Radiology - Research Publications
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ItemNo Preview AvailableCortico-Striatal Activity Characterizes Human Safety Learning via Pavlovian Conditioned Inhibition(SOC NEUROSCIENCE, 2022-06-22)Safety learning generates associative links between neutral stimuli and the absence of threat, promoting the inhibition of fear and security-seeking behaviors. Precisely how safety learning is mediated at the level of underlying brain systems, particularly in humans, remains unclear. Here, we integrated a novel Pavlovian conditioned inhibition task with ultra-high field (7 Tesla) fMRI to examine the neural basis of safety learning in 49 healthy participants. In our task, participants were conditioned to two safety signals: a conditioned inhibitor that predicted threat omission when paired with a known threat signal (A+/AX-), and a standard safety signal that generally predicted threat omission (BC-). Both safety signals evoked equivalent autonomic and subjective learning responses but diverged strongly in terms of underlying brain activation (PFDR whole-brain corrected). The conditioned inhibitor was characterized by more prominent activation of the dorsal striatum, anterior insular, and dorsolateral PFC compared with the standard safety signal, whereas the latter evoked greater activation of the ventromedial PFC, posterior cingulate, and hippocampus, among other regions. Further analyses of the conditioned inhibitor indicated that its initial learning was characterized by consistent engagement of dorsal striatal, midbrain, thalamic, premotor, and prefrontal subregions. These findings suggest that safety learning via conditioned inhibition involves a distributed cortico-striatal circuitry, separable from broader cortical regions involved with processing standard safety signals (e.g., CS-). This cortico-striatal system could represent a novel neural substrate of safety learning, underlying the initial generation of "stimulus-safety" associations, distinct from wider cortical correlates of safety processing, which facilitate the behavioral outcomes of learning.SIGNIFICANCE STATEMENT Identifying safety is critical for maintaining adaptive levels of anxiety, but the neural mechanisms of human safety learning remain unclear. Using 7 Tesla fMRI, we compared learning-related brain activity for a conditioned inhibitor, which actively predicted threat omission, and a standard safety signal (CS-), which was passively unpaired with threat. The inhibitor engaged an extended circuitry primarily featuring the dorsal striatum, along with thalamic, midbrain, and premotor/PFC regions. The CS- exclusively involved cortical safety-related regions observed in basic safety conditioning, such as the vmPFC. These findings extend current models to include learning-specific mechanisms for encoding stimulus-safety associations, which might be distinguished from expression-related cortical mechanisms. These insights may suggest novel avenues for targeting dysfunctional safety learning in psychopathology.
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ItemIn Vivo 7-Tesla MRI Investigation of Brain Iron and Its Metabolic Correlates in Chronic Schizophrenia(NATURE PORTFOLIO, 2022-10-26)Brain iron is central to dopaminergic neurotransmission, a key component in schizophrenia pathology. Iron can also generate oxidative stress, which is one proposed mechanism for gray matter volume reduction in schizophrenia. The role of brain iron in schizophrenia and its potential link to oxidative stress has not been previously examined. In this study, we used 7-Tesla MRI quantitative susceptibility mapping (QSM), magnetic resonance spectroscopy (MRS), and structural T1 imaging in 12 individuals with chronic schizophrenia and 14 healthy age-matched controls. In schizophrenia, there were higher QSM values in bilateral putamen and higher concentrations of phosphocreatine and lactate in caudal anterior cingulate cortex (caCC). Network-based correlation analysis of QSM across corticostriatal pathways as well as the correlation between QSM, MRS, and volume, showed distinct patterns between groups. This study introduces increased iron in the putamen in schizophrenia in addition to network-wide disturbances of iron and metabolic status.
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ItemApplication of 7T MRS to High-Grade Gliomas(AMER SOC NEURORADIOLOGY, 2022-10-01)MRS, including single-voxel spectroscopy and MR spectroscopic imaging, captures metabolites in high-grade gliomas. Emerging evidence indicates that 7T MRS may be more sensitive to aberrant metabolic activity than lower-field strength MRS. However, the literature on the use of 7T MRS to visualize high-grade gliomas has not been summarized. We aimed to identify metabolic information provided by 7T MRS, optimal spectroscopic sequences, and areas for improvement in and new applications for 7T MRS. Literature was found on PubMed using "high-grade glioma," "malignant glioma," "glioblastoma," "anaplastic astrocytoma," "7T," "MR spectroscopy," and "MR spectroscopic imaging." 7T MRS offers higher SNR, modestly improved spatial resolution, and better resolution of overlapping resonances. 7T MRS also yields reduced Cramér-Rao lower bound values. These features help to quantify D-2-hydroxyglutarate in isocitrate dehydrogenase 1 and 2 gliomas and to isolate variable glutamate, increased glutamine, and increased glycine with higher sensitivity and specificity. 7T MRS may better characterize tumor infiltration and treatment effect in high-grade gliomas, though further study is necessary. 7T MRS will benefit from increased sample size; reductions in field inhomogeneity, specific absorption rate, and acquisition time; and advanced editing techniques. These findings suggest that 7T MRS may advance understanding of high-grade glioma metabolism, with reduced Cramér-Rao lower bound values and better measurement of smaller metabolite signals. Nevertheless, 7T is not widely used clinically, and technical improvements are necessary. 7T MRS isolates metabolites that may be valuable therapeutic targets in high-grade gliomas, potentially resulting in wider ranging neuro-oncologic applications.
