPFC) using the sSPECIAL (TR/TE = 4000/16 ms) and MEGA-sSPECIAL sequences (TR/TE = 4000/80 ms). The metabolites were quantified using LCModel with unsuppressed water spectra. The concentrations are reported in institutional units. The test-retest reproducibility was evaluated by scanning each subject twice. Between-session reproducibility was assessed using coefficients of variation (CVs), Pearson's r correlation coefficients, and intraclass correlation coefficients (ICCs). Intersequence agreement was evaluated using Pearson's r correlation coefficients and Bland-Altman plots. Regarding GABA measurements by sSPECIAL, the GABA concentrations were 0.92 ± 0.31 (IU) in the M1 and 1.56 ± 0.49 (IU) in the mPFC. This demonstrated strong between-session correlation across both regions (r = 0.81, p < 0.01; ICC = 0.82). The CVs between the two scans were 21.8% in the M1 and 10.2% in the mPFC. On the other hand, the GABA measurements by MEGA-sSPECIAL were 0.52 ± 0.04 (IU) in the M1 and 1.04 ± 0.24 (IU) in the mPFC. MEGA-sSPECIAL demonstrated strong between-session correlation across the two regions (r = 0.98, p < 0.001; ICC = 0.98) and lower CVs than sSPECIAL, providing 4.1% in the M1 and 5.8% in the mPFC. The MEGA-editing method showed better reproducibility of GABA measurements in both brain regions compared with the short-TE sSPECIAL method. Thus it is a more sensitive method with which to detect small changes in areas with low GABA concentrations. In GABA-rich brain regions, GABA measurements can be achieved reproducibly using both methods.

Decreased Glutamatergic Activity in the Frontal Cortex of Single Prolonged Stress Model: In vivo and Ex Vivo Proton MR Spectroscopy.

Single prolonged stress (SPS) is one of the preclinical models of posttraumatic stress disorder (PTSD) in humans. Not every traumatized person develops PTSD and the onset of the disease varies from months to many years after exposure to life-threatening events. The pathogenetic neurometabolites in PTSD have not been investigated to date, and could provide a means for therapeutic interventions. Therefore the present study aimed to evaluate neurochemical changes in the frontal cortex in the SPS model during time-dependent sensitization using in vivo and ex vivo proton magnetic spectroscopy (1H-MRS). Twenty-one male Sprague-Dawley rats (200-220 g) were randomly assigned into two groups (Control, n = 10; SPS, n = 11). SPS consists of three consecutive stressors (restraint, forced swimming, and ether exposure) followed by 7 days without disturbance. In vivo 1H-MRS scans were conducted at baseline, immediately after SPS, and 3 and 7 days after SPS to quantify time-dependent alterations in the frontal cortex. On day 7, all animals were sacrificed and ex vivo 1H-MRS was performed. After SPS exposure, the SPS group showed signs of excitatory activities (glutamate) and cellular membrane turnover (choline and total choline) for 7 days. After the time-sensitization period, the SPS group showed lower glutamate and creatine levels and higher choline and lactate levels than the control group. These results indicate that SPS induces sustained adaptation of glutamatergic neuronal activity in the frontal cortex. Therefore, we conclude that SPS-induced stress reduces glutamatergic metabolism in the frontal cortex.

Improved quantitative fatty acid values with correction of T2 relaxation time in terminal methyl group: In vivo proton magnetic resonance spectroscopy at ultra high field in hepatic steatosis.

