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Contrast-enhanced MRI is the method of choice for brain tumor diagnostics, despite its low specificity for tumor tissue. This study compared the contribution of MR spectroscopic imaging (MRSI) and amino acid PET to improve the detection of tumor tissue. Methods: In 30 untreated patients with suspected glioma, O -(2-[ 18 F]fluoroethyl)-l-tyrosine ( 18 F-FET) PET; 3-T MRSI with a short echo time; and fluid-attenuated inversion recovery, T2-weighted, and contrast-enhanced T1-weighted MRI were performed for stereotactic biopsy planning. Serial samples were taken along the needle trajectory, and their masks were projected to the preoperative imaging data. Each sample was individually evaluated neuropathologically. 18 F-FET uptake and the MRSI signals choline (Cho), N -acetyl-aspartate (NAA), creatine, myoinositol, and derived ratios were evaluated for each sample and classified using logistic regression. The diagnostic accuracy was evaluated by receiver operating characteristic analysis. Results: On the basis of the neuropathologic evaluation of tissue from 88 stereotactic biopsies, supplemented with 18 F-FET PET and MRSI metrics from 20 areas on the healthy-appearing contralateral hemisphere to balance the glioma/nonglioma groups, 18 F-FET PET identified glioma with the highest accuracy (area under the receiver operating characteristic curve, 0.89; 95% CI, 0.81-0.93; threshold, 1.4 × background uptake). Among the MR spectroscopic metabolites, Cho/NAA normalized to normal brain tissue showed the highest diagnostic accuracy (area under the receiver operating characteristic curve, 0.81; 95% CI, 0.71-0.88; threshold, 2.2). The combination of 18 F-FET PET and normalized Cho/NAA did not improve the diagnostic performance. Conclusion: MRI-based delineation of gliomas should preferably be supplemented by 18 F-FET PET., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Whether brain temperature noninvasively extracted by magnetic resonance imaging has a role in identifying brain changes in the later phases of mild to moderate traumatic brain injury (TBI) is not known. This prospective study aimed to evaluate if TBI patients in subacute and chronic phases had altered brain temperature measured by whole-brain magnetic resonance spectroscopic imaging (WB-MRSI) and if the measurable brain temperature had any relationship with cognitive function scores. WB-MRSI was performed on eight TBI patients and fifteen age- and sex-matched control subjects. Brain temperature (T) was extracted from the brain's major metabolites and compared between the two groups. The T of the patients was tested for correlation with cognitive function test scores. The results showed significantly lower brain temperature in the TBI patients ( p < 0.05). Brain temperature derived from N-acetylaspartate (T NAA ) strongly correlated with the 2 s paced auditory serial addition test (PASAT-2s) score ( p < 0.05). The observation of lower brain temperature in TBI patients may be due to decreased metabolic activity resulting from glucose and oxygen depletion. The correlation of brain temperature with PASAT-2s may imply that noninvasive brain temperature may become a noninvasive index reflecting cognitive performance.

Purpose: This study aimed to detect age-related brain metabolic and microstructural changes in healthy human brains by the use of whole-brain proton magnetic resonance spectroscopic imaging ( 1 H‑MRSI) and quantitative MR imaging (qMRI)., Methods: In this study, 60 healthy participants with evenly distributed ages (between 21 and 69 years) and sex underwent MRI examinations at 3T including whole-brain 1 H‑MRSI. The concentrations of the metabolites N‑acetylaspartate (NAA), choline-containing compounds (Cho), total creatine and phosphocreatine (tCr), glutamine and glutamate (Glx), and myo-inositol (mI), as well as the brain relaxation times T2, T2' and T1 were measured in 12 regions of interest (ROI) in each hemisphere. Correlations between measured parameters and age were estimated with linear regression analysis and Pearson's correlation test., Results: Significant age-related changes of brain regional metabolite concentrations and tissue relaxation times were found: NAA decreased in eight of twelve ROIs, Cho increased in three ROIs, tCr in four ROIs, and mI in three ROIs. Glx displayed a significant decrease in one ROI and an increase in another ROI. T1 increased in four ROIs and T2 in one ROI, while T2' decreased in two ROIs. A negative correlation of tCr concentrations with T2' relaxation time was found in one ROI as well as the positive correlations of age-related T1 relaxation time with concentrations of tCr, mI, Glx and Cho in another ROI., Conclusion: Normal aging in human brain is associated with coexistent brain regional metabolic alterations and microstructural changes, which may be related to age-related decline in cognitive, affective and psychomotor domains of life in the older population., (© 2023. The Author(s).)

Background: Progressive supranuclear palsy (PSP) is an atypical Parkinsonian syndrome characterized by supranuclear gaze palsy, early postural instability, and a frontal dysexecutive syndrome. Contrary to normal brain magnetic resonance imaging in Parkinson's disease (PD), PSP shows specific cerebral atrophy patterns and alterations, but these findings are not present in every patient, and it is still unclear if these signs are also detectable in early disease stages., Objective: The aim of the present study was to analyze the metabolic profile of patients with clinically diagnosed PSP in comparison with matched healthy volunteers and PD patients using whole-brain magnetic resonance spectroscopic imaging (wbMRSI)., Methods: Thirty-nine healthy controls (HCs), 29 PD, and 22 PSP patients underwent wbMRSI. PSP and PD patients were matched for age and handedness with HCs. Clinical characterization was performed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale, PSP rating scale, and DemTect (test for cognitive assessment)., Results: In PSP patients a significant reduction in N-acetyl-aspartate (NAA) was detected in all brain lobes. Fractional volume of the cerebrospinal fluid significantly increased in PSP patients compared to PD and healthy volunteers., Conclusions: In PSP much more neuronal degeneration and cerebral atrophy have been detected compared with PD. The most relevant alteration is the decrease in NAA in all lobes of the brain, which also showed a partial correlation with clinical symptoms. However, more studies are needed to confirm the additional value of wbMRSI in clinical practice. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Purpose: In this pilot study, DKI measures of diffusivity and kurtosis were compared in active tumor regions and correlated to radiologic response to radiotherapy after completion of 2 weeks of treatment to derive potential early measures of tumor response., Methods: MRI and Magnetic Resonance Spectroscopic Imaging (MRSI) data were acquired before the beginning of RT (pre-RT) and 2 weeks after the initiation of treatment (during-RT) in 14 glioblastoma patients. The active tumor region was outlined as the union of the residual contrast-enhancing region and metabolically active tumor region. Average and standard deviation of mean, axial, and radial diffusivity (MD, AD, RD) and mean, axial, and radial kurtosis (MK, AK, RK) values were calculated for the active tumor VOI from images acquired pre-RT and during-RT and paired t-tests were executed to estimate pairwise differences. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the predictive capabilities of changes in diffusion metrics for progression-free survival (PFS)., Results: Analysis showed significant pairwise differences for AD ( p = 0.035; Cohen's d of 0.659) and AK ( p = 0.019; Cohen's d of 0.753) in diffusion measures after 2 weeks of RT. ROC curve analysis showed that percentage change differences in AD and AK between pre-RT and during-RT scans provided an Area Under the Curve (AUC) of 0.524 and 0.762, respectively, in discriminating responders (PFS>180 days) and non-responders (PFS<180 days)., Conclusion: This pilot study, although preliminary in nature, showed significant changes in AD and AK maps, with kurtosis derived AK maps showing an increased sensitivity in mapping early changes in the active tumor regions.

Perinatally acquired HIV (PHIV) has been associated with brain structural and functional deficiencies, and with poorer cognitive performance despite the advent of antiretroviral therapy (ART). However, investigation of brain metabolite levels in PHIV measured by proton magnetic resonance spectroscopy (MRS) methods, is still limited with often inconclusive or contradictory findings. In general, these MRS-based methods have used a single voxel approach that can only evaluate metabolite concentrations in a few select brain anatomical regions. Additionally, most of the published data have been on children perinatally infected with HIV with only a few studies examining adult populations, though not exclusively. Therefore, this prospective and cross-sectional study aims to evaluate metabolite differences at the whole-brain level, using a unique whole-brain proton magnetic resonance spectroscopy imaging (MRSI) method, in a group of PHIV infected young adults ( N = 28) compared to age and gender matched control sample ( N = 28), and to find associations with HIV clinical factors and neurocognitive scores. MRSI data were acquired on a 3T scanner with a TE of 70 ms. Brain metabolites levels of total N-acetylaspartate (tNAA), total choline (tCho) and total creatine (tCre), as well as ratios of tNAA/tCre, tCho/tCre, and tNAA/tCho, were obtained from the whole brain level and evaluated at the level of gray matter (GM) and white matter (WM) tissue types and anatomical regions of interest (ROI). Our results indicate extensive metabolic abnormalities throughout the brains of PHIV infected subjects with significantly elevated levels of tCre and tCho, notably in GM regions. Decreases in tNAA and ratios of tNAA/tCre and tNAA/tCho were also found mostly in WM regions. These metabolic alterations indicate increased glial activation, inflammation, neuronal dysfunction, and energy metabolism in PHIV infected individuals, which correlated with a reduction in CD4 cell count, and lower cognitive scores. Our findings suggest that significant brain metabolite alterations and associated neurological complications persist in the brains of those with PHIV on long-term ART, and advocates the need for continued monitoring of their brain health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Salan, Willen, Cuadra, Sheriff, Maudsley and Govind.)

