A preliminary study of dynamic neurochemical changes in the dorsolateral prefrontal cortex during working memory.

Working memory (WM) is one of the fundamental cognitive functions associated with the dorsolateral prefrontal cortex (DLPFC). However, the neurochemical mechanisms of WM, including the dynamic changes in neurometabolites such as glutamate and GABA in the DLPFC, remain unclear. Here, we investigated WM-related glutamate and GABA changes, alongside hemodynamic responses in the DLPFC, using a combination of functional magnetic resonance spectroscopy (fMRS) and functional magnetic resonance imaging (fMRI). During a WM task, we measured Glx (glutamate + glutamine) and GABA levels using GABA editing MEscher-GArwood Point REsolved Spectroscopy (MEGA-PRESS) sequence and blood-oxygen-level-dependent (BOLD) signal changes. In the DLPFC, we observed elevated Glx levels and increased BOLD signal changes during a 2-back task. Specifically, the Glx levels in the DLPFC were significantly higher during the 2-back task compared with fixation, although this difference was not significant when compared with a 0-back task. However, Glx levels during the 0-back task were higher than during fixation. Furthermore, there was a positive correlation between Glx levels in the DLPFC during the 2-back task and the corresponding BOLD signal changes. Notably, higher Glx increases were associated with increased DLPFC activation and lower WM task performance in individuals. No notable changes in DLPFC GABA levels were observed during WM processing. These findings suggest that the modulation of glutamatergic activity in the DLPFC may play a crucial role in both working memory processing and its associated performance outcomes.

Frequency drift in MR spectroscopy at 3T.

PURPOSE: Heating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. METHOD: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC). RESULTS: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI. DISCUSSION: This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.

Estimation and removal of spurious echo artifacts in single-voxel MRS using sensitivity encoding.

PURPOSE: In localized MRS, spurious echo artifacts commonly occur when unsuppressed signal outside the volume of interest is excited and refocused. In the spectral domain, these signals often overlap with metabolite resonances and hinder accurate quantification. Because the artifacts originate from regions separate from the target MRS voxel, this work proposes that sensitivity encoding based on receive-coil sensitivity profiles may be used to separate these signal contributions. METHODS: Numerical simulations were performed to explore the effect of sensitivity-encoded separation for unknown artifact regions. An imaging-based approach was developed to identify regions that may contribute to spurious echo artifacts, and tested for sensitivity-based unfolding of signal on six data sets from three brain regions. Spectral data reconstructed using the proposed method ("ERASE") were compared with the standard coil combination. RESULTS: The method was able to fully unfold artifact signals if regions were known a priori. Mismatch between estimated and true artifact regions reduced the efficiency of removal, yet metabolite signals were unaffected. Water suppression imaging was able to identify regions of unsuppressed signal, and ERASE (from up to eight regions) led to visible removal of artifacts relative to standard reconstruction. Fitting errors across major metabolites were also lower; for example, Cramér-Rao lower bounds of myo-inositol were 13.7% versus 17.5% for ERASE versus standard reconstruction, respectively. CONCLUSION: The ERASE reconstruction tool was demonstrated to reduce spurious echo artifacts in single-voxel MRS. This tool may be incorporated into standard workflows to improve spectral quality when hardware limitations or other factors result in out-of-voxel signal contamination.

Calibration-free regional RF shims for MRS.

PURPOSE: Achieving a desired RF transmit field ( B1+ ) in small regions of interest is critical for single-voxel MRS at ultrahigh field. Radio-frequency (RF) shimming, using parallel transmission, requires B1+ mapping and optimization, which limits its ease of use. This work aimed to generate calibration-free RF shims for predefined target regions of interest, which can be applied to any participant, to produce a desired absolute magnitude B1+ (| B1+ |). METHODS: The RF shims were found offline by joint optimization on a database comprising B1+ maps from 11 subjects, considering regions of interest in occipital cortex, hippocampus and posterior cingulate, as well as whole brain. The | B1+ | achieved was compared with a tailored shimming approach, and MR spectra were acquired using tailored and calibration-free shims in 4 participants. Global and local 10g specific-absorption-rate deposition were estimated using Duke and Ella dielectric models. RESULTS: There was no difference in the mean | B1+ | produced using calibration-free versus tailored RF shimming in the occipital cortex (p = .15), hippocampus (p = .5), or posterior cingulate (p = .98), although differences were observed in the RMS error | B1+ |. Spectra acquired using calibration-free shims had similar SNR and low residual water signal. Under identical power settings, specific-absorption-rate deposition was lower compared with operating in quadrature mode. For example, the total head specific absorption rate was around 35% less for the occipital cortex. CONCLUSION: This work demonstrates that static RF shims, optimized offline for small regions, avoid the need for B1+ mapping and optimization for each region of interest and participant. Furthermore, power settings may be increased when using calibration-free shims, to better take advantage of RF shimming.

