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Introduction: Regular aerobic exercise is associated with improved cognitive function, implicating it as a strategy to reduce dementia risk. This is reinforced by the association between greater cardiorespiratory fitness and larger brain volume, superior cognitive performance and lower dementia risk. However, the optimal aerobic exercise dose, namely the intensity and mode of delivery, to improve brain health and lower dementia risk has received less attention. We aim to determine the effect of different doses of aerobic exercise training on markers of brain health in sedentary middle-aged adults, hypothesising that high-intensity interval training (HIIT) will be more beneficial than moderate-intensity continuous training (MICT)., Methods and Analysis: In this two-group parallel, open-label blinded endpoint randomised trial, 70 sedentary middle-aged (45-65 years) adults will be randomly allocated to one of two 12-week aerobic exercise training interventions matched for total exercise training volume: (1) MICT (n=35) or HIIT (n=35). Participants will perform ~50 min exercise training sessions, 3 days per week, for 12 weeks. The primary outcome will be measured as between-group difference in cardiorespiratory fitness (peak oxygen uptake) change from baseline to the end of training. Secondary outcomes include between-group differences in cognitive function and ultra-high field MRI (7T) measured markers of brain health (brain blood flow, cerebrovascular function, brain volume, white matter microstructural integrity and resting state functional brain activity) changes from baseline to the end of training., Ethics and Dissemination: The Victoria University Human Research Ethics Committee (VUHREC) has approved this study (HRE20178), and all protocol modifications will be communicated to the relevant parties (eg, VUHREC, trial registry). Findings from this study will be disseminated via peer-review publications, conference presentations, clinical communications and both mainstream and social media., Trial Registration Number: ANZCTR12621000144819., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Visual snow syndrome (VSS) is a neurological disorder characterized by a range of continuous visual disturbances. Little is known about the functional pathological mechanisms underlying VSS and their effect on brain network topology, studied using high-resolution resting-state (RS) 7 T MRI. Forty VSS patients and 60 healthy controls underwent RS MRI. Functional connectivity matrices were calculated, and global efficiency (network integration), modularity (network segregation), local efficiency (LE, connectedness neighbors) and eigenvector centrality (significance node in network) were derived using a dynamic approach (temporal fluctuations during acquisition). Network measures were compared between groups, with regions of significant difference correlated with known aberrant ocular motor VSS metrics (shortened latencies and higher number of inhibitory errors) in VSS patients. Lastly, nodal co-modularity, a binary measure of node pairs belonging to the same module, was studied. VSS patients had lower modularity, supramarginal centrality and LE dynamics of multiple (sub)cortical regions, centered around occipital and parietal lobules. In VSS patients, lateral occipital cortex LE dynamics correlated positively with shortened prosaccade latencies (p = .041, r = .353). In VSS patients, occipital, parietal, and motor nodes belonged more often to the same module and demonstrated lower nodal co-modularity with temporal and frontal regions. This study revealed reduced dynamic variation in modularity and local efficiency strength in the VSS brain, suggesting that brain network dynamics are less variable in terms of segregation and local clustering. Further investigation of these changes could inform our understanding of the pathogenesis of the disorder and potentially lead to treatment strategies., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Visual snow syndrome is a neurological condition characterized by continuous visual disturbance and a range of non-visual symptoms, including tinnitus and migraine. Little is known about the pathological mechanisms underlying visual snow syndrome. Here, we assessed brain morphometry and microstructure in visual snow syndrome patients using high-resolution structural and quantitative MRI. Forty visual snow syndrome patients (22 with migraine) and 43 controls underwent 7-Tesla MRI (MP2RAGE, 0.75 mm isotropic resolution). Volumetric and quantitative T1 values were extracted for white and grey matter regions and compared between groups. Where regions were significantly