Bradford Moffat | University of Melbourne (original) (raw)

Papers by Bradford Moffat

Purpose: To develop a simple and robust magnetic resonance imaging (MRI) pulse sequence for the q... more Purpose: To develop a simple and robust magnetic resonance imaging (MRI) pulse sequence for the quantitative measurement of blood flow in the brain and cerebral tumors that has practical implementation advantages over currently used continuous arterial spin labeling (CASL) schemes. Materials and Methods: Presented here is a single-coil protocol that uses a train of hyperbolic secant inversion pulses to produce continuous arterial spin inversion for perfusion weighting of fast spin echo images. Flow maps of normal rat brains and those containing a 9L gliosarcoma orthotopic tumor model conditions were acquired with and without carbogen. Results: The perfusion-weighted images have reduced magnetization transfer signal degradation as compared to the traditional single-coil CASL while avoiding the use of a more complex two-coil CASL technique. Blood flow measurements in tumor and normal brain tissue were consistent with those previously reported by other CASL techniques. Contralateral and normal brain showed increased blood flow with carbogen breathing, while tumor tissue lacked the same CO 2 reactivity. Conclusion: This variation of the CASL technique is a quantitative, robust, and practical single-coil method for measuring blood flow. This CASL method does not require specialized radiofrequency coils or amplifiers that are not routinely used for anatomic imaging of the brain, therefore allowing these flow measurements to be easily incorporated into traditional rodent neuroimaging protocols.

Journal of Clinical Oncology, Jun 20, 2006

1518 Background: Current assessment of glioma treatment response relies on changes in the product... more 1518 Background: Current assessment of glioma treatment response relies on changes in the product of the maximal perpendicular tumor diameters at 2 months following treatment. Due to the fact that patients with malignant glioma have high mortality rates and a short median survival (about 41 weeks), the ability to stratify these tumors into responsive and non-responsive categories prior to treatment completion would allow for individualization of treatment. Changes in glioma water diffusion values were quantified using diffusion MRI as a biomarker for therapeutic-induced changes in tumor cellularity. Methods: A total of 37 patients with Grade III/IV supratentorial malignant gliomas (restricted to anaplastic astrocytomas (Grade III) and glioblastomas/sarcomas (Grade IV)) into a clinical imaging study. Standard and diffusion MRI scans pre-treatment and at 3 weeks post-initiation of chemo- and/or radio-therapy were acquired. Images were co-registered to pretreatment scans, and changes in tumor water diffusion values were calculated and displayed as a functional diffusion map (fDM) for correlation with clinical response. Results: Analysis of the patient data revealed that the fDM volumes of total detected diffusion change (VT) was able to statistically discriminate (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) between the stable disease (SD) and progressive disease (PD) patient populations 3 weeks into therapy. Patients classified as PD by fDM analysis at 3 weeks were found to have a shorter OS in the PD group compared with SD patients (median survival, 8.0 versus 18.2 months; p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01). The fDM measurements provided an early biomarker for response, TTP and OS in malignant glioma patients. Conclusions: This novel imaging biomarker (fDM) was found to be a viable and early predictor of WHO clinical outcome. This clinical study strongly supports the hypothesis that fDM analysis provides a sensitive measure of therapeutic-induced changes in tumor cellularity, which can thereby serve as a predictive clinical surrogate marker for treatment response. Further evaluation of this imaging biomarker is ongoing. [Table: see text]

Cambridge University Press eBooks, Mar 6, 2013

Journal of Magnetic Resonance Imaging, 2005

BMJ Open, May 1, 2023

Train Smart Study: protocol for a randomised trial investigating the role of exercise training do... more Train Smart Study: protocol for a randomised trial investigating the role of exercise training dose on markers of brain health in sedentary middle-aged adults. BMJ Open 2023;13:e069413.

