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Richard A.E. Edden

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24 papers

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YNIMG Journal 2024 Journal Article

Brain extended and closed forms glutathione levels decrease with age and extended glutathione is associated with visuospatial memory

Xin Hu
Keyu Pan
Min Zhao
Jiali Lv
Jing Wang
Xiaofeng Zhang
Yuxi Liu
Yulu Song

During aging, the brain is subject to greater oxidative stress (OS), which is thought to play a critical role in cognitive impairment. Glutathione (GSH), as a major antioxidant in the brain, can be used to combat OS. However, how brain GSH levels vary with age and their associations with cognitive function is unclear. In this study, we combined point-resolved spectroscopy and edited spectroscopy sequences to investigate extended and closed forms GSH levels in the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and occipital cortex (OC) of 276 healthy participants (extended form, 166 females, age range 20-70 years) and 15 healthy participants (closed form, 7 females, age range 26-56 years), and examined their relationships with age and cognitive function. The results revealed decreased extended form GSH levels with age in the PCC among 276 participants. Notably, the timecourse of extended form GSH level changes in the PCC and ACC differed between males and females. Additionally, positive correlations were observed between extended form GSH levels in the PCC and OC and visuospatial memory. Additionally, a decreased trend of closed form GSH levels with age was also observed in the PCC among 15 participants. Taken together, these findings enhance our understanding of the brain both closed and extended form GSH time course during normal aging and associations with sex and memory, which is an essential first step for understanding the neurochemical underpinnings of healthy aging.

YNIMG Journal 2023 Journal Article

Neurochemical and functional reorganization of the cognitive-ear link underlies cognitive impairment in presbycusis

Ning Li
Wen Ma
Fuxin Ren
Xiao Li
Fuyan Li
Wei Zong
Lili Wu
Zongrui Dai

Recent studies suggest that the interaction between presbycusis and cognitive impairment may be partially explained by the cognitive-ear link. However, the underlying neurophysiological mechanisms remain largely unknown. In this study, we combined magnetic resonance spectroscopy (MRS) and resting-state functional magnetic resonance imaging (fMRI) to investigate auditory gamma-aminobutyric acid (GABA) and glutamate (Glu) levels, intra- and inter-network functional connectivity, and their relationships with auditory and cognitive function in 51 presbycusis patients and 51 well-matched healthy controls. Our results confirmed reorganization of the cognitive-ear link in presbycusis, including decreased auditory GABA and Glu levels and aberrant functional connectivity involving auditory networks (AN) and cognitive-related networks, which were associated with reduced speech perception or cognitive impairment. Moreover, mediation analyses revealed that decreased auditory GABA levels and dysconnectivity between the AN and default mode network (DMN) mediated the association between hearing loss and impaired information processing speed in presbycusis. These findings highlight the importance of AN-DMN dysconnectivity in cognitive-ear link reorganization leading to cognitive impairment, and hearing loss may drive reorganization via decreased auditory GABA levels. Modulation of GABA neurotransmission may lead to new treatment strategies for cognitive impairment in presbycusis patients.

YNIMG Journal 2022 Journal Article

Neurometabolic timecourse of healthy aging

Tao Gong
Steve C.N. Hui
Helge J. Zöllner
Mark Britton
Yulu Song
Yufan Chen
Aaron T. Gudmundson
Kathleen E. Hupfeld

PURPOSE: The neurometabolic timecourse of healthy aging is not well-established, in part due to diversity of quantification methodology. In this study, a large structured cross-sectional cohort of male and female subjects throughout adulthood was recruited to investigate neurometabolic changes as a function of age, using consensus-recommended magnetic resonance spectroscopy quantification methods. METHODS: 102 healthy volunteers, with approximately equal numbers of male and female participants in each decade of age from the 20s, 30s, 40s, 50s, and 60s, were recruited with IRB approval. MR spectroscopic data were acquired on a 3T MRI scanner. Metabolite spectra were acquired using PRESS localization (TE=30 ms; 96 transients) in the centrum semiovale (CSO) and posterior cingulate cortex (PCC). Water-suppressed spectra were modeled using the Osprey algorithm, employing a basis set of 18 simulated metabolite basis functions and a cohort-mean measured macromolecular spectrum. Pearson correlations were conducted to assess relationships between metabolite concentrations and age for each voxel; Spearman correlations were conducted where metabolite distributions were non-normal. Paired t-tests were run to determine whether metabolite concentrations differed between the PCC and CSO. Finally, robust linear regressions were conducted to assess both age and sex as predictors of metabolite concentrations in the PCC and CSO and separately, to assess age, signal-noise ratio, and full width half maximum (FWHM) linewidth as predictors of metabolite concentrations. RESULTS: Data from four voxels were excluded (2 ethanol; 2 unacceptably large lipid signal). Statistically-significant age*metabolite Pearson correlations were observed for tCho (r(98)=0.33, p 0.20). Age associations for tCho, tCr, mI and sI in the CSO and for NAAG, tCho, and tCr in the PCC remained when controlling for sex in robust regressions. CSO NAAG and Asp, as well as PCC tNAA, sI, and Lac were higher in women; PCC Gln was higher in men. When including an age*sex interaction term in robust regression models, a significant age*sex interaction was seen for tCho (F(1,96)=11.53, p=0.001) and GSH (F(1,96)=7.15, p=0.009) in the CSO and tCho (F(1,96)=9.17, p=0.003), tCr (F(1,96)=9.59, p=0.003), mI (F(1,96)=6.48, p=0.012), and Lac (F(1,78)=6.50, p=0.016) in the PCC. In all significant interactions, metabolite levels increased with age in females, but not males. There was a significant positive correlation between linewidth and age. Age relationships with tCho, tCr, and mI in the CSO and tCho, tCr, mI, and sI in the PCC were significant after controlling for linewidth and FWHM in robust regressions. CONCLUSION: The primary (correlation) results indicated age relationships for tCho, tCr, mI, and sI in the CSO and for NAAG, tCho, tCr, and Gln in the PCC, while no age correlations were found for tNAA, NAA, Glx, Glu, GSH, PE, Lac, or Asp in either region. Our results provide a normative foundation for future work investigating the neurometabolic time course of healthy aging using MRS.

