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Clarke, W. T.

Publications and source records attributed to Clarke, W. T..

At least 19 recordsLinked to original sources

A Framework for SPICE MRSI Reconstruction Posterior Uncertainty Quantification

Purpose: Low-rank reconstruction methods such as SPICE substantially improve Magnetic Resonance Spectroscopic Imaging (MRSI) reconstruction quality. However, SPICE does not provide an estimate of reconstruction uncertainty. A framework for posterior uncertainty estimation in SPICE reconstruction is proposed, hereafter referred to as the framework. Theory and Methods: A Laplace approximation is used to estimate the covariance of the reconstructed spatial coefficients. This covariance is propagated through the spectral basis and spectral fitting to obtain metabolite concentration uncertainty. Matrix-free Hessian--vector products and voxel-wise conjugate-gradient estimation are used to avoid explicit construction or inversion of the full Hessian, making the method tractable. Results: Validation using repeated in vivo 7 T MRSI acquisitions showed that the estimated posterior uncertainty exhibited spatial and spectral patterns similar to those of empirical repeated-scan uncertainty. Experiments further demonstrated how spatial regularization and k-space undersampling affect the estimated uncertainty. Conclusion: The framework provides a practical framework for uncertainty quantification when using SPICE reconstruction of MRSI. It could be adapted to other regularised low-rank reconstruction methods.

neuroscience↗

Longitudinal neurochemical profiling after experimental stroke using edited MR spectroscopy

Background: Alterations in excitatory and inhibitory neurotransmission contribute to stroke pathology and recovery, yet longitudinal assessment of these changes in vivo remains limited. We investigated the feasibility of longitudinal edited proton magnetic resonance spectroscopy (1H-MRS) to quantify {gamma}-aminobutyric acid (GABA) and glutamate following experimental focal cerebral ischaemia. Methods: Male rats underwent endothelin-1-induced striatal ischaemia or sham surgery. Longitudinal edited 1H-MRS was performed at baseline and 2-, 7- and 30-days post-stroke at 7-tesla with a MEGA-sLASER sequence. A voxel was positioned within the ipsilesional motor cortex adjacent to the lesion. Behavioural outcomes (grip strength, adhesive removal and CatWalk gait analysis) were assessed alongside spectroscopy, and immunohistochemistry for Iba1, GFAP and ICAM-1 was performed at 30 days. Results: Stroke induced a transient reduction in GABA+/tCr within the ipsilesional motor cortex, with significantly lower concentrations than sham animals at 7 days (p<0.05), returning to baseline by 30 days. Glutamate/tCr and GABA/glutamate ratio were unchanged throughout the study. Behavioural deficits were mild, with significant effects on motor outcomes such as grip strength, gait swing speed and paw placement, while sensory areas of the brain seemed largely unaffected. Histological analysis revealed no persistent differences in cortical Iba1, GFAP or ICAM-1 immunoreactivity at 30 days. Conclusions: Longitudinal 1H-MRS is a feasible approach for monitoring dynamic changes in inhibitory neurochemistry following experimental stroke. The transient reduction in peri-lesional GABA, despite minimal behavioural impairment and an absence of persistent cortical inflammation, supports the use of edited spectroscopy as a translational tool to investigate neurochemical mechanisms underlying network dynamics in post-stroke recovery.

neuroscience↗

Breathlessness catastrophising after COVID-19 involves both interoceptive and visceromotor connectivity

Persistent breathlessness is common after COVID-19, yet its severity typically correlates weakly with objective clinical measures. This discordance is often attributed to perceptual inference amplified by anxiety. Because breathing involves a closed perception-action loop, breathlessness may also reflect alterations in interoceptive and visceromotor pathways. We acquired 7-tesla resting-state functional MRI in 53 post-COVID patients with varying breathlessness and estimated functional connectivity across 18 pre-defined interoceptive and visceromotor regions. Linear regression identified two connections associated with breathlessness catastrophising: reduced dorsal periaqueductal grey-posterior insula (dPAG-PoI1) and increased basolateral amygdala-dorsal anterior cingulate (BLA-dACC) connectivity. The dPAG-PoI1 association was stronger in patients who had required mechanical ventilation, whereas the BLA-dACC association was attenuated at higher generalised anxiety. These findings are consistent with two potentially separable contributions to symptom burden: weakened interoceptive signalling between brainstem and sensory cortex, and heightened visceromotor influence of threat processing on autonomic control, rather than anxiety-driven misperception alone.