different between groups (false discovery rate corrected for multiple comparisons), post hoc comparisons were examined between patients with and without migraine. For visual snow syndrome patients, significant MRI variables were correlated with clinical severity (number of visual symptoms, perceived visual snow intensity, disruptiveness, fatigue and quality of life) and psychiatric symptoms prevalent in visual snow syndrome (depression, anxiety and depersonalization). Finally, cortical regions and individual thalamic nuclei were studied. Compared with controls, visual snow syndrome patients demonstrated a trend towards larger brain and white matter volumes and significantly lower T1 values for the entire cortex ( P  < 0.001), thalamus ( P  = 0.001) and pallidum ( P  = 0.001). For the patient group, thalamic T1 correlated with number of visual symptoms ( P  = 0.019, r  = 0.390) and perceived disruptiveness of visual snow ( P  = 0.010, r  = 0.424). These correlations did not survive multiple comparison corrections. As for specificity in visual snow syndrome group, T1 changes were most evident in caudal regions (occipital cortices) followed by parietal, temporal and prefrontal cortices. T1 values differed between groups for most individual thalamic nuclei. No differences were revealed between patients with and without migraine. In visual snow syndrome patients, we observed no changes in morphometry, instead widespread changes in grey matter microstructure, which followed a caudal-rostral pattern and affected the occipital cortices most profoundly. Migraine did not appear to independently affect these changes. Lower T1 values may potentially result from higher neurite density, myelination or increased iron levels in the visual snow syndrome brain. Further investigation of these changes may enhance our understanding of the pathogenesis of visual snow syndrome, ultimately leading to new treatment strategies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Great attention is being paid to solving, or mitigating, the technical problems associated with MRI at ultrahigh field strengths of 7 T and higher. This paper explores the use of the semiadiabatic spin-echo (SA-SE) pulse sequence, which uses semiadiabatic radiofrequency (RF) pulses to remove and/or mitigate the effects of the nonuniform B 1 excitation field and B 0 inhomogeneity associated with the electromagnetic properties of the human brain. A semiadiabatic RF pulse version of the recently published serial transmit excitation pulse (STEP) RF pulse sequence is also presented that now incorporates semiadiabatic pulses, henceforth is called SA-STEP. As demonstrated by computer simulation, and confirmed using head imaging, both techniques can produce multislice SE MR imaging at 7 T. These new methods use relatively low RF power and achieve good coverage of the human brain in a single scan., (© 2021 John Wiley & Sons, Ltd.)

Objective: This study aimed to determine whether the visual response to flickering checkerboard patterns measured using electroencephalography (EEG) relate to excitatory or inhibitory metabolite levels measured using ultra-high (7Tesla/7T) magnetic resonance spectroscopy (MRS)., Background: Electrophysiological studies have shown altered visual cortical response amplitudes and contrast gain responses to high contrast flickering patterns in people with migraine. These contrast response anomalies have been argued to represent an imbalance between cortical inhibition and excitation, however the specific mechanism has not been elucidated., Methods: MRS-measured metabolite levels were obtained from the occipital cortex of 18 participants with migraine and 18 non-headache controls. EEG contrast gain response functions were collected on separate days from a subset of 10 participants with migraine and 12 non-headache controls. Case-control outcome measures were statistically compared between groups both before and after checkboard exposure., Results: No significant difference in GABA and glutamate levels were found between groups nor checkerboard timepoint. Glucose levels were significantly reduced after checkerboard exposure in both participant groups. There was no metabolic signature in visual cortex in response to high-contrast flickering checkboards that distinguished those with migraine and without. There was also no correlation between MRS and EEG measurements in response to the flickering checkerboard., Conclusion: Our findings suggest that the mechanisms driving contrast-flickering stimulus aversion are not simplistically reflected by gross changes in metabolic activity in the primary visual cortex., Competing Interests: The authors have declared that no competing interests exist.

