Bradford A. Moffat

This study explored the possibility of utilizing iron oxide nanoparticles as a drug delivery vehicle for minimally invasive, MRI-monitored magnetic targeting of brain tumors. In vitro determined hydrodynamic diameter of approximately 100 nm, saturation magnetization of 94 emicro/g Fe and T2 relaxivity of 43 s(-1)mm(-)(1) of the nanoparticles suggested their applicability for this purpose. In vivo effect of magnetic targeting on the extent and selectivity of nanoparticle accumulation in tumors of rats harboring orthotopic 9L-gliosarcomas was quantified with MRI. Animals were intravenously injected with nanoparticles (12 mg Fe/kg) under a magnetic field density of 0 T (control) or 0.4 T (experimental) applied for 30 min. MR images were acquired prior to administration of nanoparticles and immediately after magnetic targeting at 1h intervals for 4h. Image analysis revealed that magnetic targeting induced a 5-fold increase in the total glioma exposure to magnetic nanoparticles over non-targeted tumors (p=0.005) and a 3.6-fold enhancement in the target selectivity index of nanoparticle accumulation in glioma over the normal brain (p=0.025). In conclusion, accumulation of iron oxide nanoparticles in gliosarcomas can be significantly enhanced by magnetic targeting and successfully quantified by MR imaging. Hence, these nanoparticles appear to be a promising vehicle for glioma-targeted drug delivery.

Assessment of radiation and chemotherapy efficacy for brain cancer patients is traditionally accomplished by measuring changes in tumor size several months after therapy has been administered. The ability to use noninvasive imaging during the early stages of fractionated therapy to determine whether a particular treatment will be effective would provide an opportunity to optimize individual patient management and avoid unnecessary systemic toxicity, expense, and treatment delays. We investigated whether changes in the Brownian motion of water within tumor tissue as quantified by using diffusion MRI could be used as a biomarker for early prediction of treatment response in brain cancer patients. Twenty brain tumor patients were examined by standard and diffusion MRI before initiation of treatment. Additional images were acquired 3 weeks after initiation of chemo- and/or radiotherapy. Images were coregistered 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. Of the 20 patients imaged during the course of therapy, 6 were classified as having a partial response, 6 as stable disease, and 8 as progressive disease. The fDMs were found to predict patient response at 3 weeks from the start of treatment, revealing that early changes in tumor diffusion values could be used as a prognostic indicator of subsequent volumetric tumor response. Overall, fDM analysis provided an early biomarker for predicting treatment response in brain tumor patients.

Abstract Purpose: Development of new therapeutic drug delivery systems is an area of significant research interest. The ability to directly target a therapeutic agent to a tumor site would minimize systemic drug exposure, thus providing the potential for increasing the therapeutic index. Experimental Design: Photodynamic therapy (PDT) involves the uptake of a sensitizer by the cancer cells followed by photoirradiation to activate the sensitizer. PDT using Photofrin has certain disadvantages that include prolonged cutaneous photosensitization. Delivery of nanoparticles encapsulated with photodynamic agent specifically to a tumor site could potentially overcome the drawbacks of systemic therapy. In this study, we have developed a multifunctional polymeric nanoparticle consisting of a surface-localized tumor vasculature targeting F3 peptide and encapsulated PDT and imaging agents. Results: The nanoparticles specifically bound to the surface of MDA-435 cells in vitro and were internalized conferring photosensitivity to the cells. Significant magnetic resonance imaging contrast enhancement was achieved in i.c. rat 9L gliomas following i.v. nanoparticle administration. Serial magnetic resonance imaging was used for determination of pharmacokinetics and distribution of nanoparticles within the tumor. Treatment of glioma-bearing rats with targeted nanoparticles followed by PDT showed a significant improvement in survival rate when compared with animals who received PDT after administration of nontargeted nanoparticles or systemic Photofrin. Conclusions: This study reveals the versatility and efficacy of the multifunctional nanoparticle for the targeted detection and treatment of cancer.

Diffuse malignant gliomas, the most common type of brain tumor, carry a dire prognosis and are poorly responsive to initial treatment. The response to treatment is typically evaluated by measurements obtained from radiographic images several months after the start of treatment; therefore, an early biomarker of tumor response would be useful for making early treatment decisions and for prognostic information. Thirty-four patients with malignant glioma were examined by diffusion MRI before treatment and 3 weeks later. These images were coregistered, and differences in tumor-water diffusion values were calculated as functional diffusion maps (fDM), which were correlated with the radiographic response, time-to-progression (TTP), and overall survival (OS). Changes in fDM at 3 weeks were closely associated with the radiographic response at 10 weeks. The percentage of the tumor undergoing a significant change in the diffusion of water ( V T ) was different between patients with progressive disease (PD) vs. stable disease (SD) ( P < 0.001). Patients classified as PD by fDM analysis at 3 weeks were found to have a shorter TTP compared with SD (median TTP, 4.3 vs. 7.3 months; P < 0.04). By using fDM, early patient stratification also was correlated with shorter OS in the PD group compared with SD patients (median survival, 8.0 vs. 18.2 months; P < 0.01). On the basis of fDM, tumor assessment provided an early biomarker for response, TTP, and OS in patients with malignant glioma. Further evaluation of this technique is warranted to determine whether it may be useful in the individualization of treatment or evaluation of the response in clinical protocols.

Functional diffusion map (fDM) has been recently reported as an early and quantitative biomarker of clinical brain tumor treatment outcome. This MRI approach spatially maps and quantifies treatment-induced changes in tumor water diffusion values resulting from alterations in cell density/cell membrane function and microenvironment. This current study was designed to evaluate the capability of fDM for preclinical evaluation of dose escalation studies and to determine if these changes were correlated with outcome measures (cell kill and overall survival). Serial T2-weighted and diffusion MRI were carried out on rodents with orthotopically implanted 9L brain tumors receiving three doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (6.65, 13.3, and 26.6 mg/kg, i.p.). All images were coregistered to baseline T2-weighted images for fDM analysis. Analysis of tumor fDM data on day 4 posttreatment detected dosedependent changes in tumor diffusion values, which were also found to be spatially dependent. Histologic analysis of treated tumors confirmed spatial changes in cellularity as observed by fDM. Early changes in tumor diffusion values were found to be highly correlative with drug dose and independent biologic outcome measures (cell kill and survival). Therefore, the fDM imaging biomarker for early prediction of treatment efficacy can be used in the drug development process.

A paradigm for brain cancer detection, treatment, and monitoring is established. Multifunctional biomedical nanoparticles (30–60 nm) containing photosensitizer externally deliver reactive oxygen species (ROS) to cancer cells while simultaneously enhancing magnetic resonance imaging (MRI) contrast providing real-time tumor kill measurement. Plasma residence time control and specific cell targeting are achieved. A 5 min treatment in rats halted and even reversed in vivo tumor growth after 3–4 days post-treatment.

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.

A modified method for the production of cubic and spherical superparamagnetic nanoparticles is presented. Cubic nanoparticles can be made that are highly monodisperse down to a diameter of 8 nm. A detailed study is presented of the physical properties of these nanoparticles using high-resolution transmission electron microscopy analysis, X-ray powder diffraction, superconducting quantum interference device measurements, and relaxivity measurements performed in a magnetic resonance imaging scanner. It is found that cubic iron oxide nanoparticles have a higher degree of crystallinity and relaxivity (four times higher) than their spherical counterparts. These novel cubic iron oxide nanoparticles show great promise for use in biomedical imaging applications.

A novel polyacrylamide superparamagnetic iron oxide nanoparticle platform is described which has been synthetically prepared such that multiple crystals of iron oxide are encapsulated within a single polyacrylamide matrix (PolyAcrylamide Magnetic [PAM] nanoparticles). This formulation provides for an extremely large T2 and T2* relaxivity of between 620 and 1140 sec(-1) mM(-1). Administration of PAM nanoparticles into rats bearing orthotopic 9L gliomas allowed quantitative pharmacokinetic analysis of the uptake of nanoparticles in the vasculature, brain, and glioma. Addition of polyethylene glycol of varying sizes (0.6, 2, and 10 kDa) to the surface of the PAM nanoparticles resulted in an increase in plasma half-life and affected tumor uptake and retention of the nanoparticles as quantified by changes in tissue contrast using MRI. The flexible formulation of these nanoparticles suggests that future modifications could be accomplished allowing for their use as a targeted molecular imaging contrast agent and/or therapeutic platform for multiple indications.