Across-vendor standardization of semi-LASER for single-voxel MRS at 3T.

The semi-adiabatic localization by adiabatic selective refocusing (sLASER) sequence provides single-shot full intensity signal with clean localization and minimal chemical shift displacement error and was recommended by the international MRS Consensus Group as the preferred localization sequence at high- and ultra-high fields. Across-vendor standardization of the sLASER sequence at 3 tesla has been challenging due to the B1 requirements of the adiabatic inversion pulses and maximum B1 limitations on some platforms. The aims of this study were to design a short-echo sLASER sequence that can be executed within a B1 limit of 15 µT by taking advantage of gradient-modulated RF pulses, to implement it on three major platforms and to evaluate the between-vendor reproducibility of its perfomance with phantoms and in vivo. In addition, voxel-based first and second order B0 shimming and voxel-based B1 adjustments of RF pulses were implemented on all platforms. Amongst the gradient-modulated pulses considered (GOIA, FOCI and BASSI), GOIA-WURST was identified as the optimal refocusing pulse that provides good voxel selection within a maximum B1 of 15 µT based on localization efficiency, contamination error and ripple artifacts of the inversion profile. An sLASER sequence (30 ms echo time) that incorporates VAPOR water suppression and 3D outer volume suppression was implemented with identical parameters (RF pulse type and duration, spoiler gradients and inter-pulse delays) on GE, Philips and Siemens and generated identical spectra on the GE 'Braino' phantom between vendors. High-quality spectra were consistently obtained in multiple regions (cerebellar white matter, hippocampus, pons, posterior cingulate cortex and putamen) in the human brain across vendors (5 subjects scanned per vendor per region; mean signal-to-noise ratio > 33; mean water linewidth between 6.5 Hz to 11.4 Hz). The harmonized sLASER protocol is expected to produce high reproducibility of MRS across sites thereby allowing large multi-site studies with clinical cohorts.

Comparison of Multivendor Single-Voxel MR Spectroscopy Data Acquired in Healthy Brain at 26 Sites.

Background The hardware and software differences between MR vendors and individual sites influence the quantification of MR spectroscopy data. An analysis of a large data set may help to better understand sources of the total variance in quantified metabolite levels. Purpose To compare multisite quantitative brain MR spectroscopy data acquired in healthy participants at 26 sites by using the vendor-supplied single-voxel point-resolved spectroscopy (PRESS) sequence. Materials and Methods An MR spectroscopy protocol to acquire short-echo-time PRESS data from the midparietal region of the brain was disseminated to 26 research sites operating 3.0-T MR scanners from three different vendors. In this prospective study, healthy participants were scanned between July 2016 and December 2017. Data were analyzed by using software with simulated basis sets customized for each vendor implementation. The proportion of total variance attributed to vendor-, site-, and participant-related effects was estimated by using a linear mixed-effects model. P values were derived through parametric bootstrapping of the linear mixed-effects models (denoted Pboot). Results In total, 296 participants (mean age, 26 years ± 4.6; 155 women and 141 men) were scanned. Good-quality data were recorded from all sites, as evidenced by a consistent linewidth of N-acetylaspartate (range, 4.4-5.0 Hz), signal-to-noise ratio (range, 174-289), and low Cramér-Rao lower bounds (≤5%) for all of the major metabolites. Among the major metabolites, no vendor effects were found for levels of myo-inositol (Pboot > .90), N-acetylaspartate and N-acetylaspartylglutamate (Pboot = .13), or glutamate and glutamine (Pboot = .11). Among the smaller resonances, no vendor effects were found for ascorbate (Pboot = .08), aspartate (Pboot > .90), glutathione (Pboot > .90), or lactate (Pboot = .28). Conclusion Multisite multivendor single-voxel MR spectroscopy studies performed at 3.0 T can yield results that are coherent across vendors, provided that vendor differences in pulse sequence implementation are accounted for in data analysis. However, the site-related effects on variability were more profound and suggest the need for further standardization of spectroscopic protocols. © RSNA, 2020 Online supplemental material is available for this article.