YNIMG Journal 2021 Journal Article

Comparison of methods for spectral alignment and signal modelling of GABA-edited MR spectroscopy data

Reuben Rideaux
Mark Mikkelsen
Richard A.E. Edden

Many methods exist for aligning and quantifying magnetic resonance spectroscopy (MRS) data to measure in vivo γ-aminobutyric acid (GABA). Research comparing the performance of these methods is scarce partly due to the lack of ground-truth measurements. The concentration of GABA is approximately two times higher in grey matter than in white matter. Here we use the proportion of grey matter within the MRS voxel as a proxy for ground-truth GABA concentration to compare the performance of four spectral alignment methods (i.e., retrospective frequency and phase drift correction) and six GABA signal modelling methods. We analyse a diverse dataset of 432 MEGA-PRESS scans targeting multiple brain regions and find that alignment to the creatine (Cr) signal produces GABA+ estimates that account for approximately twice as much of the variance in grey matter as the next best performing alignment method. Further, Cr alignment was the most robust, producing the fewest outliers. By contrast, all signal modelling methods, except for the single-Lorentzian model, performed similarly well. Our results suggest that variability in performance is primarily caused by differences in the zero-order phase estimated by each alignment method, rather than frequency, resulting from first-order phase offsets within subspectra. These results provide support for Cr alignment as the optimal method of processing MEGA-PRESS to quantify GABA. However, more broadly, they demonstrate a method of benchmarking quantification of in vivo metabolite concentration from other MRS sequences.

YNIMG Journal 2021 Journal Article

Frequency drift in MR spectroscopy at 3T

Steve C.N. Hui
Mark Mikkelsen
Helge J. Zöllner
Vishwadeep Ahluwalia
Sarael Alcauter
Laima Baltusis
Deborah A. Barany
Laura R. Barlow

PURPOSE: 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.

YNIMG Journal 2021 Journal Article

GABA levels are differentially associated with bimanual motor performance in older as compared to young adults

Celine Maes
Koen Cuypers
Kirstin-Friederike Heise
Richard A.E. Edden
Jolien Gooijers
Stephan P. Swinnen

Although gamma aminobutyric acid (GABA) is of particular importance for efficient motor functioning, very little is known about the relationship between regional GABA levels and motor performance. Some studies suggest this relation to be subject to age-related differences even though literature is scarce. To clarify this matter, we employed a comprehensive approach and investigated GABA levels within young and older adults across multiple motor tasks as well as multiple brain regions. Specifically, 30 young and 30 older adults completed a task battery of three different bimanual tasks. Furthermore, GABA levels were obtained within bilateral primary sensorimotor cortex (SM1), bilateral dorsal premotor cortex, the supplementary motor area and bilateral dorsolateral prefrontal cortex (DLPFC) using magnetic resonance spectroscopy. Results indicated that older adults, as compared to their younger counterparts, performed worse on all bimanual tasks and exhibited lower GABA levels in bilateral SM1 only. Moreover, GABA levels across the motor network and DLPFC were differentially associated with performance in young as opposed to older adults on a manual dexterity and bimanual coordination task but not a finger tapping task. Specifically, whereas higher GABA levels related to better manual dexterity within older adults, higher GABA levels predicted poorer bimanual coordination performance in young adults. By determining a task-specific and age-dependent association between GABA levels across the cortical motor network and performance on distinct bimanual tasks, the current study advances insights in the role of GABA for motor performance in the context of aging.