Pain perception can be powerfully influenced by an individual's expectations and beliefs. Although the cortical circuitry responsible for pain modulation has been thoroughly investigated, the brainstem pathways involved in the modulatory phenomena of placebo analgesia and nocebo hyperalgesia remain to be directly addressed. This study used ultra-high-field 7 tesla functional MRI (fMRI) to accurately resolve differences in brainstem circuitry present during the generation of placebo analgesia and nocebo hyperalgesia in healthy human participants ( N = 25, 12 male). Over 2 successive days, through blinded application of altered thermal stimuli, participants were deceptively conditioned to believe that two inert creams labeled lidocaine (placebo) and capsaicin (nocebo) were acting to modulate their pain relative to a third Vaseline (control) cream. In a subsequent test phase, fMRI image sets were collected while participants were given identical noxious stimuli to all three cream sites. Pain intensity ratings were collected and placebo and nocebo responses determined. Brainstem-specific fMRI analysis revealed altered activity in key pain modulatory nuclei, including a disparate recruitment of the periaqueductal gray (PAG)-rostral ventromedial medulla (RVM) pathway when both greater placebo and nocebo effects were observed. Additionally, we found that placebo and nocebo responses differentially activated the parabrachial nucleus but overlapped in engagement of the substantia nigra and locus coeruleus. These data reveal that placebo and nocebo effects are generated through differential engagement of the PAG-RVM pathway, which in concert with other brainstem sites likely influences the experience of pain by modulating activity at the level of the dorsal horn. SIGNIFICANCE STATEMENT Understanding endogenous pain modulatory mechanisms would support development of effective clinical treatment strategies for both acute and chronic pain. Specific brainstem nuclei have long been known to play a central role in nociceptive modulation; however, because of the small size and complex organization of the nuclei, previous neuroimaging efforts have been limited in directly identifying how these subcortical networks interact during the development of antinociceptive and pro-nociceptive effects. We used ultra-high-field fMRI to resolve brainstem structures and measure signal change during placebo analgesia and nocebo hyperalgesia. We define overlapping and disparate brainstem circuitry responsible for altering pain perception. These findings extend our understanding of the detailed organization and function of discrete brainstem nuclei involved in pain processing and modulation., (Copyright © 2021 the authors.)

Upper and lower limb impairments are common in people with multiple sclerosis (pwMS), yet difficult to clinically identify in early stages of disease progression. Tasks involving complex motor control can potentially reveal more subtle deficits in early stages, and can be performed during functional MRI (fMRI) acquisition, to investigate underlying neural mechanisms, providing markers for early motor progression. We investigated brain activation during visually guided force matching of hand or foot in 28 minimally disabled pwMS (Expanded Disability Status Scale (EDSS) < 4 and pyramidal and cerebellar Kurtzke Functional Systems Scores ≤ 2) and 17 healthy controls (HC) using ultra-high field 7-Tesla fMRI, allowing us to visualise sensorimotor network activity in high detail. Task activations and performance (tracking lag and error) were compared between groups, and correlations were performed. PwMS showed delayed (+124 s, p = .002) and more erroneous (+0.15 N, p = .001) lower limb tracking, together with lower cerebellar, occipital and superior parietal cortical activation compared to HC. Lower activity within these regions correlated with worse EDSS (p = .034), lower force error (p = .006) and higher lesion load (p < .05). Despite no differences in upper limb task performance, pwMS displayed lower inferior occipital cortical activation. These results demonstrate that ultra-high field fMRI during complex hand and foot tracking can identify subtle impairments in lower limb movements and upper and lower limb brain activity, and differentiates upper and lower limb impairments in minimally disabled pwMS., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Introduction: Stroke is a common cause of epilepsy that may be mediated via glutamate dysregulation. There is currently no evidence to support the use of antiseizure medications as primary prevention against poststroke epilepsy. Perampanel has a unique antiglutamatergic mechanism of action and may have antiepileptogenic properties. This study aims to evaluate the efficacy and safety of perampanel as an antiepileptogenic treatment in patients at high risk of poststroke epilepsy., Methods and Analysis: Up to 328 patients with cortical ischaemic stroke or lobar haemorrhage will be enrolled, and receive their first treatment within 7 days of stroke onset. Patients will be randomised (1:1) to receive perampanel (titrated to 6 mg daily over 4 weeks) or matching placebo, stratified by stroke subtype (ischaemic or haemorrhagic). Treatment will be continued for 12 weeks after titration. 7T MRI will be performed at baseline for quantification of cerebral glutamate by magnetic resonance spectroscopy and glutamate chemical exchange saturation transfer imaging. Blood will be collected for measurement of plasma glutamate levels. Participants will be followed up for 52 weeks after randomisation.The primary study outcome will be the proportion of participants in each group free of late (more than 7 days after stroke onset) poststroke seizures by the end of the 12-month study period, analysed by Fisher's exact test. Secondary outcomes will include time to first seizure, time to treatment withdrawal and 3-month modified Rankin Scale score. Quality of life, cognitive function, mood and adverse events will be assessed by standardised questionnaires. Exploratory outcomes will include correlation between cerebral and plasma glutamate concentration and stroke and seizure outcomes., Ethics and Dissemination: This study was approved by the Alfred Health Human Research Ethics Committee (HREC No 44366, Reference 287/18)., Trial Registration Number: ACTRN12618001984280; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Quantitative susceptibility mapping (QSM) is a novel MR technique that allows mapping of tissue susceptibility values from MR phase images. QSM is an ill-conditioned inverse problem, and although several methods have been proposed in the field, in the presence of a wide range of susceptibility sources, streaking artifacts appear around high susceptibility regions and contaminate the whole QSM map. QSMART is a post-processing pipeline that uses two-stage parallel inversion to reduce the streaking artifacts and remove banding artifact at the cortical surface and around the vasculature., Method: Tissue and vein susceptibility values were separately estimated by generating a mask of vasculature driven from the magnitude data using a Frangi filter. Spatially dependent filtering was used for the background field removal step and the two susceptibility estimates were combined in the final QSM map. QSMART was compared to RESHARP/iLSQR and V-SHARP/iLSQR inversion in a numerical phantom, 7T in vivo single and multiple-orientation scans, 9.4T ex vivo mouse data, and 4.7T in vivo rat brain with induced focal ischemia., Results: Spatially dependent filtering showed better suppression of phase artifacts near cortex compared to RESHARP and V-SHARP, while preserving voxels located within regions of interest without brain edge erosion. QSMART showed successful reduction of streaking artifacts as well as improved contrast between different brain tissues compared to the QSM maps obtained by RESHARP/iLSQR and V-SHARP/iLSQR., Conclusion: QSMART can reduce QSM artifacts to enable more robust estimation of susceptibility values in vivo and ex vivo., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Multiple sclerosis is a neuroinflammatory disease of the CNS that is associated with significant irreversible neuro-axonal loss, leading to permanent disability. There is thus an urgent need for in vivo markers of axonal loss for use in patient monitoring or as end-points for trials of neuroprotective agents. Advanced diffusion MRI can provide markers of diffuse loss of axonal fibre density or atrophy within specific white matter pathways. These markers can be interrogated in specific white matter tracts that underpin important functional domains such as sensorimotor function. This study aimed to evaluate advanced diffusion MRI markers of axonal loss within the major sensorimotor tracts of the brain, and to correlate the degree of axonal loss in these tracts to precise kinematic measures of hand and foot motor control and gait in minimally disabled people with multiple sclerosis. Twenty-eight patients (Expanded Disability Status Scale < 4, and Kurtzke Functional System Scores for pyramidal and cerebellar function ≤ 2) and 18 healthy subjects underwent ultra-high field 7 Tesla diffusion MRI for calculation of fibre-specific measures of axonal loss (fibre density, reflecting diffuse axonal loss and fibre cross-section reflecting tract atrophy) within three tracts: cortico-spinal tract, interhemispheric sensorimotor tract and cerebello-thalamic tracts. A visually guided force-matching task involving either the hand or foot was used to assess visuomotor control, and three-dimensional marker-based video tracking was used to assess gait. Fibre-specific axonal markers for each tract were compared between groups and correlated with visuomotor task performance (force error and lag) and gait parameters (stance, stride length, step width, single and double support) in patients. Patients displayed significant regional loss of fibre cross-section with minimal loss of fibre density in all tracts of interest compared to healthy subjects (family-wise error corrected p -value < 0.05), despite relatively few focal lesions within these tracts. In patients, reduced axonal fibre density and cross-section within the corticospinal tracts and interhemispheric sensorimotor tracts were associated with larger force tracking error and gait impairments (shorter stance, smaller step width and longer double support) (family-wise error corrected p -value < 0.05). In conclusion, significant gait and motor control impairments can be detected in minimally disabled people with multiple sclerosis that correlated with axonal loss in major sensorimotor pathways of the brain. Given that axonal loss is irreversible, the combined use of advanced imaging and kinematic markers could be used to identify patients at risk of more severe motor impairments as they emerge for more aggressive therapeutic interventions., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Quantitative susceptibility mapping (QSM) provides a valuable MRI contrast mechanism that has demonstrated broad clinical applications. However, the image reconstruction of QSM is challenging due to its ill-posed dipole inversion process. In this study, a new deep learning method for QSM reconstruction, namely xQSM, was designed by introducing noise regularization and modified octave convolutional layers into a U-net backbone and trained with synthetic and in vivo datasets, respectively. The xQSM method was compared with two recent deep learning (QSMnet + and DeepQSM) and two conventional dipole inversion (MEDI and iLSQR) methods, using both digital simulations and in vivo experiments. Reconstruction error metrics, including peak signal-to-noise ratio, structural similarity, normalized root mean squared error and deep gray matter susceptibility measurements, were evaluated for comparison of the different methods. The results showed that the proposed xQSM network trained with in vivo datasets achieved the best reconstructions of all the deep learning methods. In particular, it led to, on average, 32.3%, 25.4% and 11.7% improvement in the accuracy of globus pallidus susceptibility estimation for digital simulations and 39.3%, 21.8% and 6.3% improvements for in vivo acquisitions compared with DeepQSM, QSMnet + and iLSQR, respectively. It also exhibited the highest linearity against different susceptibility intensity scales and demonstrated the most robust generalization capability to various spatial resolutions of all the deep learning methods. In addition, the xQSM method also substantially shortened the reconstruction time from minutes using MEDI to only a few seconds., (© 2020 John Wiley & Sons, Ltd.)