Traumatic brain injury (TBI) can lead to a variety of comorbidities, including chronic pain. Although brain tissue metabolite alterations have been extensively examined in several chronic pain populations, it has received less attention in people with TBI. Thus, the primary aim of this study was to compare brain tissue metabolite levels in people with TBI and chronic pain ( n = 16), TBI without chronic pain ( n = 17), and pain-free healthy controls ( n = 31). The metabolite data were obtained from participants using whole-brain proton magnetic resonance spectroscopic imaging ( 1 H-MRSI) at 3 Tesla. The metabolite data included N -acetylaspartate, myo -inositol, total choline, glutamate plus glutamine, and total creatine. Associations between N -acetylaspartate levels and pain severity, neuropathic pain symptom severity, and psychological variables, including anxiety, depression, post-traumatic stress disorder (PTSD), and post-concussive symptoms, were also explored. Our results demonstrate N -acetylaspartate, myo -inositol, total choline, and total creatine alterations in pain-related brain regions such as the frontal region, cingulum, postcentral gyrus, and thalamus in individuals with TBI with and without chronic pain. Additionally, NAA levels in the left and right frontal lobe regions were positively correlated with post-concussive symptoms; and NAA levels within the left frontal region were also positively correlated with neuropathic pain symptom severity, depression, and PTSD symptoms in the TBI with chronic pain group. These results suggest that neuronal integrity or density in the prefrontal cortex, a critical region for nociception and pain modulation, is associated with the severity of neuropathic pain symptoms and psychological comorbidities following TBI. Our data suggest that a combination of neuronal loss or dysfunction and maladaptive neuroplasticity may contribute to the development of persistent pain following TBI, although no causal relationship can be determined based on these data., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Robayo, Govind, Salan, Cherup, Sheriff, Maudsley and Widerström-Noga.)

Purpose: At ultra-high field (UHF), B 1 + -inhomogeneities and high specific absorption rate (SAR) of adiabatic slice-selective RF-pulses make spatial resolved spectral-editing extremely challenging with the conventional MEGA-approach. The purpose of the study was to develop a whole-brain resolved spectral-editing MRSI at UHF (UHF, B 0  ≥ 7T) within clinical acceptable measurement-time and minimal chemical-shift-displacement-artifacts (CSDA) allowing for simultaneous GABA/Glx-, 2HG-, and PE-editing on a clinical approved 7T-scanner., Methods: Slice-selective adiabatic refocusing RF-pulses (2π-SSAP) dominate the SAR to the patient in (semi)LASER based MEGA-editing sequences, causing large CSDA and long measurement times to fulfill SAR requirements, even using SAR-minimized GOIA-pulses. Therefore, a novel type of spectral-editing, called SLOW-editing, using two different pairs of phase-compensated chemical-shift selective adiabatic refocusing-pulses (2π-CSAP) with different refocusing bandwidths were investigated to overcome these problems., Results: Compared to conventional echo-planar spectroscopic imaging (EPSI) and MEGA-editing, SLOW-editing shows robust refocusing and editing performance despite to B 1 + -inhomogeneity, and robustness to B 0 -inhomogeneities (0.2 ppm ≥ ΔB 0  ≥ -0.2 ppm). The narrow bandwidth (∼0.6-0.8 kHz) CSAP reduces the SAR by 92%, RF peak power by 84%, in-excitation slab CSDA by 77%, and has no in-plane CSDA. Furthermore, the CSAP implicitly dephases water, lipid and all the other signals outside of range (≥ 4.6 ppm and ≤1.4 ppm), resulting in additional water and lipid suppression (factors ≥ 1000s) at zero SAR-cost, and no spectral aliasing artifacts., Conclusion: A new spectral-editing has been developed that is especially suitable for UHF, and was successfully applied for 2HG, GABA+, PE, and Glx-editing within 10 min clinical acceptable measurement time., (© 2022 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

This prospective study aimed to evaluate the variation in magnetic resonance spectroscopic imaging (MRSI)-observed brain metabolite concentrations according to anatomical location, sex, and age, and the relationships among regional metabolite distributions, using short echo time (TE) whole-brain MRSI (WB-MRSI). Thirty-eight healthy participants underwent short TE WB-MRSI. The major metabolite ratios, i.e., N-acetyl aspartate (NAA)/creatine (Cr), choline (Cho)/Cr, glutamate + glutamine (Glx)/Cr, and myoinositol (mI)/Cr, were calculated voxel-by-voxel. Their variations according to anatomical regions, sex, and age, and their relationship to each other were evaluated by using repeated-measures analysis of variance, t-tests, and Pearson’s product-moment correlation analyses. All four metabolite ratios exhibited widespread regional variation across the cerebral hemispheres (corrected p < 0.05). Laterality between the two sides and sex-related variation were also shown (p < 0.05). In several regions, NAA/Cr and Glx/Cr decreased and mI/Cr increased with age (corrected p < 0.05). There was a moderate positive correlation between NAA/Cr and mI/Cr in the insular lobe and thalamus and between Glx/Cr and mI/Cr in the parietal lobe (r ≥ 0.348, corrected p ≤ 0.025). These observations demand age- and sex- specific regional reference values in interpreting these metabolites, and they may facilitate the understanding of glial-neuronal interactions in maintaining homeostasis.

Background: Evidence suggests that neurometabolic abnormalities can persist after traumatic brain injury (TBI) and drive clinical symptoms such as fatigue and cognitive disruption. Magnetic resonance spectroscopy has been used to investigate metabolite abnormalities following TBI, but few studies have obtained data beyond the subacute stage or over large brain regions., Objective: To measure whole-brain metabolites in chronic stages of TBI., Design: Observational study., Setting: University., Participants: Eleven men with a moderate or severe TBI more than 12 months prior and 10 age-matched healthy controls completed whole-brain spectroscopic imaging., Main Measures: Ratios of N-acetylaspartate (NAA), choline (CHO), and myo-inositol (MI) to creatine (CR) were measured in whole-brain gray and white matter as well as 64 brain regions of interest. Arterial spin labeling (ASL) data were also collected to investigate whether metabolite abnormalities were accompanied by differences in cerebral perfusion., Results: There were no differences in metabolite ratios within whole-brain gray and white matter regions of interest (ROIs). Linear regression showed lower NAA/CR in the white matter of the left occipital lobe but higher NAA/CR in the gray matter of the left parietal lobe. Metabolite abnormalities were observed in several brain regions in the TBI group including the corpus callosum, putamen, and posterior cingulate. However, none of the findings survived correction for multiple comparison. There were no differences in cerebral blood flow between patients and controls., Conclusion: Higher MI/CR may indicate ongoing gliosis, and it has been suggested that low CHO/CR at chronic time points may indicate cell death or lack of healthy turnover and repair. However, with the small sample size of this study, we caution against the over interpretation of our results. None of the findings within ROIs survived correction for multiple comparison. Thus, they may be considered possible avenues for future research in this area., (© 2021 American Academy of Physical Medicine and Rehabilitation.)