British Journal of Cancer, 2002

International Journal of Radiation Oncology Biology Physics, Oct 1, 2005

Learning disorders can have a devastating impact upon the quality of life of children treated wit... more Learning disorders can have a devastating impact upon the quality of life of children treated with cranial irradiation. Lithium has long been recognized as a neuro-protector in the setting of oxidative stress. Lithium has been shown to decrease levels of the pro-apoptotic (Bax) and increase levels of Bcl-2. We therefore examined the ability of Lithium Chloride to prevent radiation induced brain injury in mice and rats. Materials/Methods: Immunoblotting and clonogenic assays were used to study the effects of LiCl on irradiated hippocampal neurons. Apoptotic cells in the hippocampus were studied using TUNEL stain of brain sections from animals sacrificed 10 hours after exposure to cranial radiation. Morris Water Maze was used to measure learning and memory in mice following treatment with cranial irradiation with/without LiCl. Results: To determine whether lithium treatment increases phosphorylation of GSK3 in hippocampal neurons, protein was extracted from treated and untreated neurons. Western immunoblotting with antibody specific for phospho-GSK3 showed that LiCl treatment significantly increased concentrations of phospho-GSK3 and increased Bcl-2 and decreased Bax levels in hippocampal neurons. Rodent models have been useful to study histological changes in the hippocampus. To determine the effect of radiation dose on the amount of apoptosis in the hippocampal neurons, we exposed two week old mice to various doses of cranial radiation. Coronal sections of hippocampus showed that doses as low as 1-2 Gy induced apoptosis in the neuronal precursor cells of the SGZ of the hippocampus. The observed dose-dependent increase in neuronal apoptosis began to plateau at 8 Gy. To determine whether lithium attenuates radiation induced apoptosis in the SGZ, we treated one week-old pups with daily injections of LiCl. Mice were then irradiated and neuronal apoptosis was analyzed after 10 hr in sections of hippocampus using TUNEL staining. LiCl treatment resulted in a two fold decrease in radiation-induced apoptosis (pϭ0.03). Lithium treatment also significantly increased the survival of irradiated hippocampal neurons in vitro (pϭ0.01). To determine if a similar survival benefit occurred in medulloblastoma and glioblastoma, cells were treated LiCl and irradiated. LiCl treatment had no effect on the clonogenic survival of medulloblastoma or glioblastoma cells. Cranial irradiation in newborn rodents is associated with severe spatial navigation deficits in the Morris Water Maze, and other cognitive functions. These deficits can be accounted for by radiation induced apoptosis in the SGZ. To determine if lithium attenuated these deficits, mice were treated with LiCl and irradiated with 7 Gy. Six weeks later, mice were subjected to Morris Water Maze testing. We found that female mice were particularly debilitated by irradiation, taking an average of twice as long to locate the hidden platform on day 9 of testing as compared to their male littermates (28 vs 14 seconds, pϭ.027), which supports clinical findings that females are at increased risk for developing severe cognitive deficits as compared to their male counterparts. While all groups of mice achieved comparable learning deficits on the first day of training, significant improvement in learning was observed on day 9 in mice treated with lithium prior to radiation as compared to animals treated with radiation alone (pϭ.02 for both males and females). Conclusions: Mechanisms of action of LiCl are through the inhibition of GSK3, and altered expression of Bcl2 and Bax. LiCl prevents radiation induced apoptosis of hippocampal neurons in the irradiated rodent brain. Mice treated with LiCl during irradiation demonstrate significant improvements in learning as compared to littermates treated with brain irradiation alone.

NMR in Biomedicine, Nov 17, 2020

Ultra-high field MRI offers many opportunities to expand the applications of MRI. In order for th... more 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 Tesla 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 (e.g. the human brain). Several techniques based on STEP sequences are introduced and their application to human brain imaging is presented and evaluated.

Current Opinion in Chemical Biology, Aug 1, 2005

High-throughput mouse magnetic resonance imaging (MRI) is seeing rapidly increasing demand in dev... more High-throughput mouse magnetic resonance imaging (MRI) is seeing rapidly increasing demand in development of therapeutics. Recent advances including higher-field systems, new gradient and radio frequency coils and new pulse sequences, coupled with efficient animal preparation and data handling, allow high-throughput MRI under certain protocols. However, with current shifts from anatomic to functional and molecular imaging, innovative technology is required to meet new throughput demands. The first multiple mouse imaging strategies have provided a glimpse of the future state-of-theart. However, the successful translation of standard clinical MRI technology to preclinical MRI is required to facilitate next-generation high-throughput MRI.

