Microstructural and neurochemical plasticity mechanisms interact to enhance human perceptual decision-making.

Experience and training are known to boost our skills and mold the brain's organization and function. Yet, structural plasticity and functional neurotransmission are typically studied at different scales (large-scale networks, local circuits), limiting our understanding of the adaptive interactions that support learning of complex cognitive skills in the adult brain. Here, we employ multimodal brain imaging to investigate the link between microstructural (myelination) and neurochemical (GABAergic) plasticity for decision-making. We test (in males, due to potential confounding menstrual cycle effects on GABA measurements in females) for changes in MRI-measured myelin, GABA, and functional connectivity before versus after training on a perceptual decision task that involves identifying targets in clutter. We demonstrate that training alters subcortical (pulvinar, hippocampus) myelination and its functional connectivity to visual cortex and relates to decreased visual cortex GABAergic inhibition. Modeling interactions between MRI measures of myelin, GABA, and functional connectivity indicates that pulvinar myelin plasticity interacts-through thalamocortical connectivity-with GABAergic inhibition in visual cortex to support learning. Our findings propose a dynamic interplay of adaptive microstructural and neurochemical plasticity in subcortico-cortical circuits that supports learning for optimized decision-making in the adult human brain.

3D balanced SSFP UTE MRI for multiple contrasts whole brain imaging.

PURPOSE: This study aimed to develop a new high-resolution MRI sequence for the imaging of the ultra-short transverse relaxation time (uT2) components in the brain, while simultaneously providing proton density (PD) contrast for reference and quantification. THEORY: The sequence combines low flip angle balanced SSFP (bSSFP) and UTE techniques, together with a 3D dual-echo rosette k-space trajectory for readout. METHODS: The expected image contrast was evaluated by simulations. A study cohort of six healthy volunteers and eight multiple sclerosis (MS) patients was recruited to test the proposed sequence. Subtraction between two TEs was performed to extract uT2 signals. In addition, conventional longitudinal relaxation time (T1) weighted, T2-weighted, and PD-weighted MRI sequences were also acquired for comparison. RESULTS: Typical PD-contrast was found in the second TE images, while uT2 signals were selectively captured in the first TE images. The subtraction images presented signals primarily originating from uT2 components, but only if the first TE is short enough. Lesions in the MS subjects showed hyperintense signals in the second TE images but were hypointense signals in the subtraction images. The lesions had significantly lower signal intensity in subtraction images than normal white matter (WM), which indicated a reduction of uT2 components likely associated with myelin. CONCLUSION: 3D isotropic sub-millimeter (0.94 mm) spatial resolution images were acquired with the novel bSSFP UTE sequence within 3 min. It provided easy extraction of uT2 signals and PD-contrast for reference within a single acquisition.

Predicting learning and achievement using GABA and glutamate concentrations in human development.

Previous research has highlighted the role of glutamate and gamma-aminobutyric acid (GABA) in learning and plasticity. What is currently unknown is how this knowledge translates to real-life complex cognitive abilities that emerge slowly and how the link between these neurotransmitters and human learning and plasticity is shaped by development. While some have suggested a generic role of glutamate and GABA in learning and plasticity, others have hypothesized that their involvement shapes sensitive periods during development. Here we used a cross-sectional longitudinal design with 255 individuals (spanning primary school to university) to show that glutamate and GABA in the intraparietal sulcus explain unique variance both in current and future mathematical achievement (approximately 1.5 years). Furthermore, our findings reveal a dynamic and dissociable role of GABA and glutamate in predicting learning, which is reversed during development, and therefore provide novel implications for models of learning and plasticity during childhood and adulthood.

Cerebellar GABA Change during Visuomotor Adaptation Relates to Adaptation Performance and Cerebellar Network Connectivity: A Magnetic Resonance Spectroscopic Imaging Study.