Modulating Regional Motor Cortical Excitability with Noninvasive Brain Stimulation Results in Neurochemical Changes in Bilateral Motor Cortices.

Learning a novel motor skill is dependent both on regional changes within the primary motor cortex (M1) contralateral to the active hand and also on modulation between and within anatomically distant but functionally connected brain regions. Interregional changes are particularly important in functional recovery after stroke, when critical plastic changes underpinning behavioral improvements are observed in both ipsilesional and contralesional M1s. It is increasingly understood that reduction in GABA in the contralateral M1 is necessary to allow learning of a motor task. However, the physiological mechanisms underpinning plasticity within other brain regions, most importantly the ipsilateral M1, are not well understood. Here, we used concurrent two-voxel magnetic resonance spectroscopy to simultaneously quantify changes in neurochemicals within left and right M1s in healthy humans of both sexes in response to transcranial direct current stimulation (tDCS) applied to left M1. We demonstrated a decrease in GABA in both the stimulated (left) and nonstimulated (right) M1 after anodal tDCS, whereas a decrease in GABA was only observed in nonstimulated M1 after cathodal stimulation. This GABA decrease in the nonstimulated M1 during cathodal tDCS was negatively correlated with microstructure of M1:M1 callosal fibers, as quantified by diffusion MRI, suggesting that structural features of these fibers may mediate GABA decrease in the unstimulated region. We found no significant changes in glutamate. Together, these findings shed light on the interactions between the two major network nodes underpinning motor plasticity, offering a potential framework from which to optimize future interventions to improve motor function after stroke.SIGNIFICANCE STATEMENT Learning of new motor skills depends on modulation both within and between brain regions. Here, we use a novel two-voxel magnetic resonance spectroscopy approach to quantify GABA and glutamate changes concurrently within the left and right primary motor cortex (M1) during three commonly used transcranial direct current stimulation montages: anodal, cathodal, and bilateral. We also examined how the neurochemical changes in the unstimulated hemisphere were related to white matter microstructure between the two M1s. Our results provide insights into the neurochemical changes underlying motor plasticity and may therefore assist in the development of further adjunct therapies.

Water removal in MR spectroscopic imaging with L2 regularization.

PURPOSE: An L2-regularization based postprocessing method is proposed and tested for removal of residual or unsuppressed water signals in proton MR spectroscopic imaging (MRSI) data recorded from the human brain at 3T. METHODS: Water signals are removed by implementation of the L2 regularization using a synthesized water-basis matrix that is orthogonal to metabolite signals of interest in the spectral dimension. Simulated spectra with variable water amplitude and in vivo brain MRSI datasets were used to demonstrate the proposed method. Results were compared with two commonly-used postprocessing methods for removing water signals. RESULTS: The L2 method yielded metabolite signals that were close to true values for the simulated spectra. Residual/unsuppressed water signals in human brain short- and long-echo time MRSI datasets were efficiently removed by the proposed method allowing good quality metabolite maps to be reconstructed with minimized contamination from water signals. Significant differences of the creatine signal were observed between brain long-echo time MRSI without and with water saturation, attributable to the previously described magnetization transfer effect. CONCLUSIONS: With usage of a synthesized water matrix generated based on reasonable prior knowledge about water and metabolite resonances, the L2 method is shown to be an effective way to remove water signals from MRSI of the human brain.

Simultaneous editing of GABA and glutathione at 7T using semi-LASER localization.