The use of anatomical imaging in clinical oncology practice traditionally relies on comparison of patient scans acquired before and following completion of therapeutic intervention. Therapeutic success is typically determined from inspection of gross anatomical images to assess changes in tumor size. Imaging could provide significant additional insight into therapeutic impact if a specific parameter or combination of parameters could be identified which reflect tissue changes at the cellular or physiologic level. This would provide an early indicator or treatment response/outcome in an individual patient before completion of therapy. Moreover, response of a tumor to therapeutic intervention may be heterogeneous. The use of imaging could assist in delineating therapeutic-induced spatial heterogeneity within a tumor mass by providing information related to specific regions that are resistant or responsive to treatment. Largely untapped potential resides in exploratory methods such as diffusion MRI, which is a nonvolumetric intravoxel measure of tumor response based upon water molecular mobility. Alterations in water mobility reflect changes in tissue structure at the cellular level. While the clinical utility of diffusion MRI for oncologic practice is still under active investigation, this overview on the use of diffusion MRI for the evaluation of brain tumors will serve to introduce how this approach may be applied in the future for the management of patients with solid tumors.

The increasing development of novel targeted therapies for treating solid tumors has necessitated the development of technology to determine their efficacy in preclinical animal models. One such technology that can non-invasively quantify early changes in tumor cellularity as a result of an efficacious therapy is diffusion MRI. In this overview we present some theories as to the origin of diffusion changes as a result of tumor therapy, a robust methodology for acquisition of apparent diffusion coefficient maps and some applications of determining therapeutic efficacy in a variety therapeutic regimens and animal models.

The development of improved, low toxicity, clinically viable nanomaterials that provide MRI contrast have tremendous potential to form the basis of translatable theranostic agents. Herein we describe a class of MRI visible materials based on lyotropic liquid crystal nanoparticles loaded with a paramagnetic nitroxide lipid. These readily synthesized nanoparticles achieved enhanced proton-relaxivities on the order of clinically used gadolinium complexes such as Omniscan™ without the use of heavy metal coordination complexes. Their low toxicity, high water solubility and colloidal stability in buffer resulted in them being well tolerated in vitro and in vivo. The nanoparticles were initially screened in vitro for cytotoxicity and subsequently a defined concentration range was tested in rats to determine the maximum tolerated dose. Pharmacokinetic profiles of the candidate nanoparticles were established in vivo on IV administration to rats. The lyotropic liquid crystal nanoparticles were proven to be effective liver MRI contrast agents. We have demonstrated the effective in vivo performance of a T1 enhancing, biocompatible, colloidally stable, amphiphilic MRI contrast agent that does not contain a metal.

Engineered nanoparticles with multiple complementary imaging modalities are of great benefit to the rapid treatment and diagnosis of disease in various organs. Herein, we report the formulation of cubosomes and hexosomes that carry multiple amphiphilic imaging contrast agents in their self-assembled lipid bilayers. This is the first report of the use of both near infrared fluorescent (NIRF) imaging and gadolinium lipid based magnetic resonance (MR) imaging modalities in cubosomes and hexosomes. High-throughput screening was used to rapidly optimize formulations with desirable nano-architectures and low in vitro cytotoxicity. The dual-modal imaging nanoparticles in vivo biodistribution and organ specific contrast enhancement were then studied. The NIRF in vivo imaging results indicated accumulation of both cubosomes and hexosomes in the liver and spleen of mice up to 20h post-injection. Remarkably, the biodistribution of the nanoparticle formulations was affected by the mesophase (i.e. cubic or hexagonal), a finding of significant importance for the future use of these compounds, with hexosomes showing higher accumulation in the spleen than the liver compared to cubosomes. Furthermore, in vivo MRI data of animals injected with either type of lyotropic liquid crystal nanoparticle displayed enhanced contrast in the liver and spleen.

The isocitrate dehydrogenase 1 (IDH1) R132H mutation is the most common mutation in World Health Organization (WHO) grade II gliomas, reported to be expressed in 70-80%, but only 5-10% of high grade gliomas. Low grade tumors, especially the protoplasmic subtype, have the highest incidence of tumor associated epilepsy (TAE). The IDH1 mutation leads to the accumulation of 2-hydroxyglutarate (2HG), a metabolite that bears a close structural similarity to glutamate, an excitatory neurotransmitter that has been implicated in the pathogenesis of TAE. We hypothesized that expression of mutated IDH1 may play a role in the pathogenesis of TAE in low grade gliomas.Thirty consecutive patients with WHO grade II gliomas were analyzed for the presence of the IDH1-R132H mutation using immunohistochemistry. The expression of IDH1 mutation was semiquantified using open-source biologic-imaging analysis software.The percentage of cells positive for the IDH1-R132H mutation was found to be higher in patients with TAE compared to those without TAE (median and interquartile range (IQR) 25.3% [8.6-53.5] vs. 5.2% [0.6-13.4], p = 0.03). In addition, we found a significantly higher median IDH1 mutation expression level in the protoplasmic subtype of low grade glioma (52.2% [IQR 19.9-58.6] vs. 13.8% [IQR 3.9-29.4], p = 0.04).Increased expression of the IDH1-R132H mutation is associated with seizures in low grade gliomas and also with the protoplasmic subtype. This supports the hypothesis that this mutation may play a role in the pathogenesis of both TAE and low grade gliomas.

Polymerization-induced self-assembly (PISA) is an easily applied synthetic technique for the preparation of polymer nanoparticles with various shapes and at high concentrations.

Subtle gait and balance dysfunction is a precursor to loss of mobility in multiple sclerosis (MS). Biomechanical assessments using advanced gait and balance analysis technologies can identify these subtle changes and could be used to predict mobility loss early in the disease. This update critically evaluates advanced gait and balance analysis technologies and their applicability to identifying early lower limb dysfunction in people with MS. Non-wearable (motion capture systems, force platforms, and sensor-embedded walkways) and wearable (pressure and inertial sensors) biomechanical analysis systems have been developed to provide quantitative gait and balance assessments. Non-wearable systems are highly accurate, reliable and provide detailed outcomes, but require cumbersome and expensive equipment. Wearable systems provide less detail but can be used in community settings and can provide real-time feedback to patients and clinicians. Biomechanical analysis using advanced gait and balance analysis technologies can identify changes in gait and balance in early MS and consequently have the potential to significantly improve monitoring of mobility changes in MS.

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. 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. 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). 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.

We report a new technique for non-invasively mapping the refractive index distribution through the eye lens using magnetic resonance micro-imaging. The technique is applied to map the refractive index distribution throughout the sagittal plane of 18 human eye lenses ranging in age from 14 to 82 years in vitro. The results are compared with standard models for the human eye lens. They confirm that the refractive index distribution, when plotted as a function of normalised lens radius, is a function of lens age and differs both between the equatorial and axial directions and between the anterior and posterior halves of the optical axis. The refractive index of the lens nucleus exhibits a significant reduction with age amounting to 3.4+/-0.6 x 10(-4) years(-1). The contribution of the gradient index (GRIN) to the lens power decreases by 0.286+/-0.067 D/year, accounting almost entirely for the estimated overall change in lens power with age for these lenses, which were probably in their most accommodated state. The results provide experimental verification of hypothesised changes in the GRIN that have previously been invoked as contributing to presbyopia and support the hypothesis that changes in the GRIN are sufficient to offset effects of increasing curvature of human lenses with age in their unaccommodated state.

Magnetic resonance microscopy (MRM) has been used to study the kinetics of water transport in human eye lenses. Fresh lenses obtained from the Queensland Eye Bank were incubated at 34.5°C in artificial aqueous humour (AAH) containing nutrients and metabolites similar to those that are present in vivo. MR images were acquired over approximately a 20 hr period following replacement of H2O based AAH with deuterium oxide (D2O) based AAH. NMR signal intensity from the lenses decreased with time corresponding to a decrease in concentration of H2O within the lenses. A statistically significant correlation (P<0.001) was found between the rate of NMR signal loss from the lens nuclei and increasing age of the lenses. The results show that as lenses age, there is a reduction in the rate at which water and presumably also water soluble low molecular weight metabolites, can enter the cells of the lens nucleus via the epithelium and cortex. A decrease in the rate of transport of water, nutrients and anti-oxidants (e.g. glutathione) would be expected to lead to progressive oxidative damage to lenses with age, and may ultimately contribute to presbyopia and senile nuclear cataract.