Background: Glioblastomas (GBMs) are aggressive brain tumors despite radiation therapy (RT) to 60 Gy and temozolomide (TMZ). Spectroscopic magnetic resonance imaging (sMRI), which measures levels of specific brain metabolites, can delineate regions at high risk for GBM recurrence not visualized on contrast-enhanced (CE) MRI. We conducted a clinical trial to assess the feasibility, safety, and efficacy of sMRI-guided RT dose escalation to 75 Gy for newly diagnosed GBMs., Methods: Our pilot trial (NCT03137888) enrolled patients at 3 institutions (Emory University, University of Miami, Johns Hopkins University) from September 2017 to June 2019. For RT, standard tumor volumes based on T2-FLAIR and T1w-CE MRIs with margins were treated in 30 fractions to 50.1 and 60 Gy, respectively. An additional high-risk volume based on residual CE tumor and Cho/NAA (on sMRI) ≥2× normal was treated to 75 Gy. Survival curves were generated by the Kaplan-Meier method. Toxicities were assessed according to CTCAE v4.0., Results: Thirty patients were treated in the study. The median age was 59 years. 30% were MGMT promoter hypermethylated; 7% harbored IDH1 mutation. With a median follow-up of 21.4 months for censored patients, median overall survival (OS) and progression-free survival were 23.0 and 16.6 months, respectively. This regimen appeared well-tolerated with 70% of grade 3 or greater toxicity ascribed to TMZ and 23% occurring at least 1 year after RT., Conclusion: Dose-escalated RT to 75 Gy guided by sMRI appears feasible and safe for patients with newly diagnosed GBMs. OS outcome is promising and warrants additional testing. Based on these results, a randomized phase II trial is in development., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Aging effects on striato-thalamic metabolism in healthy human brains were studied in vivo using short-TE whole brain 1 H-MR spectroscopic imaging (wbMRSI) on eighty healthy subjects aged evenly between 20 to 70 years at 3T. Relative concentrations of N-acetyl-aspartate (NAA), choline, total creatine (tCr), myo-inositol (mI), glutamate, and glutamine in bilateral caudate nucleus, putamen, pallidum, and thalamus were determined using signal normalization relative to brain tissue water. Linear regression analysis was used to analyze the age-dependence of the metabolite concentrations. The metabolite concentrations revealed spatial inhomogeneity across brain regions and metabolites. With age, NAA decreased significantly in bilateral caudate nucleus and putamen, left pallidum, and left thalamus, tCr decreased in left putamen and bilateral pallidum, mI increased in bilateral caudate nucleus and right thalamus, and spectral linewidth increased in left putamen and right thalamus. In conclusion, normal aging of striato-thalamic metabolism in healthy human is associated with regional specific decreases of NAA and tCr and increases of mI, which may reflect the individual role of each brain structure within brain functionality.

The translation of MRS to clinical practice has been impeded by the lack of technical standardization. There are multiple methods of acquisition, post-processing, and analysis whose details greatly impact the interpretation of the results. These details are often not fully reported, making it difficult to assess MRS studies on a standardized basis. This hampers the reviewing of manuscripts, limits the reproducibility of study results, and complicates meta-analysis of the literature. In this paper a consensus group of MRS experts provides minimum guidelines for the reporting of MRS methods and results, including the standardized description of MRS hardware, data acquisition, analysis, and quality assessment. This consensus statement describes each of these requirements in detail and includes a checklist to assist authors and journal reviewers and to provide a practical way for journal editors to ensure that MRS studies are reported in full., (© 2021 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Magnetic resonance spectroscopic imaging (MRSI) offers considerable promise for monitoring metabolic alterations associated with disease or injury; however, to date, these methods have not had a significant impact on clinical care, and their use remains largely confined to the research community and a limited number of clinical sites. The MRSI methods currently implemented on clinical MRI instruments have remained essentially unchanged for two decades, with only incremental improvements in sequence implementation. During this time, a number of technological developments have taken place that have already greatly benefited the quality of MRSI measurements within the research community and which promise to bring advanced MRSI studies to the point where the technique becomes a true imaging modality, while making the traditional review of individual spectra a secondary requirement. Furthermore, the increasing use of biomedical MR spectroscopy studies has indicated clinical areas where advanced MRSI methods can provide valuable information for clinical care. In light of this rapidly changing technological environment and growing understanding of the value of MRSI studies for biomedical studies, this article presents a consensus from a group of experts in the field that reviews the state-of-the-art for clinical proton MRSI studies of the human brain, recommends minimal standards for further development of vendor-provided MRSI implementations, and identifies areas which need further technical development., (© 2020 John Wiley & Sons, Ltd.)

Proton ( 1 H) magnetic resonance spectroscopy provides a non-invasive and quantitative measure of brain metabolites. Traumatic brain injury impacts cerebral metabolism and a number of research groups have successfully used this technique as a biomarker of injury and/or outcome in both pediatric and adult TBI populations. However, this technique is underutilized, with studies being performed primarily at centers with access to MR research support. In this paper we present a technical introduction to the acquisition and analysis of in vivo 1 H magnetic resonance spectroscopy and review 1 H magnetic resonance spectroscopy findings in different injury populations. In addition, we propose a basic 1 H magnetic resonance spectroscopy data acquisition scheme (Supplemental Information) that can be added to any imaging protocol, regardless of clinical magnetic resonance platform. We outline a number of considerations for study design as a way of encouraging the use of 1 H magnetic resonance spectroscopy in the study of traumatic brain injury, as well as recommendations to improve data harmonization across groups already using this technique.

Background and Purpose: To evaluate the performance of multiparametric MR images in differentiation of different regions of the gross tumor area and for assessment of glioma grade., Methods: Forty-six glioma subjects (18 grade II, 11 grade III, and 17 grade IV) underwent a comprehensive MR and spectroscopic imaging procedure. Maps were generated by subtraction of T1-weighted images from contrast-enhanced T1-weighted images (ΔT1 map) and T1-weighted images from T2-weighted images (ΔT2 map). Regions of interest (ROIs) were positioned in normal-appearing white matter (NAWM), enhancing tumor, hyperintense T2, necrotic region, and immediate and distal peritumoral regions (IPR and DPR). Relative signal contrast was estimated as difference between mean intensities in ROIs and NAWM. Classification using support vector machines was applied to all image series to determine the efficacy of regional contrast measures for differentiation of low- and high-grade lesions and grade III and IV lesions., Results: ΔT1 and ΔT2 maps offered higher contrast as compared to other parametric maps in differentiating enhancing tumor and edematous regions, respectively, and provided the highest classification accuracy for differentiating low- and high-grade tumors, of 91% and 90.4%. Choline/N-acetylaspartate maps provided significant contrast for delineating IPR and DPR. For differentiating high-grade gliomas, ΔT2 and ΔT1 maps provided a mean accuracy of 90.9% and 88.2%, which was lower than that obtained using cerebral blood volume (93.7%) and choline/creatine (93.3%) maps., Conclusion: This study showed that subtraction maps provided significant contrast in differentiating several regions of the gross tumor area and are of benefit for accurate tumor grading., (© 2020 American Society of Neuroimaging.)

Background: Magnetic resonance spectroscopic imaging (MRSI) is a neuroimaging technique that may be useful for non-invasive mapping of brain temperature (i.e., thermometry) over a large brain volume. To date, intra-subject reproducibility of MRSI-based brain temperature (MRSI-t) has not been investigated. The objective of this repeated measures MRSI-t study was to establish intra-subject reproducibility and repeatability of brain temperature, as well as typical brain temperature range. Methods: Healthy participants aged 23-46 years ( N = 18; 7 females) were scanned at two time points ~12-weeks apart. Volumetric MRSI data were processed by reconstructing metabolite and water images using parametric spectral analysis. Brain temperature was derived using the frequency difference between water and creatine (T CRE ) for 47 regions of interest (ROIs) delineated by the modified Automated Anatomical Labeling (AAL) atlas. Reproducibility was measured using the coefficient of variation for repeated measures (COVrep), and repeatability was determined using the standard error of measurement (SEM). For each region, the upper and lower bounds of Minimal Detectable Change (MDC) were established to characterize the typical range of T CRE values. Results: The mean global brain temperature over all subjects was 37.2°C with spatial variations across ROIs. There was a significant main effect for time [ F (1, 1,591) = 37.0, p < 0.0001] and for brain region [ F (46, 1,591) = 2.66, p < 0.0001]. The time * brain region interaction was not significant [ F (46, 1,591) = 0.80, p = 0.83]. Participants' T CRE was stable for each ROI across both time points, with ROIs' COVrep ranging from 0.81 to 3.08% (mean COVrep = 1.92%); majority of ROIs had a COVrep <2.0%. Conclusions: Brain temperature measurements were highly consistent between both time points, indicating high reproducibility and repeatability of MRSI-t. MRSI-t may be a promising diagnostic, prognostic, and therapeutic tool for non-invasively monitoring brain temperature changes in health and disease. However, further studies of healthy participants with larger sample size(s) and numerous repeated acquisitions are imperative for establishing a reference range of typical brain T CRE , as well as the threshold above which T CRE is likely pathological., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Sharma, Nenert, Mueller, Maudsley, Younger and Szaflarski.)