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Fully automated open-source analysis and interactive visualization of magnetic resonance spectroscopic imaging (MRSI) data in Osprey-MRSI

Purpose: Magnetic resonance spectroscopic imaging (MRSI) is a versatile technique to investigate the spatial distribution of in vivo metabolism. However, processing MRSI data is demanding, and only a few software packages support end-to-end analysis. The goal of this study was to implement fully automated, end-to-end MRSI analysis into the open-source 'Osprey-MRSI' software package. Methods: MRSI-specific analysis and visualization capabilities were implemented, building on the existing Osprey workflow. Modifications included spatial transformation and filtering operations, automated brain masking and tissue segmentation of the MRSI data, improved lipid filtering, rapid integral maps, linear-combination modeling with explicit B0 frequency-shift correction, and generation of quality-control maps and metabolic images. A fully interactive GUI and semi-interactive HTML reports provide a user-friendly way to inspect each step of the analysis. All analysis derivatives are also exported in NIfTI and NIfTI-MRS format for easy visualization and synergies with other toolboxes and modalities. Results: The automated MRSI workflow was successfully used to analyze short- and medium-TE 3T in vivo MRSI datasets from all major vendors (Philips, GE, Siemens) across multiple sites. Correct coregistration of MRSI data and MR images was validated using phantom data from each vendor and existing MRSI processing tools. Conclusion: Osprey-MRSI offers state-of-the-art methods with minimal user interaction available for non-expert users. The modularity of the workflow and the modeling algorithm will foster innovation and development of novel MRSI-specific analysis methods.

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Age-related differences in neurometabolite concentrations during early infancy: A cross-sectional analysis of the HBCD Release 1.0

Background: Developmental trajectories of low-concentration neurometabolites such as the neurotransmitter {gamma}-aminobutyric acid (GABA), and the antioxidants glutathione (GSH) and ascorbate (Asc) across early infancy remain unexplored. Advances in spectral editing enabled the measurement of these key molecules together with high-concentration metabolites like N-acetylaspartate (NAA) and glutamate (Glu) in the HEALthy Brain and Child Development (HBCD) study, the largest longitudinal study of early brain development in the United States. Purpose: To determine the age-associated trajectories of 14 key neurometabolites during early infancy from a cross-sectional 1H-MRS dataset. Materials and Methods: HBCD utilizes ISTHMUS, an integrated MRS sequence that includes both an unedited short-echo-time PRESS acquisition and an advanced 4-step Hadamard-encoded sequence, HERCULES to enable measurement of both high- and low-concentration metabolites. Metabolite quantification was carried out by the HBCD Data Coordinating Center (HDCC) using an automated Osprey pipeline, with data from 201 infants ages 0 - 10 weeks adjusted age included in the tabular imaging results in HBCD data release 1.0. After excluding preterm born infants and data with poor linewidth or model quality metric, we tested for linear associations with adjusted age for each metabolite. Results: Concentration estimates of total NAA (tNAA), total creatine (tCr) and glutamate (Glu) as well as the combined sum of glutamate and glutamine (Glx) significantly increased across ages 0 - 10 weeks, while myo-inositol (mI) decreased. GABA and GSH showed age-related trends, but did not reach significance. Levels of the lipid precursor phosphorylethanolamine (PE) and Asc are higher in the first months than established adult values. Conclusion: Multiple metabolites showed significant age-related changes during early infancy. While GABA and GSH did not, future work will establish whether the trends suggested here contribute to linear or non-linear patterns across the first years of life.