The American Cancer Society estimates that in 2006, 212,920 women will be diagnosed with breast cancer and that 40,970 women will die from the disease. The development of more efficacious chemotherapies has improved outcomes, but the rapid assessment of clinical benefit from these agents remains challenging. In breast cancer patients receiving neoadjuvant chemotherapy, treatment response is traditionally assessed by physical examination and volumetric-based measurements, which are subjective and require macroscopic changes in tumor morphology. In this study, we evaluate the feasibility of using diffusion magnetic resonance imaging (MRI) as a reliable and quantitative measure for the early assessment of response in a breast cancer model.Mice implanted with human breast cancer (MX-1) were treated with cyclophosphamide and evaluated using diffusion MRI and growth kinetics. Histologic analyses using terminal nucleotidyl transferase-mediated nick end labeling and H&E were done on tumor samples for correlation with imaging results.Cyclophosphamide treatment resulted in a significant reduction in tumor volumes compared with controls. The mean apparent diffusion change for treated tumors at days 4 and 7 posttreatment was 44 +/- 5% and 94 +/- 7%, respectively, which was statistically greater (P < 0.05) than the control tumors at the same time intervals. The median time-to-progression for control and treated groups was 11 and 32 days, respectively (P < 0.05).Diffusion MRI was shown to detect early changes in the tumor microenvironment, which correlated with standard measures of tumor response as well as overall outcome. Moreover, these findings show the feasibility of using diffusion MRI for assessing treatment response of a breast tumor model in a neoadjuvant setting.

Prostate cancer ranks as the most common lethal malignancy diagnosed and the second leading cause of cancer mortality in American men. Although high response rates are achieved using androgen blockade as first-line therapy, most men progress toward hormone-refractory prostate cancer. Systemic chemotherapies have been shown to improve clinical outcome in hormone refractory prostate cancer patients; however, they are not curative. Due to the high incidence of bone involvement in hormone-refractory prostate cancer, assessment of treatment response in metastatic prostate cancer to the bone remains a major clinical need. In this current study, we investigated the feasibility of using the functional diffusion map (fDM) as an imaging biomarker for assessing early treatment response in a preclinical model of metastatic prostate cancer. The fDM biomarker requires a pretreatment and midtreatment magnetic resonance imaging diffusion map, which is used to quantify spatially distinct therapeutic-induced changes in the Brownian motion (or diffusion) of water within tumor tissue. Because water within tumor cells is in a restricted environment relative to extracellular water, loss of cell membrane integrity and cellular density during therapy will be detected by fDM as an increase in diffusion. Regions of significantly increased diffusion values were detected early using fDM in docetaxel-treated versus untreated metastatic prostate bone tumors at 7 days post treatment initiation (P < 0.05), indicating loss of tumor cell viability. Validation of fDM results was accomplished by histologic analysis of excised tissue. Results from this study show the capability of fDM as a biomarker for detection of bone cancer treatment efficacy, thus warranting clinical evaluation.

An efficient MRI T2-weighted contrast agent incorporating a potential liver targeting functionality was synthesized via the combination of superparamagnetic iron oxide (SPIO) nanoparticles with multiwalled carbon nanotubes (MWCNTs). Poly(diallyldimethylammonium chloride) (PDDA) was coated on the surface of acid treated MWCNTs via electrostatic interactions and SPIO nanoparticles modified with a potential targeting agent, lactose–glycine adduct (Lac–Gly), were subsequently immobilized on the surface of the PDDA–MWCNTs. A narrow magnetic hysteresis loop indicated that the product displayed superparamagnetism at room temperature which was further confirmed by ZFC (zero field cooling)/FC (field cooling) curves measured by SQUID. The multifunctional MWCNT-based magnetic nanocomposites showed low cytotoxicity in vitro to HEK293 and Huh7 cell lines. Enhanced T2 relaxivities were observed for the hybrid material (186 mm−1 s−1) in comparison with the pure magnetic nanoparticles (92 mm−1 s−1) due to the capacity of the MWCNTs to “carry” more nanoparticles as clusters. More importantly, after administration of the composite material to an in vivo liver cancer model in mice, a significant increase in tumor to liver contrast ratio (277%) was observed in T2 weighted magnetic resonance images.

The purpose of this work was to synthesize and screen, for their effectiveness to act as T1-enhancing magnetic resonance imaging (MRI) contrast agents, a small library of nitroxide lipids incorporated into cubic-phase lipid nanoparticles (cubosomes). The most effective nitroxide lipid was then formulated into lower-toxicity lipid nanoparticles (hexosomes), and effective MR contrast was observed in the aorta and spleen of live rats in vivo. This new class of lower-toxicity lipid nanoparticles allowed for higher relaxivities on the order of those of clinically used gadolinium complexes. The new hexosome formulation presented herein was significantly lower in toxicity and higher in relaxivity than cubosome formulations previously reported by us.

The optimal timing of initiating low-molecular weight heparin (LMWH) in patients who have undergone nonoperative management (NOM) of blunt solid organ injuries (SOIs) remains controversial. We describe the safety of early initiation of chemical venous thromboembolism (VTE) prophylaxis among patients undergoing NOM of blunt SOIs.We retrospectively studied severely injured adults who sustained blunt SOI without significant intracranial hemorrhage and underwent an initial NOM at a Canadian lead trauma hospital between 2010 and 2014. Safety was assessed based on failure of NOM, defined as the need for operative intervention, in patients who received early (< 48 h) or late LMWH (≥ 48 h, or early discharge [< 72 h] without LMWH).We included 162 patients in our analysis. Most were men (69%), and the average age was 42 ± 18 years. The median injury severity score was 17, and splenic injuries were most common (97 [60%], median grade 2), followed by liver (57 [35%], median grade 2) and kidney injuries (31 [19%], median grade 1). Combined injuries were present in 14% of patients. A total of 78 (48%) patients received early LMWH, while 84 (52%) received late LMWH. The groups differed only in percent of high-grade splenic injury (14% v. 32%). Overall 2% of patients failed NOM, none after receiving LMWH. Semielective angiography was performed in 23 (14%) patients. The overall rate of confirmed VTE on imaging was 1.9%.Early initiation of medical thromboembolic prophylaxis appears safe in select patients with isolated SOI following blunt trauma. A prospective multicentre study is warranted.

Glioblastoma is the most common aggressive primary central nervous system cancer in adults characterised by uniformly poor survival. Despite maximal safe resection and postoperative radiotherapy with concurrent and adjuvant temozolomide-based chemotherapy, tumours inevitably recur. Imaging with O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) has the potential to impact adjuvant radiotherapy (RT) planning, distinguish between treatment-induced pseudoprogression versus tumour progression as well as prognostication.The FET-PET in Glioblastoma (FIG) study is a prospective, multicentre, non-randomised, phase II study across 10 Australian sites and will enrol up to 210 adults aged ≥18 years with newly diagnosed glioblastoma. FET-PET will be performed at up to three time points: (1) following initial surgery and prior to commencement of chemoradiation (FET-PET1); (2) 4 weeks following concurrent chemoradiation (FET-PET2); and (3) within 14 days of suspected clinical and/or radiological progression on MRI (performed at the time of clinical suspicion of tumour recurrence) (FET-PET3). The co-primary outcomes are: (1) to investigate how FET-PET versus standard MRI impacts RT volume delineation and (2) to determine the accuracy and management impact of FET-PET in distinguishing pseudoprogression from true tumour progression. The secondary outcomes are: (1) to investigate the relationships between FET-PET parameters (including dynamic uptake, tumour to background ratio, metabolic tumour volume) and progression-free survival and overall survival; (2) to assess the change in blood and tissue biomarkers determined by serum assay when comparing FET-PET data acquired prior to chemoradiation with other prognostic markers, looking at the relationships of FET-PET versus MRI-determined site/s of progressive disease post chemotherapy treatment with MRI and FET-PET imaging; and (3) to estimate the health economic impact of incorporating FET-PET into glioblastoma management and in the assessment of post-treatment pseudoprogression or recurrence/true progression. Exploratory outcomes include the correlation of multimodal imaging, blood and tumour biomarker analyses with patterns of failure and survival.The study protocol V.2.0 dated 20 November 2020 has been approved by a lead Human Research Ethics Committee (Austin Health, Victoria). Other clinical sites will provide oversight through local governance processes, including obtaining informed consent from suitable participants. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results of the FIG study (TROG 18.06) will be disseminated via relevant scientific and consumer forums and peer-reviewed publications.ANZCTR ACTRN12619001735145.