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ItemA Thalamo-Centric Neural Signature for Restructuring Negative Self-Beliefs(ELSEVIER SCIENCE INC, 2022-05-01)Negative self-beliefs are a core feature of psychopathology. Despite this, we have a limited understanding of the brain mechanisms by which negative self-beliefs are cognitively restructured. Using a novel paradigm, we had participants use Socratic questioning techniques to restructure negative beliefs during ultra-high resolution 7-Tesla functional magnetic resonance imaging (UHF 7 T fMRI) scanning. Cognitive restructuring elicited prominent activation in a fronto-striato-thalamic circuit, including the mediodorsal thalamus (MD), a group of deep subcortical nuclei believed to synchronize and integrate prefrontal cortex activity, but which has seldom been directly examined with fMRI due to its small size. Increased activity was also identified in the medial prefrontal cortex (MPFC), a region consistently activated by internally focused mental processing, as well as in lateral prefrontal regions associated with regulating emotional reactivity. Using Dynamic Causal Modelling (DCM), evidence was found to support the MD as having a strong excitatory effect on the activity of regions within the broader network mediating cognitive restructuring. Moreover, the degree to which participants modulated MPFC-to-MD effective connectivity during cognitive restructuring predicted their individual tendency to engage in repetitive negative thinking. Our findings represent a major shift from a cortico-centric framework of cognition and provide important mechanistic insights into how the MD facilitates key processes in cognitive interventions for common psychiatric disorders. In addition to relaying integrative information across basal ganglia and the cortex, we propose a multifaceted role for the MD whose broad excitatory pathways act to increase synchrony between cortical regions to sustain complex mental representations, including the self.
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ItemDynamic Subcortical Modulators of Human Default Mode Network Function(OXFORD UNIV PRESS INC, 2022-09-19)The brain's "default mode network" (DMN) enables flexible switching between internally and externally focused cognition. Precisely how this modulation occurs is not well understood, although it may involve key subcortical mechanisms, including hypothesized influences from the basal forebrain (BF) and mediodorsal thalamus (MD). Here, we used ultra-high field (7 T) functional magnetic resonance imaging to examine the involvement of the BF and MD across states of task-induced DMN activity modulation. Specifically, we mapped DMN activity suppression ("deactivation") when participants transitioned between rest and externally focused task performance, as well as DMN activity engagement ("activation") when task performance was internally (i.e., self) focused. Consistent with recent rodent studies, the BF showed overall activity suppression with DMN cortical regions when comparing the rest to external task conditions. Further analyses, including dynamic causal modeling, confirmed that the BF drove changes in DMN cortical activity during these rest-to-task transitions. The MD, by comparison, was specifically engaged during internally focused cognition and demonstrated a broad excitatory influence on DMN cortical activation. These results provide the first direct evidence in humans of distinct BF and thalamic circuit influences on the control of DMN function and suggest novel mechanistic avenues for ongoing translational research.
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ItemRelating the cortical visual contrast gain response to spectroscopy-measured excitatory and inhibitory metabolites in people who experience migraine(PUBLIC LIBRARY SCIENCE, 2022)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.
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ItemCompressed sensing effects on quantitative analysis of undersampled human brain sodium MRI(Wiley, 2020-03)Purpose The clinical application of sodium MRI is hampered due to relatively low image quality and associated long acquisition times. Compressed sensing (CS) aims at a reduction of measurement time, but has been found to encompass quantitative estimation bias when used in low SNR x‐Nuclei imaging. This work analyses CS in quantitative human brain sodium MRI from undersampled acquisitions and provides recommendations for tissue sodium concentration (TSC) estimation. Methods CS reconstructions from 3D radial acquisitions of 5 healthy volunteers were investigated over varying undersampling factors (USFs) and CS penalty weights on different sparsity domains, Wavelet, Discrete Cosine Transform (DCT), and Identity. Resulting images were compared with highly sampled and undersampled NUFFT‐based images and evaluated for image quality (i.e. structural similarity), image intensity bias, and its effect on TSC estimates in gray and white matter. Results Wavelet‐based CS reconstructions show highest image quality with stable TSC estimates for most USFs. Up to an USF of 4, images showed good structural detail. DCT and Identity‐based CS enable good image quality, however show a bias in TSC with a reduction in estimates across USFs. Conclusions The image intensity bias is lowest in Wavelet‐based reconstructions and enables an up to fourfold acquisition speed up while maintaining good structural detail. The associated acquisition time reduction can facilitate a translation of sodium MRI into clinical routine.
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ItemExtracting more for less: multi-echo MP2RAGE for simultaneous T1-weighted imaging, T1 mapping, R2*mapping, SWI, and QSM from a single acquisition(WILEY, 2020-04)PURPOSE: To demonstrate simultaneous T1 -weighted imaging, T1 mapping, R2∗ 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. T1 -weighted images and T1 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, R2∗ , and T1 of brain tissue from ME-MP2RAGE were compared with those from standard ME-gradient echo and SE-MP2RAGE. RESULTS: The ME combined T1 -weighted, T1 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. T1 -weighted, T1 , and susceptibility maps from ME-MP2RAGE were comparable to those obtained from SE-MP2RAGE and ME-gradient echo, whereas R2∗ maps showed increased blurring and reduced SNR. T1 , R2∗ , and susceptibility values of brain tissue from ME-MP2RAGE were consistent with those from SE-MP2RAGE and ME-gradient echo. CONCLUSION: High-resolution structural T1 weighted imaging, T1 mapping, R2∗ 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.
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Item7T Magnetic Resonance Imaging Quantification of Brain Glutamate in Acute Ischaemic Stroke(Korean Stroke Society, 2021-05-01)
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ItemStudy protocol for a phase II randomised, double-blind, placebo-controlled trial of perampanel as an antiepileptogenic treatment following acute stroke(BMJ PUBLISHING GROUP, 2021-05)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.