Acute nicotinamide riboside supplementation increases human cerebral NAD+ levels in vivo.

PURPOSE: The purpose of this study was to determine the effect of acute nicotinamide riboside (NR) supplementation on cerebral nicotinamide adenine dinucleotide (NAD+) levels in the human brain in vivo by means of downfield proton MRS (DF 1H MRS). METHODS: DF 1H MRS was performed on 10 healthy volunteers in a 7.0 T MRI scanner with spectrally selective excitation and spatially selective localization to determine cerebral NAD+ levels on two back-to-back days: once after an overnight fast (baseline) and once 4 h after oral ingestion of nicotinamide riboside (900 mg). Additionally, two more baseline scans were performed following the same paradigm to assess test-retest reliability of the NAD+ levels in the absence of NR. RESULTS: NR supplementation increased mean NAD+ concentration compared to the baseline (0.458 ± 0.053 vs. 0.392 ± 0.058 mM; p < 0.001). The additional two baseline scans demonstrated no differences in mean NAD+ concentrations (0.425 ± 0.118 vs. 0.405 ± 0.082 mM; p = 0.45), and no difference from the first baseline scan (F(2, 16) = 0.907; p = 0.424). CONCLUSION: These preliminary results confirm that acute NR supplementation increases cerebral NAD+ levels in healthy human volunteers and shows the promise of DF 1H MRS utility for robust detection of NAD+ in humans in vivo.

The impact of gut microbial dysbiosis on the atrophy of the hippocampus and abnormal metabolism of N-acetyl aspartate in type 2 diabetic rats.

Rationale and objectives: This study aimed to investigate the effect of intestinal dysbiosis on the hippocampal volume using proton magnetic resonance spectroscopy (1H-MRS) in a type 2 diabetes mellitus (T2DM) rat model. Materials and methods: We established a T2DM animal model with high-fat diet and streptozotocin (HFD/STZ) administration to Sprague-Dawley rats. Short-term ceftriaxone sodium administration was used to establish a T2DM intestinal dysbiosis (T2DM-ID) model. After establishing the model, fecal microbiota were detected using 16S rRNA sequencing. The models were then subjected to magnetic resonance imaging (MRI). Associations between MRI findings and fecal microbiota were evaluated. Results: Magnetic resonance imaging (MRI) showed that the bilateral hippocampal voxel value and N-acetylaspartate (NAA) level were lower in the experimental group than in the normal control (NC) group (p < 0.05) and that NAA/creatine in the left hippocampus was lower in the T2DM-ID group than in the NC group (p < 0.05). α and ß diversities differed significantly among the three groups (p < 0.05). In the T2DM and T2DM-ID groups, the abundance of bacteria in the phylum Proteobacteria increased significantly, whereas that of bacteria in the phylum Firmicutes decreased. The relative abundance of Actinobacteria was significantly increased in the T2DM-ID group. The Chao1 index (r = 0.33, p < 0.05) and relative abundance of Firmicutes (r = 0.48, p < 0.05) were positively correlated with the left hippocampal voxel, while the relative abundance of Proteobacteria was negatively correlated with the left hippocampal voxel (r = -0.44, p < 0.05). NAA levels, bilateral hippocampal voxels, and the relative abundance of Lactobacillus, Clostridia_UCG_014, and other genera were correlated positively (r = 0.34-0.70, p < 0.05). NAA levels and the relative abundances of Blautia and Enterococcus were correlated negatively (r = -0.32-0.44, p < 0.05). Conclusion: The T2DM-ID rat model showed hippocampal volume atrophy and decreased levels of neuronal markers (such as NAA). The abnormal content of specific gut microorganisms may be a key biomarker of T2DM-associated brain damage.

Impact of therapeutic inhibition of oncogenic cell signaling tyrosine kinase on cell metabolism: in vivo-detectable metabolic biomarkers of inhibition.