To investigate diffusion weighted magnetic resonance imaging as a quantitative surrogate marker for evaluating the therapy-induced cellular changes in an orthotopic experimental glioma model, tumors were treated with direct intratumoral administration of DTI-015, a solution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in 100% EtOH. Intracerebral 9L tumors were induced in Fischer 344 rats, and three treatment groups were established: DTI-015, EtOH, and sham. Two groups of rats received intratumoral injection of either 67 mg/mL BCNU in EtOH or EtOH alone at 50% of the tumor volume up to a maximum of 30 mul under stereotactic guidance. Diffusion magnetic resonance images were acquired before treatment and after treatment at 1, 24, 48, and 72 hours and then 3 times per week thereafter. Tumor cell viability was examined using multislice diffusion weighted magnetic resonance imaging with diffusion weighted transverse magnetic resonance images and histogram plots of each tumor quantified over time. Control animals (EtOH- or sham-treated animals) showed mean apparent diffusion coefficients (ADCs) that remained essentially unchanged over the experimental time course. In contrast, rats treated with DTI-015 showed a significant increase in ADC relative to the pretreatment within 24 hours, which further increased over time, followed by a significant therapeutic response as evidenced by subsequent tumor volume shrinkage, development of a cystic region, and enhanced animal survival. Finally, not only were ADC measurements predictive of differences between treatment groups, but they also yielded spatial and temporal data regarding the efficacy of treatment within individual treated animals that could be used to guide subsequent therapy.

To evaluate noninvasive measures of gene expression and tumor response in a gene-dependent enzyme prodrug therapy (GDEPT), a bifunctional fusion gene between Saccharomyces cerevisiae cytosine deaminase (CD) and Haemophilus influenzae uracil phosphoribosyltransferase (UPRT) was constructed. CD deaminates 5-fluorocytosine (5FC) to 5-fluorouracil (5FU), and UPRT subsequently converts 5FU to fluorouridine monophosphate, and both of these reactions can be monitored noninvasively in vitro and in vivo using 19F magnetic resonance spectroscopy (MRS). Following transient transfection the CD-UPRT fusion protein exhibited both UPRT and CD enzymatic activities as documented by 19F MRS. In addition, an increase in CD activity and thermal stability was witnessed for the fusion protein compared to native CD. Stable expression of CD-UPRT in 9L glioma cells increased both 5FC and 5FU sensitivity in vitro compared to CD-expressing and wild-type 9L cells. Noninvasive 19F MRS of both CD and UPRT gene function in vivo demonstrated that in animals bearing CD-expressing tumors there was limited conversion of 5FC to 5FU with no measurable accumulation of cytotoxic fluorinated nucleotides (F-nucs). In contrast, CD-UPRT-expressing tumors had increased CD gene activity with a threefold higher intratumoral accumulation of 5FU and significant generation of F-nucs. Finally, CD-UPRT yielded increased efficacy in an orthotopic animal model of high-grade glioma. More importantly, early changes in cellular water mobility, which are felt to reflect cellular death, as measured by diffusion-weighted MRI, were predictive of both durable response and increased animal survival. These results demonstrate the increased efficacy of the CD-UPRT GDEPT compared to CD alone both biochemically and in a preclinical model and validate both 19F MRS and diffusion-weighted MRI as tools to assess gene function and therapeutic efficacy.

We present a method for registering histology and in vivo imaging that requires minimal microtoming and is automatic following the user's initialization. In this demonstration, we register a single hematoxylin-and-eosin-stained histological slide of a coronal section of a rat brain harboring a 9L gliosarcoma with an in vivo 7T MR image volume of the same brain. Because the spatial resolution of the in vivo MRI is limited, we add the step of obtaining a high spatial resolution, ex vivo MRI in situ for intermediate registration. The approach taken was to maximize mutual information in order to optimize the registration between all pairings of image data whether the sources are MRI, tissue block photograph, or stained sample photograph. The warping interpolant used was thin plate splines with the appropriate basis function for either 2-D or 3-D applications. All registrations were implemented by user initialization of the approximate pose between the two data sets, followed by automatic optimization based on maximizing mutual information. Only the higher quality anatomical images were used in the registration process; however, the spatial transformation was directly applied to a quantitative diffusion image. Quantitative diffusion maps from the registered location appeared highly correlated with the H&E slide. Overall, this approach provides a robust method for coregistration of in vivo images with histological sections and will have broad applications in the field of functional and molecular imaging.

Impaired social cognition, including emotion recognition, may explain dysfunctional emotional and social behaviour in patients with lesions to the ventromedial prefrontal cortex (VMPFC). However, the VMPFC is a large, poorly defined area that can be sub-divided into orbital and medial sectors. We sought to investigate social cognition in patients with discrete, surgically circumscribed prefrontal lesions. Twenty-seven patients between 1 and 12 months post-neurosurgery were divided into groups based on Brodmann areas resected, determined by post-surgical magnetic resonance imaging. We hypothesised that patients with lesions to the VMPFC (n=5), anterior cingulate cortex (n=4), orbitofrontal cortex (n=7) and dorsolateral prefrontal cortex (DLPFC, n=11) would perform worse than a control group of 26 extra-cerebral neurosurgery patients on measures of dynamic facial emotion recognition, theory of mind (ToM) and empathy. Results indicated the VMPFC-lesioned group performed significantly worse than the control group on the facial emotion recognition task overall, and for fear specifically, and performed worse on the ToM measure. The DLPFC group also performed worse on the ToM and empathy measures, but DLPFC lesion location was not a predictor of performance in hierarchical multiple regressions that accounted for other variables, including the reduced estimated verbal IQ in this group. It was concluded that isolated orbital or medial prefrontal lesions are not sufficient to produce impairments in social cognition. This is the first study to demonstrate that it is the combination of lesions to both areas that affect social cognition, irrespective of lesion volume. While group sizes were similar to other comparable studies that included patients with discrete, surgically circumscribed lesions to the prefrontal cortex, future large, multi-site studies are needed to collect larger samples and confirm these results.

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 Tesla (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 net magnetization per voxel 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), observed 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-tapping task. Our results revealed an average increase of 22% in %∆S (p=0.006) and 9% in decoding performance (p=0.015) with temporal resolution only at the highest spatial resolution of 1.5×1.5×1.5mm3, despite a 29% decrease in tSNR (p<0.001) and plateaued Z-scores. Further, the volume of significant activation was indifferent (p>0.05) across spatial resolution specifically at the highest temporal resolution of 500ms. These results demonstrate that the overall BOLD sensitivity can be increased significantly with temporal resolution, granted an adequately high spatial resolution with minimal physiological noise level. This shows the feasibility of diffuse motor-network imaging at high spatial and temporal resolution with robust BOLD sensitivity with 7T-fMRI. Importantly, we show that this sensitivity improvement could be extended to an fMRI application such as BCIs.

Abstract One of the greatest challenges in developing therapeutic regimens is the inability to rapidly and objectively assess tumor response due to treatment. Moreover, tumor response to therapeutic intervention in many cases is transient, and progressive alterations within the tumor may mask the effectiveness of an initially successful therapy. The ability to detect these changes as they occur would allow timely initiation of alternative approaches, maximizing therapeutic outcome. We investigated the ability of diffusion magnetic resonance imaging (MRI) to provide a sensitive measure of tumor response throughout the course of treatment, possibly identifying changes in sensitivity to the therapy. Orthotopic 9L gliomas were subjected to two separate therapeutic regimens, with one group receiving a single 5-day cycle (1ω) of low-dose 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and a second group receiving two cycles at the same dose, bisected with 2 days of rest (2ω). Apparent diffusion coefficient maps were acquired before and throughout treatment to observe changes in water mobility, and these observations were correlated to standard measures of therapeutic response and outcome. Our results showed that diffusion MRI was indeed able to detect the emergence of a drug-resistant tumor subpopulation subsequent to an initially successful cycle of BCNU therapy, leading to minimal gains from a second cycle. These diffusion MRI findings were highly correlated with tumor growth delay, animal survival, and ex vivo growth inhibition assays showing emerging resistance in excised tumors. Overall, this study highlights the ability of diffusion MRI to provide sensitive dynamic assessment of therapy-induced response, allowing early opportunities for optimization of therapeutic protocols. (Cancer Res 2006; 66(9): 4687-92)

Cationic magnetic nanoparticles are attractive as potential vehicles for tumor drug delivery due to their favorable interactions with both the tumor milieu and the therapeutic cargo. However, systemic delivery of these nanoparticles to the tumor site is compromised by their rapid plasma clearance. We developed a simple method for in vivo protection of cationic nanocarriers, using non-covalent surface masking with a conjugate of low molecular weight heparin and polyethylene glycol. Surface masking resulted in a 11-fold increase in plasma AUC and a 2-fold increase in the magnetic capture of systemically injected nanoparticles in orthotopic rodent brain tumors. Overall, the described methodology could expand the prospective applications for cationic magnetic nanoparticles in magnetically mediated gene/drug delivery.