YNIMG Journal 2021 Journal Article

Hippocampal and striatal responses during motor learning are modulated by prefrontal cortex stimulation

Mareike A. Gann
Bradley R. King
Nina Dolfen
Menno P. Veldman
Kimberly L. Chan
Nicolaas A.J. Puts
Richard A.E. Edden
Marco Davare

While it is widely accepted that motor sequence learning (MSL) is supported by a prefrontal-mediated interaction between hippocampal and striatal networks, it remains unknown whether the functional responses of these networks can be modulated in humans with targeted experimental interventions. The present proof-of-concept study employed a multimodal neuroimaging approach, including functional magnetic resonance (MR) imaging and MR spectroscopy, to investigate whether individually-tailored theta-burst stimulation of the dorsolateral prefrontal cortex can modulate responses in the hippocampus and the basal ganglia during motor learning. Our results indicate that while stimulation did not modulate motor performance nor task-related brain activity, it influenced connectivity patterns within hippocampo-frontal and striatal networks. Stimulation also altered the relationship between the levels of gamma-aminobutyric acid (GABA) in the stimulated prefrontal cortex and learning-related changes in both activity and connectivity in fronto-striato-hippocampal networks. This study provides the first experimental evidence, to the best of our knowledge, that brain stimulation can alter motor learning-related functional responses in the striatum and hippocampus.

YNIMG Journal 2021 Journal Article

Simultaneous quantification of GABA, Glx and GSH in the neonatal human brain using magnetic resonance spectroscopy

Maria Yanez Lopez
Anthony N. Price
Nicolaas A.J. Puts
Emer J. Hughes
Richard A.E. Edden
Grainne M. McAlonan
Tomoki Arichi
Enrico De Vita

Balance between inhibitory and excitatory neurotransmitter systems and the protective role of the major antioxidant glutathione (GSH) are central to early healthy brain development. Disruption has been implicated in the early life pathophysiology of psychiatric disorders and neurodevelopmental conditions including Autism Spectrum Disorder. Edited magnetic resonance spectroscopy (MRS) methods such as HERMES have great potential for providing important new non-invasive insights into these crucial processes in human infancy. In this work, we describe a systematic approach to minimise the impact of specific technical challenges inherent to acquiring MRS data in a neonatal population, including automatic segmentation, full tissue-correction and optimised GABA+ fitting and consider the minimum requirements for a robust edited-MRS acquisition. With this approach we report for the first time simultaneous GABA+, Glx (glutamate + glutamine) and GSH concentrations in the neonatal brain (n = 18) in two distinct regions (thalamus and anterior cingulate cortex (ACC)) using edited MRS at 3T. The improved sensitivity provided by our method allows specific regional neurochemical differences to be identified including: significantly lower Glx and GSH ratios to total creatine in the thalamus compared to the ACC (p < 0.001 for both), and significantly higher GSH levels in the ACC following tissue-correction (p < 0.01). Furthermore, in contrast to adult GABA+ which can typically be accurately fitted with a single peak, all neonate spectra displayed a characteristic doublet GABA+ peak at 3 ppm, indicating a lower macromolecule (MM) contribution to the 3 ppm signal in neonates. Relatively high group-level variance shows the need to maximise voxel size/acquisition time in edited neonatal MRS acquisitions for robust estimation of metabolites. Application of this method to study how these levels and balance are altered by early-life brain injury or genetic risk can provide important new knowledge about the pathophysiology underlying neurodevelopmental disorders.

YNICL Journal 2020 Journal Article

Brain GABA+ changes in primary hypothyroidism patients before and after levothyroxine treatment: A longitudinal magnetic resonance spectroscopy study

Bo Liu
Zhensong Wang
Liangjie Lin
Huan Yang
Fei Gao
Tao Gong
Richard A.E. Edden
Guangbin Wang

OBJECTIVE: Increasing evidence indicates the involvement of the GABAergic system in the pathophysiology of hypothyroidism. We aimed to investigate longitudinal changes of brain GABA in primary hypothyroidism before and after levothyroxine (L-T4) treatment. MATERIAL AND METHODS: In 18 patients with hypothyroidism, we used the MEGA-PRESS (Mescher-Garwood point-resolved spectroscopy) editing sequence to measure brain GABA levels from medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC) at baseline and after 6-months of L-T4 treatment. Sex- and age-matched healthy controls (n = 18) were scanned at baseline. Thyroid function and neuropsychological tests were also performed. RESULTS: GABA signals were successfully quantified from all participants with fitting errors lower than 15%. GABA signal was labeled as GABA+ due to contamination from co-edited macromoleculars and homocarnosine. In hypothyroid patients, mean GABA+ was significantly lower in the mPFC region compared with controls (p = 0.031), and the mPFC GABA+ measurements were significantly correlated with depressive symptoms and memory function (r = -0.558, p = 0.016; r = 0.522, p = 0.026, respectively). After adequate L-T4 treatment, the mPFC GABA+ in hypothyroid patients increased to normal level, along with relieved neuropsychological impairments. CONCLUSION: The study suggested the decrease of GABA+ may be an important neurobiological factor in the pathophysiology of hypothyroidism. Treatment of L-T4 may reverse the abnormal GABA+ and hypothyroidism-induced neuropsychiatric impairments, indicating the action mode of L-T4 in adjunctive treatment of affective disorders.