BACKGROUND: Inhibition of kinases is the ever-expanding therapeutic approach to various types of cancer. Typically, assessment of the treatment response is accomplished by standard, volumetric imaging procedures, performed weeks to months after the onset of treatment, given the predominantly cytostatic nature of the kinase inhibitors, at least when used as single agents. Therefore, there is a great clinical need to develop new monitoring approaches to detect the response to kinase inhibition much more promptly. Noninvasive 1H magnetic resonance spectroscopy (MRS) can measure in vitro and in vivo concentration of key metabolites which may potentially serve as biomarkers of response to kinase inhibition. METHODS: We employed mantle cell lymphoma (MCL) cell lines demonstrating markedly diverse sensitivity of inhibition of Bruton's tyrosine kinase (BTK) regarding their growth and studied in-depth effects of the inhibition on various aspects of cell metabolism including metabolite synthesis using metabolomics, glucose and oxidative metabolism by Seahorse XF technology, and concentration of index metabolites lactate, alanine, total choline and taurine by 1H MRS. RESULTS: Effective BTK inhibition profoundly suppressed key cell metabolic pathways, foremost pyrimidine and purine synthesis, the citrate (TCA) cycle, glycolysis, and pyruvate and glutamine/alanine metabolism. It also inhibited glycolysis and amino acid-related oxidative metabolism. Finally, it profoundly and quickly decreased concentration of lactate (a product of mainly glycolysis) and alanine (an indicator of amino acid metabolism) and, less universally total choline both in vitro and in vivo, in the MCL xenotransplant model. The decrease correlated directly with the degree of inhibition of lymphoma cell expansion and tumor growth. CONCLUSIONS: Our results indicate that BTK inhibition exerts a broad and profound suppressive effect on cell metabolism and that the affected index metabolites such as lactate, alanine may serve as early, sensitive, and reliable biomarkers of inhibition in lymphoma patients detectable by noninvasive MRS-based imaging method. This kind of imaging-based detection may also be applicable to other kinase inhibitors, as well as diverse lymphoid and non-lymphoid malignancies.

The association of tobacco smoking and metabolite levels in the anterior cingulate cortex of first-episode psychosis patients: A case-control and 6-month follow-up 1H-MRS study.

Tobacco smoking is highly prevalent among patients with psychosis and associated with worse clinical outcomes. Neurometabolites, such as glutamate and choline, are both implicated in psychosis and tobacco smoking. However, the specific associations between smoking and neurometabolites have yet to be investigated in patients with psychosis. The current study examines associations of chronic smoking and neurometabolite levels in the anterior cingulate cortex (ACC) in first-episode psychosis (FEP) patients and controls. Proton magnetic resonance spectroscopy (1H MRS) data of 59 FEP patients and 35 controls were analysed. Associations between smoking status (i.e., smoker yes/no) or cigarettes per day and Glx (glutamate + glutamine, as proxy for glutamate) and total choline (tCh) levels were assessed at baseline in both groups separately. For patients, six months follow-up data were acquired for multi-cross-sectional analysis using linear mixed models. No significant differences in ACC Glx levels were found between smoking (n = 28) and non-smoking (n = 31) FEP patients. Smoking patients showed lower tCh levels compared to non-smoking patients at baseline, although not surving multiple comparisons correction, and in multi-cross-sectional analysis (pFDR = 0.08 and pFDR = 0.044, respectively). Negative associations were observed between cigarettes smoked per day, and ACC Glx (pFDR = 0.02) and tCh levels (pFDR = 0.02) in controls. Differences between patients and controls regarding Glx might be explained by pre-existing disease-related glutamate deficits or alterations at nicotine acetylcholine receptor level, resulting in differences in tobacco-related associations with neurometabolites. Additionally, observed alterations in tCh levels, suggesting reduced cellular proliferation processes, might result from exposure to the neurotoxic effects of smoking.

Changes in the central nervous system in football players: an MRI study.

BACKGROUND: Football (soccer) is the world's most popular team sport. PURPOSE: To comprehensively examine the brain in football (soccer) players, with the use of magnetic resonance imaging (MRI) techniques. MATERIAL AND METHODS: The study involved 65 football players and 62 controls. The MR examinations were performed using MR 1.5-T system (Optima MR 360; GE Medical Systems). The examinations were carried out in the 3D Bravo, CUBE, FSEpropeller, and diffusion-weighted imaging (DWI) sequences. The 1HMRS signal was obtained from the volume of interest in the frontal and occipital lobes on both sides. RESULTS: The present study, based on structural MRI, shows some changes in the brains of the group of football players. The findings show asymmetry of the ventricular system in four football players, arachnoid cysts in the parieto-occipital region, and pineal cysts. NAA/Cr concentration in the right frontal lobe was lower in the football players than in the controls, and the Glx/Cr concentration in the right occipital lobe was higher. The apparent diffusion coefficient value is lower in football players in the occipital lobes. CONCLUSION: Playing football can cause measurable changes in the brain, known to occur in patients diagnosed with traumatic brain injury. The present findings fill the gap in the literature by contributing evidence showing that playing football may lead to changes in the brain, without clinical symptoms of concussion.