For the treatment of squamous cell cancer of the head and neck (SCCHN), the assessment of treatment response is traditionally accomplished by volumetric measurements and has been suggested to be prognostic for an eventual response to treatment. An early evaluation response during the course of radiation therapy could provide an opportunity to tailor treatment to individual patients. Diffusion magnetic resonance imaging (MRI) allows for the quantification of tissue water diffusion values, thus treatment-induced loss of tumor cells will result in the increase in water mobility at the microscopic level, which can be detected as an increase in tumor diffusion values before any volumetric changes occur. We evaluated the use of diffusion MRI as an imaging biomarker of treatment response in an orthotopic mouse model of SCCHN. Mice with murine squamous cells expressing the yeast transgene cytosine deaminase were treated with 5-fluorocytosine (5FC), ionizing radiation, and combined therapy and were compared with control animals both during and after treatment for changes in tumor volumes, diffusion values, and survival. Radiation therapy had minimal effect on volumetric growth rate, diffusion, or survival. Although 5FC and combination treatment resulted in similar reductions in tumor volumes, the combination treatment elicited a much greater increase in tumor diffusion values, which correlated with improved survival. Thus, diffusion MRI as an imaging biomarker has a potential for early evaluation of the response to chemoradiation treatment in SCCHN.

Glioblastoma multiforme (GBM) has a poor prognosis despite maximal multimodal therapy. Biomarkers of relevance to prognosis which may also identify treatment targets are needed. A few hundred genetic and molecular predictors have been implicated in the literature, however with the exception of IDH1 and O6-MGMT, there is uncertainty regarding their true prognostic relevance. This study analyses reported genetic and molecular predictors of prognosis in GBM. For each, its relationship with univariate overall survival in adults with GBM is described. A systematic search of MEDLINE (1998–July 2010) was performed. Eligible papers studied the effect of any genetic or molecular marker on univariate overall survival in adult patients with histologically diagnosed GBM. Primary outcomes were median survival difference in months and univariate hazard ratios. Analyses included converting 126 Kaplan–Meier curves and 27 raw data sets into primary outcomes. Seventy-four random effects meta-analyses were performed on 39 unique genetic or molecular factors. Objective criteria were designed to classify factors into the categories of clearly prognostic, weakly prognostic, non-prognostic and promising. Included were 304 publications and 174 studies involving 14,678 unique patients from 33 countries. We identified 422 reported genetic and molecular predictors, of which 52 had ⩾2 studies. IDH1 mutation and O6-MGMT were classified as clearly prognostic, validating the methodology. High Ki-67/MIB-1 and loss of heterozygosity of chromosome 10/10q were classified as weakly prognostic. Four factors were classified as non-prognostic and 13 factors were classified as promising and worthy of additional investigation. Funnel plot analysis did not identify any evidence of publication bias. This study demonstrates a novel literature and meta-analytical based approach to maximise the value that can be derived from the plethora of literature reports of molecular and genetic factors in GBM. Caution is advised in over-interpreting the results due to study limitations. Further research to develop this methodology and improvements in study reporting are suggested.

Imaging the optic radiation (OR) is of considerable interest in studying diseases affecting the visual pathway and for pre-surgical planning of temporal lobe resections. The purpose of this study was to investigate the clinical feasibility of using probabilistic diffusion tractography based on constrained spherical deconvolution (CSD) to image the optic radiation. It was hypothesized that CSD would provide improved tracking of the OR compared with the widely used ball-and-stick model.Diffusion weighted MRI (30 directions) was performed on twenty patients with no known visual deficits. Tractography was performed using probabilistic algorithms based on fiber orientation distribution models of local white matter trajectories. The performance of these algorithms was evaluated by comparing computational times and receiver operating characteristic results, and by correlation of anatomical landmark distances to dissection estimates.The results showed that it was consistently feasible to reconstruct individual optic radiations from clinically practical (4.5 minute acquisition) diffusion weighted imaging data sets using CSD. Tractography based on the CSD model resulted in significantly shorter computational times, improved receiver operating characteristic results, and shorter Meyer's loop to temporal pole distances (in closer agreement with dissection studies) when compared to the ball-and-stick based algorithm.Accurate tractography of the optic radiation can be accomplished using diffusion MRI data collected within a clinically practical timeframe. CSD based tractography was faster, more accurate and had better correlation with known anatomical landmarks than ball-and-stick tractography.

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 thalamic volume negatively correlated with Bain tremor severity score (ρ = - 0.65, p = 0.03). Left thalamic volume negatively correlated with general Bain tremor severity score (ρ = - 0.65, p = 0.03) and the Bain writing score (ρ = - 0.65, p = 0.03). Right SCP area negatively correlated with Bain writing score (ρ = - 0.69, p = 0.02). Finally, Bain Archimedes score was significantly higher in patients with lesions in the contralateral thalamus. Whole brain lesion load showed no relationship with tremor severity. These results implicate degeneration of key structures within the cerebello-thalamic pathway as pathological substrates for tremor in MS patients.

Purpose To demonstrate simultaneous T 1 ‐weighted imaging, T 1 mapping, 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, , 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 maps showed increased blurring and reduced SNR. T 1 , , 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, 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.

MOFFAT, BRAD A. PhD; ATCHISON, DAVID A. PhD, FAAO; POPE, JAMES M. DPhil, FAIP Author Information

Abstract Purpose: Vascular endothelial growth factor (VEGF)-A is an important mediator of angiogenesis in almost all solid tumors. The aim of this study was to evaluate the effect of VEGF-A expression on tumor growth, perfusion, and chemotherapeutic efficacy in orthotopic 9L gliosarcomas. Experimental Design: Stable 9L cell lines underexpressing and overexpressing VEGF-A were generated. Anatomic, susceptibility contrast, and continuous arterial spin-labeling magnetic resonance imaging were used to quantify the volume, blood volume, and blood flow of tumors orthotopically grown from these and wild-type 9L cells. Histologic, immunohistochemical, and quantitative reverse transcription-PCR analyses were also done on excised tumors. Finally, the effects of carmustine chemotherapy were also evaluated. Results: Orthotopic tumors underexpressing VEGF-A had slower growth rates (increased median survival), greater blood flow, vessel density, and VEGF-D expression, but no statistical difference in blood volume and chemotherapeutic sensitivity, compared with tumors with wild-type levels of VEGF-A. Tumors overexpressing VEGF-A had faster growth rates, greater blood volume, vessel density, and blood flow but no statistical difference in VEGF-D expression and chemotherapeutic sensitivity compared with wild-type VEGF-A-expressing tumors. Conclusion: Blood volume and blood flow are independent and different biomarkers of tumor perfusion. Therefore, both should be measured when characterizing the efficacy of antiangiogenic therapies. Underexpression of VEGF-A does not result in complete inhibition of angiogenesis. Moreover, these tumors have a different perfusion phenotype, suggesting that angiogenesis is mediated by an alternative pathway. The results indicate that VEGF-D is a plausible alternative mediator of this angiogenesis.

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Remote structural and functional changes have been previously described after stroke and may have an impact on clinical outcome. We aimed to use multimodal MRI to investigate contralesional subcortical structural and functional changes 3 months after anterior circulation ischemic stroke. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Fifteen patients with acute ischemic stroke had multimodal MRI imaging (including high resolution structural T1-MPRAGE and resting state fMRI) within 1 week of onset and at 1 and 3 months. Seven healthy controls of similar age group were also imaged at a single time point. Contralesional subcortical structural volume was assessed using an automated segmentation algorithm in FMRIB's Integrated Registration and Segmentation Tool (FIRST). Functional connectivity changes were assessed using the intrinsic connectivity contrast (ICC), which was calculated using the functional connectivity toolbox for correlated and anticorrelated networks (Conn). &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Contralesional thalamic volume in the stroke patients was significantly reduced at 3 months compared to baseline (median change -2.1%, interquartile range [IQR] -3.4-0.4, p = 0.047), with the predominant areas demonstrating atrophy geometrically appearing to be the superior and inferior surface. The difference in volume between the contralesional thalamus at baseline (mean 6.41 ml, standard deviation [SD] 0.6 ml) and the mean volume of the 2 thalami in controls (mean 7.22 ml, SD 1.1 ml) was not statistically significant. The degree of longitudinal thalamic atrophy in patients was correlated with baseline stroke severity with more severe strokes being associated with a greater degree of atrophy (Spearman's rho -0.54, p = 0.037). There was no significant difference between baseline contralesional thalamic ICC in patients and control thalamic ICC. However, in patients, there was a significant linear reduction in the mean ICC of the contralesional thalamus over the imaging time points (p = 0.041), indicating reduced connectivity to the remainder of the brain. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; These findings highlight the importance of remote brain areas, such as the contralesional thalamus, in stroke recovery. Similar methods have the potential to be used in the prediction of stroke outcome or as imaging biomarkers of stroke recovery.