YNIMG Journal 2020 Journal Article

Neurometabolic underpinning of the intergenerational transmission of prosociality

Naohiro Okada
Noriaki Yahata
Daisuke Koshiyama
Kentaro Morita
Kingo Sawada
Sho Kanata
Shinya Fujikawa
Noriko Sugimoto

Parent-child personality transmission can occur via biological gene-driven processes as well as through environmental factors such as shared environment and parenting style. We recently revealed a negative association between prosociality, a highly valued personality attribute in human society, and anterior cingulate cortex (ACC) γ-aminobutyric acid (GABA) levels in children at the age of 10 years. We thus hypothesized that prosociality would be intergenerationally transmitted, and that transmission would be underwritten by neurometabolic heritability. Here, we collected prosociality data from children aged 10 years and their parents in a large-scale population-based birth cohort study. We also measured ACC GABA+ and glutamate plus glutamine (Glx) levels in a follow-up assessment with a subsample of the participants (aged 11 years) using magnetic resonance spectroscopy. We analyzed the associations among children’s and parents’ prosociality and GABA+/Glx ratios. We also examined the effect of socioeconomic status (SES) and verbalized parental affection (VPA) on these associations. We found a significant positive parent-child association for prosociality (N = 3026; children’s mean age 10. 2 years) and GABA+/Glx ratio (N = 99; children’s mean age 11. 4 years). There was a significant negative association between GABA+/Glx ratio and prosociality in both children (N = 208) and parents (N = 128). Our model accounting for the effects of neurometabolic heritability on prosociality transmission fitted well. Moreover, in this model, a significant positive effect of VPA but not SES on children’s prosociality was observed independently of the effect of neurometabolic transmission, while SES but not VPA was significantly associated with parental prosociality. Our results provide novel insights into the neurometabolic substrates of parent-child transmission of social behavior.

YNIMG Journal 2020 Journal Article

Regional balance between glutamate+glutamine and GABA+ in the resting human brain

Adam Steel
Mark Mikkelsen
Richard A.E. Edden
Caroline E. Robertson

Models of healthy brain function and psychiatric conditions assume that excitatory and inhibitory activity are balanced in the human brain at multiple spatial and temporal scales. In human neuroimaging, concentrations of the major excitatory (glutamate) and inhibitory (γ-aminobutyric acid, GABA) neurotransmitters are measured in vivo using magnetic resonance spectroscopy (MRS). However, despite the central importance of E/I balance to theories of brain function, a relationship between regional glutamate and GABA levels in the human brain has not been shown. We addressed this question in a large corpus of edited MRS data collected at 19 different sites (n = 220). Consistent with the notion of E/I balance, we found that levels of glutamate+glutamine (Glx) and GABA+ were highly correlated (R = 0. 52, p = 2. 86 x 10−14). This relationship held when controlling for site, scanner vendor, and demographics. Controlling for neurochemicals associated with neuronal density and metabolism (i. e. N-acetylaspartate and creatine) significantly reduced the correlation between GABA+ and Glx, suggesting that the levels of GABA+ and Glx may be critically linked to regional metabolism. These results are consistent with the notion that excitation and inhibition are balanced in the human brain.

YNIMG Journal 2019 Journal Article

Advanced Hadamard-encoded editing of seven low-concentration brain metabolites: Principles of HERCULES

Georg Oeltzschner
Muhammad G. Saleh
Daniel Rimbault
Mark Mikkelsen
Kimberly L. Chan
Nicolaas A.J. Puts
Richard A.E. Edden

Purpose To demonstrate the framework of a novel Hadamard-encoded spectral editing approach for simultaneously detecting multiple low-concentration brain metabolites in vivo at 3T. Methods HERCULES (Hadamard Editing Resolves Chemicals Using Linear-combination Estimation of Spectra) is a four-step Hadamard-encoded editing scheme. 20-ms editing pulses are applied at: (A) 4. 58 and 1. 9 ppm; (B) 4. 18 and 1. 9 ppm; (C) 4. 58 ppm; and (D) 4. 18 ppm. Edited signals from γ-aminobutyric acid (GABA), glutathione (GSH), ascorbate (Asc), N-acetylaspartate (NAA), N-acetylaspartylglutamate (NAAG), aspartate (Asp), lactate (Lac), and likely 2-hydroxyglutarate (2-HG) are separated with reduced signal overlap into distinct Hadamard combinations: (A+B+C+D); (A+B–C–D); and (A–B+C–D). HERCULES uses a novel multiplexed linear-combination modeling approach, fitting all three Hadamard combinations at the same time, maximizing the amount of information used for model parameter estimation, in order to quantify the levels of these compounds. Fitting also allows estimation of the levels of total choline (tCho), myo-inositol (Ins), glutamate (Glu), and glutamine (Gln). Quantitative HERCULES results were compared between two grey- and white-matter-rich brain regions (11 min acquisition time each) in 10 healthy volunteers. Coefficients of variation (CV) of quantified measurements from the HERCULES fitting approach were compared against those from a single-spectrum fitting approach, and against estimates from short-TE PRESS data. Results HERCULES successfully segregates overlapping resonances into separate Hadamard combinations, allowing for the estimation of levels of seven coupled metabolites that would usually require a single 11-min editing experiment each. Metabolite levels and CVs agree well with published values. CVs of quantified measurements from the multiplexed HERCULES fitting approach outperform single-spectrum fitting and short-TE PRESS for most of the edited metabolites, performing only slightly to moderately worse than the fitting method that gives the lowest CVs for tCho, NAA, NAAG, and Asp. Conclusion HERCULES is a new experimental approach with the potential for simultaneous editing and multiplexed fitting of up to seven coupled low-concentration and six high-concentration metabolites within a single 11-min acquisition at 3T.