1H and 31P magnetic resonance spectroscopy reveals potential pathogenic and biomarker metabolite alterations in Lafora disease.

Lafora disease is a fatal teenage-onset progressive myoclonus epilepsy and neurodegenerative disease associated with polyglucosan bodies. Polyglucosans are long-branched and as a result precipitation- and aggregation-prone glycogen. In mouse models, downregulation of glycogen synthase, the enzyme that elongates glycogen branches, prevents polyglucosan formation and rescues Lafora disease. Mouse work, however, has not yet revealed the mechanisms of polyglucosan generation, and few in vivo human studies have been performed. Here, non-invasive in vivo magnetic resonance spectroscopy (1H and 31P) was applied to test scan feasibility and assess neurotransmitter balance and energy metabolism in Lafora disease towards a better understanding of pathogenesis. Macromolecule-suppressed gamma-aminobutyric acid (GABA)-edited 1H magnetic resonance spectroscopy and 31P magnetic resonance spectroscopy at 3 and 7 tesla, respectively, were performed in 4 Lafora disease patients and a total of 21 healthy controls (12 for the 1H magnetic resonance spectroscopy and 9 for the 31PMRS). Spectra were processed using in-house software and fit to extract metabolite concentrations. From the 1H spectra, we found 33% lower GABA concentrations (P = 0.013), 34% higher glutamate + glutamine concentrations (P = 0.011) and 24% lower N-acetylaspartate concentrations (P = 0.0043) in Lafora disease patients compared with controls. From the 31P spectra, we found 34% higher phosphoethanolamine concentrations (P = 0.016), 23% lower nicotinamide adenine dinucleotide concentrations (P = 0.003), 50% higher uridine diphosphate glucose concentrations (P = 0.004) and 225% higher glucose 6-phosphate concentrations in Lafora disease patients versus controls (P = 0.004). Uridine diphosphate glucose is the substrate of glycogen synthase, and glucose 6-phosphate is its extremely potent allosteric activator. The observed elevated uridine diphosphate glucose and glucose 6-phosphate levels are expected to hyperactivate glycogen synthase and may underlie the generation of polyglucosans in Lafora disease. The increased glutamate + glutamine and reduced GABA indicate altered neurotransmission and energy metabolism, which may contribute to the disease's intractable epilepsy. These results suggest a possible basis of polyglucosan formation and potential contributions to the epilepsy of Lafora disease. If confirmed in larger human and animal model studies, measurements of the dysregulated metabolites by magnetic resonance spectroscopy could be developed into non-invasive biomarkers for clinical trials.

Interactions of catecholamines and GABA+ in cognitive control: Insights from EEG and 1H-MRS.

Catecholamines and amino acid transmitter systems are known to interact, the exact links and their impact on cognitive control functions have however remained unclear. Using a multi-modal imaging approach combining EEG and proton-magnetic resonance spectroscopy (1H-MRS), we investigated the effect of different degrees of pharmacological catecholaminergic enhancement onto theta band activity (TBA) as a measure of interference control during response inhibition and execution. It was central to our study to evaluate the predictive impact of in-vivo baseline GABA+ concentrations in the striatum, the anterior cingulate cortex (ACC) and the supplemental motor area (SMA) of healthy adults under varying degrees of methylphenidate (MPH) stimulation. We provide evidence for a predictive interrelation of baseline GABA+ concentrations in cognitive control relevant brain areas onto task-induced TBA during response control stimulated with MPH. Baseline GABA+ concentrations in the ACC, the striatum, and the SMA had a differential impact on predicting interference control-related TBA in response execution trials. GABA+ concentrations in the ACC appeared to be specifically important for TBA modulations when the cognitive effort needed for interference control was high - that is when no prior task experience exists, or in the absence of catecholaminergic enhancement with MPH. The study highlights the predictive role of baseline GABA+ concentrations in key brain areas influencing cognitive control and responsiveness to catecholaminergic enhancement, particularly in high-effort scenarios.