Purpose: 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.

We report in vitro measurements of effective diffusion tensors characterising the anisotropic transport of water in human eye lenses ranging in age from 13 to 86 years. The measurements were obtained by means of a pulsed field gradient spin echo (PFGSE) magnetic resonance imaging (MRI) technique at a spatial resolution of 218 x 218 x 1000 microm(3). The results show that water diffusion is both spatially inhomogeneous and highly anisotropic on the timescale of the measurements (approximately 15 msec). Diffusion parallel to the long axes of the lens fibre cells is relatively unrestricted, whereas that between cells is substantially inhibited by the cell membranes, particularly in the inner cortex region of the lens. The data confirm the presence of a diffusion barrier surrounding the lens nucleus, which inhibits transport of water and other small molecules into and out of the nucleus. The results shed light on factors that may influence the onset of presbyopia and senile cataract. They also have implications for delivery of drugs to the lens nucleus.

The ability of superparamagnetic iron oxide nanoparticles (SPIONs) to shorten the effective transverse relaxation time (T2) during magnetic resonance imaging (MRI) makes them excellent contrast agents in diagnostic applications. Here we describe a new class of hybrid MRI contrast agent using dispersions of lyotropic bicontinuous cubic phase nanoparticles doped with SPIONs. Hybrid mesophase nanoparticles (HMNs) combining the cubic order of a lyotropic lipid system and SPIONs were successfully prepared and characterized. Highly monodisperse 8 nm spherical SPIONs coated with oleic acid were dispersed in the bulk cubic phase forming lipid matrix of phytantriol nanoparticles 180 nm in size. Transverse relaxivity (r2) measurements show that enhancement of the T2 relaxation time of the HMNs is proportional to the loading of SPIONs in the mesophase nanoparticles. Excellent contrast enhancement in T2 weighted images in the kidney and liver of live rats was observed after intravenous injection of the hybrid mesophase nanoparticles. Results indicate that the HMNs are rapidly transported to the renal system making them useful for contrast enhancement of renal and hepatic systems.

Tumour associated epilepsy (TAE) is common, debilitating and often not successfully controlled by surgical resection of the tumour and administration of multiple anti-epileptic drugs. It represents a cause of significant lost quality of life in an incurable disease and is therefore an important subject for ongoing research. The pathogenesis of TAE is likely to be multifactorial and involve, on the microscopic level, the interaction of genetic factors, changes in the peritumoural microenvironment, alterations in synaptic neurotransmitter release and re-uptake, and the excitotoxic effects of glutamate. On a macroscopic level, the occurrence of TAE is likely to be influenced by tumour size, location and interaction with environmental factors. The optimal treatment of TAE requires a multi-disciplinary approach with input from neurosurgeons, neurologists, radiologists, pathologists and basic scientists. This article reviews the current literature regarding the incidence, treatment, and aetiology of TAE.

To evaluate the use of high-resolution MRI for hippocampal volumetry in dogs and to define a lower reference limit for hippocampal formation (HF) volume.20 dogs (with no history of seizures and no underlying structural brain disease) that underwent MRI of the brain.The MRI protocol included a high-resolution T1-weighted 3-D ultrafast gradient-echo sequence aligned in a dorsal plane perpendicular to the long axis of the HF. Images obtained with MRI were retrospectively analyzed by 2 observers (A and B). Intraobserver and interobserver agreement were calculated with the Lin concordance correlation coefficient. Volume measurements of the HF were adjusted for intracranial volume, and a lower 95% reference limit for adjusted HF volume was calculated.There was substantial intraobserver agreement (Lin concordance correlation coefficient, 0.97 [95% confidence interval {CI}, 0.94 to 0.99]) but poor interobserver agreement (Lin concordance correlation coefficient, 0.63 [95% CI, 0.37 to 0.79]). The lower 95% reference limit for adjusted HF volume was 0.56 cm(3) (90% CI, 0.52 to 0.60 cm(3)) for the right HF and 0.55 cm(3) (90% CI, 0.52 to 0.58 cm(3)) for the left HF.HF volumes should be adjusted for intracranial volume to account for the large variation in canine skull size. The amount of time required to perform HF volumetry and low interobserver agreement may restrict this technique to research applications, such as the investigation of epileptic patients for hippocampal sclerosis or other cognitive disorders.

Purpose This work demonstrates a 3D radial multi‐echo acquisition scheme for time‐efficient sodium ( 23 Na) MR‐signal acquisition and analysis. Echo reconstructions were used to produce signal‐to‐noise ratio (SNR)‐enhanced 23 Na‐images and parameter maps of the biexponential observed transverse relaxation time ( ) decay. Methods A custom‐built sequence for radial multi‐echo acquisition was proposed for acquisition of a series of 3D volumetric 23 Na‐images. Measurements acquired in a phantom and in vivo human brains were analyzed for SNR enhancement and multi‐component estimation. Results Rapid gradient refocused imaging acquired 38 echoes within a repetition time of 160 ms. Signal averaging of multi‐echo time (TE) measurements showed an average brain tissue SNR enhancement of 34% compared to single‐TE images across subjects. Phantom and in vivo measurements detected distinguishable signal decay characteristics for fluid and solid media. Mapping results were investigated in phantom and in vivo experiments for sequence timing optimization and signal decay analysis. The mapping results were consistent with previously reported values and facilitated fluid‐signal discrimination. Conclusion The proposed method offers an efficient 23 Na‐imaging scheme that extends existing 23 Na‐MRI sequences by acquiring signal decay information with no increase in time or specific absorption rate. The resultant SNR‐enhanced 23 Na‐images and estimated signal decay characteristics offer great potential for detailed investigation of tissue compartment characterization and clinical application. Magn Reson Med 79:1950–1961, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

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.

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.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.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.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.

A major limitation in cancer gene therapy, specifically gene-dependent enzyme prodrug therapy (GDEPT), is inefficient gene delivery and expression. The suicide gene cytosine deaminase (CD) and its substrate, 5-fluorocytosine (5-FC), have been extensively explored due to the inherent ‘bystander’ effect achieved through diffusion of the toxic metabolite 5-fluorouracil (5-FU). In this study, we aimed to enhance this ‘bystander’ effect by fusing the Saccharomyces cerevisiae CD to the HSV-1 tegument protein vp22, a novel translocating protein. Two constructs were created: one with vp22 fused to CD (vp22CD) and a second wherein a truncated vp22, lacking the necessary residues for trafficking, fused to CD (delvp22CD). The generated 9L stable lines exhibited similar growth rates, enzyme expression, CD activity, and sensitivity to 5-FC and 5-FU. However, mixed population colony formation assays demonstrated greater bystander effect with the vp22CD fusion as compared to delvp22CD. This enhancement was maintained in vivo where 9L tumors expressing 20 or 50% vp22CD exhibited increased growth delay compared to the respective delvp22CD tumors. Moreover, adenoviral transduction of established wild-type 9L tumors showed increased growth delay with vp22CD (Ad-EF_vp22CD) as compared to equivalent CD (Ad-EF_CD) transduced tumors. Finally, confirming the increased efficacy, 19F magnetic resonance spectroscopy (MRS) of vp22CD-expressing tumors demonstrated increased 5-FU levels as compared to tumors expressing the nontranslocating CD. These results together demonstrated that fusion of vp22 to CD resulted in CD translocation, which in turn amplified conversion of 5-FC to 5-FU in vivo and enhanced the therapeutic benefit of this GDEPT strategy.

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-the-art. However, the successful translation of standard clinical MRI technology to preclinical MRI is required to facilitate next-generation high-throughput MRI.