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Open-Source Framework for Measurement of the Gradient Impulse Response Function

The Gradient Impulse Response Function (GIRF) is widely used to model and correct gradient system imperfections in MRI, but scanner-specific GIRF measurement remains inaccessible to many research groups because existing approaches rely on specialised field monitoring hardware or fragmented and non-reproducible software workflows. To address this limitation, an open-source, end-to-end framework for phantom-based GIRF measurement is presented, providing a reproducible workflow requiring only standard MRI hardware and a spherical water phantom. The framework integrates vendor-independent pulse sequence generation, phantom-based data acquisition, automated data processing, and GIRF estimation. The framework was validated by comparing GIRF-predicted non-Cartesian k-space trajectories with independent measurements acquired using NMR field probes, which served as the gold-standard for trajectory characterization. Accurate prediction of rosette and spiral trajectories was demonstrated across multiple imaging orientations, with substantially lower trajectory error than the corresponding nominal trajectories. By providing the first openly available end-to-end implementation for phantom-based GIRF measurement, the barrier to routine scanner-specific GIRF characterisation is reduced, facilitating broader adoption of GIRF-based methods across the MRI community.

bioengineering↗

A hippocampal neuroimaging signature of neurovascular insulin signalling links metabolism to mood

Depression is a leading cause of global disability and is increasingly linked to systemic metabolic dysfunctions, including insulin resistance. However, the biological pathways connecting metabolic state to affective symptoms are unresolved. A growing body of evidence indicates that insulin, beyond its role in systemic glucose homeostasis, supports brain metabolism, synaptic function and cognition, yet its contribution to mood regulation remains unclear. Here, we identify a human hippocampal metabolic signature associated with glycaemic variation in individuals with depression. Using multimodal neuroimaging, we show that hippocampal concentrations of GABA and lactate correlate with HbA1c and with mood severity, while functional connectivity between the hippocampus and the default mode network tracks affective symptoms independently of adiposity. To causally probe these relationships, we generated a mouse model of hippocampus-specific insulin receptor depletion. Unexpectedly, reducing insulin signalling at the blood brain barrier enhanced neuronal metabolism and attenuated anxiety-like behaviour. Notably, hippocampal lactate and GABA levels similarly tracked anxiety-related behaviour in mice, mirroring their association with symptom severity in humans. Together, these findings identify a conserved neurometabolic signature linking hippocampal insulin signalling to affective state, and reveal that brain insulin resistance exerts context- and cell-type-specific effects on behaviour. This work establishes a mechanistic basis for brain insulin resistance in depression and highlights the hippocampus as a critical hub for metabolic modulation of mood.

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Ultrasound-mediated focal serotonin delivery causally modulates motivation in primates

Causal manipulation of neuromodulatory systems has been constrained by a trade-off between spatial precision and translational relevance: circuit-specific techniques are invasive, whereas systemic pharmacology lacks anatomical specificity. Here, we establish ultrasound-mediated neuromodulator delivery as a non-invasive, spatially precise approach for causal neuropharmacology in awake, behaving primates. By transiently opening the blood-brain barrier, we delivered systemically administered serotonin to the perigenual anterior cingulate cortex (pgACC) during a decision-making task. Combining computational modelling with multimodal imaging, pupillometry and histology, we show that elevating pgACC serotonin altered local neural activity and weakened the influence of reward environment on motivational state while leaving sensitivity to immediate reward opportunities intact. This was accompanied by reduced functional coupling, decreased local glutamatergic metabolite signal and increased serotonergic signal at the target, with repeated delivery well tolerated. Together, these findings establish a translatable platform for focal neuropharmacology and identify pgACC serotonin as a regulator of context-dependent motivation.