PURPOSE: To demonstrate simultaneous editing of the two most commonly edited and overlapping signals, γ-aminobutyric acid (GABA), and glutathione (GSH), with Hadamard encoding and reconstruction of MEGA-edited spectroscopy (HERMES) using sLASER localization at 7T. METHODS: Density matrix simulations of HERMES at 7T were carried out and compared with phantom experiments. Additional phantom experiments were performed to characterize the echo time (TE) -dependent modulation of GABA- and GSH-edited HERMES spectra at TE of 80-160 ms. In vivo experiments were performed in 10 healthy volunteers, comparing HERMES (11 min) to sequentially acquired MEGA-sLASER detection of GABA and GSH (2 × 11 min). RESULTS: Simulations of HERMES show GABA- and GSH-edited spectra with negligible levels of crosstalk, and give modest agreement with phantom spectra. The TE series of GABA- and GSH-edited HERMES spectra modulate as a result of T2 relaxation and coupling evolution, with GABA showing a stronger TE-dependence. In vivo HERMES experiments show well-edited GABA and GSH signals. Measured concentrations are not statistically different between HERMES and MEGA-sLASER for GABA (1. 051 ± 0.254 i.u. and 1.053 ± 0.248 i.u; P > 0.985) or GSH (0.300 ± 0.091 i.u. and 0.302 ± 0.093 i.u; P > 0.940). CONCLUSION: Simulated, phantom and in vivo measurements of HERMES show excellent segregation of GABA- and GSH-edited signals, and excellent agreement with separately acquired MEGA-sLASER data. HERMES allows two-fold acceleration of editing while maintaining spectral quality compared with sequentially acquired MEGA-sLASER measurements. Magn Reson Med 80:474-479, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

AutoVOI: real-time automatic prescription of volume-of-interest for single voxel spectroscopy.

PURPOSE: To develop a fast and automated volume-of-interest (VOI) prescription pipeline (AutoVOI) for single-voxel MRS that removes the need for manual VOI placement, allows flexible VOI planning in any brain region, and enables high inter- and intra-subject consistency of VOI prescription. METHODS: AutoVOI was designed to transfer pre-defined VOIs from an atlas to the 3D anatomical data of the subject during the scan. The AutoVOI pipeline was optimized for consistency in VOI placement (precision), enhanced coverage of the targeted tissue (accuracy), and fast computation speed. The tool was evaluated against manual VOI placement using existing T1 -weighted data sets and corresponding VOI prescriptions. Finally, it was implemented on 2 scanner platforms to acquire MRS data from clinically relevant VOIs that span the cerebrum, cerebellum, and the brainstem. RESULTS: The AutoVOI pipeline includes skull stripping, non-linear registration of the atlas to the subject's brain, and computation of the VOI coordinates and angulations using a minimum oriented bounding box algorithm. When compared against manual prescription, AutoVOI showed higher intra- and inter-subject spatial consistency, as quantified by generalized Dice coefficients (GDC), lower intra- and inter-subject variability in tissue composition (gray matter, white matter, and cerebrospinal fluid) and higher or equal accuracy, as quantified by GDC of prescribed VOI with targeted tissues. High quality spectra were obtained on Siemens and Philips 3T systems from 6 automatically prescribed VOIs by the tool. CONCLUSION: Robust automatic VOI prescription is feasible and can help facilitate clinical adoption of MRS by avoiding operator dependence of manual selection.

A comparison of 2-hydroxyglutarate detection at 3 and 7 T with long-TE semi-LASER.

Abnormally high levels of the 'oncometabolite' 2-hydroxyglutarate (2-HG) occur in many grade II and III gliomas, and correlate with mutations in the genes of isocitrate dehydrogenase (IDH) isoforms. In vivo measurement of 2-HG in patients, using magnetic resonance spectroscopy (MRS), has largely been carried out at 3 T, yet signal overlap continues to pose a challenge for 2-HG detection. To combat this, several groups have proposed MRS methods at ultra-high field (≥7 T) where theoretical increases in signal-to-noise ratio and spectral resolution could improve 2-HG detection. Long echo time (long-TE) semi-localization by adiabatic selective refocusing (semi-LASER) (TE = 110 ms) is a promising method for improved 2-HG detection in vivo at either 3 or 7 T owing to the use of broad-band adiabatic localization. Using previously published semi-LASER methods at 3 and 7 T, this study directly compares the detectability of 2-HG in phantoms and in vivo across nine patients. Cramér-Rao lower bounds (CRLBs) of 2-HG fitting were found to be significantly lower at 7 T (6 ± 2%) relative to 3 T (15 ± 7%) (p = 0.0019), yet were larger at 7 T in an IDH wild-type patient. Although no increase in SNR was detected at 7 T (77 ± 26) relative to 3 T (77 ± 30), the detection of 2-HG was greatly enhanced through an improved spectral profile and increased resolution at 7 T. 7 T had a large effect on pairwise fitting correlations between γ-aminobutyric acid (GABA) and 2-HG (p = 0.004), and resulted in smaller coefficients. The increased sensitivity for 2-HG detection using long-TE acquisition at 7 T may allow for more rapid estimation of 2-HG (within a few spectral averages) together with other associated metabolic markers in glioma.