In this paper, we present a new approach to the combinatorial discovery of amphiphilic maleic anhydride copolymers which can be used as a generic method for the optimization and control of hydrophobic nanoparticle phase transfer into the aqueous phase. This combinatorial multiwell chemical screening process resulted in the discovery of ‘hit’ polymer ring opened chemistries that allow the spontaneous and highly efficient phase transfer of superparamagnetic iron oxide (SPIO) nanoparticles into water under ambient conditions. Effective polymer−SPIO materials were screened for magnetic properties via a high-throughput (HT) magnetic resonance imaging (MRI) technique and nanoparticles were successfully tested for stability in buffer. It was found that the water-soluble SPIO nanoparticles could be tuned somewhat in terms of their MRI relaxivities via the specific ring-opening molecules used. To impart effective charge and steric stability of the water-soluble nanoparticles in buffer, the molecular weight, and chemistry of any given maleic anhydride copolymer was critical. Particle sizing via dynamic light scattering and cryo-transmission electron microscopy analysis showed significant discrepancies in the mean particle sizes obtained. This HT approach and the new amphiphilic polymers discovered have potential for use in various nanotechnology applications.

Functional imaging biomarkers of cancer treatment response offer the potential for early determination of outcome through the assessment of biochemical, physiologic, and microenvironmental readouts. Cell death may result in an immunologic response, thus complicating the interpretation of biomarker readouts. This study evaluated the temporal effect of treatment-associated inflammatory activity on diffusion magnetic resonance imaging and 2-[(18)F]-fluoro-2-deoxy-D-glucose-positron emission tomography imaging (FDG-PET) biomarkers to delineate the effects of the inflammatory response on imaging readouts.Rats with intracerebral 9L gliosarcomas were separated into four groups consisting of control, an immunosuppressive agent dexamethasone (Dex), 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and BCNU+Dex. Animals were imaged using diffusion-weighted magnetic resonance imaging and FDG-PET at 0, 3, and 7 days posttreatment.In the BCNU- and BCNU+Dex-treated animal groups, diffusion values increased progressively over the 7-day study period to approximately 23% over baseline. The FDG percentage change of standard uptake value decreased at day 3 (-30.9%) but increased over baseline levels at day 7 (+20.1%). FDG-PET of BCNU+Dex-treated animals were found to have percentage of standard uptake value reductions of -31.4% and -24.7% at days 3 and 7, respectively, following treatment. Activated macrophages were observed on day 7 in the BCNU treatment group with much fewer found in the BCNU+Dex group.Results revealed that treatment-associated inflammatory response following tumor therapy resulted in the accentuation of tumor diffusion response along with a corresponding increase in tumor FDG uptake due to the presence of glucose-consuming activated macrophages. The dynamics and magnitude of potential inflammatory response should be considered when interpreting imaging biomarker results.

Bevacizumab, an anti-angiogenic agent, is FDA-approved for use in patients with recurrent glioblastoma multiforme (rGBM). The radiologic evaluation of tumor response to bevacizumab is complex and there is no validated method of monitoring tumor vascularity during therapy. We evaluated perfusion-weighted MR imaging (PWI) in our cohort of patients enrolled in the CABARET trial, which examined the effectiveness of bevacizumab with or without carboplatin in patients with rGBM. Pre-treatment and early follow-up (4- and 8-week) PWI were used to calculate relative cerebral blood volume (rCBV) histogram statistics of the contrast-enhancing and FLAIR hyperintense tumor volumes. A novel rCBV measurement (load) was developed to estimate the total volume of perfused tumor blood vessels. Changes in all rCBV measures were examined for correlations with progression-free (PFS) and overall survival (OS). All of our 15 patients enrolled in the CABARET trial were included. Median PFS and OS were 23 and 45 weeks respectively. Kaplan–Meier analysis of pre-treatment PWI revealed an 18 week reduction in median OS in patients with high tumor rCBV (p = 0.031). Changes in rCBV measures, especially load, correlated significantly with PFS and OS at both follow-up time-points. Patients with the greatest reduction in rCBVload by 8-weeks of therapy had a significantly increased median OS (30 weeks; p = 0.013). PWI may be of significant clinical utility in managing patients with rGBM, particularly those treated with anti-angiogenic agents such as bevacizumab. These findings need to be confirmed prospectively in larger studies.

To develop representative MRI atlases of the canine brain and to evaluate 3 methods of atlas-based segmentation (ABS).62 dogs without clinical signs of epilepsy and without MRI evidence of structural brain disease.The MRI scans from 44 dogs were used to develop 4 templates on the basis of brain shape (brachycephalic, mesaticephalic, dolichocephalic, and combined mesaticephalic and dolichocephalic). Atlas labels were generated by segmenting the brain, ventricular system, hippocampal formation, and caudate nuclei. The MRI scans from the remaining 18 dogs were used to evaluate 3 methods of ABS (manual brain extraction and application of a brain shape-specific template [A], automatic brain extraction and application of a brain shape-specific template [B], and manual brain extraction and application of a combined template [C]). The performance of each ABS method was compared by calculation of the Dice and Jaccard coefficients, with manual segmentation used as the gold standard.Method A had the highest mean Jaccard coefficient and was the most accurate ABS method assessed. Measures of overlap for ABS methods that used manual brain extraction (A and C) ranged from 0.75 to 0.95 and compared favorably with repeated measures of overlap for manual extraction, which ranged from 0.88 to 0.97.Atlas-based segmentation was an accurate and repeatable method for segmentation of canine brain structures. It could be performed more rapidly than manual segmentation, which should allow the application of computer-assisted volumetry to large data sets and clinical cases and facilitate neuroimaging research and disease diagnosis.

While brain iron dysregulation has been observed in several neurodegenerative disorders, its association with the progressive neurodegeneration in Niemann-Pick type C is unknown. Systemic iron abnormalities have been reported in patients with Niemann-Pick type C and in animal models of Niemann-Pick type C. In this study, we examined brain iron using quantitative susceptibility mapping MR imaging in individuals with Niemann-Pick type C compared with healthy controls.A cohort of 10 patients with adolescent- and adult-onset Niemann-Pick type C and 14 age- and sex-matched healthy controls underwent 7T brain MR imaging with T1 and quantitative susceptibility mapping acquisitions. A probing whole-brain voxelwise comparison of quantitative susceptibility mapping between groups was conducted. Mean quantitative susceptibility mapping in the ROIs (thalamus, hippocampus, putamen, caudate nucleus, and globus pallidus) was further compared. The correlations between regional volume, quantitative susceptibility mapping values, and clinical features, which included disease severity on the Iturriaga scale, cognitive function, and the Social and Occupational Functioning Assessment Scale, were explored as secondary analyses.We observed lower volume in the thalamus and voxel clusters of higher quantitative susceptibility mapping in the pulvinar nuclei bilaterally in patients with Niemann-Pick type C compared with the control group. In patients with Niemann-Pick type C, higher quantitative susceptibility mapping in the pulvinar nucleus clusters correlated with lower volume of the thalamus on both sides. Moreover, higher quantitative susceptibility mapping in the right pulvinar cluster was associated with greater disease severity.Our findings suggest iron deposition in the pulvinar nucleus in Niemann-Pick type C disease, which is associated with thalamic atrophy and disease severity. This preliminary evidence supports the link between iron and neurodegeneration in Niemann-Pick type C, in line with existing literature on other neurodegenerative disorders.

Abstract Background and Purpose Magnetic resonance spectroscopy (MRS) measures neurochemicals in vivo. Glutathione (GSH) is a neuroprotective chemical shown to vary significantly in patients with Alzheimer's disease (AD). This work investigates the reproducibility of GSH measures in the mesial temporal lobe (MTL) to identify its potential clinical utility. Methods MRS data were acquired from eight healthy volunteers (31.1 ± 5.2 years; 4 male/female) using Mescher‐Garwood‐Point Resolved Spectroscopy (MEGA‐PRESS) from the MTL in the left hemisphere across two scan sessions in the same visit. Total N‐acetylaspartate (tNAA), choline (tCho), creatine (tCr), and GSH were quantified. Reproducibility of quantifications of these neurochemicals were tested using coefficient of variance (CV) between scan sessions. Reproducibility of voxel placement on the left MTL was calculated by measuring the tissue overlap and percent of hippocampus within that voxel. CV measured across different scan sessions in each individual, with a CV&lt;15% was accepted as “good” reproducibility. Paired t ‐tests were carried out to establish the significant differences between the two scans across each individual with p &lt;.05 as significant. Results TNAA (%CV = 7.2; p = .5), tCr (%CV = 7.8; p = .6) and tCho (%CV = 9.3; p = .4), and GSH (%CV = 22; p = .1). The dice coefficient that reflects the level of overlap of hippocampal tissue in the voxel was shown to be 0.8 ± 0.1. Voxel tissue composition were: Scan 1 (cerebrospinal fluid [CSF]: 5 ± 1%, white matter [WM]: 52 ± 3%, gray matter [GM]: 43 ± 3%); Scan 2 (CSF: 5 ± 1%, WM: 52 ± 4%, GM: 44 ± 4%). Conclusion The data suggest measures of abundant metabolites in the MTL using the MEGA‐PRESS sequence has a high reproducibility. Reproducibility of GSH in this area was poorer requiring care when interpreting measures of GSH in the MTL for clinical translational purposes.