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Non-invasive measurement of neurotransmitter-specific glucose metabolism in the human brain using proton-observed proton-edited 13C-MRS (POPE13C-MRS)

Non-invasive measurement of neurotransmitter-specific glucose metabolism in the human brain remains a major challenge, limiting mechanistic insight into excitatory-inhibitory imbalance across neurological and psychiatric disorders. Existing approaches either lack neurotransmitter specificity or require specialised hardware that constrains clinical applicability. Here, we introduce proton-observed proton-edited 13C magnetic resonance spectroscopy (POPE13C-MRS), an approach that enables non-invasive detection of glutamate, GABA, and lactate metabolism using standard proton MRI hardware. The method combines administration of 13C-labelled glucose with targeted proton editing to detect 1H-13C satellite resonances. Using a cross-species proof-of-concept approach, we demonstrate consistent detection of neurotransmitter-specific 13C labelling in mice and feasibility in the human brain at ultra-high field. POPE13C-MRS provides a readout of glutamatergic and GABAergic metabolism, enabling in vivo assessment of excitatory-inhibitory metabolic balance. This establishes a means for probing neurometabolic coupling with potential applications in translational and clinical neuroscience.

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The Impact of BOLD Induced Linewidth Modulation on Functional 1H MRS Analysis

Functional MRS can measure the neurometabolic response to neuronal activation, therapeutic interventions and changes in physiology. Substantial technical challenges currently present a barrier to reproducible findings and broader adoption by the neuroscientific community. One such challenge is the conflation between genuine metabolic changes and bias caused by subtle spectral lineshape changes associated with the BOLD response. Previous studies have demonstrated an approximately 1% bias for glutamate estimates at 7T based on experimentally acquired data and a single conventional fitting algorithm. In this study, we use synthetic MRS data to estimate the bias for two conventional fitting methods (LCModel and ABfit-reg) at 3T and 7T and evaluate the efficacy of dynamic lineshape adjustment, during preprocessing and fitting analysis stages, to reduce bias. Using the same dataset, we also explore the potential bias in 2D fitting approaches, comparing several fitting models implemented in FSL-MRS. Bias between two conventional fitting methods without explicit linewidth correction was similar ([~]1% for glutamate) and in good agreement with previous experimental studies at 7T. Lineshape changes from the BOLD response cause similar bias in conventional and 2D fitting packages for 3T and 7T data, resulting in an overestimation of metabolic changes associated with neuronal activation. This bias may be significantly reduced (<0.2%) by incorporating a BOLD linewidth matching step for conventional analysis or by direct modelling for 2D analysis. We therefore recommend explicit BOLD lineshape correction or modelling for future task-based fMRS studies at 3T and above.

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MR Spectroscopy without Water Suppression using the Gradient Impulse Response Function

PurposeNon-water-suppressed proton spectroscopy, 1H-MRS, is desirable, as retaining the strong water resonance can facilitate automated online data corrections, internal concentration referencing, and monitoring of line narrowing effects in functional MRS. Removal of the water suppression module can also mitigate magnetization transfer effects and slightly reduce the minimum achievable TR and total RF power deposition. However, water suppression is typically considered essential due to eddy current-induced antisymmetric sidebands on the water resonance that distort the spectral baseline and obscure metabolite signals. Theory and MethodsThe Gradient Impulse Response Function (GIRF) was used to predict time-dependent magnetic field perturbations during the FID that generate the artefactual sidebands. The GIRF was measured in a one-time calibration, independent of spectroscopy acquisitions, enabling post-processing correction of the sidebands without sequence modification or additional dedicated hardware. GIRF-corrected non-water-suppressed single-voxel-spectroscopy (SVS) was compared to otherwise identical water-suppressed acquisitions in eight participants at 3T using semi-LASER and MEGA-PRESS sequences. ResultsAcross participants, GIRF correction reduced sideband amplitudes to levels comparable with the spectral baseline, enabling recovery of the underlying metabolite signals. Systematic increases in quantified metabolite concentrations were observed relative to water-suppressed acquisitions, consistent with water-suppression-induced magnetization transfer effects. Total creatine exhibited the largest increase, with enhancement ratios of 1.069{+/-}0.039 for MEGA-PRESS and 1.535{+/-}0.160 for semi-LASER acquisitions. ConclusionGradient-induced artefactual sidebands in non-water-suppressed MR spectroscopy can be effectively corrected using the GIRF to predict time-dependent magnetic field perturbations during the FID. In principle, the approach extends to other SVS sequences and field strengths following appropriate GIRF calibration.