Proton magnetic resonance spectroscopy ( 1 H-MRS) studies have examined glutamatergic abnormalities in schizophrenia, mostly in single voxels. Though the critical brain nodes remain unknown, schizophrenia involves networks with broad abnormalities. Hence, glutamine plus glutamate (Glx) and other metabolites were examined with whole-brain 1 H-MRS, in early schizophrenia. Three dimensional 1 H-MRS was acquired in young schizophrenia subjects (N = 36, 19 antipsychotic-naïve and 17 antipsychotic-treated) and healthy controls (HC, N = 29). Glx (as well as N-acetylaspartate, choline, myo-inositol and creatine) group contrasts from all individual voxels that met spectral quality, were analyzed in common brain space, followed by cluster-corrected level alpha-value (CCLAV ≤ 0.05). Schizophrenia subjects had lower Glx in the left superior (STG) and middle temporal gyri (16 voxels, CCLAV = 0.04) and increased creatine in two clusters involving left temporal, parietal and occipital regions (32, and 18 voxels, CCLAV = 0.02 and 0.04, respectively). Antipsychotic-treated and naïve patients (vs HC) had similar Glx reductions (8/16 vs 10/16 voxels respectively, but CCLAV's > 0.05). However, creatine was higher in antipsychotic-treated vs HC's in a larger left hemisphere cluster (100 voxels, CCLAV = 0.01). Also in treated patients, choline was increased in left middle frontal gyrus (18 voxels, CCLAV = 0.04). Finally in antipsychotic-naive patients, NAA was reduced in right frontal gyri (19 voxels, CCLAV = 0.05) and myo-inositol was reduced in the left cerebellum (34 voxels, CCLAV = 0.02). We conclude that data-driven spectroscopic brain examination supports that reductions in Glx in the left STG may be critical to the pathophysiology of schizophrenia. Postmortem and neuromodulation schizophrenia studies focusing on left STG, may provide critical mechanistic and therapeutic advancements, respectively.

Purpose: To study brain metabolic changes under normal aging and to collect reference data for the study of neurodegenerative diseases., Methods: A total of 55 healthy subjects aged 20-70 years (n ≥ 5 per age decade for each gender) underwent whole-brain magnetic resonance spectroscopic imaging at 3T after completing a DemTect test and the Beck depressions inventory II to exclude cognitive impairment and mental disorder. Regional concentrations of N-acetylaspartate (NAA), choline-containing compounds (Cho), total creatine (tCr), glutamine and glutamate (Glx), and myo-inositol (mI) were determined in 12 brain regions of interest (ROIs). The two-sided t‑test was used to estimate gender differences and linear regression analysis was carried out to estimate age dependence of brain regional metabolite contents., Results: Brain regional metabolite concentrations changed with age in the majority of selected brain regions. The NAA decreased in 8 ROIs with a rate varying from -4.9% to -1.9% per decade, reflecting a general reduction of brain neuronal function or volume and density in older age; Cho increased in 4 ROIs with a rate varying from 4.3% to 6.1%; tCr and mI increased in one ROI (4.2% and 8.2% per decade, respectively), whereas Glx decreased in one ROI (-5.1% per decade), indicating an inhomogeneous increase of cell membrane turnover (Cho) with altered energy metabolism (tCr) and glutamatergic neuronal activity (Glx) as well as function of glia cell (mI) in normal aging brain., Conclusion: Healthy aging up to the seventh decade of life is associated with regional dependent alterations of brain metabolism. These results provide a reference database for future studies of patients.

With a 40-year history of use for in vivo studies, the terminology used to describe the methodology and results of magnetic resonance spectroscopy (MRS) has grown substantially and is not consistent in many aspects. Given the platform offered by this special issue on advanced MRS methodology, the authors decided to describe many of the implicated terms, to pinpoint differences in their meanings and to suggest specific uses or definitions. This work covers terms used to describe all aspects of MRS, starting from the description of the MR signal and its theoretical basis to acquisition methods, processing and to quantification procedures, as well as terms involved in describing results, for example, those used with regard to aspects of quality, reproducibility or indications of error. The descriptions of the meanings of such terms emerge from the descriptions of the basic concepts involved in MRS methods and examinations. This paper also includes specific suggestions for future use of terms where multiple conventions have emerged or coexisted in the past., (© 2020 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Introduction: Major depressive disorder (MDD) is a severe mental disorder with a neurobiological basis that is poorly understood. Several studies demonstrated widespread, functional and neurometabolic alterations in MDD. However, little is known about whole brain neurometabolic alterations in MDD., Method: Thirty-two patients with MDD and 32 paired on a one-to-one basis healthy controls (CTRL) underwent 1 H-whole brain spectroscopic ( 1 H-WBS) imaging. Lobar and cerebellar metabolite concentrations of brain N-acetylaspartate (NAA), total choline (tCho), total creatine (tCr), glutamine (Gln), glutamate (Glu), and myo-Inositol (mI) were assessed in patients and controls., Results: Decreased NAA, tCho, and tCr were found in the right frontal and right parietal lobe in MDD compared to CTRL, and to a lesser extent in the left frontal lobe. Furthermore, in MDD increased glutamine was observed in the right frontal lobe and bitemporal lobes, and increased glutamate in the cerebellum., Conclusion: Altered global neurometabolism examined using 1 H-WBS imaging in MDD may be interpreted as signs of neuronal dysfunction, altered energy metabolism, and oligodendrocyte dysfunction. In particular, the parallel decrease in NAA, tCr and tCho in the same brain regions may be indicative of neuronal dysfunction that may be counterbalanced by an increase of the neuroprotective metabolite glutamine. Future prospective investigations are warranted to study the functional importance of these findings., Competing Interests: Declaration of competing interest Kai G. Kahl has received speaker honoraria by Servier, Janssen, EliLilly and Trommsdorff. Helge Frieling has received speaker honoraria by Otsuka, Recordati, and Janssen. All other authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Visual review of individual spectra in magnetic resonance spectroscopic imaging (MRSI) data benefits from the application of spectral smoothing; however, if this processing step is applied prior to spectral analysis this can impact the accuracy of the quantitation. This study aims to analyze the effect of spectral denoising and apodization smoothing on the quantitation of whole-brain MRSI data obtained at short TE., Methods: Short-TE MRSI data obtained at 3 T were analyzed with no spectral smoothing, following (i) Gaussian apodization with values of 1, 2, 4, 6, and 8 Hz, and (ii) denoising using principal component analysis (dnPCA) with 3 different values for the number of retained principal components. The mean lobar white matter estimates for four metabolites, signal-to-noise ratio (SNR), spectral linewidth, and confidence intervals were compared to data reconstructed using no smoothing. Additionally, a voxel-wise comparison for N-acetylaspartate quantitation with different smoothing schemes was performed., Results: Significant pairwise differences were seen for all Gaussian smoothing methods as compared to no smoothing (p<0.001) in linewidth and metabolite estimates, whereas dnPCA methods showing no statistically significant differences in these measures. Confidence intervals decreased, and SNR increased with increasing levels of apodization smoothing or dnPCA denoising., Conclusion: Mild Gaussian apodization (≤2 Hz at 3 T) can be applied with minimal (1%) errors in quantitation; however, smoothing values greater than that can significantly affect metabolite quantification. In contrast, mild to moderate dnPCA based denoising provides quantitative results that are consistent with the analysis of unsmoothed data and this method is recommended for spectral denoising., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to compare a recently established whole brain MR spectroscopic imaging (wbMRSI) technique using spin-echo planar spectroscopic imaging (EPSI) acquisition and the Metabolic Imaging and Data Analysis System (MIDAS) software package with single voxel spectroscopy (SVS) technique and LCModel analysis for determination of relative metabolite concentrations in aging human brain., Methods: A total of 59 healthy subjects aged 20-70 years (n ≥ 5 per age decade for each gender) underwent a wbEPSI scan and 3 SVS scans of a 4 ml voxel volume located in the right basal ganglia, occipital grey matter and parietal white matter. Concentration ratios to total creatine (tCr) for N‑acetylaspartate (NAA/tCr), total choline (tCho/tCr), glutamine (Gln/tCr), glutamate (Glu/tCr) and myoinositol (mI/tCr) were obtained both from EPSI and SVS acquisitions with either LCModel or MIDAS. In addition, an aqueous phantom containing known metabolite concentrations was also measured., Results: Metabolite concentrations obtained with wbMRSI and SVS were comparable and consistent with those reported previously. Decreases of NAA/tCr and increases of line width with age were found with both techniques, while the results obtained from EPSI acquisition revealed generally narrower line widths and smaller Cramer-Rao lower bounds than those from SVS data., Conclusion: The wbMRSI could be used to estimate metabolites in vivo and in vitro with the same reliability as using SVS, with the main advantage being the ability to determine metabolite concentrations in multiple brain structure simultaneously in vivo. It is expected to be widely used in clinical diagnostics and neuroscience.