Motor adaptation is crucial for performing accurate movements in a changing environment and relies on the cerebellum. Although cerebellar involvement has been well characterized, the neurochemical changes in the cerebellum underpinning human motor adaptation remain unknown. We used a novel magnetic resonance spectroscopic imaging (MRSI) technique to measure changes in the inhibitory neurotransmitter GABA in the human cerebellum during visuomotor adaptation. Participants (n = 17, six female) used their right hand to adapt to a rotated cursor in the scanner, compared with a control task requiring no adaptation. We spatially resolved adaptation-driven GABA changes at the cerebellar nuclei and cerebellar cortex in the left and the right cerebellar hemisphere independently and found that simple right-hand movements increase GABA in the right cerebellar nuclei and decreases GABA in the left. When isolating adaptation-driven GABA changes, we found that GABA in the left cerebellar nuclei and the right cerebellar nuclei diverged, although GABA change from baseline at the right cerebellar nuclei was not different from zero at the group level. Early adaptation-driven GABA fluctuations in the right cerebellar nuclei correlated with adaptation performance. Participants showing greater GABA decrease adapted better, suggesting early GABA change is behaviorally relevant. Early GABA change also correlated with functional connectivity change in a cerebellar network. Participants showing greater decreases in GABA showed greater strength increases in cerebellar network connectivity. Results were specific to GABA, to adaptation, and to the cerebellar network. This study provides first evidence for plastic changes in cerebellar neurochemistry during motor adaptation. Characterizing these naturally occurring neurochemical changes may provide a basis for developing therapeutic interventions to facilitate human motor adaptation.SIGNIFICANCE STATEMENT Despite motor adaptation being fundamental to maintaining accurate movements, its neurochemical basis remains poorly understood, perhaps because measuring neurochemicals in the human cerebellum is technically challenging. Using a novel magnetic resonance spectroscopic imaging method, this study provides evidence for GABA changes in the left compared with the right cerebellar nuclei driven by both simple movement and motor adaptation. Although right cerebellar GABA changes were not significantly different from zero at the group level, the adaptation-driven GABA fluctuations in the right cerebellar nuclei correlated with adaptation performance and with functional connectivity change in a cerebellar network. These results show the first evidence for plastic changes in cerebellar neurochemistry during a cerebellar learning task. This provides the basis for developing therapeutic interventions that facilitate these naturally occurring changes to amplify cerebellar-dependent learning.

Event-related functional magnetic resonance spectroscopy.

Proton-Magnetic Resonance Spectroscopy (MRS) is a non-invasive brain imaging technique used to measure the concentration of different neurochemicals. "Single-voxel" MRS data is typically acquired across several minutes, before individual transients are averaged through time to give a measurement of neurochemical concentrations. However, this approach is not sensitive to more rapid temporal dynamics of neurochemicals, including those that reflect functional changes in neural computation relevant to perception, cognition, motor control and ultimately behaviour. In this review we discuss recent advances in functional MRS (fMRS) that now allow us to obtain event-related measures of neurochemicals. Event-related fMRS involves presenting different experimental conditions as a series of trials that are intermixed. Critically, this approach allows spectra to be acquired at a time resolution in the order of seconds. Here we provide a comprehensive user guide for event-related task designs, choice of MRS sequence, analysis pipelines, and appropriate interpretation of event-related fMRS data. We raise various technical considerations by examining protocols used to quantify dynamic changes in GABA, the primary inhibitory neurotransmitter in the brain. Overall, we propose that although more data is needed, event-related fMRS can be used to measure dynamic changes in neurochemicals at a temporal resolution relevant to computations that support human cognition and behaviour.

Ultra-short T2 components imaging of the whole brain using 3D dual-echo UTE MRI with rosette k-space pattern.

PURPOSE: This study aimed to develop a new 3D dual-echo rosette k-space trajectory, specifically designed for UTE MRI applications. The imaging of the ultra-short transverse relaxation time (uT2 ) of brain was acquired to test the performance of the proposed UTE sequence. THEORY AND METHODS: The rosette trajectory was developed based on rotations of a "petal-like" pattern in the kx -ky plane, with oscillated extensions in the kz -direction for 3D coverage. Five healthy volunteers underwent 10 dual-echo 3D rosette UTE scans with various TEs. Dual-exponential complex model fitting was performed on the magnitude data to separate uT2 signals, with the output of uT2 fraction, uT2 value, and long-T2 value. RESULTS: The 3D rosette dual-echo UTE sequence showed better performance than a 3D radial UTE acquisition. More significant signal intensity decay in white matter than gray matter was observed along with the TEs. The white matter regions had higher uT2 fraction values than gray matter (10.9% ± 1.9% vs. 5.7% ± 2.4%). The uT2 value was approximately 0.10 ms in white matter . CONCLUSION: The higher uT2 fraction value in white matter compared to gray matter demonstrated the ability of the proposed sequence to capture rapidly decaying signals.