Proton magnetic resonance spectroscopy (MRS) with optimized relaxation time is an effective method to quantify hepatic fatty acid values and characterize steatosis. The aim of this study is to quantify the difference in hepatic lipid content with metabolic changes during the progression of steatosis by using localized MRS sequence with T2 relaxation time determination. Fatty liver disease was induced in C57BL/6N mice through a high-fat diet (HFD) of pellets containing 60% fat, 20% protein, and 20% carbohydrates. We used stimulated echo acquisition mode (repetition time: 3500 ms; mixing time: 10 ms; echo time: 20 ms) sequence. Using enhanced and mono exponential curve-fitting methods, the lipid relaxation time in mice was estimated at a fixed repetition time of 5000 ms and echo time ranging from 20 to 70 ms. The calculated lipid contents with incorrect and correct relaxation times were as follows: total saturated fatty acid (4.00 ±â€¯2.90 vs 6.74 ±â€¯2.25, p < 0.05 at week 0; 15.23 ±â€¯9.94 vs 25.53 ±â€¯10.49, p < 0.05 at week 4); total unsaturated fatty acid (0.40 ±â€¯0.49 vs 0.56 ±â€¯0.47, p < 0.05 at week 4; 0.33 ±â€¯0.26 vs 0.60 ±â€¯0.21, p < 0.01 at week 7); total unsaturated bond (0.48 ±â€¯0.52 vs 1.05 ±â€¯0.58, p < 0.05 at week 10). Furthermore, we determined that the correct relaxation times of triglycerides between 0 and 10 weeks were significantly altered in the resonances (∼2.03 ppm: 31.07 ±â€¯1.00 vs 27.62 ±â€¯1.20, p < 0.01; ∼2.25 ppm: 29.10 ±â€¯1.52 vs 26.39 ±â€¯1.08, p < 0.05; ∼2.78 ppm: 37.67 ±â€¯2.92 vs 29.37 ±â€¯2.64, p < 0.001). The work presented focused on the significance of the J-coupling effect. The selection of an appropriate relaxation time considering the J-coupling effect provides an effective method for quantifying lipid contents and characterizing hepatic steatosis.

High-fat diet-induced hyperglutamatergic activation of the hippocampus in mice: A proton magnetic resonance spectroscopy study at 9.4T.

The aim of this study was to investigate the long-term neurochemical alterations in the hippocampus of mice fed a high-fat diet (HFD) while plasma leptin and corticosterone levels were monitored. Although metabolic disturbances induced by the excess intake of fat are assumed to cause depression, the relationship underlying dysfunctional adipose tissue, stress hormone release, and excitatory metabolism has not been fully understood yet. Four-week-old male C57BL/6 mice were separated into a HFD-fed group (n = 8) and low-fat diet-fed group (n = 8). Proton magnetic resonance spectroscopy was used to measure the long-term changes in neurochemicals in the hippocampus at 0, 5, and 10 weeks and blood samples were taken at the same time to assess plasma hormones levels. At the end of the experiment, magnetic resonance imaging was performed to quantify abdominal fat accumulation. At 10 weeks, corticosterone and leptin levels were significantly increased in the HFD group compared with the low-fat diet group. In addition, aspartate, glutamate, total choline, and N-acetylaspartic acid levels were significantly increased, but glutamine/glutamate ratios were substantially decreased at 10 weeks in the HFD group. These results were compatible with HFD-induced acute stress responses and changes in N-methyl-d-aspartate receptor-induced plasticity. These findings demonstrated that the long-term ingestion of a HFD induced hyperglutamatergic metabolism and altered glutamine-glutamate cycling. Therfore, it is suggested that hypothalamic-pituitary-adrenal dysfunction and hyperglutamatergic activation in the hippocampus resulting from the HFD.

Metabolic effects of light deprivation in the prefrontal cortex of rats with depression-like behavior: In vivo proton magnetic resonance spectroscopy at 7T.

Recent evidence suggests that the glutamate system plays an important role in the pathogenesis of major depressive disorder (MDD). The aim of this study was to investigate the effects of light deprivation (LD) in the prefrontal cortex (PFC) of animals with depression-like behavior, targeting the glutamate system, using in vivo proton magnetic resonance spectroscopy (1H MRS). Male Sprague-Dawley rats were housed in constant darkness for six weeks (n = 12; LD group), while controls (n = 8) were housed under normal light cycles. The animals were assessed with forced swim tests. Point-resolved spectroscopy was used to quantify metabolite levels in the PFC. To substantiate the validity of the use of in vivo1H MRS in this study, the spectra obtained in the in vivo1H MRS, parametrically matched spectral simulation, and in vitro experiments were analyzed. The results of the spectral analyses showed that the quantification of glutamate and glutamine was not significantly affected by spectral overlaps. Thus, these results suggested that in vivo1H MRS can be used to reliably investigate the glutamate system. The results of the forced swim test showed LD-induced behavioral despairs in the animals. The levels of glutamate, myo-inositol, phosphocreatine, and total creatine were found significantly (p < 0.010) increased in the PFC of the LD animals compared with the controls. These results suggested that the LD-induced metabolic changes were consistent with the previous findings in patients with MDD and that short-echo-time in vivo1H MRS can be used to effectively measure depression-induced alterations in glutamate systems.