Assessment of sepsis-associated encephalopathy by quantitative magnetic resonance spectroscopy in a rat model of cecal ligation and puncture.

Proton magnetic resonance spectroscopy (1H-MRS) is the only non-invasive technique to quantify neurometabolic compounds in the living brain. We used 1H-MRS to evaluate the brain metabolites in a rat model of Sepsis-associated encephalopathy (SAE) established by cecal ligation and puncture (CLP). 36 male Sprague-Dawley rats were randomly divided into sham and CLP groups. Each group was further divided into three subgroups: subgroup O, subgroup M, and subgroup N. Neurological function assessments were performed on the animals in the subgroup O and subgroup N at 24 h, 48 h, and 72 h. The animals in the subgroup M were examined by magnetic resonance imaging (MRI) at 12 h after CLP. Compared with the sham group, the ratio of N-acetylaspartate (NAA) to creatine (Cr) in the hippocampus was significantly lower in the CLP group. The respective ratios of lactate (Lac), myo-inositol (mIns), glutamate and glutamine (Glx), lipid (Lip), and choline (Cho) to Cr in the CLP group were clearly higher than those in the sham group. Cytochrome c, intimately related to oxidative stress, was elevated in the CLP group. Neurofilament light (NfL) chain and glial fibrillary acidic protein (GFAP) scores in the CLP group were significantly higher than those in the sham group, while zonula occludens-1 (ZO-1) was downregulated. Compared with the sham group, the CLP group displayed higher values of oxygen extraction fraction (OEF), central venous-arterial partial pressure of carbon dioxide (P (cv-a) CO2), and central venous lactate (VLac). In contrast, jugular venous oxygen saturation (SjvO2) declined. In the present study, 1H-MRS could be used to quantitatively assess brain injury in terms of microcirculation disorder, oxidative stress, blood-brain barrier disruption, and glial cell activation through changes in metabolites within brain tissue.

The effectiveness of vortioxetine on neurobiochemical metabolites and cognitive of major depressive disorders patients: A 8-week follow-up study.

OBJECTIVE: Vortioxetine has been shown to improve cognitive performance in people with depression. This study will look at the changes in neurobiochemical metabolites that occur when vortioxetine improves cognitive performance in MDD patients, with the goal of determining the neuroimaging mechanism through which vortioxetine improves cognitive function. METHODS: 30 depressed patients and 30 demographically matched healthy controls (HC) underwent MCCB cognitive assessment and 1H-MRS. After 8 weeks of vortioxetine medication, MCCB and 1H-MRS tests were retested in the MDD group. Before and after therapy, changes in cognitive performance, NAA/Cr, and Cho/Cr were examined in the MDD group. RESULTS: Compared with the HC group, the MDD group had significant reduced in verbal learning, social cognition, and total cognition (all p < 0.05). And the MDD group had lower NAA/Cr in Right thalamus and Left PFC; the Cho/Cr in Right thalamus was lower than HC; the Cho/Cr in Left ACC had significantly increase (all p < 0.05). The MDD group showed significant improvements in the areas of verbal learning, attention/alertness, and total cognitive function before and after Vortioxetine treatment (all p < 0.05). The NAA/Cr ratio of the right PFC before and after treatment (t = 2.338, p = 0.026) showed significant changes. CONCLUSIONS: Vortioxetine can enhance not just the depression symptoms of MDD patients in the initial period, but also their verbal learning, social cognition, and general cognitive capacities after 8 weeks of treatment. Furthermore, vortioxetine has been shown to enhance cognitive function in MDD patients by altering NAA/Cr and Cho/Cr levels in the frontal-thalamic-ACC.

The contribution of preclinical magnetic resonance imaging and spectroscopy to Huntington's disease.