The effect of parietal glutamate/GABA balance on test anxiety levels in early childhood in a cross-sectional and longitudinal study.

The increased prevalence of test anxiety in our competitive society makes it a health issue of public concern. However, its neurobiological basis, especially during the years of formal education, is currently scant. Previous research has highlighted the association between neural excitation/inhibition balance and psychopathology and disease. We examined whether the glutamate/GABA profile tracks test anxiety levels in development, using a cross-sectional and longitudinal design in a cohort spanning from early childhood to early adulthood (N = 289), reassessed approximately 21 months later (N = 194). We used magnetic resonance spectroscopy to noninvasively quantify glutamate and gamma-Aminobutyric acid (GABA) levels in the intraparietal sulcus (IPS) and the middle frontal gyrus. We show that the glutamate/GABA balance within the IPS relates to current individual variation in test anxiety levels and predict future test anxiety approximately 21 months later. Critically, this relationship was observed during early childhood but not during the later developmental stages. Our results extend the use of the excitation/inhibition balance framework to characterize the psychopathology mechanisms of test anxiety, an underexplored yet widespread and debilitating condition that can impact early child development. Our findings provide a better understanding of the neurotransmitter basis underlying the emergence of anxiety disorders during development.

Neurochemical and functional interactions for improved perceptual decisions through training.

Learning and experience are known to improve our ability to make perceptual decisions. Yet, our understanding of the brain mechanisms that support improved perceptual decisions through training remains limited. Here, we test the neurochemical and functional interactions that support learning for perceptual decisions in the context of an orientation identification task. Using magnetic resonance spectroscopy (MRS), we measure neurotransmitters (i.e., glutamate, GABA) that are known to be involved in visual processing and learning in sensory [early visual cortex (EV)] and decision-related [dorsolateral prefrontal cortex (DLPFC)] brain regions. Using resting-state functional magnetic resonance imaging (rs-fMRI), we test for functional interactions between these regions that relate to decision processes. We demonstrate that training improves perceptual judgments (i.e., orientation identification), as indicated by faster rates of evidence accumulation after training. These learning-dependent changes in decision processes relate to lower EV glutamate levels and EV-DLPFC connectivity, suggesting that glutamatergic excitation and functional interactions between visual and dorsolateral prefrontal cortex facilitate perceptual decisions. Further, anodal transcranial direct current stimulation (tDCS) in EV impairs learning, suggesting a direct link between visual cortex excitation and perceptual decisions. Our findings advance our understanding of the role of learning in perceptual decision making, suggesting that glutamatergic excitation for efficient sensory processing and functional interactions between sensory and decision-related regions support improved perceptual decisions.NEW & NOTEWORTHY Combining multimodal brain imaging [magnetic resonance spectroscopy (MRS), functional connectivity] with interventions [transcranial direct current stimulation (tDCS)], we demonstrate that glutamatergic excitation and functional interactions between sensory (visual) and decision-related (dorsolateral prefrontal cortex) areas support our ability to optimize perceptual decisions through training.

NIfTI-MRS: A standard data format for magnetic resonance spectroscopy.