YNIMG Journal 2019 Journal Article

Big GABA II: Water-referenced edited MR spectroscopy at 25 research sites

Mark Mikkelsen
Daniel L. Rimbault
Peter B. Barker
Pallab K. Bhattacharyya
Maiken K. Brix
Pieter F. Buur
Kim M. Cecil
Kimberly L. Chan

Accurate and reliable quantification of brain metabolites measured in vivo using 1H magnetic resonance spectroscopy (MRS) is a topic of continued interest. Aside from differences in the basic approach to quantification, the quantification of metabolite data acquired at different sites and on different platforms poses an additional methodological challenge. In this study, spectrally edited γ-aminobutyric acid (GABA) MRS data were analyzed and GABA levels were quantified relative to an internal tissue water reference. Data from 284 volunteers scanned across 25 research sites were collected using GABA+ (GABA + co-edited macromolecules (MM)) and MM-suppressed GABA editing. The unsuppressed water signal from the volume of interest was acquired for concentration referencing. Whole-brain T 1-weighted structural images were acquired and segmented to determine gray matter, white matter and cerebrospinal fluid voxel tissue fractions. Water-referenced GABA measurements were fully corrected for tissue-dependent signal relaxation and water visibility effects. The cohort-wide coefficient of variation was 17% for the GABA + data and 29% for the MM-suppressed GABA data. The mean within-site coefficient of variation was 10% for the GABA + data and 19% for the MM-suppressed GABA data. Vendor differences contributed 53% to the total variance in the GABA + data, while the remaining variance was attributed to site- (11%) and participant-level (36%) effects. For the MM-suppressed data, 54% of the variance was attributed to site differences, while the remaining 46% was attributed to participant differences. Results from an exploratory analysis suggested that the vendor differences were related to the unsuppressed water signal acquisition. Discounting the observed vendor-specific effects, water-referenced GABA measurements exhibit similar levels of variance to creatine-referenced GABA measurements. It is concluded that quantification using internal tissue water referencing is a viable and reliable method for the quantification of in vivo GABA levels.

YNIMG Journal 2019 Journal Article

Glutamatergic facilitation of neural responses in MT enhances motion perception in humans

Michael-Paul Schallmo
Rachel Millin
Alex M. Kale
Tamar Kolodny
Richard A.E. Edden
Raphael A. Bernier
Scott O. Murray

There is large individual variability in human neural responses and perceptual abilities. The factors that give rise to these individual differences, however, remain largely unknown. To examine these factors, we measured fMRI responses to moving gratings in the motion-selective region MT, and perceptual duration thresholds for motion direction discrimination. Further, we acquired MR spectroscopy data, which allowed us to quantify an index of neurotransmitter levels in the region of area MT. These three measurements were conducted in separate experimental sessions within the same group of male and female subjects. We show that stronger Glx (glutamate + glutamine) signals in the MT region are associated with both higher fMRI responses and superior psychophysical task performance. Our results suggest that greater baseline levels of glutamate within MT facilitate motion perception by increasing neural responses in this region.

YNIMG Journal 2019 Journal Article

Multi-vendor standardized sequence for edited magnetic resonance spectroscopy

Muhammad G. Saleh
Daniel Rimbault
Mark Mikkelsen
Georg Oeltzschner
Anna M. Wang
Dengrong Jiang
Ali Alhamud
Jamie Near

Spectral editing allows direct measurement of low-concentration metabolites, such as GABA, glutathione (GSH) and lactate (Lac), relevant for understanding brain (patho)physiology. The most widely used spectral editing technique is MEGA-PRESS, which has been diversely implemented across research sites and vendors, resulting in variations in the final resolved edited signal. In this paper, we describe an effort to develop a new universal MEGA-PRESS sequence with HERMES functionality for the major MR vendor platforms with standardized RF pulse shapes, durations, amplitudes and timings. New RF pulses were generated for the universal sequence. Phantom experiments were conducted on Philips, Siemens, GE and Canon 3 T MRI scanners using 32-channel head coils. In vivo experiments were performed on the same six subjects on Philips and Siemens scanners, and on two additional subjects, one on GE and one on Canon scanners. On each platform, edited MRS experiments were conducted with the vendor-native and universal MEGA-PRESS sequences for GABA (TE = 68 ms) and Lac editing (TE = 140 ms). Additionally, HERMES for GABA and GSH was performed using the universal sequence at TE = 80 ms. The universal sequence improves inter-vendor similarity of GABA-edited and Lac-edited MEGA-PRESS spectra. The universal HERMES sequence yields both GABA- and GSH-edited spectra with negligible levels of crosstalk on all four platforms, and with strong agreement among vendors for both edited spectra. In vivo GABA+/Cr, Lac/Cr and GSH/Cr ratios showed relatively low variation between scanners using the universal sequence. In conclusion, phantom and in vivo experiments demonstrate successful implementation of the universal sequence across all four major vendors, allowing editing of several metabolites across a range of TEs.