Purpose: We aimed to image the optic nerve, subarachnoid space and optic nerve sheath in emmetropes and myopes ultra-high field (7-Tesla) magnetic resonance imaging (MRI). We targeted the retrobulbar distance of approximately 3 mm behind the eyeball, an area of clinical interest because of optic nerve sheath distensibility and pressure-related enlargement., Methods: Eleven emmetropes (+0.75 to -0.50D, aged 20-41 years) and 10 myopes (-4.5 to -12D, aged 21-37 years) participated. Cross-sectional area of the optic nerve, subarachnoid space and optic nerve sheath at approximately 3 mm behind the eye were measured from two-dimensional T2-weighted coronal oblique MRI images obtained through the left optic nerve. Axial length of the left eye was measured from T2-weighted axial MRI images. In nine emmetropes and seven myopes, the optic nerve head was imaged with optical coherence tomography to compare retrobulbar and intraocular measures., Results: Retrobulbar optic nerve, subarachnoid space and optic nerve sheath dimensions differed between myopes and emmetropes. Myopes tended to have smaller optic nerve and subarachnoid space. Longer MRI-derived axial length was associated with smaller optic nerve area (P = 0.03). Bruch's membrane opening area did not predict retrobulbar optic nerve area (P = 0.48)., Conclusions: This study demonstrates the feasibility of using 7-Tesla MRI to measure optic nerve, subarachnoid space, and optic nerve sheath dimensions behind the eye. In healthy adults, the retrobulbar optic nerve and subarachnoid space size are influenced by the degree of myopia., Translational Relevance: ultra-high field MRI is a practical tool for assessing the morphometry of the optic nerve and surrounding anatomy behind the eye.

Ultra-high field MRI offers many opportunities to expand the applications of MRI. In order for this to be realized, the technical problems associated with MRI at field strengths of 7 T and greater need to be solved or mitigated. This paper explores the use of new variations of composite RF pulses, named serial transmit excitation pulses (STEP), in contrast to parallel pulse techniques, in order to remove and/or mitigate the effects of non-uniform B 1 excitation fields associated with the subject (eg the human brain). Several techniques based on STEP sequences are introduced and their application to human brain imaging is presented and evaluated., (© 2020 John Wiley & Sons, Ltd.)