PURPOSE: Multiple data formats in the MRS community currently hinder data sharing and integration. NIfTI-MRS is proposed as a standard spectroscopy data format, implemented as an extension to the Neuroimaging informatics technology initiative (NIfTI) format. This standardized format can facilitate data sharing and algorithm development as well as ease integration of MRS analysis alongside other imaging modalities. METHODS: A file format using the NIfTI header extension framework incorporates essential spectroscopic metadata and additional encoding dimensions. A detailed description of the specification is provided. An open-source command-line conversion program is implemented to convert single-voxel and spectroscopic imaging data to NIfTI-MRS. Visualization of data in NIfTI-MRS is provided by development of a dedicated plugin for FSLeyes, the FMRIB Software Library (FSL) image viewer. RESULTS: Online documentation and 10 example datasets in the proposed format are provided. Code examples of NIfTI-MRS readers are implemented in common programming languages. Conversion software, spec2nii, currently converts 14 formats where data is stored in image-space to NIfTI-MRS, including Digital Imaging and Communications in Medicine (DICOM) and vendor proprietary formats. CONCLUSION: NIfTI-MRS aims to solve issues arising from multiple data formats being used in the MRS community. Through a single conversion point, processing and analysis of MRS data are simplified, thereby lowering the barrier to use of MRS. Furthermore, it can serve as the basis for open data sharing, collaboration, and interoperability of analysis programs. Greater standardization and harmonization become possible. By aligning with the dominant format in neuroimaging, NIfTI-MRS enables the use of mature tools present in the imaging community, demonstrated in this work by using a dedicated imaging tool, FSLeyes, for visualization.

Relapsing antibody-negative patients with features of neuromyelitis optica spectrum disorders: Differences in N-acetylaspartate level in the cervical spinal cord indicate distinct underlying processes.

BACKGROUND: Due to lack of biomarkers, antibody-negative patients with features of neuromyelitis optica spectrum disorders (NMOSD) are among the most challenging to diagnose and treat. Using unsupervised clustering, we recently identified 'MS-like', 'spinal MS-like', 'classic NMOSD-like' and 'NMOSD-like with brain involvement' subgroups in this cohort. OBJECTIVE: We used magnetic resonance spectroscopy (MRS) to examine differences in the level of key metabolites in the spinal cord between the four identified subgroups. METHODS: Twenty-five relapsing antibody-negative patients with NMOSD features classified by the unsupervised algorithm to one of the subgroups underwent a prospective cervical spinal cord MRS. Spectra from 16 patients fulfilled quality criteria and were included in the analysis. RESULTS: Total N-acetylaspartate (tNAA), but not total choline (tCho) or myo-inositol (Ins), was significantly different between the four subgroups (p = 0.03). In particular, tNAA was 47.8% lower in the 'MS-like' subgroup as compared with the 'classic NMOSD-like' subgroup (p = 0.02). While we found a negative overall correlation between tNAA and disability score (r = -0.514, p = 0.04) in the whole cohort, the disability score did not differ significantly between the subgroups to explain subgroup differences in tNAA level. CONCLUSIONS: Significant differences in the cervical spinal cord tNAA measurements confirm that the previously identified clinico-radiologic subgroups contain patients with distinct underlying disease processes.

Age-related decline in cortical inhibitory tone strengthens motor memory.

Ageing disrupts the finely tuned excitation/inhibition balance (E:I) across cortex via a natural decline in inhibitory tone (γ-amino butyric acid, GABA), causing functional decrements. However, in young adults, experimentally lowering GABA in sensorimotor cortex enhances a specific domain of sensorimotor function: adaptation memory. Here, we tested the hypothesis that as sensorimotor cortical GABA declines naturally with age, adaptation memory would increase, and the former would explain the latter. Results confirmed this prediction. To probe causality, we used brain stimulation to further lower sensorimotor cortical GABA during adaptation. Across individuals, how stimulation changed memory depended on sensorimotor cortical E:I. In those with low E:I, stimulation increased memory; in those with high E:I stimulation reduced memory. Thus, we identified a form of motor memory that is naturally strengthened by age, depends causally on sensorimotor cortex neurochemistry, and may be a potent target for motor skill preservation strategies in healthy ageing and neurorehabilitation.

An In-vivo 1H-MRS short-echo time technique at 7T: Quantification of metabolites in chronic multiple sclerosis and neuromyelitis optica brain lesions and normal appearing brain tissue.