Previous neuroimaging studies have detected markers of neuroinflammation in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Magnetic Resonance Spectroscopy (MRS) is suitable for measuring brain metabolites linked to inflammation, but has only been applied to discrete regions of interest in ME/CFS. We extended the MRS analysis of ME/CFS by capturing multi-voxel information across the entire brain. Additionally, we tested whether MRS-derived brain temperature is elevated in ME/CFS patients. Fifteen women with ME/CFS and 15 age- and gender-matched healthy controls completed fatigue and mood symptom questionnaires and whole-brain echo-planar spectroscopic imaging (EPSI). Choline (CHO), myo-inositol (MI), lactate (LAC), and N-acetylaspartate (NAA) were quantified in 47 regions, expressed as ratios over creatine (CR), and compared between ME/CFS patients and controls using independent-samples t-tests. Brain temperature was similarly tested between groups. Significant between-group differences were detected in several regions, most notably elevated CHO/CR in the left anterior cingulate (p < 0.001). Metabolite ratios in seven regions were correlated with fatigue (p < 0.05). ME/CFS patients had increased temperature in the right insula, putamen, frontal cortex, thalamus, and the cerebellum (all p < 0.05), which was not attributable to increased body temperature or differences in cerebral perfusion. Brain temperature increases converged with elevated LAC/CR in the right insula, right thalamus, and cerebellum (all p < 0.05). We report metabolite and temperature abnormalities in ME/CFS patients in widely distributed regions. Our findings may indicate that ME/CFS involves neuroinflammation.

Background and Purpose: Mutations in isocitrate dehydrogenase (IDH) have a direct effect on gliomagenesis. The purpose of this study is to quantify differences in brain metabolites due to IDH mutations., Methods: Magnetic Resonance Spectroscopic Imaging (MRSI) was performed in 35 patients with gliomas of different grade and varied IDH mutation status. Volumes of interest (VOIs) for active tumor (tVOI), peritumoral area (pVOI), and contralateral normal-appearing white matter (cVOI) were created. Metabolite ratios of Choline (Cho) to both N-acetylaspartate (NAA) and Creatine (Cr) were estimated. Ratios of Glutamate/Glutamine complex (Glx) and myoinositol (mIno) to Cr were also quantified. General linear models (GLMs) were used to estimate the effects of IDH mutation on metabolite measures, with age, gender, and tumor grade used as covariates., Results: GLM analysis showed that maximum Cho/NAA and Cho/Cr in the tVOI were significantly (P < .05) higher in IDH mutant lesions as compared to wild-type. In the pVOI, mean Cho/Cr was found to be significantly different among IDH mutant and wild-type gliomas. Mean Cho/NAA (P = .306) and Cho/Cr (P = .292) within the tVOI were not significantly different. Ratios of Glx/Cr and mIno/Cr in any region showed no significant differences between IDH mutant and wild-type gliomas. No significant differences in metabolite ratios were seen in the cVOI between IDH mutants and wild-types., Conclusion: IDH mutation's effect in gliomas show an increase in Cho in the tumor and perilesional regions as compared to wild-type lesions but do not show widespread changes across the brain., (© 2019 by the American Society of Neuroimaging.)

Cardiovascular risk factors such as dyslipidemia and hypertension increase the risk for white matter pathology and cognitive decline. We hypothesize that white matter levels of N -acetylaspartate (NAA), a chemical involved in the metabolic pathway for myelin lipid synthesis, could serve as a biomarker that tracks the influence of cardiovascular risk factors on white matter prior to emergence of clinical changes. To test this, we measured levels of NAA across white matter and gray matter in the brain using echo planar spectroscopic imaging (EPSI) in 163 individuals and examined the relationship of regional NAA levels and cardiovascular risk factors as indexed by the Framingham Cardiovascular Risk Score (FCVRS). NAA was strongly and negatively correlated with FCVRS across the brain, but, after accounting for age and sex, the association was found primarily in white matter regions, with additional effects found in the thalamus, hippocampus, and cingulate gyrus. FCVRS was also negatively correlated with creatine levels, again primarily in white matter. The results suggest that cardiovascular risks are related to neurochemistry with a predominantly white matter pattern and some subcortical and cortical gray matter involvement. NAA mapping of the brain may provide early surveillance for the potential subclinical impact of cardiovascular and metabolic risk factors on the brain., Competing Interests: Competing interest statement: L.E.H. has received or plans to receive research funding or consulting fees from Mitsubishi, Your Energy Systems LLC, Neuralstem, Taisho Pharmaceutical, Luye Pharma, Sound Pharma, Heptares, Takeda, and Pfizer. L.M.R. has received or plans to receive consulting fees from Otsuka America Pharmaceutical, Inc. A.R.S. is a full-time employee of Regeneron Pharmaceuticals, Inc. All other authors declare no competing interest.

Proton MRS ( 1 H MRS) provides noninvasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Although most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges toward obtaining reliable good-quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the PRESS localization sequence was found to be unacceptably high at 3 T, and use of the semi-adiabatic localization by adiabatic selective refocusing sequence is a recommended solution. Incorporation of simulated metabolite basis sets into analysis routines is recommended for reliably capturing the full spectral detail available from short TE acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B 0 ) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. Implementation of these recommendations should strengthen current clinical applications and advance progress toward developing and validating new MRS biomarkers for clinical use., (© 2019 International Society for Magnetic Resonance in Medicine.)

Objective: To estimate alterations in neurometabolic profile of patients with early stage Parkinson's disease (PD) by using a short echo-time whole brain magnetic resonance spectroscopic imaging (wbMRSI) as possible biomarker for early diagnosis and monitoring of PD. Methods: 20 PD patients in early stage (H&Y ≤ 2) without evidence of severe other diseases and 20 age and sex matched healthy controls underwent wbMRSI. In each subject brain regional concentrations of metabolites N-acetyl-aspartate (NAA), choline (Cho), total creatine (tCr), glutamine (Gln), glutamate (Glu), and myo-inositol (mIns) were obtained in atlas-defined lobar structures including subcortical basal ganglia structures (the left and right frontal lobes, temporal lobes, parietal lobes, occipital lobes, and the cerebellum) and compared between patients and matched healthy controls. Clinical characteristics of the PD patients were correlated with spectroscopic findings. Results: In comparison to controls the PD patients revealed altered lobar metabolite levels in all brain lobes contralateral to dominantly affected body side, i.e., decreases of temporal NAA, Cho, and tCr, parietal NAA and tCr, and frontal as well as occipital NAA. The frontal NAA correlated negatively with the MDS-UPDRS II ( R = 22120.585, p = 0.008), MDS-UPDRS IV ( R = -0.458, p = 0.048) and total MDS-UPDRS scores ( R = -0.679, p = 0.001). Conclusion: In early PD stages metabolic alterations are evident in all contralateral brain lobes demonstrating that the neurodegenerative process affects not only local areas by dopaminergic denervation, but also the functional network within different brain regions. The wbMRSI-detectable brain metabolic alterations reveal the potential to serve as biomarkers for early PD.

Purpose: MRSI has shown great promise in the detection and monitoring of neurologic pathologies such as tumor. A necessary component of data processing includes the quantitation of each metabolite, typically done through fitting a model of the spectrum to the data. For high-resolution volumetric MRSI of the brain, which may have ~10,000 spectra, significant processing time is required for spectral analysis and generation of metabolite maps., Methods: A novel unsupervised deep learning architecture that combines a convolutional neural network with a priori models of the spectrum is presented. This architecture, a convolutional encoder-model decoder (CEMD), combines the strengths of adaptive and unbiased convolutional networks with models of magnetic resonance and is readily interpretable., Results: The CEMD architecture performs accurate spectral fitting for volumetric MRSI in patients with glioblastoma, provides whole-brain fitting in 1 min on a standard computer, and handles a variety of spectral artifacts., Conclusion: A new architecture combining physics domain knowledge with convolutional neural networks has been developed and is able to perform rapid spectral fitting of whole-brain data. Rapid processing is a critical step toward routine clinical practice., (© 2019 International Society for Magnetic Resonance in Medicine.)