Schizophrenia

Brain iron is central to dopaminergic neurotransmission, a key component in schizophrenia patholo... more 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 netwo...

BMJ Open, 2021

IntroductionStroke is a common cause of epilepsy that may be mediated via glutamate dysregulation... more IntroductionStroke 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 analysisUp 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...

Iron has been found to play an important role in neurodegeneration. Quantitative susceptibility m... more Iron has been found to play an important role in neurodegeneration. Quantitative susceptibility mapping (QSM) is a relatively new – and the most accurate - MRI technique available for assessment of iron deposition in the brain. There is a rapidly growing number of studies using QSM to investigate brain iron distribution in neurodegenerative diseases including but not limited to Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, Huntington disease and Wilson’s disease. These studies have shown increased iron deposition in the brain regions that are associated with the pathology of the disease. Additionally, QSM is found to be accurate in differential diagnosis of neurodegenerative diseases where clinical presentations are indistinguishable. Structural changes evidenced by QSM are reported to precede the onset of clinical manifestation of neurodegenerative diseases suggesting its benefit in early diagnosis. To our knowledge, no systematic review of QSM findings i...

Frontiers in neurology, 2018

Tremor of the upper limbs is a disabling symptom that is present during several neurological diso... more Tremor of the upper limbs is a disabling symptom that is present during several neurological disorders and is currently without treatment. Functional MRI (fMRI) is an essential tool to investigate the pathophysiology of tremor and aid the development of treatment options. However, no adequately or standardized protocols for fMRI exists at present. Here we present a novel, online available fMRI task that could be used to assess the pathology of tremor. This study aims to validate the tremor-evoking potential of the fMRI task in a small group of tremor patients outside the scanner and assess the reproducibility of the fMRI task related activation in healthy controls. Twelve HCs were scanned at two time points (baseline and after 6-weeks). There were two runs of multi-band fMRI and the tasks included a "brick-breaker" joystick game. The game consisted of three conditions designed to control for most of the activation related to performing the task by contrasting the condition...

Asia-Pacific journal of clinical oncology, Jan 8, 2017

Assessment of magnetic resonance imaging (MRI) in glioblastoma can be challenging. For patients w... more Assessment of magnetic resonance imaging (MRI) in glioblastoma can be challenging. For patients with recurrent glioblastoma managed on the CABARET trial, we compared disease status assessed at hospitals and subsequent blinded central expert radiological review. MRI results and clinical status at specified time points were used for site and central assessment of disease status. Clinical status was determined by the site. Response Assessment in Neuro-Oncology (RANO) criteria were used for both assessments. Site and central assessments of progression-free survival (PFS) and response rates were compared. Inter-rater variability for central review progression dates was assessed. Central review resulted in shorter PFS in 45% of 89 evaluable patients (n = 40). Median PFS was 3.6 (central) versus 3.9 months (site) (hazard ratio 1.5, 95% confidence interval 1.3-1.8, P < 0.001). Responses were documented more frequently by sites (n = 16, 18%) than centrally (n = 11, 12%). Seven of 120 pati...

Journal of neural transmission (Vienna, Austria : 1996), 2017

Tremor in people with multiple sclerosis (MS) is a frequent and debilitating symptom with a relat... more Tremor in people with multiple sclerosis (MS) is a frequent and debilitating symptom with a relatively poorly understood pathophysiology. To determine the relationship between clinical tremor severity and structural magnetic resonance imaging parameters. Eleven patients with clinically definite MS and right-sided upper limb tremor were studied. Tremor severity was assessed using the Bain score (overall severity, writing, and Archimedes spiral drawing). Cerebellar dysfunction was assessed using the Scale for the Assessment and Rating of Ataxia. Dystonia was assessed using the Global Dystonia Scale adapted for upper limb. For all subjects, volume was calculated for the thalamus from T1-weighted volumetric scans using Freesurfer. Superior cerebellar peduncle (SCP) cross-sectional areas were measured manually. The presence of lesions was visually determined and the lesion volumes were calculated by the lesion growth algorithm as implemented in the Lesion Segmentation Toolbox. Right thal...