Huntington's disease is an inherited disorder characterized by psychiatric, cognitive, and motor symptoms due to degeneration of medium spiny neurons in the striatum. A prodromal phase precedes the onset, lasting decades. Current biomarkers include clinical score and striatal atrophy using Magnetic Resonance Imaging (MRI). These markers lack sensitivity for subtle cellular changes during the prodromal phase. MRI and MR spectroscopy offer different contrasts for assessing metabolic, microstructural, functional, or vascular alterations in the disease. They have been used in patients and mouse models. Mouse models can be of great interest to study a specific mechanism of the degenerative process, allow better understanding of the pathogenesis from the prodromal to the symptomatic phase, and to evaluate therapeutic efficacy. Mouse models can be divided into three different constructions: transgenic mice expressing exon-1 of human huntingtin (HTT), mice with an artificial chromosome expressing full-length human HTT, and knock-in mouse models with CAG expansion inserted in the murine htt gene. Several studies have used MRI/S to characterized these models. However, the multiplicity of modalities and mouse models available complicates the understanding of this rich corpus. The present review aims at giving an overview of results obtained using MRI/S for each mouse model of HD, to provide a useful resource for the conception of neuroimaging studies using mouse models of HD. Finally, despite difficulties in translating preclinical protocols to clinical applications, many biomarkers identified in preclinical models have already been evaluated in patients. This review also aims to cover this aspect to demonstrate the importance of MRI/S for studying HD.

Preliminary study on early diagnosis of Alzheimer's disease in APP/PS1 transgenic mice using multimodal magnetic resonance imaging.

Alzheimer's disease (AD) has an insidious onset and lacks clear early diagnostic markers, and by the time overt dementia symptoms appear, the disease is already in the mid-to-late stages. The search for early diagnostic markers of AD may open a critical window for Alzheimer's treatment and facilitate early intervention to slow the progression of AD. In this study, we aimed to explore the imaging markers for early diagnosis of AD through the combined application of structural magnetic resonance imaging (sMRI), resting-state functional magnetic resonance imaging (rs-fMRI), and 1H-magnetic resonance spectroscopy (1H-MRS) multimodal magnetic resonance imaging (MRI) techniques at the animal experimental level, with the aim to provide a certain reference for early clinical diagnosis of AD. First, sMRI scans were performed on 4-month-old amyloid beta precursor protein/presenilin 1 (APP/PS1) transgenic AD model mice and wild type mice of the same litter using a 7.0 T animal MRI scanner to analyze the differential brain regions with structural changes in the gray matter of the brain by voxel-based morphometry (VBM). Next, rs-fMRI scans were performed to analyze the differential brain regions between groups for local spontaneous brain activity and functional connectivity (FC) between brain regions. Finally, 1H-MRS scans were performed to quantify and analyze intergroup differences in the relative concentrations of different metabolites within regions of interest (cortex and hippocampus). Compared with wild type mice, the volume of the left hippocampus, and right olfactory bulb of APP/PS1 transgenic AD model mice were reduced, the functional activity of the bilateral hippocampus, right piriform cortex and right caudate putamen was reduced, the functional network connectivity of the hippocampus was impaired, and the relative content of N-acetylaspartate (NAA)in the hippocampus was decreased. In addition, this study found that imaging changes in olfactory-related brain regions were closely associated with AD diagnosis, and these findings may provide some reference for the early diagnosis of AD.

Resting state and activated brain glutamate-glutamine, brain lactate, cognition, and psychopathology among males with schizophrenia: A 3 Tesla proton magnetic resonance spectroscopic (1H-MRS) study.

Background: Research on glutamate (Glu) in schizophrenia has so far been inconclusive. Based on preclinical studies on Glu lactate interaction, researchers have now focused on brain lactate level as a sign of major pathology, including cognitive dysfunctions in the brain. Our study aimed to examine changes at resting and activated states in brain lactate and Glu-glutamine (Glx) at the anterior cingulate cortex (ACC) in schizophrenia. Methods: A hospital-based prospective study was conducted with twenty-two male cases of schizophrenia and matched healthy controls (HCs). Positive and Negative Syndrome Scale (PANSS), Montreal Cognitive Assessment (MoCA), and Stroop tasks were administered among patients. Brain lactate and Glx at ACC were measured at resting state and during the Stroop test with proton magnetic resonance spectroscopy (1H-MRS) both at baseline and at remission and once among HC. Result: Though MoCA scores improved significantly (P < 0.001) at remission from baseline among cases, repeated-measures analysis of variance (RM-ANOVA) did not find a significant time effect for Glx (P = 0.82) and lactate (P = 0.30) among cases from baseline to remission. Glx and lactate changed differently from baseline to remission. Conclusion: Our study did not find significant differences in Glx and lactate between schizophrenia patients and HC. No significant time effect on Glx and lactate was observed from baseline to remission among schizophrenia cases. Different changes observed in Glx and lactate from baseline to remission require replication in future studies with larger sample size, longer follow-up period, and multivoxel MR assessment.