YNIMG Journal 2017 Journal Article

Big GABA: Edited MR spectroscopy at 24 research sites

Mark Mikkelsen
Peter B. Barker
Pallab K. Bhattacharyya
Maiken K. Brix
Pieter F. Buur
Kim M. Cecil
Kimberly L. Chan
David Y.-T. Chen

Magnetic resonance spectroscopy (MRS) is the only biomedical imaging method that can noninvasively detect endogenous signals from the neurotransmitter γ-aminobutyric acid (GABA) in the human brain. Its increasing popularity has been aided by improvements in scanner hardware and acquisition methodology, as well as by broader access to pulse sequences that can selectively detect GABA, in particular J-difference spectral editing sequences. Nevertheless, implementations of GABA-edited MRS remain diverse across research sites, making comparisons between studies challenging. This large-scale multi-vendor, multi-site study seeks to better understand the factors that impact measurement outcomes of GABA-edited MRS. An international consortium of 24 research sites was formed. Data from 272 healthy adults were acquired on scanners from the three major MRI vendors and analyzed using the Gannet processing pipeline. MRS data were acquired in the medial parietal lobe with standard GABA+ and macromolecule- (MM-) suppressed GABA editing. The coefficient of variation across the entire cohort was 12% for GABA+ measurements and 28% for MM-suppressed GABA measurements. A multilevel analysis revealed that most of the variance (72%) in the GABA+ data was accounted for by differences between participants within-site, while site-level differences accounted for comparatively more variance (20%) than vendor-level differences (8%). For MM-suppressed GABA data, the variance was distributed equally between site- (50%) and participant-level (50%) differences. The findings show that GABA+ measurements exhibit strong agreement when implemented with a standard protocol. There is, however, increased variability for MM-suppressed GABA measurements that is attributed in part to differences in site-to-site data acquisition. This study's protocol establishes a framework for future methodological standardization of GABA-edited MRS, while the results provide valuable benchmarks for the MRS community.

YNIMG Journal 2017 Journal Article

Impact of tissue correction strategy on GABA-edited MRS findings

Eric C. Porges
Adam J. Woods
Damon G. Lamb
John B. Williamson
Ronald A. Cohen
Richard A.E. Edden
Ashley D. Harris

Tissue composition impacts the interpretation of magnetic resonance spectroscopy metabolite quantification. The goal of applying tissue correction is to decrease the dependency of metabolite concentrations on the underlying voxel tissue composition. Tissue correction strategies have different underlying assumptions to account for different aspects of the voxel tissue fraction. The most common tissue correction is the CSF-correction that aims to account for the cerebrospinal fluid (CSF) fraction in the voxel, in which it is assumed there are no metabolites. More recently, the α-correction was introduced to account for the different concentrations of GABA+in gray matter and white matter. In this paper, we show that the selected tissue correction strategy can alter the interpretation of results using data from a healthy aging cohort with GABA+ measurements in a frontal and posterior voxel. In a frontal voxel, we show an age-related decline in GABA+ when either no tissue correction (R2 = 0. 25, p < 0. 001) or the CSF-correction is applied (R2 = 0. 08, p < 0. 01). When applying the α-correction to the frontal voxel data, we find no relationship between age and GABA+ (R2 = 0. 02, p = 0. 15). However, with the α-correction we still find that cognitive performance is correlated with GABA+ (R2 = 0. 11, p < 0. 01). These data suggest that in healthy aging, while there is normal atrophy in the frontal voxel, GABA+ in the remaining tissue is not decreasing on average. This indicates that the selection of tissue correction can significantly impact the interpretation of MRS results.

YNIMG Journal 2017 Journal Article

Simultaneous measurement of Aspartate, NAA, and NAAG using HERMES spectral editing at 3 Tesla

Kimberly L. Chan
Muhammad G. Saleh
Georg Oeltzschner
Peter B. Barker
Richard A.E. Edden

It has previously been shown that the HERMES method (‘Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy’) can be used to simultaneously edit pairs of metabolites (such as N-acetyl-aspartate (NAA) and N-acetyl aspartyl glutamate (NAAG), or glutathione and GABA). In this study, HERMES is extended for the simultaneous editing of three overlapping signals, and illustrated for the example of NAA, NAAG and Aspartate (Asp). Density-matrix simulations were performed in order to optimize the HERMES sequence. The method was tested in NAA and Asp phantoms, and applied to the centrum semiovale of the nine healthy control subjects that were scanned at 3T. Both simulations and phantom experiments showed similar metabolite multiplet patterns with good segregation of all three metabolites. In vivo measurements show consistent relative signal intensities and multiplet patterns with concentrations in agreement with literature values. Simulations indicate co-editing of glutathione, glutamine, and glutamate, but their signals do not significantly overlap with the detected aspartyl resonances. This study demonstrates that a four-step Hadamard-encoded editing scheme can be used to simultaneously edit three otherwise overlapping metabolites, and can measure NAA, NAAG, and Asp in vivo in the brain at 3T with minimal crosstalk.