Magnetic Resonance Spectroscopy (MRS) allows for the non-invasive quantification of neurochemicals and has the potential to differentiate between the pathologically distinct diseases, multiple sclerosis (MS) and AQP4Ab-positive neuromyelitis optica spectrum disorder (AQP4Ab-NMOSD). In this study we characterised the metabolite profiles of brain lesions in 11 MS and 4 AQP4Ab-NMOSD patients using an optimised MRS methodology at ultra-high field strength (7T) incorporating correction for T2 water relaxation differences between lesioned and normal tissue. MS metabolite results were in keeping with the existing literature: total N-acetylaspartate (NAA) was lower in lesions compared to normal appearing brain white matter (NAWM) with reciprocal findings for myo-Inositol. An unexpected subtlety revealed by our technique was that total NAA differences were likely driven by NAA-glutamate (NAAG), a ubiquitous CNS molecule with functions quite distinct from NAA though commonly quantified together with NAA in MRS studies as total NAA. Surprisingly, AQP4Ab-NMOSD showed no significant differences for total NAA, NAA, NAAG or myo-Inositol between lesion and NAWM sites, nor were there any differences between MS and AQP4Ab-NMOSD for a priori hypotheses. Post-hoc testing revealed a significant correlation between NAWM Ins:NAA and disability (as measured by EDSS) for disease groups combined, driven by the AP4Ab-NMOSD group. Utilising an optimised MRS methodology, our study highlights some under-explored subtleties in MRS profiles, such as the absence of myo-Inositol concentration differences in AQP4Ab-NMOSD brain lesions versus NAWM and the potential influence of NAAG differences between lesions and normal appearing white matter in MS.

The cross-sectional interplay between neurochemical profile and brain connectivity.

Neurochemical profile and brain connectivity are both critical aspects of brain function. However, our knowledge of their interplay across development is currently poor. We combined single-voxel magnetic resonance spectroscopy and resting functional magnetic resonance imaging in a cross-sectional sample spanning from childhood to adulthood which was reassessed in ~1.5 years (N = 293). We revealed the developmental trajectories of 20 neurochemicals in two key developmental brain regions (the intraparietal sulcus, IPS, and the middle frontal gyrus, MFG). We found that certain neurochemicals exhibited similar developmental trajectories across the two regions, while other trajectories were region-specific. Crucially, we mapped the connectivity of the brain regions IPS and MFG to the rest of the brain across development as a function of regional glutamate and GABA concentration. We demonstrated that glutamate concentration within the IPS is modulated by age in explaining IPS connectivity with frontal, temporal and parietal regions. In mature participants, higher glutamate within the IPS was related to more negative connectivity while the opposite pattern was found for younger participants. Our findings offer specific developmental insights on the interplay between the brain's resting activity and the glutamatergic system both of which are crucial for regulating normal functioning and are dysregulated in several clinical conditions.

High-resolution metabolic mapping of the cerebellum using 2D zoom magnetic resonance spectroscopic imaging.

PURPOSE: The human cerebellum plays an important role in the functional activity of the cerebrum, ranging from motor to cognitive systems given its relaying role between the spinal cord and cerebrum. The cerebellum poses many challenges to Magnetic Resonance Spectroscopic Imaging (MRSI) due to its caudal location, susceptibility to physiological artifacts, and partial volume artifacts resulting from its complex anatomical structure. Thus, in the present study, we propose a high-resolution MRSI acquisition scheme for the cerebellum. METHODS: A zoom or reduced field of view (rFOV) metabolite-cycled MRSI acquisition at 3 Tesla, with a grid of 48 × 48, was developed to achieve a nominal resolution of 62.5 µL. Single-slice rFOV MRSI data were acquired from the cerebellum of 5 healthy subjects with a nominal resolution of 2.5 × 2.5 × 10 mm3 in 9.6 min. Spectra were quantified using the LCModel package. A spatially unbiased atlas template of the cerebellum was used to analyze metabolite distributions in the cerebellum. RESULTS: The superior quality of the achieved spectra-enabled generation of high-resolution metabolic maps of total N-acetylaspartate, total Creatine (tCr), total Choline (tCho), glutamate+glutamine, and myo-inositol, with Cramér-Rao lower bounds below 50%. A template-based regions of interest (ROI) analysis resulted in spatially dependent metabolite distributions in 9 ROIs. The group-averaged high-resolution metabolite maps across subjects increased the contrast-to-noise ratio between cerebellum regions. CONCLUSION: These findings indicate that very high-resolution metabolite probing of the cerebellum is feasible using rFOV or zoomed MRSI at 3 Tesla.