Acetaldehyde-mediated increase in glutamatergic and N-acetylaspartate neurometabolite levels in the midcingulate cortex of ALDH2*1/*2 heterozygous young adults.

BACKGROUND: To elucidate the neurobiology underlying alcohol's effect on the human brain, we examined the acute effects of moderate alcohol administration on levels of glutamatergic neurometabolites and N-acetylaspartate, an amino acid found in neurons, may reflect disordered neuronal integrity. METHODS: Eighteen healthy Japanese participants (7 males/11 females) aged 20-30 years who were heterozygous for an inactive allele of acetaldehyde dehydrogenase-2 (ALDH/*1/*2) were included. Participants underwent an intravenous alcohol infusion using the clamp method at a target blood alcohol concentration (BAC) of 0.50 mg/mL for 90 min within a range of ±0.05 mg/mL. We examined glutamate + glutamine (Glx) and N-acetylaspartate N-acetylaspartylglutamate (NAA) levels in the midcingulate cortex (MCC) using 3 T 1 H-MRS PRESS at baseline, 90 min, and 180 min (i.e., 90 min after alcohol infusion was finished). A two-way repeated-measures analysis of variance was used to assess longitudinal changes in Glx and NAA levels, with time and sex as within- and between-subject factors, respectively. Pearson's correlation coefficients were calculated among neurometabolite levels and BAC or blood acetaldehyde concentration (BAAC). RESULTS: Both Glx (F(2,32) = 8.15, p = 0.004, η2 = 0.15) and NAA (F(2,32) = 5.01, p = 0.04, η2 = 0.07) levels were increased after alcohol injection. There were no sex or time × sex interaction effects observed. NAA levels were positively correlated with BAAC at 90 min (r(13) = 0.77, p = 0.01). There were no associations between neurometabolite levels and BAC. CONCLUSIONS: Both Glx and NAA levels in the MCC increased in response to the administration of moderate concentrations of alcohol. Given positive associations between NAA levels and BAAC and the hypothetical glutamate release via dopamine pathways, the effects of drinking on the MCC in the acute phase may be ascribed to acetaldehyde metabolized from alcohol.

3T 31P/1H calf muscle coil for 1H and 31P MRI/MRS integrated with NIRS data acquisition.

PURPOSE: Our aim was to design and build a 3T 31P/1H calf coil that is capable of providing both good 31P and 1H transmit and receive performance, as well as being capable of accommodating a near-infrared spectroscopy (NIRS) device for simultaneous NIRS data and MRI/MRS acquisition. METHOD: In this work, we propose a new 3T 31P/1H birdcage combination design consisting of two co-centrically positioned birdcages on the same surface to maximize transmit efficiency and sensitivity for both nuclei. The 31P birdcage is a high-pass birdcage, whereas the 1H birdcage is a low-pass one to minimize coupling. The diameter of the 31P/1H birdcage combination was designed to be large enough to accommodate a NIRS device for simultaneous NIRS data and MRI/MRS acquisition. RESULTS: The one-layer coil structure of the birdcage combination significantly streamlines the mechanical design and coil assembly process. Full-wave simulation results show that the 31P and 1H are very well decoupled with each other, and the 1H and 31P SNR surpasses that of their standalone counterparts in the central area. Experiment results show that the inclusion of a NIRS device does not significantly affect the performance of the coil, thus enabling simultaneous NIRS and MRI readouts during exercise. CONCLUSION: Our findings demonstrate the feasibility and effectiveness of this dual-tuned coil design for combined NIRS and MRS measurements, offering potential benefits for studying metabolic and functional changes in the skeletal muscle in vivo.

MR Spectroscopy Assessment of Daily Variations of GABA Levels within the Parietal Lobe and Anterior Cingulate Gyrus Regions of Healthy Young Adults.