Purpose: Delineation of lesion boundaries from volumetric MRSI metabolite ratio maps using a method that accounts for the spatial response function of the acquisition and variable spectral quality and is robust to signal heterogeneity within the lesion., Methods: A novel method for lesion segmentation, termed convolution difference, has been developed that is robust to signal heterogeneity within the lesion and to differences in the spatial response function. Procedures are described for processing metabolite ratio maps and to exclude regions of inadequate spectral quality. This method was evaluated using computer simulations, and the results were compared with an iterative thresholding technique that determines an optimal amplitude threshold, and with the use of a fixed amplitude threshold. These methods were evaluated for segmentation of volumetric MRSI studies of gliomas using maps of the choline to N-acetylaspartate ratio, and a qualitative comparison of lesion volumes carried out., Results: Simulation studies indicated improved performance for the convolution difference method when applied to ratio maps. Variations in tumor volume were observed for the in vivo studies between the convolution difference and the iterative thresholding methods; however, visual analysis indicates that both showed improved accuracy in comparison to using a fixed amplitude threshold., Conclusion: This study reinforces previous reports indicating that the use of fixed threshold values for segmentation of maps with broad spatial response functions can result in errors in lesion volume definition. A novel segmentation method, termed the convolution difference, has been introduced and demonstrated to be robust for segmentation of volumetric MRSI metabolite data., (© 2018 International Society for Magnetic Resonance in Medicine.)

Accurate differentiation of true progression (TP) from pseudoprogression (PsP) in patients with glioblastomas (GBMs) is essential for planning adequate treatment and for estimating clinical outcome measures and future prognosis. The purpose of this study was to investigate the utility of three-dimensional echo planar spectroscopic imaging (3D-EPSI) in distinguishing TP from PsP in GBM patients. For this institutional review board approved and HIPAA compliant retrospective study, 27 patients with GBM demonstrating enhancing lesions within six months of completion of concurrent chemo-radiation therapy were included. Of these, 18 were subsequently classified as TP and 9 as PsP based on histological features or follow-up MRI studies. Parametric maps of choline/creatine (Cho/Cr) and choline/N-acetylaspartate (Cho/NAA) were computed and co-registered with post-contrast T 1 -weighted and FLAIR images. All lesions were segmented into contrast enhancing (CER), immediate peritumoral (IPR), and distal peritumoral (DPR) regions. For each region, Cho/Cr and Cho/NAA ratios were normalized to corresponding metabolite ratios from contralateral normal parenchyma and compared between TP and PsP groups. Logistic regression analyses were performed to obtain the best model to distinguish TP from PsP. Significantly higher Cho/NAA was observed from CER (2.69 ± 1.00 versus 1.56 ± 0.51, p = 0.003), IPR (2.31 ± 0.92 versus 1.53 ± 0.56, p = 0.030), and DPR (1.80 ± 0.68 versus 1.19 ± 0.28, p = 0.035) regions in TP patients compared with those with PsP. Additionally, significantly elevated Cho/Cr (1.74 ± 0.44 versus 1.34 ± 0.26, p = 0.023) from CER was observed in TP compared with PsP. When these parameters were incorporated in multivariate regression analyses, a discriminatory model with a sensitivity of 94% and a specificity of 87% was observed in distinguishing TP from PsP. These results indicate the utility of 3D-EPSI in differentiating TP from PsP with high sensitivity and specificity., (© 2018 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Background: Increase of brain total sodium concentrations (TSC) is present in multiple sclerosis (MS), but its pathological involvement has not been assessed yet., Objective: To determine in vivo the metabolic counterpart of brain sodium accumulation., Materials/methods: Whole brain 23 Na-MR imaging and 3D- 1 H-EPSI data were collected in 21 relapsing-remitting multiple sclerosis (RRMS) patients and 20 volunteers. Metabolites and sodium levels were extracted from several regions of grey matter (GM), normal-appearing white matter (NAWM) and white matter (WM) T 2 lesions. Metabolic and ionic levels expressed as Z-scores have been averaged over the different compartments and used to explain sodium accumulations through stepwise regression models., Results: MS patients showed significant 23 Na accumulations with lower choline and glutamate-glutamine (Glx) levels in GM; 23 Na accumulations with lower N-acetyl aspartate (NAA), Glx levels and higher Myo-Inositol (m-Ins) in NAWM; and higher 23 Na, m-Ins levels with lower NAA in WM T 2 lesions. Regression models showed associations of TSC increase with reduced NAA in GM, NAWM and T 2 lesions, as well as higher total-creatine, and smaller decrease of m-Ins in T 2 lesions. GM Glx levels were associated with clinical scores., Conclusion: Increase of TSC in RRMS is mainly related to neuronal mitochondrial dysfunction while dysfunction of neuro-glial interactions within GM is linked to clinical scores.

Background: Diffusion kurtosis imaging (DKI) measures have been shown to provide increased sensitivity relative to diffusion tensor imaging (DTI) in detecting pathologies., Purpose: To compare the sensitivity of DKI-derived kurtosis and diffusion maps for assessment of low-grade gliomas (LGG)., Study Type: Prospective study., Population: In all, 19 LGG patients and 26 healthy control subjects were recruited., Field Strength/sequence: Echo-planar-imaging diffusion-weighted MR images (b-values = 0, 1000, and 2000 with 30 diffusion gradient directions) were acquired on a 3T scanner., Assessment: Maps for mean, axial, and radial diffusivity (MD, AD, and RD) and kurtosis (MK, AK, and RK), and fractional anisotropy (FA) were evaluated in the tumor, perilesional white matter, and contralateral normal-appearing white matter regions., Statistical Testing: General linear models (GLM), Cohen's d for effect size estimates, false discovery rate (FDR) for multiple corrections, Cochran Q-test., Results: Pairwise differences were observed for all diffusion and kurtosis measures between the studied regions (FDR P < 0.001), except an FA map that failed to show significant differences between the lesion and perilesional white matter (FDR P = 0.373). Effect size analysis showed that kurtosis metrics were found to be 18.8% (RK, P = 0.144) to 29.1% (AK, P < 0.05) more sensitive in discriminating perilesional regions from the lesion than corresponding diffusion metrics, whereas AK provided a 25.0% (P < 0.05) increase in sensitivity in discriminating perilesional and contralateral white matter. RK was found to be the most sensitive to contralateral white matter differences between low-grade gliomas and controls, with MK and RK providing a significantly greater sensitivity of 587.2% (P < 0.001) and 320.7% (P < 0.001) than MD and RD, respectively., Data Conclusion: Kurtosis maps showed increased sensitivity, as compared to counterpart diffusion maps, for evaluation of microstructural changes in gliomas with a 3-6-fold increment in assessing changes in contralateral white matter., Level of Evidence: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;48:1551-1558., (© 2018 International Society for Magnetic Resonance in Medicine.)

Purpose: Proton MRSI is a noninvasive modality capable of generating volumetric maps of in vivo tissue metabolism without the need for ionizing radiation or injected contrast agent. Magnetic resonance spectroscopic imaging has been shown to be a viable imaging modality for studying several neuropathologies. However, a key hurdle in the routine clinical adoption of MRSI is the presence of spectral artifacts that can arise from a number of sources, possibly leading to false information., Methods: A deep learning model was developed that was capable of identifying and filtering out poor quality spectra. The core of the model used a tiled convolutional neural network that analyzed frequency-domain spectra to detect artifacts., Results: When compared with a panel of MRS experts, our convolutional neural network achieved high sensitivity and specificity with an area under the curve of 0.95. A visualization scheme was implemented to better understand how the convolutional neural network made its judgement on single-voxel or multivoxel MRSI, and the convolutional neural network was embedded into a pipeline capable of producing whole-brain spectroscopic MRI volumes in real time., Conclusion: The fully automated method for assessment of spectral quality provides a valuable tool to support clinical MRSI or spectroscopic MRI studies for use in fields such as adaptive radiation therapy planning., (© 2018 International Society for Magnetic Resonance in Medicine.)