YNIMG Journal 2016 Journal Article

Simultaneous edited MRS of GABA and glutathione

Muhammad G. Saleh
Georg Oeltzschner
Kimberly L. Chan
Nicolaas A.J. Puts
Mark Mikkelsen
Michael Schär
Ashley D. Harris
Richard A.E. Edden

Edited MRS allows the detection of low-concentration metabolites, whose signals are not resolved in the MR spectrum. Tailored acquisitions can be designed to detect, for example, the inhibitory neurotransmitter γ-aminobutyric acid (GABA), or the reduction-oxidation (redox) compound glutathione (GSH), and single-voxel edited experiments are generally acquired at a rate of one metabolite-per-experiment. We demonstrate that simultaneous detection of the overlapping signals of GABA and GSH is possible using Hadamard Encoding and Reconstruction of Mega-Edited Spectroscopy (HERMES). HERMES applies orthogonal editing encoding (following a Hadamard scheme), such that GSH- and GABA-edited difference spectra can be reconstructed from a single multiplexed experiment. At a TE of 80ms, 20-ms editing pulses are applied at 4. 56ppm (on GSH), 1. 9ppm (on GABA), both offsets (using a dual-lobe cosine-modulated pulse) or neither. Hadamard combinations of the four sub-experiments yield GABA and GSH difference spectra. It is shown that HERMES gives excellent separation of the edited GABA and GSH signals in phantoms, and resulting edited lineshapes agree well with separate Mescher-Garwood Point-resolved Spectroscopy (MEGA-PRESS) acquisitions. In vivo, the quality and signal-to-noise ratio (SNR) of HERMES spectra are similar to those of sequentially acquired MEGA-PRESS spectra, with the benefit of saving half the acquisition time.

YNIMG Journal 2015 Journal Article

Decreased auditory GABA+ concentrations in presbycusis demonstrated by edited magnetic resonance spectroscopy

Fei Gao
Guangbin Wang
Wen Ma
Fuxin Ren
Muwei Li
Yuling Dong
Cheng Liu
Bo Liu

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central auditory system. Altered GABAergic neurotransmission has been found in both the inferior colliculus and the auditory cortex in animal models of presbycusis. Edited magnetic resonance spectroscopy (MRS), using the MEGA-PRESS sequence, is the most widely used technique for detecting GABA in the human brain. However, to date there has been a paucity of studies exploring changes to the GABA concentrations in the auditory region of patients with presbycusis. In this study, sixteen patients with presbycusis (5 males/11 females, mean age 63. 1±2. 6years) and twenty healthy controls (6 males/14 females, mean age 62. 5±2. 3years) underwent audiological and MRS examinations. Pure tone audiometry from 0. 125 to 8kHz and tympanometry were used to assess the hearing abilities of all subjects. The pure tone average (PTA; the average of hearing thresholds at 0. 5, 1, 2 and 4kHz) was calculated. The MEGA-PRESS sequence was used to measure GABA+ concentrations in 4×3×3cm3 volumes centered on the left and right Heschl's gyri. GABA+ concentrations were significantly lower in the presbycusis group compared to the control group (left auditory regions: p =0. 002, right auditory regions: p =0. 008). Significant negative correlations were observed between PTA and GABA+ concentrations in the presbycusis group (r =−0. 57, p =0. 02), while a similar trend was found in the control group (r =−0. 40, p =0. 08). These results are consistent with a hypothesis of dysfunctional GABAergic neurotransmission in the central auditory system in presbycusis and suggest a potential treatment target for presbycusis.

YNIMG Journal 2015 Journal Article

fMRI and MRS measures of neuroplasticity in the pharyngeal motor cortex

Emilia Michou
Steve Williams
Rishma Vidyasagar
Darragh Downey
Satish Mistry
Richard A.E. Edden
Shaheen Hamdy

Introduction Paired associative stimulation (PAS), is a novel non-invasive technique where two neural substrates are employed in a temporally coordinated manner in order to modulate cortico-motor excitability within the motor cortex (M1). In swallowing, combined pharyngeal electrical and transcranial-magnetic-stimulation induced beneficial neurophysiological and behavioural effects in healthy subjects and dysphagic stroke patients. Here, we aimed to investigate the whole-brain changes in neural activation during swallowing using functional magnetic resonance imaging (fMRI) following PAS application and in parallel assess associated GABA changes with magnetic resonance spectroscopy (MRS). Methods Healthy adults (n=11, 38±9years old) were randomised to receive real and sham PAS to the ‘stronger’ motor cortex pharyngeal representation, on 2 separate visits. Following PAS, event-related fMRI was performed to assess changes in brain activation in response to water and saliva swallowing and during rest. Data were analysed (SPM8) at P<. 001. MRS data were acquired using MEGA-PRESS before and after the fMRI acquisitions on both visits and GABA concentrations were measured (AMARES, jMRUI). Results Following real PAS, BOLD signal changes (group analyses) increased at the site of stimulation during water and saliva swallowing, compared to sham PAS. It is also evident that PAS induced significant increases in BOLD signal to contralateral (to stimulation) hemispheric areas that are of importance to the swallowing neural network. Following real PAS, GABA: creatine ratio showed a trend to increase contralateral to PAS. Conclusion Targeted PAS applied to the human pharyngeal motor cortex induces local and remote changes in both primary and non-primary areas for water and saliva tasks. There is a possibility that changes of the inhibitory neurotransmitter, GABA, may play a role in the changes in BOLD signal. These findings provide evidence for the mechanisms underlying the beneficial effects of PAS on the brain swallowing network.