BACKGROUND: The changes that occur in the gamma-aminobutyric acid (GABA) levels within specific brain regions throughout the day are less clear. PURPOSE: To evaluate the daily fluctuations of GABA levels within the parietal lobe (PL) and anterior cingulate gyrus (ACC) regions and explore their association with melatonin (MT) levels, heart rate (HR), and blood pressure. STUDY TYPE: Prospective. SUBJECTS: 26 healthy young adults (15 males and 11 females aged 22-27 years). FIELD STRENGTH/SEQUENCE: 3.0T, T1-weighted imaging, Mescher-Garwood point resolved spectroscopy (MEGA-PRESS) sequence. ASSESSMENT: The acquired GABA signal contained the overlapping signals of macromolecules and homocarnosine, hence expressed as GABA+. The creatine (Cr) signal was applied as an endogenous reference. The GABA+, GABA+/Cr were measured at six different time points (1:00, 5:00, 9:00, 13:00, 17:00, and 21:00 hours) using MEGA-PRESS. The blood pressure, HR and sputum MT levels, were also acquired. STATISTICAL TESTS: The one-way repeated-measures analysis of variance (ANOVA) was used to evaluate the GABA, blood pressure, HR, and MT levels throughout the day. A general linear model was used to find the correlation between GABA and blood pressure, HR, and MT. P < 0.05 was statistically significant. RESULTS: Significant variations in GABA+/Cr and GABA+ levels were observed throughout the day within the PL region. The lowest levels were recorded at 9:00 hour (GABA+/Cr: 0.100 ± 0.003，GABA+:1.877 ± 0.051 i.u) and the highest levels were recorded at 21:00 hour (GABA+/Cr: 0.115 ± 0.003, GABA+:2.122 ± 0.052 i.u). The MT levels were positively correlated with GABA+/Cr (r = 0.301) and GABA+ (r = 0.312) within the ACC region. DATA CONCLUSION: GABA+/Cr and GABA+ in ACC are positively correlated with MT. GABA levels in the PL have diurnal differences. These findings may indicate that the body's GABA level change in response to the light-dark cycle. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.

Greater Choline-Containing Compounds and Myo-inositol in Treatment-Resistant Versus Responsive Schizophrenia: A 1H-Magnetic Resonance Spectroscopy Meta-analysis.

BACKGROUND: The neurobiology of treatment-resistant schizophrenia (TRS) is poorly understood, and meta-analytic consensus regarding magnetic resonance spectroscopic profiles of glutamate, choline-containing compounds, myo-inositol, and other metabolites in the condition is lacking. METHODS: In this meta-analysis, we examined published findings for N-acetylaspartate, choline-containing compounds (phosphocholine+glycerophosphocholine), myo-inositol, creatine+phosphocreatine, glutamate, and glutamate+glutamine in the anterior cingulate cortex and dorsal striatum in people with TRS versus non-TRS as well as TRS versus healthy control participants (HCs) and TRS versus ultra TRS (i.e., TRS with clozapine resistance). A MEDLINE search revealed 9 articles including 239 people with pooled TRS and ultra TRS, 59 with ultra TRS, 175 with non-TRS, and 153 (HCs) that met meta-analytic criteria. RESULTS: Significant effects included higher anterior cingulate cortex phosphocholine+glycerophosphocholine and myo-inositol in the pooled TRS and ultra TRS group than in both the non-TRS group and HCs as well as higher dorsal striatal phosphocholine+glycerophosphocholine in ultra TRS versus HCs, but no differences in other regional metabolites. CONCLUSIONS: The observed metabolite profile in TRS (higher phosphocholine+glycerophosphocholine and myo-inositol signal) is consistent with the hypothesis that TRS has a neuroinflammatory component, although this meta-analysis is not a critical test of that hypothesis. A similar profile is seen in healthy aging, which is known to involve increased neuroinflammation and glial activation. Because the overall number of datasets was low, however, results should be considered preliminary and highlight the need for additional studies of brain metabolites in TRS and their possible association with inflammatory processes.

Uncertainty propagation in absolute metabolite quantification for in vivo MRS of the human brain.