NeuroImage, Jan 7, 2017

Recent developments in accelerated imaging methods allow faster acquisition of high spatial resol... more Recent developments in accelerated imaging methods allow faster acquisition of high spatial resolution images. This could improve the applications of functional magnetic resonance imaging at 7 T (7T-fMRI), such as neurosurgical planning and Brain Computer Interfaces (BCIs). However, increasing the spatial and temporal resolution will both lead to signal-to-noise ratio (SNR) losses due to decreased signal intensity and T1-relaxation effect, respectively. This could potentially offset the SNR efficiency gains made with increasing temporal resolution. We investigated the effects of varying spatial and temporal resolution on fMRI sensitivity measures and their implications on fMRI-based BCI simulations. We compared temporal signal-to-noise ratio (tSNR), normalized percent signal change (%∆S), volumes of significant activation, Z-scores and decoding performance of linear classifiers commonly used in BCIs across a range of spatial and temporal resolution images acquired during an ankle-ta...

Investigative Opthalmology & Visual Science, 2016

The purpose of this study was to investigate correlations between retinal fiber thickness measure... more The purpose of this study was to investigate correlations between retinal fiber thickness measured by optical coherence tomography (OCT) and anterograde functional and structural differences in the optic pathway of patients with compression of the optic chiasm. Our hypothesis was that loss of visual acuity caused by chronic compressive pathologies may lead to an irreversible decline in vision because of permanent neurodegeneration of the optic radiations and visual cortex. METHODS. Quantitative OCT, functional magnetic resonance imaging (MRI) and diffusion tensor MRI measurements were made in 17 patients being surgically treated for chiasmal compression. RESULTS. In our study we found that surgically irreversible visual field defects and reduced retinal nerve fiber layer thickness were significantly associated with lower fractional diffusion anisotropy and higher diffusivities in optic radiations and less functional MRI activation in the visual cortex. CONCLUSIONS. Damage to the retinal nerve fiber layer is associated with downstream structural and functional degradation of the optic pathway. This may be related to trans-synaptic degeneration and the fact that these factors are important potential imaging biomarkers for predicting visual recovery after surgical decompression.

Clinical MR Neuroimaging, 2004

... The calculation of FA is relatively simple Fig. ... Improved margin detection could lead to b... more ... The calculation of FA is relatively simple Fig. ... Improved margin detection could lead to better surgical accu-racy and assessment of risk. The use of DWI and DTI also has the potential for monitoring early changes in tumor cellularity pos-sibly reflecting treatment response. ...

Translational Oncology, 2009

The parametric response map (PRM) was evaluated as an early surrogate biomarker for monitoring tr... more The parametric response map (PRM) was evaluated as an early surrogate biomarker for monitoring treatment-induced tissue alterations in patients with head and neck squamous cell carcinoma (HNSCC). Diffusion-weighted magnetic resonance imaging (DW-MRI) was performed on 15 patients with HNSCC at baseline and 3 weeks after treatment initiation of a nonsurgical organ preservation therapy (NSOPT) using concurrent radiation and chemotherapy. PRM was applied on serial apparent diffusion coefficient (ADC) maps that were spatially aligned using a deformable image registration algorithm to measure the tumor volume exhibiting significant changes in ADC (PRM ADC). Pretherapy and midtherapy ADC maps, quantified from the DWIs, were analyzed by monitoring the percent change in whole-tumor mean ADC and the PRM metric. The prognostic values of percentage change in tumor volume and mean ADC and PRM ADC as a treatment response biomarker were assessed by correlating with tumor control at 6 months. Pixel-wise differences as part of PRM ADC analysis revealed regions where water mobility increased. Analysis of the tumor ADC histograms also showed increases in mean ADC as early as 3 weeks into therapy in patients with a favorable outcome. Nevertheless, the percentage change in mean ADC was found to not correlate with tumor control at 6 months. In contrast, significant differences in PRM ADC and percentage change in tumor volume were observed between patients with pathologically different outcomes. Observations from this study have found that diffusion MRI, when assessed by PRM ADC , has the potential to provide both prognostic and spatial information during NSOPT of head and neck cancer.