Investigating the metabolic alterations in a depressive-like rat model of chronic forced swim stress: An in vivo proton magnetic resonance spectroscopy study at 7T.

Although recent investigations of major depressive disorder (MDD) have focused on the monoaminergic system, accumulating evidences suggest that alternative pathophysiological models of MDD and treatment options for patients with MDD are needed. Animals subjected to chronic forced swim stress (CFSS) develop behavioral despair. The purpose of this study was to investigate the in vivo effects of CFSS on systems other than the monoamine system in the rat prefrontal cortex (PFC) with 7T and short-echo-time (16.3 ms) proton magnetic resonance spectroscopy (1H MRS). Ten male Wistar rats underwent 14 days of CFSS, and in vivo1H MRS and forced swim tests were performed before and after CFSS. Point-resolved spectroscopy was used to quantify metabolite levels in the rat PFC. To investigate spectral overlap in glutamate and glutamine, spectral analyses in the spectra obtained in the in vivo1H MRS, parametrically matched spectral simulation, and in vitro experiments were performed. The results of the spectral analyses showed that the glutamate/glutamine spectral overlap was not critical, which suggested that in vivo1H MRS can be used to reliably assess the glutamate system. The rats showed significantly increased immobility times and decreased climbing times in the FST after CFSS, which suggested that the rats developed behavioral despair. The pre-CFSS and post-CFSS glutamate and glutamine levels did not significantly differ (p > 0.050). The levels of myo-inositol, total choline, and N-acetylaspartate, myo-inositol/creatine, and total choline/creatine increased significantly (p < 0.050). Similar findings have been reported in patients with MDD. Taken together, these results suggest that the CFSS-induced metabolic alterations were similar to those found in patients and that high-field and short-echo-time in vivo1H MRS can be used to investigate depression-induced metabolic alterations. Such investigations might provide alternative insights into the nonmonoaminergic pathophysiology and treatment of depression.

Effects of repeated dizocilpine treatment on glutamatergic activity in the prefrontal cortex in an animal model of schizophrenia: An in vivo proton magnetic resonance spectroscopy study at 9.4T.

Repeated exposure to dizocilpine (MK-801) can be used as a model of schizophrenia that incorporates disease progression. Proton magnetic resonance spectroscopy (1H MRS) has been widely used to investigate schizophrenia-related alterations in glutamate (Glu). The purpose of this study was to investigate metabolic alterations in the prefrontal cortex (PFC) in an animal model of schizophrenia by using in vivo 1H MRS. Because of the spectral overlap of Glu and glutamine (Gln), high-field 1H MRS with short echo time (TE) was used. A point-resolved spectroscopy sequence was used to measure the levels of Glu and Gln, and the brain metabolites in a volume of interest (22.5µL) located in the PFC region of rats (n=13) before and after 6days of MK-801 (0.5mg/kg) treatment. Analysis of the spectra showed that the cross-contamination of Glu and Gln can be considered to comparably low. No metabolic parameters were altered (p>0.05). However, differences in Glu and N-acetylaspartate (NAA) levels between two times were significantly correlated (p<0.01). The results showed both decreased (in 6 of the 13 rats) and increased (7 of the 13 rats) levels of Glu and NAA, which suggested that these opposite metabolic alterations reflect two stage of disease progression. The results suggest that high-field and short TE in vivo 1H MRS can quantify Glu and Gln with reliably low level of cross-contamination and that repeated exposure to MK-801 induces the progressive development of schizophrenia.