PURPOSE: Absolute spectral quantification is the standard method for deriving estimates of the concentration from metabolite signals measured using in vivo proton MRS (1 H-MRS). This method is often reported with minimum variance estimators, specifically the Cramér-Rao lower bound (CRLB) of the metabolite signal amplitude's scaling factor from linear combination modeling. This value serves as a proxy for SD and is commonly reported in MRS experiments. Characterizing the uncertainty of absolute quantification, however, depends on more than simply the CRLB. The uncertainties of metabolite-specific (T1m , T2m ), reference-specific (T1ref , T2ref ), and sequence-specific (TR , TE ) parameters are generally ignored, potentially leading to an overestimation of precision. In this study, the propagation of uncertainty is used to derive a comprehensive estimate of the overall precision of concentrations from an internal reference. METHODS: The propagated uncertainty is calculated using analytical derivations and Monte Carlo simulations and subsequently analyzed across a set of commonly measured metabolites and macromolecules. The effect of measurement error from experimentally obtained quantification parameters is estimated using published uncertainties and CRLBs from in vivo 1 H-MRS literature. RESULTS: The additive effect of propagated measurement uncertainty from applied quantification correction factors can result in up to a fourfold increase in the concentration estimate's coefficient of variation compared to the CRLB alone. A case study analysis reveals similar multifold increases across both metabolites and macromolecules. CONCLUSION: The precision of absolute metabolite concentrations derived from 1 H-MRS experiments is systematically overestimated if the uncertainties of commonly applied corrections are neglected as sources of error.

Optimization of the flip angles of narrow-band editing pulses in J-difference edited MRS of lactate at 3T.

PURPOSE: Application of highly selective editing RF pulses provides a means of minimizing co-editing of contaminants in J-difference MRS (MEGA), but it causes reduction in editing yield. We examined the flip angles (FAs) of narrow-band editing pulses to maximize the lactate edited signal with minimal co-editing of threonine. METHODS: The effect of editing-pulse FA on the editing performance was examined, with numerical and phantom analyses, for bandwidths of 17.6-300 Hz in MEGA-PRESS editing of lactate at 3T. The FA and envelope of 46 ms Gaussian editing pulses were tailored to maximize the lactate edited signal at 1.3 ppm and minimize co-editing of threonine. The optimized editing-pulse FA MEGA scheme was tested in brain tumor patients. RESULTS: Simulation and phantom data indicated that the optimum FA of MEGA editing pulses is progressively larger than 180° as the editing-pulse bandwidth decreases. For 46 ms long 17.6 Hz bandwidth Gaussian pulses and other given sequence parameters, the lactate edited signal was maximum at the first and second editing-pulse FAs of 241° and 249°, respectively. The edit-on and difference-edited lactate peak areas of the optimized FA MEGA were greater by 43% and 25% compared to the 180°-FA MEGA, respectively. In-vivo data confirmed the simulation and phantom results. The lesions of the brain tumor patients showed elevated lactate and physiological levels of threonine. CONCLUSION: The lactate MEGA editing yield is significantly increased with editing-pulse FA much larger than 180° when the editing-pulse bandwidth is comparable to the lactate quartet frequency width.

Selectively Probing the Magnetic Resonance Signals of γ-Aminobutyric Acid in Human Brains In Vivo.

BACKGROUND: Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in human brains, playing a role in the pathogenesis of various psychiatric disorders. Current methods have some non-neglectable shortcomings and noninvasive and accurate detection of GABA in human brains is long-term challenge. PURPOSE: To develop a pulse sequence capable of selectively detecting and quantifying the 1 H signal of GABA in human brains based on optimal controlled spin singlet order. STUDY TYPE: Prospective. SUBJECTS/PHANTOM: A phantom of GABA (pH = 7.3 ± 0.1) and 11 healthy subjects (5 females and 6 males, body mass index: 21 ± 3 kg/m2 , age: 25 ± 4 years). FIELD STRENGTH/SEQUENCE: 7 Tesla, 3 Tesla, GABA-targeted magnetic resonance spectroscopy (GABA-MRS-7 T, GABA-MRS-3 T), magnetization prepared two rapid acquisition gradient echoes sequence. ASSESSMENT: By using the developed pulse sequences applied on the phantom and healthy subjects, the signals of GABA were successfully selectively probed. Quantification of the signals yields the concentration of GABA in the dorsal anterior cingulate cortex (dACC) in human brains. STATISTICAL TESTS: Frequency. RESULTS: The 1 H signals of GABA in the phantom and in the human brains of healthy subjects were successfully detected. The concentration of GABA in the dACC of human brains was 3.3 ± 1.5 mM. DATA CONCLUSION: The developed pulse sequences can be used to selectively probe the 1 H MR signals of GABA in human brains in vivo. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY STAGE: 1.