Purpose: Estimation of brain metabolite concentrations by MR spectroscopic imaging (MRSI) is complicated by partial volume contributions from different tissues. This study evaluates a method for increasing tissue specificity that incorporates prior knowledge of tissue distributions., Methods: A spectral decomposition (sDec) technique was evaluated for separation of spectra from white matter (WM) and gray matter (GM), and for measurements in small brain regions using whole-brain MRSI. Simulation and in vivo studies compare results of metabolite quantifications obtained with the sDec technique to those obtained by spectral fitting of individual voxels using mean values and linear regression against tissue fractions and spectral fitting of regionally integrated spectra., Results: Simulation studies showed that, for GM and the putamen, the sDec method offers < 2% and 3.5% error, respectively, in metabolite estimates. These errors are considerably reduced in comparison to methods that do not account for partial volume effects or use regressions against tissue fractions. In an analysis of data from 197 studies, significant differences in mean metabolite values and changes with age were found. Spectral decomposition resulted in significantly better linewidth, signal-to-noise ratio, and spectral fitting quality as compared to individual spectral analysis. Moreover, significant partial volume effects were seen on correlations of neurometabolite estimates with age., Conclusion: The sDec analysis approach is of considerable value in studies of pathologies that may preferentially affect WM or GM, as well as smaller brain regions significantly affected by partial volume effects. Magn Reson Med 79:2886-2895, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

PET imaging of amino acid transport using O -(2- 18 F-fluoroethyl)-l-tyrosine ( 18 F-FET) and proton MR spectroscopy (MRS) imaging of cell turnover measured by the ratio of choline to N -acetyl-aspartate (Cho/NAA) may provide additional information on tumor extent of cerebral gliomas compared with anatomic imaging; however, comparative studies are rare. Methods: In this prospective study, 41 patients (16 women, 25 men; mean age ± SD, 48 ± 14 y) with cerebral gliomas (World Health Organization [WHO] grade II: 10 [including 1 patient with 2 lesions], WHO III: 17, WHO IV: 13, without biopsy low-grade: 1, high-grade: 1) were investigated with a hybrid PET/MR scanner. Tumor extent, spatial overlap, and the distance between the corresponding centers of mass in 18 F-FET PET and MRS imaging of Cho/NAA, determined by simultaneously acquired, 3-dimensional spatially resolved MRS imaging data, were compared. Results: The average tumor volumes for 18 F-FET uptake and increased Cho/NAA were 19 ± 20 cm 3 (mean ± SD) and 22 ± 24 cm 3 , respectively, with an overlap of 40% ± 25% and separation of the centers of mass by 9 ± 8 mm. None of the parameters showed a significant correlation with tumor grade. Conclusion: 18 F-FET uptake and increased Cho/NAA ratio are not always congruent and may represent different properties of glioma metabolism. The relationship to histologic tumor extent needs to be further analyzed., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

To date, single voxel spectroscopy (SVS) is the most commonly used MRS technique. SVS is relatively easy to use and provides automated and immediate access to the resulting spectra. However, it is also limited in spatial coverage. A new and very promising MRS technique allows for whole-brain MR spectroscopic imaging (WB-MRSI) with much improved spatial resolution. Establishing the reproducibility of data obtained using SVS and WB-MRSI is an important first step for using these techniques to evaluate longitudinal changes in metabolite concentration. The purpose of this study was to assess and directly compare the reproducibility of metabolite quantification at 3T using SVS and WB-MRSI in 'hand-knob' areas of motor cortices and hippocampi in healthy volunteers. Ten healthy adults were scanned using both SVS and WB-MRSI on three occasions one week apart. N-acetyl aspartate (NAA), creatine (Cr), choline (Cho) and myo-inositol (mI) were quantified using SVS and WB-MRSI with reference to both Cr and H 2 O. The reproducibility of each technique was evaluated using the coefficient of variation (CV), and the correspondence between the two techniques was assessed using Pearson correlation analysis. The measured mean (range) intra-subject CVs for SVS were 5.90 (2.65-10.66)% for metabolites (i.e. NAA, Cho, mI) relative to Cr, and 8.46 (4.21-21.07)% for metabolites (NAA, Cr, Cho, mI) relative to H 2 O. The mean (range) CVs for WB-MRSI were 7.56 (2.78-11.41)% for metabolites relative to Cr, and 7.79 (4.57-14.11)% for metabolites relative to H 2 O. Significant positive correlations were observed between metabolites quantified using SVS and WB-MRSI techniques when the Cr but not H 2 O reference was used. The results demonstrate that reproducibilities of SVS and WB-MRSI are similar for quantifying the four major metabolites (NAA, Cr, Cho, mI); both SVS and WB-MRSI exhibited good reproducibility. Our findings add reference information for choosing the appropriate 1 H-MRS technique in future studies., (Copyright © 2018 John Wiley & Sons, Ltd.)

Adaptive response of human brain to stress plays a key role in maintaining health. Knowledge about how stress affects neurometabolism may help to understand adaptive stress responses, and distinguish maladaptation in neuropsychiatric disorders. In this study, neurometabolic responses to fasting stress in healthy women were investigated. Fifteen healthy females were examined for mood and cognition and using whole-brain MR spectroscopic imaging before and immediately after a 72-h fasting. Results were compared to 15 age-matched healthy females who did not taken part in fasting (non-fasting). Maps of the distributions in the brain of N-acetylaspartate (NAA), total choline (tCho), total creatine (tCr), glutamine/glutamate (Glx), and myo-Inositol (mI) were derived. Metabolite concentrations of each brain lobe and cerebellum measured before fasting were compared to those of post-fasting and non-fasting by repeated-measures ANOVA. After fasting, mood scores significantly increased. Glx decreased in all nine brain regions, tCho in eight, NAA in four and tCr in one, with Glx having the greatest change and the frontal lobes being the most affected brain region. In conclusion, fasting directly influences neurometabolism, and the adaptive brain response to maintain energy homeostasis under food deprivation in healthy women is associated with metabolite-selective and region-dependent changes of metabolite contents.

Background and Purpose: Brain trauma is known to result in heterogeneous patterns of tissue damage and altered neuronal and glial metabolism that evolve over time following injury; however, little is known on the longitudinal evolution of these changes. In this study, magnetic resonance spectroscopic imaging (MRSI) was used to map the distributions of altered metabolism in a single subject at five time points over a period of 28 months following injury., Methods: Magnetic resonance imaging and volumetric MRSI data were acquired in a subject that had experienced a moderate traumatic brain injury (Glasgow Coma Scale 13) at five time points, from 7 weeks to 28 months after injury. Maps of N-acetylaspartate (NAA), total choline (Cho), and total creatine signal were generated and differences from normal control values identified using a z-score image analysis method., Results: The z-score metabolite maps revealed areas of significantly reduced NAA and increased Cho, predominately located in frontal and parietal white matter, which evolved over the complete course of the study. A map of the ratio of Cho/NAA showed the greatest sensitivity to change, which indicated additional metabolic changes throughout white matter. The metabolic changes reduced over time following injury, though with abnormal values remaining in periventricular regions., Conclusions: The use of z-score image analysis for MRSI provides a method for visualizing diffuse changes of tissue metabolism in the brain. This image visualization method is of particularly effective for visualizing widespread and diffuse metabolic changes, such as that due to traumatic injury., (Copyright © 2017 by the American Society of Neuroimaging.)

A method for mapping of temperature over a large volume of the brain using volumetric proton MR spectroscopic imaging has been implemented and applied to 150 normal subjects. Magnetic susceptibility-induced frequency shifts in gray- and white-matter regions were measured and included as a correction in the temperature mapping calculation. Additional sources of magnetic susceptibility variations of the individual metabolite resonance frequencies were also observed that reflect the cellular-level organization of the brain metabolites, with the most notable differences being attributed to changes of the N-Acetylaspartate resonance frequency that reflect the intra-axonal distribution and orientation of the white-matter tracts with respect to the applied magnetic field. These metabolite-specific susceptibility effects are also shown to change with age. Results indicate no change of apparent brain temperature with age from 18 to 84 years old, with a trend for increased brain temperature throughout the cerebrum in females relative for males on the order of 0.1°C; slightly increased temperatures in the left hemisphere relative to the right; and a lower temperature of 0.3°C in the cerebellum relative to that of cerebral white-matter. This study presents a novel acquisition method for noninvasive measurement of brain temperature that is of potential value for diagnostic purposes and treatment monitoring, while also demonstrating limitations of the measurement due to the confounding effects of tissue susceptibility variations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To evaluate a new denoising method for MR spectroscopic imaging (MRSI) data based on selection of signal-related principal components (SSPCs) from principal components analysis (PCA)., Materials and Methods: A PCA-based method was implemented for selection of signal-related PCs and denoising achieved by reconstructing the original data set utilizing only these PCs. Performance was evaluated using simulated MRSI data and two volumetric in vivo MRSIs of human brain, from a normal subject and a patient with a brain tumor, using variable signal-to-noise ratios (SNRs), metabolite peak areas, Cramer-Rao bounds (CRBs) of fitted metabolite peak areas and metabolite linewidth., Results: In simulated data, SSPC determined the correct number of signal-related PCs. For in vivo studies, the SSPC denoising resulted in improved SNRs and reduced metabolite quantification uncertainty compared to the original data and two other methods for denoising. The method also performed very well in preserving the spectral linewidth and peak areas. However, this method performs better for regions that have larger numbers of similar spectra., Conclusion: The proposed SSPC denoising improved the SNR and metabolite quantification uncertainty in MRSI, with minimal compromise of the spectral information, and can result in increased accuracy.

