Changes in functional connectivity and GABA levels with long-term motor learning

Learning novel motor skills alters local inhibitory circuits within primary motor cortex (M1) (Floyer-Lea et al., 2006) and changes long-range functional connectivity (Albert et al., 2009). Whether such effects occur with long-term training is less well established. In addition, the relationship between learning-related changes in functional connectivity and local inhibition, and their modulation by practice, has not previously been tested. Here, we used resting-state functional magnetic resonance imaging (rs-fMRI) to assess functional connectivity and MR spectroscopy to quantify GABA in primary motor cortex (M1) before and after a 6 week regime of juggling practice. Participants practiced for either 30 min (high intensity group) or 15 min (low intensity group) per day. We hypothesized that different training regimes would be reflected in distinct changes in brain connectivity and local inhibition, and that correlations would be found between learning-induced changes in GABA and functional connectivity. Performance improved significantly with practice in both groups and we found no evidence for differences in performance outcomes between the low intensity and high intensity groups. Despite the absence of behavioral differences, we found distinct patterns of brain change in the two groups: the low intensity group showed increases in functional connectivity in the motor network and decreases in GABA, whereas the high intensity group showed decreases in functional connectivity and no significant change in GABA. Changes in functional connectivity correlated with performance outcome. Learning-related changes in functional connectivity correlated with changes in GABA. The results suggest that different training regimes are associated with distinct patterns of brain change, even when performance outcomes are comparable between practice schedules. Our results further indicate that learning-related changes in resting-state network strength in part reflect GABAergic plastic processes

Unedited in vivo detection and quantification of gamma-aminobutyric acid in the occipital cortex using short-TE MRS at 3 T

Short-TE MRS has been proposed recently as a method for the in vivo detection and quantification of gamma-aminobutyric acid (GABA) in the human brain at 3 T. In this study, we investigated the accuracy and reproducibility of short-TE MRS measurements of GABA at 3 T using both simulations and experiments. LCModel analysis was performed on a large number of simulated spectra with known metabolite input concentrations. Simulated spectra were generated using a range of spectral linewidths and signal-to-noise ratios to investigate the effect of varying experimental conditions, and analyses were performed using two different baseline models to investigate the effect of an inaccurate baseline model on GABA quantification. The results of these analyses indicated that, under experimental conditions corresponding to those typically observed in the occipital cortex, GABA concentration estimates are reproducible (mean reproducibility error, <20%), even when an incorrect baseline model is used. However, simulations indicate that the accuracy of GABA concentration estimates depends strongly on the experimental conditions (linewidth and signal-to-noise ratio). In addition to simulations, in vivo GABA measurements were performed using both spectral editing and short-TE MRS in the occipital cortex of 14 healthy volunteers. Short-TE MRS measurements of GABA exhibited a significant positive correlation with edited GABA measurements (R = 0.58, p < 0.05), suggesting that short-TE measurements of GABA correspond well with measurements made using spectral editing techniques. Finally, within-session reproducibility was assessed in the same 14 subjects using four consecutive short-TE GABA measurements in the occipital cortex. Across all subjects, the average coefficient of variation of these four GABA measurements was 8.7 +/- 4.9%. This study demonstrates that, under some experimental conditions, short-TE MRS can be employed for the reproducible detection of GABA at 3 T, but that the technique should be used with caution, as the results are dependent on the experimental conditions. Copyright (c) 2013 John Wiley & Sons, Ltd

Phosphene Perception Relates to Visual Cortex Glutamate Levels and Covaries with Atypical Visuospatial Awareness

Phosphenes are illusory visual percepts produced by the application of transcranial magnetic stimulation to occipital cortex. Phosphene thresholds, the minimum stimulation intensity required to reliably produce phosphenes, are widely used as an index of cortical excitability. However, the neural basis of phosphene thresholds and their relationship to individual differences in visual cognition are poorly understood. Here, we investigated the neurochemical basis of phosphene perception by measuring basal GABA and glutamate levels in primary visual cortex using magnetic resonance spectroscopy. We further examined whether phosphene thresholds would relate to the visuospatial phenomenology of grapheme-color synesthesia, a condition characterized by atypical binding and involuntary color photisms. Phosphene thresholds negatively correlated with glutamate concentrations in visual cortex, with lower thresholds associated with elevated glutamate. This relationship was robust, present in both controls and synesthetes, and exhibited neurochemical, topographic, and threshold specificity. Projector synesthetes, who experience color photisms as spatially colocalized with inducing graphemes, displayed lower phosphene thresholds than associator synesthetes, who experience photisms as internal images, with both exhibiting lower thresholds than controls. These results suggest that phosphene perception is driven by interindividual variation in glutamatergic activity in primary visual cortex and relates to cortical processes underlying individual differences in visuospatial awareness

Effect of age and the APOE gene on metabolite concentrations in the posterior cingulate cortex.