Combined fMRI-MRS acquires simultaneous glutamate and BOLD-fMRI signals in the human brain.

Combined fMRI-MRS is a novel method to non-invasively investigate functional activation in the human brain using simultaneous acquisition of hemodynamic and neurochemical measures. The aim of the current study was to quantify neural activity using combined fMRI-MRS at 7T. BOLD-fMRI and semi-LASER localization MRS data were acquired from the visual cortex of 13 participants during short blocks (64s) of flickering checkerboards. We demonstrate a correlation between glutamate and BOLD-fMRI time courses (R=0.381, p=0.031). In addition, we show increases in BOLD-fMRI (1.43±0.17%) and glutamate concentrations (0.15±0.05 I.U., ~2%) during visual stimulation. In contrast, we observed no change in glutamate concentrations in resting state MRS data during sham stimulation periods. Spectral line width changes generated by the BOLD-response were corrected using line broadening. In summary, our results establish the feasibility of concurrent measurements of BOLD-fMRI and neurochemicals using a novel combined fMRI-MRS sequence. Our findings strengthen the link between glutamate and functional activity in the human brain by demonstrating a significant correlation of BOLD-fMRI and glutamate over time, and by showing ~2% glutamate increases during 64s of visual stimulation. Our tool may become useful for studies characterizing functional dynamics between neurochemicals and hemodynamics in health and disease.

tDCS induced GABA change is associated with the simulated electric field in M1, an effect mediated by grey matter volume in the MRS voxel.

BACKGROUND AND OBJECTIVE: Transcranial direct current stimulation (tDCS) has wide ranging applications in neuro-behavioural and physiological research, and in neurological rehabilitation. However, it is currently limited by substantial inter-subject variability in responses, which may be explained, at least in part, by anatomical differences that lead to variability in the electric field (E-field) induced in the cortex. Here, we tested whether the variability in the E-field in the stimulated cortex during anodal tDCS, estimated using computational simulations, explains the variability in tDCS induced changes in GABA, a neurophysiological marker of stimulation effect. METHODS: Data from five previously conducted MRS studies were combined. The anode was placed over the left primary motor cortex (M1, 3 studies, N = 24) or right temporal cortex (2 studies, N = 32), with the cathode over the contralateral supraorbital ridge. Single voxel spectroscopy was performed in a 2x2x2cm voxel under the anode in all cases. MRS data were acquired before and either during or after 1 mA tDCS using either a sLASER sequence (7T) or a MEGA-PRESS sequence (3T). sLASER MRS data were analysed using LCModel, and MEGA-PRESS using FID-A and Gannet. E-fields were simulated in a finite element model of the head, based on individual structural MR images, using SimNIBS. Separate linear mixed effects models were run for each E-field variable (mean and 95th percentile; magnitude, and components normal and tangential to grey matter surface, within the MRS voxel). The model included effects of time (pre or post tDCS), E-field, grey matter volume in the MRS voxel, and a 3-way interaction between time, E-field and grey matter volume. Additionally, we ran a permutation analysis using PALM to determine whether E-field anywhere in the brain, not just in the MRS voxel, correlated with GABA change. RESULTS: In M1, higher mean E-field magnitude was associated with greater anodal tDCS-induced decreases in GABA (t(24) = 3.24, p = 0.003). Further, the association between mean E-field magnitude and GABA change was moderated by the grey matter volume in the MRS voxel (t(24) = -3.55, p = 0.002). These relationships were consistent across all E-field variables except the mean of the normal component. No significant relationship was found between tDCS-induced GABA decrease and E-field in the temporal voxel. No significant clusters were found in the whole brain analysis. CONCLUSIONS: Our data suggest that the electric field induced by tDCS within the brain is variable, and is significantly related to anodal tDCS-induced decrease in GABA, a key neurophysiological marker of stimulation. These findings strongly support individualised dosing of tDCS, at least in M1. Further studies examining E-fields in relation to other outcome measures, including behaviour, will help determine the optimal E-fields required for any desired effects.