YNIMG Journal 2014 Journal Article

Current practice in the use of MEGA-PRESS spectroscopy for the detection of GABA

Paul G. Mullins
David J. McGonigle
Ruth L. O'Gorman
Nicolaas A.J. Puts
Rishma Vidyasagar
C. John Evans
Richard A.E. Edden

There is increasing interest in the use of edited proton magnetic resonance spectroscopy for the detection of GABA in the human brain. At a recent meeting held at Cardiff University, a number of spectroscopy groups met to discuss the acquisition, analysis and interpretation of GABA-edited MR spectra. This paper aims to set out the issues discussed at this meeting, reporting areas of consensus around parameters and procedures in the field and highlighting those areas where differences remain. It is hoped that this paper can fulfill two needs, providing a summary of the current ‘state-of-the-art’ in the field of GABA-edited MRS at 3T using MEGA-PRESS and a basic guide to help researchers new to the field to avoid some of the pitfalls inherent in the acquisition and processing of edited MRS for GABA.

YNIMG Journal 2013 Journal Article

Edited magnetic resonance spectroscopy detects an age-related decline in brain GABA levels

Fei Gao
Richard A.E. Edden
Muwei Li
Nicolaas A.J. Puts
Guangbin Wang
Cheng Liu
Bin Zhao
Huiquan Wang

Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain. Although measurements of GABA levels in vivo in the human brain using edited proton magnetic resonance spectroscopy (1H-MRS) have been established for some time, it is has not been established how regional GABA levels vary with age in the normal human brain. In this study, 49 healthy men and 51 healthy women aged between 20 and 76years were recruited and J-difference edited spectra were recorded at 3T to determine the effect of age on GABA levels, and to investigate whether there are regional and gender differences in GABA in mesial frontal and parietal regions. Because the signal detected at 3. 02ppm using these experimental parameters is also expected to contain contributions from both macromolecules (MM) and homocarnosine, in this study the signal is labeled GABA+ rather than GABA. Significant negative correlations were observed between age and GABA+ in both regions studied (GABA+/Cr: frontal region, r=−0. 68, p<0. 001, parietal region, r=−0. 54, p<0. 001; GABA+/NAA: frontal region, r=−0. 58, p<0. 001, parietal region, r=−0. 49, p<0. 001). The decrease in GABA+ with age in the frontal region was more rapid in women than men. Evidence of a measureable decline in GABA is important in considering the neurochemical basis of the cognitive decline that is associated with normal aging.

YNIMG Journal 2013 Journal Article

Nuclear Overhauser enhancement (NOE) imaging in the human brain at 7T

Craig K. Jones
Alan Huang
Jiadi Xu
Richard A.E. Edden
Michael Schär
Jun Hua
Nikita Oskolkov
Domenico Zacà

Chemical exchange saturation transfer (CEST) is a magnetization transfer (MT) technique to indirectly detect pools of exchangeable protons through the water signal. CEST MRI has focused predominantly on signals from exchangeable protons downfield (higher frequency) from water in the CEST spectrum. Low power radiofrequency (RF) pulses can slowly saturate protons with minimal interference of conventional semi-solid based MT contrast (MTC). When doing so, saturation-transfer signals are revealed upfield from water, which is the frequency range of non-exchangeable aliphatic and olefinic protons. The visibility of such signals indicates the presence of a relayed transfer mechanism to the water signal, while their finite width reflects that these signals are likely due to mobile solutes. It is shown here in protein phantoms and the human brain that these signals build up slower than conventional CEST, at a rate typical for intramolecular nuclear Overhauser enhancement (NOE) effects in mobile macromolecules such as proteins/peptides and lipids. These NOE-based saturation transfer signals show a pH dependence, suggesting that this process is the inverse of the well-known exchange-relayed NOEs in high resolution NMR protein studies, thus a relayed-NOE CEST process. When studying 6 normal volunteers with a low-power pulsed CEST approach, the relayed-NOE CEST effect was about twice as large as the CEST effects downfield and larger in white matter than gray matter. This NOE contrast upfield from water provides a way to study mobile macromolecules in tissue. First data on a tumor patient show reduction in both relayed NOE and CEST amide proton signals leading to an increase in magnetization transfer ratio asymmetry, providing insight into previously reported amide proton transfer (APT) effects in tumors.