bioengineering↗

Low-intensity focused ultrasound to human amygdala reveals a causal role in ambiguous emotion processing and alters local and network-level activity

The amygdala is a core region changed in depression, a disorder characterized by compromised emotion, motivation and learning processes. However, lesion studies in humans examining amygdala function have largely focused on its role in processing fear. It currently remains unclear what causal role the human amygdala plays in more complex emotion, motivation and learning processes in daily life. This is because it has not been possible to reversibly modulate amygdala activity non-invasively in humans. Here, we used transcranial focused ultrasound stimulation (TUS) to bilaterally perturb neural activity in the basolateral amygdala (BLA). In separate sessions (n = 87), 29 healthy volunteers received offline-TUS to bilateral BLA, mid-insula or sham before playing a novel emotional learning task validated in an independent large cohort online (n = 210). 7T-resting-state and metabolite signals clearly demonstrated target engagement. BLA-TUS reduced the BLAs connectivity fingerprint and decreased its excitation/inhibition balance, suggesting an inhibitory effect of our TUS protocol on BLA activity. In behaviour, BLA-TUS caused a stimulation volume-dependent increase in the tendency to approach neutral, emotionally ambiguous faces, treating them more similarly to happy faces, and a slowing of reaction times for those two emotion categories. These effects were functionally and regionally specific and suggest a causal role for the amygdala in resolving emotional ambiguity. Our results provide important insights for future studies into mood disorders where ambiguous situations might be harder to resolve, which could contribute to existing emotional and learning biases.

neuroscience↗

Baclofen, a GABAB receptor agonist, impairs motor learning in healthy people and changes inhibitory dynamics in motor areas

Inhibition mediated by {gamma}-aminobutyric acid (GABA) is implicated in motor plasticity and learning, with [GABA] in the motor cortex decreasing during motor learning. However, the causal relationship between [GABA] and learning has yet to be determined. Here, we conducted a within-subject, double-blind, placebo-controlled, crossover study to investigate the effect of increased GABAergic inhibition via GABAB-receptor agonist baclofen on motor learning and Magnetic Resonance Spectroscopic Imaging (MRSI) metrics. Increasing GABA-mediated inhibition with baclofen did not change response times, but significantly impaired motor sequence learning. In parallel, we demonstrated a blunting of the expected decrease in [GABA] during motor learning. These results highlight a causal role for GABAergic inhibition in motor learning and may have clinical implications: baclofen is commonly used to treat post brain-injury spasticity, but may impair motor learning during rehabilitation.

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Correlated and Anticorrelated Binocular Disparity Modulate GABA+ and Glutamate/glutamine Concentrations in the Human Visual Cortex