Fast in vivo 23 Na imaging and T2∗ mapping using accelerated 2D-FID UTE magnetic resonance spectroscopic imaging at 3 T: Proof of concept and reliability study.

PURPOSE: To implement an accelerated MR-acquisition method allowing to map T2∗ relaxation and absolute concentration of sodium within skeletal muscles at 3T. METHODS: A fast-UTE-2D density-weighted concentric-ring-trajectory 23 Na-MRSI technique was used to acquire 64 time points of FID with a spectral bandwidth of 312.5 Hz with an in-plane resolution of 2.5 × 2.5 mm2 in ~15 min. The fast-relaxing 23 Na signal was localized with a single-shot, inversion-recovery-based, non-echo (SIRENE) outer volume suppression (OVS) method. The sequence was verified using simulation and phantom studies before implementing it in human calf muscles. To evaluate the 2D-SIRENE-MRSI (UTE = 0.55 ms) imaging performance, it was compared to a 3D-MRI (UTE = 0.3 ms) sequence. Both data sets were acquired within 2 same-day sessions to assess repeatability. The T2∗ values were fitted voxel-by-voxel using a biexponential model for the 2D-MRSI data. Finally, intra-subject coefficients of variation (CV) were estimated. RESULTS: The MRSI-FID data allowed us to map the fast and slow components of T2∗ in the calf muscles. The spatial distributions of 23 Na concentration for both MRSI and 3D-MRI acquisitions were significantly correlated (P < .001). The test-retest analysis rendered high repeatability for MRSI with a CV of 5%. The mean T2Fast∗ in muscles was 0.7 ± 0.1 ms (contribution fraction = 37%), whereas T2Slow∗ was 13.2 ± 0.2 ms (63%). The mean absolute muscle 23 Na concentration calculated from the T2∗ -corrected data was 28.6 ± 3.3 mM. CONCLUSION: The proposed MRSI technique is a reliable technique to map sodium's absolute concentration and T2∗ within a clinically acceptable scan time at 3T.

Comparison of Neurochemical and BOLD Signal Contrast Response Functions in the Human Visual Cortex.

We investigated the relationship between neurochemical and hemodynamic responses as a function of image contrast in the human primary visual cortex (V1). Simultaneously acquired BOLD-fMRI and single voxel proton MR spectroscopy signals were measured in V1 of 24 healthy human participants of either sex at 7 tesla field strength, in response to presentations (64 s blocks) of different levels of image contrast (3%, 12.5%, 50%, 100%). Our results suggest that complementary measures of neurotransmission and energy metabolism are in partial agreement: BOLD and glutamate signals were linear with image contrast; however, a significant increase in glutamate concentration was evident only at the highest intensity level. In contrast, GABA signals were steady across all intensity levels. These results suggest that neurochemical concentrations are maintained at lower ranges of contrast levels, which match the statistics of natural vision, and that high stimulus intensity may be critical to increase sensitivity to visually modulated glutamate signals in the early visual cortex using MR spectroscopy.SIGNIFICANCE STATEMENT Glutamate and GABA are the major excitatory and inhibitory neurotransmitters of the brain. To better understand the relationship between MRS-visible neurochemicals, the BOLD signal change, and stimulus intensity, we measured combined neurochemical and BOLD signals (combined fMRI-MRS) to different image contrasts in human V1 at 7 tesla. While a linear change to contrast was present for both signals, the increase in glutamate was significant only at the highest stimulus intensity. These results suggest that hemodynamic and neurochemical signals reflect common metabolic markers of neural activity, whereas the mismatch at lower contrast levels may indicate a sensitivity threshold for detecting neurochemical changes during visual processing. Our results highlight the challenge and importance of reconciling cellular and metabolic measures of neural activity in the human brain.

Fat-water separation by fast metabolite cycling magnetic resonance spectroscopic imaging at 3 T: A method to generate separate quantitative distribution maps of musculoskeletal lipid components.