Proton magnetic resonance spectroscopy (1H-MRS) has provided valuable information about the neurochemical profile of Alzheimer's disease (AD). However, its clinical utility has been limited in part by the lack of consistent information on how metabolite concentrations vary in the normal aging brain and in carriers of apolipoprotein E (APOE) ε4, an established risk gene for AD. We quantified metabolites within an 8cm3 voxel within the posterior cingulate cortex (PCC)/precuneus in 30 younger (20-40 years) and 151 cognitively healthy older individuals (60-85 years). All 1H-MRS scans were performed at 3T using the short-echo SPECIAL sequence and analyzed with LCModel. The effect of APOE was assessed in a sub-set of 130 volunteers. Older participants had significantly higher myo-inositol and creatine, and significantly lower glutathione and glutamate than younger participants. There was no significant effect of APOE or an interaction between APOE and age on the metabolite profile. Our data suggest that creatine, a commonly used reference metabolite in 1H-MRS studies, does not remain stable across adulthood within this region and therefore may not be a suitable reference in studies involving a broad age-range. Increases in creatine and myo-inositol may reflect age-related glial proliferation; decreases in glutamate and glutathione suggest a decline in synaptic and antioxidant efficiency. Our findings inform longitudinal clinical studies by characterizing age-related metabolite changes in a non-clinical sample

Comparison of seven modelling algorithms for γ-aminobutyric acid–edited proton magnetic resonance spectroscopy

Edited MRS sequences are widely used for studying γ-aminobutyric acid (GABA) in the human brain. Several algorithms are available for modelling these data, deriving metabolite concentration estimates through peak fitting or a linear combination of basis spectra. The present study compares seven such algorithms, using data obtained in a large multisite study. GABA-edited (GABA+, TE = 68 ms MEGA-PRESS) data from 222 subjects at 20 sites were processed via a standardised pipeline, before modelling with FSL-MRS, Gannet, AMARES, QUEST, LCModel, Osprey and Tarquin, using standardised vendor-specific basis sets (for GE, Philips and Siemens) where appropriate. After referencing metabolite estimates (to water or creatine), systematic differences in scale were observed between datasets acquired on different vendors' hardware, presenting across algorithms. Scale differences across algorithms were also observed. Using the correlation between metabolite estimates and voxel tissue fraction as a benchmark, most algorithms were found to be similarly effective in detecting differences in GABA+. An interclass correlation across all algorithms showed single-rater consistency for GABA+ estimates of around 0.38, indicating moderate agreement. Upon inclusion of a basis set component explicitly modelling the macromolecule signal underlying the observed 3.0 ppm GABA peaks, single-rater consistency improved to 0.44. Correlation between discrete pairs of algorithms varied, and was concerningly weak in some cases. Our findings highlight the need for consensus on appropriate modelling parameters across different algorithms, and for detailed reporting of the parameters adopted in individual studies to ensure reproducibility and meaningful comparison of outcomes between different studies.publishedVersio

Multi-vendor standardized sequence for edited magnetic resonance spectroscopy

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.publishedVersio

Frequency drift in MR spectroscopy at 3T

Purpose: Heating of gradient coils and passive shim components is a common cause of instability in the B-0 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 &lt; 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.</p

Preprocessing, analysis and quantification in single-voxel magnetic resonance spectroscopy: experts' consensus recommendations.

Once an MRS dataset has been acquired, several important steps must be taken to obtain the desired metabolite concentration measures. First, the data must be preprocessed to prepare them for analysis. Next, the intensity of the metabolite signal(s) of interest must be estimated. Finally, the measured metabolite signal intensities must be converted into scaled concentration units employing a quantitative reference signal to allow meaningful interpretation. In this paper, we review these three main steps in the post-acquisition workflow of a single-voxel MRS experiment (preprocessing, analysis and quantification) and provide recommendations for best practices at each step

Effect of interferon-α on cortical glutamate in patients with chronic hepatitis C:a proton MRS study

BACKGROUND: The development of depressive symptomatology is a recognised complication of treatment with the cytokine, interferon-α, and has been seen as supporting inflammatory theories of the pathophysiology of major depression. Major depression has been associated with changes in glutamatergic activity and recent formulations of interferon-induced depression have implicated neurotoxic influences which could also lead to changes in glutamate function. The present study used magnetic resonance spectroscopy (MRS) to measure both glutamate and its major metabolite, glutamine in patients with hepatitis C who received treatment with pegylated-interferon-α and ribavirin. METHODS: MRS measurements of glutamate and glutamine were taken from a 25×20×20mm voxel including pregenual anterior cingulate cortex in 12 patients before and after 4-6 weeks treatment with interferon. RESULTS: Interferon treatment led to an increase in cortical levels of glutamine (p= 0.02) and a significant elevation in the ratio of glutamine to glutamate (p<.01). Further, changes in glutamine level correlated significantly with ratings of depression and anxiety at the time of the second scan. CONCLUSIONS: We conclude that treatment with interferon-α is associated with MRS-visible changes in glutamatergic metabolism. However, the changes seen differ from those reported in major depression which suggests that the pathophysiology of interferon-induced depression may be distinct from that of major depression more generally