Binocular disparity is used for perception and action in three dimensions. Neurons in the primary visual cortex respond to binocular disparity in random dot patterns, even when the contrast is inverted between eyes (false depth cue). In contrast, neurons in the ventral stream largely cease to respond to false depth cues. This study evaluated whether GABAergic inhibition is involved in suppressing false depth cues in the human ventral visual cortex. We compared GABAergic inhibition (GABA+) and glutamatergic excitation (Glx) during the viewing of correlated and anticorrelated binocular disparity in 18 participants using single voxel proton magnetic-resonance spectroscopy (MRS). Measurements were taken from the early visual cortex (EVC) and the lateral occipital cortex (LO). Three visual conditions were presented per voxel location: correlated binocular disparity; anticorrelated binocular disparity; or a blank grey screen with a fixation cross. To identify differences in neurochemistry, GABA+ or Glx levels were compared across viewing conditions. In EVC, correlated disparity increased Glx over anticorrelated and rest conditions, also mirrored in the Glx/GABA+ ratio. In LO, anticorrelated disparity decreased GABA+ and increased Glx. Joint effects on GABA+ and Glx were summarised by the Glx/GABA+ ratio, which showed increased excitatory over inhibitory drive to anticorrelated disparity in LO. Glx during viewing of anticorrelation in LO was predictive of its object-selective BOLD-activity. We provide evidence that early and ventral visual cortices change GABA+ and Glx concentrations during presentation of correlated and anticorrelated disparity, suggesting a contribution of cortical excitation and inhibition in disparity selectivity. Significance StatementThe visual system must correctly match elements from the left and right eye for proper reconstruction of binocular depth. At the earliest part of binocular processing, false matches can activate depth detectors, however, the activation to false matches is absent in the ventral visual stream. We tested whether GABAergic inhibition contributes to the suppression of false matches in the ventral stream by measuring GABAergic inhibition and glutamatergic excitation in the human visual cortex during the presentation of correct and false matches. Correct matches increased excitation in response in the early visual cortex, and false matches increased excitation and decreased in the ventral visual cortex. These results suggest a role for excitation and inhibition in distinguishing depth cues for stereoscopic vision.

neuroscience↗

Noradrenaline causes a spread of association in the hippocampal cognitive map

The mammalian brain stores relationships between items and events in the world as cognitive maps in the hippocampal system. However, the neural mechanisms that control cognitive map formation remain unclear. Here, using a double-blind study design with a pharmacological intervention in humans, we show that the neuromodulator noradrenaline elicits a significant spread of association across the hippocampal cognitive map. This neural spread of association predicts overgeneralisation errors measured in behaviour, and is predicted by physiological markers for noradrenergic arousal, namely an increase in the pupil dilation response and reduced cortical GABAergic tone. Thus, noradrenaline sets the width of the smoothing kernel for plasticity across the cognitive map. Elevated noradrenaline can allow disparate memories to become linked, introducing potential for distortions in the cognitive map that deviate from direct experience. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=137 HEIGHT=200 SRC="FIGDIR/small/610602v3_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@85d4ceorg.highwire.dtl.DTLVardef@564073org.highwire.dtl.DTLVardef@a16111org.highwire.dtl.DTLVardef@ebe1fc_HPS_FORMAT_FIGEXP M_FIG C_FIG

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7 Tesla MRS estimates of GABA concentration relate to physiological measures of tonic inhibition in the human motor cortex

GABAergic neurotransmission within the cortex plays a key role in learning and is altered in several brain diseases. Quantification of bulk GABA in the human brain is typically obtained by Magnetic Resonance Spectroscopy (MRS). However, the interpretation of MRS-GABA is still debated. A recent mathematical simulation contends that MRS detects extrasynaptic GABA, mediating tonic inhibition. Nevertheless, no empirical data have yet confirmed this hypothesis. Here we collected ultra-high field 7 Tesla MRS and Transcranial Magnetic Stimulation coupled with high-density Electroencephalography (TMS-hdEEG) from the motor cortex of twenty healthy participants (age 23.95{+/-}6.4), while they were at rest. We first applied a Neural Mass Model to TMS-evoked potentials to disentangle the contribution of different GABAergic pools. We then assessed to which of these different pools MRS-GABA was related to by means of Parametric Empirical Bayesian (PEB) analysis. We found that MRS-GABA was mostly positively related to the NMM-derived measures of tonic inhibition and overall functionality of the GABAergic synapse. This relationship was reliable enough to predict MRS-GABA from NMM-GABA. These findings clarify the mesoscopic underpinnings of GABA levels measured by MRS and will contribute to the concretization of MRS-GABA promises to improve our understanding of human behaviour, brain physiology and pathophysiology. Key pointsO_LIGABA neurotransmission is essential for synaptic plasticity and learning (especially motor learning) and is altered in several brain disorders, such as epilepsy and stroke. C_LIO_LIQuantification of GABA in the human brain is typically obtained by Magnetic Resonance Spectroscopy (MRS). However, the interpretation of MRS-GABA is still debated. C_LIO_LIBy using a biophysical Neural Mass Model, here we show that MRS-GABA relates to physiological measures of tonic inhibition in the human cortex. C_LI