PURPOSE: To provide a rapid, noninvasive fat-water separation technique that allows producing quantitative maps of particular lipid components. METHODS: The calf muscles in 5 healthy adolescents (age 12-16 years; body mass index = 20 ± 3 kg/m2 ) were scanned by two different fat fraction measurement methods. A density-weighted concentric-ring trajectory metabolite-cycling MRSI technique was implemented to collect data with a nominal resolution of 0.25 mL within 3 minutes and 16 seconds. For comparative purposes, the standard Dixon technique was performed. The two techniques were compared using structural similarity analysis. Additionally, the difference in the distribution of each lipid over the adolescent calf muscles was assessed based on the MRSI data. RESULTS: The proposed MRSI technique provided individual fat fraction maps for eight musculoskeletal lipid components identified by LCModel analysis (IMC/L [CH3 ], EMCL [CH3 ], IMC/L [CH2 ]n , EMC/L [CH2 ]n , IMC/L [CH2 -CH], EMC/L [CH2 -CH], IMC/L [-CH=CH-], and EMC/L [-CH=CH-]) with mean structural similarity indices of 0.19, 0.04, 0.03, 0.50, 0.45, 0.04, 0.07, and 0.12, respectively, compared with the maps generated by the used Dixon method. Further analysis of voxels with zero structural similarity demonstrated an increased sensitivity of fat fraction lipid maps from the data acquired using this MRSI technique over the standard Dixon technique. The lipid spatial distribution over calf muscles was consistent with previously published findings in adults. CONCLUSION: This MRSI technique can be a useful tool when individual lipid fat fraction maps are desired within a clinically acceptable time and with a nominal spatial resolution of 0.25 mL.

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.

The dynamics of cortical GABA in human motor learning.

KEY POINTS: The ability to learn new motor skills is supported by plasticity in the structural and functional organisation of the primary motor cortex in the human brain. Changes inhibitory to signalling by GABA are thought to be crucial in inducing motor cortex plasticity. This study used magnetic resonance spectroscopy (MRS) to quantify the concentration of GABA in human motor cortex during a period of motor learning, as well as during a period of movement and a period at rest. We report evidence for a reduction in the MRS-measured concentration of GABA specific to learning. Further, the GABA concentration early in the learning task was strongly correlated with the magnitude of subsequent learning: higher GABA concentrations were associated with poorer learning. The results provide initial insight into the neurochemical correlates of cortical plasticity associated with motor learning, specifically relevant in therapeutic efforts to induce cortical plasticity during recovery from stroke. ABSTRACT: The ability to learn novel motor skills is a central part of our daily lives and can provide a model for rehabilitation after a stroke. However, there are still fundamental gaps in our understanding of the physiological mechanisms that underpin human motor plasticity. The acquisition of new motor skills is dependent on changes in local circuitry within the primary motor cortex (M1). This reorganisation has been hypothesised to be facilitated by a decrease in local inhibition via modulation of the neurotransmitter GABA, but this link has not been conclusively demonstrated in humans. Here, we used 7 T magnetic resonance spectroscopy to investigate the dynamics of GABA concentrations in human M1 during the learning of an explicit, serial reaction time task. We observed a significant reduction in GABA concentration during motor learning that was not seen in an equivalent motor task lacking a learnable sequence, nor during a passive resting task of the same duration. No change in glutamate was observed in any group. Furthermore, M1 GABA measured early in task performance was strongly correlated with the degree of subsequent learning, such that greater inhibition was associated with poorer subsequent learning. This result suggests that higher levels of cortical inhibition may present a barrier that must be surmounted in order to achieve an increase in M1 excitability, and hence encoding of a new motor skill. These results provide strong support for the mechanistic role of GABAergic inhibition in motor plasticity, raising questions regarding the link between population variability in motor learning and GABA metabolism in the brain.

Methodological consensus on clinical proton MRS of the brain: Review and recommendations.

Proton MRS (1 H MRS) provides noninvasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Although most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges toward obtaining reliable good-quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the PRESS localization sequence was found to be unacceptably high at 3 T, and use of the semi-adiabatic localization by adiabatic selective refocusing sequence is a recommended solution. Incorporation of simulated metabolite basis sets into analysis routines is recommended for reliably capturing the full spectral detail available from short TE acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B0 ) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. Implementation of these recommendations should strengthen current clinical applications and advance progress toward developing and validating new MRS biomarkers for clinical use.