Connectivity-Guided Theta Burst Transcranial Magnetic Stimulation Versus Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Moderate to Severe Depression: Magnetic Resonance Imaging Protocol and SARS-CoV-2-Induced Changes for a Randomized Double-blind Controlled Trial.

BACKGROUND: Depression is a substantial health and economic burden. In approximately one-third of patients, depression is resistant to first-line treatment; therefore, it is essential to find alternative treatments. Transcranial magnetic stimulation (TMS) is a neuromodulatory treatment involving the application of magnetic pulses to the brain that is approved in the United Kingdom and the United States in treatment-resistant depression. This trial aims to compare the clinical effectiveness, cost-effectiveness, and mechanism of action of standard treatment repetitive TMS (rTMS) targeted at the F3 electroencephalogram site with a newer treatment-a type of TMS called theta burst stimulation (TBS) targeted based on measures of functional brain connectivity. This protocol outlines brain imaging acquisition and analysis for the Brain Imaging Guided Transcranial Magnetic Stimulation in Depression (BRIGhTMIND) study trial that is used to create personalized TMS targets and answer the proposed mechanistic hypotheses. OBJECTIVE: The aims of the imaging arm of the BRIGhTMIND study are to identify functional and neurochemical brain signatures indexing the treatment mechanisms of rTMS and connectivity-guided intermittent theta burst TMS and to identify imaging-based markers predicting response to treatment. METHODS: The study is a randomized double-blind controlled trial with 1:1 allocation to either 20 sessions of TBS or standard rTMS. Multimodal magnetic resonance imaging (MRI) is acquired for each participant at baseline (before TMS treatment) with T1-weighted and task-free functional MRI during rest used to estimate TMS targets. For participants enrolled in the mechanistic substudy, additional diffusion-weighted sequences are acquired at baseline and at posttreatment follow-up 16 weeks after treatment randomization. Core data sets of T1-weighted and task-free functional MRI during rest are acquired for all participants and are used to estimate TMS targets. Additional sequences of arterial spin labeling, magnetic resonance spectroscopy, and diffusion-weighted images are acquired depending on the recruitment site for mechanistic evaluation. Standard rTMS treatment is targeted at the F3 electrode site over the left dorsolateral prefrontal cortex, whereas TBS treatment is guided using the coordinate of peak effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. Both treatment targets benefit from the level of MRI guidance, but only TBS is provided with precision targeting based on functional brain connectivity. RESULTS: Recruitment began in January 2019 and is ongoing. Data collection is expected to continue until January 2023. CONCLUSIONS: This trial will determine the impact of precision MRI guidance on rTMS treatment and assess the neural mechanisms underlying this treatment in treatment-resistant depressed patients. TRIAL REGISTRATION: ISRCTN Registry ISRCTN19674644; https://www.isrctn.com/ISRCTN19674644. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31925.

Feasibility and Biological Activity of a Ketogenic/Intermittent-Fasting Diet in Patients With Glioma.