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Diffusion MRS tracks distinct trajectories of neuronal development in the cerebellum and thalamus of rat neonates.

It is currently impossible to non-invasively assess cerebellar cell structure during early development. Here we propose a novel approach to non-invasively and longitudinally track cell-specific development using diffusion-weighted magnetic resonance spectroscopy in combination with microstructural modelling. Tracking metabolite diffusion allows us to probe cell-specific developmental trajectories in the cerebellum and thalamus of healthy rat neonates from post-natal day (P) 5 to P30. Additionally, by comparing different analytical and biophysical microstructural models we can follow the differential contribution of cell bodies and neurites during development. The thalamus serves as a control region to assess the sensitivity of our method to microstructural differences between the regions. We found significant differences between cerebellar and thalamic metabolites diffusion properties. For most metabolites, the signal attenuation is stronger in the thalamus, suggesting less restricted diffusion compared to the cerebellum. There is also a trend for lower signal attenuation and lower ADCs with increasing age, suggesting increasing restriction of metabolite diffusion. This is particularly striking for taurine in the thalamus. We use biophysical modelling to interpret these differences. We report a decreased sphere fraction (or an increased neurite fraction) with age for taurine and total creatine in the cerebellum, marking dendritic growth. Surprisingly, we also report a U-shape trend for segment length (the distance between two embranchments in a dendritic tree) in the cerebellum agreeing with age-matching morphometry of openly available 3D-Purkinje reconstructions. Results demonstrate that diffusion-weighted MRS probes early cerebellar neuronal development non-invasively.

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A 7T interleaved fMRS and fMRI study on visual contrast dependency in the human brain.

IntroductionsFunctional magnetic resonance spectroscopy (fMRS) is a non-invasive technique for measuring dynamic changes in neurometabolites. While previous studies have observed concentration changes in metabolites during neural activation, the relationship between neurometabolite response and stimulus intensity and timing requires further investigation. To address this, we conducted an interleaved fMRS and functional magnetic resonance imaging (fMRI) experiment using a visual stimulus with varying contrast levels. MethodsA total of 20 datasets were acquired on a 7T MRI scanner. The visual task consisted of two STIM blocks (30s/20s ON/OFF, four minutes), with 10% or 100% contrast, interleaved with a four minutes REST block. A dynamic fitting approach was used for fMRS data analysis. For metabolite level changes, the STIM conditions were modeled in two different ways: either considering the full STIM block as active condition (full-block model) or only modeling the ON blocks as active condition (sub-block model). For linewidth changes due to the BOLD effect, STIM conditions were modeled using the sub-block model. ResultsFor both models, we observed significant increases in glutamate levels for both the 10% and 100% visual contrasts, but no significant difference between the contrasts. Decreases in aspartate, and glucose, and increases in total N-acetylaspartate and total creatine were also detected, although less consistently across both 10% and 100% visual contrasts. BOLD-driven linewidth decreases and fMRI-derived BOLD increases within the MRS voxel were observed at both 10% and 100% contrasts, with larger changes at 100% compared to 10% in the fMRI-derived BOLD only. We observed a non-linear relation between visual contrast, the BOLD response, and the glutamate response. ConclusionOur study highlights the potential of fMRS as a complementary technique to BOLD fMRI for investigating the complex interplay between visual contrast, neural activity, and neurometabolism. Future studies should further explore the temporal response profiles of different neurometabolites and refine the statistical models used for fMRS analysis.

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