23 Na provides the second strongest MR-observable signal in biological tissue and exhibits bi-exponential T 2 ∗ relaxation in micro-environments such as the brain. There is significant interest in developing 23 Na biomarkers for neurological diseases that are associated with sodium channel dysfunction such as multiple sclerosis and epilepsy. We have previously reported methods for acquisition of multi-echo sodium MRI and continuous distribution modelling of sodium relaxation properties as surrogate markers of brain microstructure. This study aimed to compare 23 Na T 2 ∗ relaxation times to more established measures of tissue microstructure derived from advanced diffusion MRI at 7 ​T. Six healthy volunteers were scanned using a 3D multi-echo radial ultra-short TE sequence using a dual-tuned 1 H/ 23 Na birdcage coil, and a high-resolution multi-shell, high angular resolution diffusion imaging sequence using a 32-channel 1 H receive coil. 23 Na T 2 ∗ relaxation parameters [mean T 2 ∗ (T 2 ∗ mean ) and fast relaxation fraction (T 2 ∗ ff )] were calculated from a voxel-wise continuous gamma distribution signal model. White matter (restricted anisotropic diffusion) and grey matter (restricted isotropic diffusion) density were calculated from multi-shell multi-tissue constrained spherical deconvolution. Sodium parameters were compared with white and grey matter diffusion properties. Sodium T 2 ∗ mean and T 2 ∗ ff showed little variation across a range of white matter axonal fibre and grey matter densities. We conclude that sodium T 2 ∗ relaxation parameters are not greatly influenced by relative differences in intra- and extracellular partial volumes. We suggest that care be taken when interpreting sodium relaxation changes in terms of tissue microstructure in healthy tissue., Competing Interests: Declaration of competing interest The authors report no conflicts of interest relating to this work., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To demonstrate simultaneous T 1 -weighted imaging, T 1 mapping, R 2 ∗ mapping, SWI, and QSM from a single multi-echo (ME) MP2RAGE acquisition., Methods: A single-echo (SE) MP2RAGE sequence at 7 tesla was extended to ME with 4 bipolar gradient echo readouts. T 1 -weighted images and T 1 maps calculated from individual echoes were combined using sum of squares and averaged, respectively. ME-combined SWI and associated minimum intensity projection images were generated with TE-adjusted homodyne filters. A QSM reconstruction pipeline was used, including a phase-offsets correction and coil combination method to properly combine the phase images from the 32 receiver channels. Measurements of susceptibility, R 2 ∗ , and T 1 of brain tissue from ME-MP2RAGE were compared with those from standard ME-gradient echo and SE-MP2RAGE., Results: The ME combined T 1 -weighted, T 1 map, SWI, and minimum intensity projection images showed increased SNRs compared to the SE results. The proposed coil combination method led to QSM results free of phase-singularity artifacts, which were present in the standard adaptive combination method. T 1 -weighted, T 1 , and susceptibility maps from ME-MP2RAGE were comparable to those obtained from SE-MP2RAGE and ME-gradient echo, whereas R 2 ∗ maps showed increased blurring and reduced SNR. T 1 , R 2 ∗ , and susceptibility values of brain tissue from ME-MP2RAGE were consistent with those from SE-MP2RAGE and ME-gradient echo., Conclusion: High-resolution structural T 1 weighted imaging, T 1 mapping, R 2 ∗ mapping, SWI, and QSM can be extracted from a single 8.5-min ME-MP2RAGE acquisition using a customized reconstruction pipeline. This method can be applied to replace separate SE-MP2RAGE and ME-gradient echo acquisitions to significantly shorten total scan time., (© 2019 International Society for Magnetic Resonance in Medicine.)

Introduction: Diffuse gliomas are incurable malignancies, which undergo inevitable progression and are associated with seizure in 50-90% of cases. Glutamate has the potential to be an important glioma biomarker of survival and local epileptogenicity if it can be accurately quantified noninvasively., Methods: We applied the glutamate-weighted imaging method GluCEST (glutamate chemical exchange saturation transfer) and single voxel MRS (magnetic resonance spectroscopy) at 7 Telsa (7 T) to patients with gliomas. GluCEST contrast and MRS metabolite concentrations were quantified within the tumour region and peritumoural rim. Clinical variables of tumour aggressiveness (prior adjuvant therapy and previous radiological progression) and epilepsy (any prior seizures, seizure in last month and drug refractory epilepsy) were correlated with respective glutamate concentrations. Images were separated into post-hoc determined patterns and clinical variables were compared across patterns., Results: Ten adult patients with a histo-molecular (n = 9) or radiological (n = 1) diagnosis of grade II-III diffuse glioma were recruited, 40.3 +/- 12.3 years. Increased tumour GluCEST contrast was associated with prior adjuvant therapy (p = .001), and increased peritumoural GluCEST contrast was associated with both recent seizures (p = .038) and drug refractory epilepsy (p = .029). We distinguished two unique GluCEST contrast patterns with distinct clinical and radiological features. MRS glutamate correlated with GluCEST contrast within the peritumoural voxel (R = 0.89, p = .003) and a positive trend existed in the tumour voxel (R = 0.65, p = .113)., Conclusion: This study supports the role of glutamate in diffuse glioma biology. It further implicates elevated peritumoural glutamate in epileptogenesis and altered tumour glutamate homeostasis in glioma aggressiveness. Given the ability to non-invasively visualise and quantify glutamate, our findings raise the prospect of 7 T GluCEST selecting patients for individualised therapies directed at the glutamate pathway. Larger studies with prospective follow-up are required., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)