OBJECTIVE: To examine the feasibility, safety, systemic biological activity, and cerebral activity of a ketogenic dietary intervention in patients with glioma. METHODS: Twenty-five patients with biopsy-confirmed World Health Organization grade 2 to 4 astrocytoma with stable disease after adjuvant chemotherapy were enrolled in an 8-week Glioma Atkins-Based Diet (GLAD). GLAD consisted of 2 fasting days (calories <20% calculated estimated needs) interleaved between 5 modified Atkins diet days (net carbohydrates ≤20 g/d) each week. The primary outcome was dietary adherence by food records. Markers of systemic and cerebral activity included weekly urine ketones, serum insulin, glucose, hemoglobin A1c, insulin-like growth factor-1, and magnetic resonance spectroscopy at baseline and week 8. RESULTS: Twenty-one patients (84%) completed the study. Eighty percent of patients reached ≥40 mg/dL urine acetoacetate during the study. Forty-eight percent of patients were adherent by food record. The diet was well tolerated, with two grade 3 adverse events (neutropenia, seizure). Measures of systemic activity, including hemoglobin A1c, insulin, and fat body mass, decreased significantly, while lean body mass increased. Magnetic resonance spectroscopy demonstrated increased ketone concentrations (ß-hydroxybutyrate [bHB] and acetone) in both lesional and contralateral brain compared to baseline. Average ketonuria correlated with cerebral ketones in lesional (tumor) and contralateral brain (bHB R s = 0.52, p = 0.05). Subgroup analysis of isocitrate dehydrogenase-mutant glioma showed no differences in cerebral metabolites after controlling for ketonuria. CONCLUSION: The GLAD dietary intervention, while demanding, produced meaningful ketonuria and significant systemic and cerebral metabolic changes in participants. Ketonuria in participants correlated with cerebral ketone concentration and appears to be a better indicator of systemic activity than patient-reported food records. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02286167.

Effects of the potential lithium-mimetic, ebselen, on brain neurochemistry: a magnetic resonance spectroscopy study at 7 tesla.

RATIONALE: Lithium is an effective treatment for bipolar disorder, but safety issues complicate its clinical use. The antioxidant drug, ebselen, may be a possible lithium-mimetic based on its ability to inhibit inositol monophosphatase (IMPase), an action which it shares with lithium. OBJECTIVES: Our primary aim was to determine whether ebselen lowered levels of inositol in the human brain. We also assessed the effect of ebselen on other brain neurometabolites, including glutathione, glutamate, glutamine, and glutamate + glutamine (Glx) METHODS: Twenty healthy volunteers were tested on two occasions receiving either ebselen (3600 mg over 24 h) or identical placebo in a double-blind, random-order, crossover design. Two hours after the final dose of ebselen/placebo, participants underwent proton magnetic resonance spectroscopy ((1)H MRS) at 7 tesla (T) with voxels placed in the anterior cingulate and occipital cortex. Neurometabolite levels were calculated using an unsuppressed water signal as a reference and corrected for individual cerebrospinal fluid content in the voxel. RESULTS: Ebselen produced no effect on neurometabolite levels in the occipital cortex. In the anterior cingulate cortex, ebselen lowered concentrations of inositol (p = 0.028, Cohen's d = 0.60) as well as those of glutathione (p = 0.033, d = 0.58), glutamine (p = 0.024, d = 0.62), glutamate (p = 0.01, d = 0.73), and Glx (p = 0.001, d = 1.0). CONCLUSIONS: The study suggests that ebselen produces a functional inhibition of IMPase in the human brain. The effect of ebselen to lower glutamate is consistent with its reported ability to inhibit the enzyme, glutaminase. Ebselen may have potential as a repurposed treatment for bipolar disorder.

Improved localisation for 2-hydroxyglutarate detection at 3T using long-TE semi-LASER.

2-hydroxyglutarate (2-HG) has emerged as a biomarker of tumour cell IDH mutations that may enable the differential diagnosis of glioma patients. At 3 Tesla, detection of 2-HG with magnetic resonance spectroscopy is challenging because of metabolite signal overlap and a spectral pattern modulated by slice selection and chemical shift displacement. Using density matrix simulations and phantom experiments, an optimised semi-LASER scheme (TE = 110 ms) improves localisation of the 2-HG spin system considerably compared to an existing PRESS sequence. This results in a visible 2-HG peak in the in vivo spectra at 1.9 ppm in the majority of IDH mutated tumours. Detected concentrations of 2-HG were similar using both sequences, although the use of semi-LASER generated narrower confidence intervals. Signal overlap with glutamate and glutamine, as measured by pairwise fitting correlation was reduced. Lactate was readily detectable across glioma patients using the method presented here (mean CLRB: (10±2)%). Together with more robust 2-HG detection, long TE semi-LASER offers the potential to investigate tumour metabolism and stratify patients in vivo at 3T.