Purpose: To evaluate methods for multichannel combination of three-dimensional MR spectroscopic imaging (MRSI) data with a focus on using information from a water-reference spectroscopic image., Methods: Volumetric MRSI data were acquired for a phantom and for human brain using 8- and 32-channel detection. Acquisition included a water-reference dataset that was used to determine the weights for several multichannel combination methods. Results were compared using the signal-to-noise ratio (SNR) of the N-acetylaspartate resonance., Results: Performance of all methods was very similar for the phantom study, with the whitened singular value decomposition (WSVD) and signal magnitude (S) weighting combination having a small advantage. For in vivo studies, the S weighting, SNR weighting and signal to noise squared (S/N(2) ) weighting were the three best methods and performed similarly. Example spectra and SNR maps indicated that the SVD and WSVD methods tend to fail for voxels at the outer edges of the brain that include strong lipid signal contributions., Conclusion: For data combination of MRSI data using water-reference information, the S/N(2) weighting, SNR and S weighting were the best methods in terms of spectral quality SNR. These methods are also computationally efficient and easy to implement. Magn Reson Med 76:733-741, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Knowledge of physiological aging in healthy human brain is increasingly important for neuroscientific research and clinical diagnosis. To investigate neuronal decline in normal aging brain eighty-one healthy subjects aged between 20 and 70years were studied with MRI and whole-brain (1)H MR spectroscopic imaging. Concentrations of brain metabolites N-acetyl-aspartate (NAA), choline (Cho), total creatine (tCr), myo-inositol (mI), and glutamine+glutamate (Glx) in ratios to internal water, and the fractional volumes of brain tissue were estimated simultaneously in eight cerebral lobes and in cerebellum. Results demonstrated that an age-related decrease in gray matter volume was the largest contribution to changes in brain volume. Both lobar NAA and the fractional volume of gray matter (FVGM) decreased with age in all cerebral lobes, indicating that the decreased NAA was predominantly associated with decreased gray matter volume and neuronal density or metabolic activity. In cerebral white matter Cho, tCr, and mI increased with age in association with increased fractional volume, showing altered cellular membrane turn-over, energy metabolism, and glial activity in human aging white matter. In cerebellum tCr increased while brain tissue volume decreased with age, showing difference to cerebral aging. The observed age-related metabolic and microstructural variations suggest that physiological neuronal decline in aging human brain is associated with a reduction of gray matter volume and neuronal density, in combination with cellular aging in white matter indicated by microstructural alterations and altered energy metabolism in the cerebellum., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To detect local metabolic abnormalities over the complete human brain in multiple sclerosis (MS) patients, we used optimized fast volumic echo planar spectroscopic imaging (3D-EPSI)., Materials and Methods: Weighted mean combination of two 3D-EPSI covering the whole brain acquired at 3T in AC-PC and AC-PC+15° axial planes was performed to obtain high-quality metabolite maps for five metabolites: N-acetyl aspartate (NAA), glutamate+glutamine (Glx), choline (Cho), myo-inositol (m-Ins), and creatine+phosphocreatine (tCr). After spatial normalization, maps from 19 patients suffering from relapsing-remitting MS were compared to 19 matched controls using statistical mapping analyses to determine the topography of metabolic abnormalities. Probabilistic white matter (WM) T2 lesion maps and gray matter (GM) atrophy maps were also generated., Results: Two-group analysis of variance (ANOVA) (SPM8, P < 0.005, false discovery rate [FDR]-corrected P < 0.05 at the cluster level with age and sex as confounding covariates) comparing patients and controls matched for age and sex showed clusters of abnormal metabolite levels with 1) decreased NAA (around -15%) and Glx (around 20%) predominantly in GM within prefrontal cortices, motor cortices, bilateral thalami, and mesial temporal cortices in line with neuronal/neuro-astrocytic dysfunction; 2) increased m-Ins (around + 20%) inside WM T2 lesions and in the normal-appearing WM of temporal-occipital lobes, suggesting glial activation., Conclusion: We demonstrate the ability to noninvasively map over the complete brain-from vertex to cerebellum-with a validated sequence, the metabolic abnormalities associated with MS, for characterizing the topography of pathological processes affecting widespread areas of WM and GM and its functional impact. J. Magn. Reson. Imaging 2016;44:411-419., (© 2016 Wiley Periodicals, Inc.)

Glutamate (Glu) and glutamine (Gln) play an important role in neuronal regulation and are of value as MRS-observable diagnostic biomarkers. In this study the relative concentrations of these metabolites have been measured in multiple regions in the normal brain using a short-TE whole-brain MRSI measurement at 3 T combined with a modified data analysis approach that used spatial averaging to obtain high-SNR spectra from atlas-registered anatomic regions or interest. By spectral fitting of high-SNR spectra this approach yielded reliable measurements across a wide volume of the brain. Spectral averaging also demonstrated increased SNR and improved fitting accuracy for the sum of Glu and Gln (Glx) compared with individual voxel fitting. Results in 26 healthy controls showed relatively constant Glu/Cr and Gln/Cr throughout the cerebrum, although with increased values in the anterior cingulum and paracentral lobule, and increased Gln/Cr in the superior motor area. The deep gray-matter regions of thalamus, putamen, and pallidum show lower Glu/Cr compared with cortical white-matter regions. Lobar measurements demonstrated reduced Glu/Cr and Gln/Cr in the cerebellum as compared with the cerebrum, where white-matter regions show significantly lower Glu/Cr and Gln/Cr as compared with gray-matter regions across multiple brain lobes. Regression analysis showed no significant effect of gender on Glu/Cr or Gln/Cr measurement; however, Glx/Cr ratio was found to be significantly negatively correlated with age in some lobar brain regions. In summary, this methodology provides the spectral quality necessary for reliable separation of Glu and Gln at 3 T from a single MRSI acquisition enabling generation of regional distributions of metabolites over a large volume of the brain, including cortical regions. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Persistent pain is experienced by more than 50% of persons who sustain a traumatic brain injury (TBI), and more than 30% experience significant pain as early as 6 weeks after injury. Although neuropathic pain is a common consequence after CNS injuries, little attention has been given to neuropathic pain symptoms after TBI. Magnetic resonance spectroscopy (MRS) studies in subjects with TBI show decreased brain concentrations of N-acetylaspartate (NAA), a marker of neuronal density and viability. Although decreased brain NAA has been associated with neuropathic pain associated with spinal cord injury (SCI) and diabetes, this relationship has not been examined after TBI. The primary purpose of this study was to test the hypothesis that lower NAA concentrations in brain areas involved in pain perception and modulation would be associated with greater severity of neuropathic pain symptoms. Participants with TBI underwent volumetric MRS, pain and psychosocial interviews. Cluster analysis of the Neuropathic Pain Symptom Inventory subscores resulted in two TBI subgroups: The Moderate Neuropathic Pain (n = 17; 37.8%), with significantly (p = 0.038) lower insular NAA than the Low or no Neuropathic Pain group (n = 28; 62.2%), or age- and sex-matched controls (n = 45; p < 0.001). A hierarchical linear regression analysis controlling for age, sex, and time post-TBI showed that pain severity was significantly (F = 11.0; p < 0.001) predicted by a combination of lower insular NAA/Creatine (p < 0.001), lower right insular gray matter fractional volume (p < 0.001), female sex (p = 0.005), and older age (p = 0.039). These findings suggest that neuronal dysfunction in brain areas involved in pain processing is associated with pain after TBI.