The use of medical imaging contrast agents may lead to improved patient prognosis by potentially enabling an earlier detection of diseases and therefore an earlier initiation of treatments. In this study, we fabricated superparamagnetic iron oxide (SPIO) nanoparticles within the inner cavity of multiwalled carbon nanotubes (MWCNTs) for the first time; thereby ensuring high mechanical stability of the nanoparticles. A simple, but effective, self-assembled coating with RAFT diblock copolymers ensured the SPIO-MWCNTs have a high dispersion stability under physiological conditions. In vivo acute tolerance testing in mice showed a high tolerance dose up to 100 mg kg(-1). Most importantly, after administration of the material a 55% increase in tumor to liver contrast ratio was observed with in vivo MRI measurements compared to the preinjection image enhancing the detection of the tumor.

We aimed to elicit emotion in patients with surgically circumscribed lesions of the prefrontal cortex (PFC) in order to elucidate the precise functional roles in emotion processing of the discrete subregions comprising the ventromedial PFC, including the medial PFC and orbitofrontal cortex (OFC). Three components of emotional reactivity were measured: subjective experience, behaviour, and physiological response. These included measures of self-reported emotion, observer-rated facial expression of emotion and measurements of heart rate and heart rate variability (HRV) during film viewing, and a measure of subjective emotional change since surgery. Patients with lesions to the ventromedial PFC demonstrated significant differences compared with controls in HRV during the film clips, suggesting a shift to greater dominance of sympathetic input. In contrast, patients with lesions restricted to the OFC showed significant differences in HRV suggesting reduced sympathetic input. They also showed less facial expression of emotion during positive film clips, and reported more subjective emotional change since surgery compared with controls. This human lesion study is important for refining theoretical models of emotion processing by the ventromedial PFC, which until now have primarily been based on anatomical connectivity, animal lesion, and human functional neuroimaging research. Such theories have implications for the treatment of a wide variety of emotional disorders.

Segmentation is the process of partitioning an image into subdivisions and can be applied to medical images to isolate anatomical or pathological areas for further analysis. This process can be done manually or automated by the use of image processing computer packages. Atlas-based segmentation automates this process by the use of a pre-labelled template and a registration algorithm. We developed an ovine brain atlas that can be used as a model for neurological conditions such as Parkinson's disease and focal epilepsy. 17 female Corriedale ovine brains were imaged in-vivo in a 1.5T (low-resolution) MRI scanner. 13 of the low-resolution images were combined using a template construction algorithm to form a low-resolution template. The template was labelled to form an atlas and tested by comparing manual with atlas-based segmentations against the remaining four low-resolution images. The comparisons were in the form of similarity metrics used in previous segmentation research. Dice Similarity Coefficients were utilised to determine the degree of overlap between eight independent, manual and atlas-based segmentations, with values ranging from 0 (no overlap) to 1 (complete overlap). For 7 of these 8 segmented areas, we achieved a Dice Similarity Coefficient of 0.5-0.8. The amygdala was difficult to segment due to its variable location and similar intensity to surrounding tissues resulting in Dice Coefficients of 0.0-0.2. We developed a low resolution ovine brain atlas with eight clinically relevant areas labelled. This brain atlas performed comparably to prior human atlases described in the literature and to intra-observer error providing an atlas that can be used to guide further research using ovine brains as a model and is hosted online for public access.

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.

Abstract The mesoporous structure of sol‐gel prepared gadolinium and europium doped silicate nanoparticles has been found to be highly dependent on the formulated composition, with synthesised samples displaying both disordered and hexagonally ordered mesoporous packing symmetry. The degree of pore ordering within the nanoparticles has a strong correlation with the total lanthanide (Gd 3+ and Eu 3+ ) concentration. The gadolinosilicates are excellent magnetic resonance imaging (MRI) longitudinal (T 1 ) agents. The longitudinal relaxivity (r 1 ) and transverse (r 2 ) relaxivity, a measure of MRI contrast agent efficiency, were up to four times higher than the clinically employed Omniscan (gadodiamide); with r 1 up to 20.6 s −1 mM −1 and r 2 of 66.2 s −1 mM −1 compared to 5.53 and 4.64 s −1 mM −1 , respectively, for Omniscan. In addition, the europium content of all the samples studied is below the self‐quenching limit, which results in a strong luminescence response from the nanoparticles on excitation at 250 nm. The Eu‐Gd silicate nanoparticles act as bimodal imaging agents for MRI and luminescence. These mesoporous nanoparticles also have the potential to serve as encapsulation and controlled release matrices for pharmaceuticals. They are therefore a promising multimodal theranostic platform.

Background: Tremor is present in almost half of multiple sclerosis (MS) patients. The lack of understanding of its pathophysiology is hampering progress in development of treatments. Objectives: To clarify the structural and functional brain changes associated with the clinical phenotype of upper limb tremor in people with MS. Methods: Fifteen healthy controls (46.1 ± 15.4 years), 27 MS participants without tremor (46.7 ± 11.6 years) and 42 with tremor (46.6 ± 11.5 years) were included. Tremor was quantified using the Bain score (0–10) for overall severity, handwriting and Archimedes spiral drawing. Functional magnetic resonance imaging activations were compared between participants groups during performance of a joystick task designed to isolate tremulous movement. Inflammation and atrophy of cerebello-thalamo-cortical brain structures were quantified. Results: Tremor participants were found to have atrophy of the cerebellum and thalamus, and higher ipsilateral cerebellar lesion load compared to participants without tremor ( p &lt; 0.020). We found higher ipsilateral activation in the inferior parietal lobule, the premotor cortex and supplementary motor area in MS tremor participants compared to MS participants without tremor during the joystick task. Finally, stronger activation in those areas was associated with lower tremor severity. Conclusion: Subcortical neurodegeneration and inflammation along the cerebello-thalamo-cortical and cortical functional neuroplasticity contribute to the severity of tremor in MS.

Solvent facilitated perfusion (SFP) has been proposed as a technique to increase the delivery of chemotherapeutic agents to tumors. SFP entails direct injection of the agent into the tumor in a water-miscible organic solvent, and because the solvent moves easily through both aqueous solutions and cellular membranes it drives the penetration of the solubilized anticancer agent throughout the tumor. To test this hypothesis, we compared the pharmacokinetics (PK) of 14C-labeled 1,3-bis-chlorethyl-1-nitrosourea (BCNU) in intra-cerebral 9L rat gliomas after intravenous (IV) infusion in 90% saline--10% ethanol or direct intratumoral (IT) injection of 14C-BCNU in 100% ethanol (DTI-015). Treatment with DTI-015 yielded a peak radioactive count (Cmax) for the 14C label that was 100-1000 fold higher in the tumor than in all other tissues in addition to a concentration in the tumor that was 100-fold higher than that achieved following IV infusion of 14C-BCNU. Pathologic and auto-radiographic analysis of tissue sections following IT injection of 14C-BCNU in ethanol into either tumor or normal rat brain revealed both an enhanced local volume of distribution and an increased concentration of BCNU delivered to tumor compared to non-tumor bearing brain. To investigate the mechanism behind the SFP of BCNU to the tumor both dynamic contrast and perfusion MRI were performed on 9L tumors before and after treatment and demonstrated a decrease in tumor perfusion following IT injection of DTI-015. Finally, initial PK of patient blood samples following administration of DTI-015 into relapsed high-grade glioma indicated a 20-fold decrease in systemic exposure to BCNU compared to IV infusion of BCNU providing further evidence for the enhanced therapeutic ratio observed for DTI-015.

Abstract Continuous arterial spin labeling experiments typically use flow‐driven adiabatic fast passage inversion of the arterial blood water protons. In this article, we measure the effect of magnetization transfer in blood and how it affects the inversion label. We use modified Bloch equations to model flow‐driven adiabatic inversion in the presence of magnetization transfer in blood flowing at velocities from 1 to 30 cm/s in order to explain our findings. Magnetization transfer results in a reduction of the inversion efficiency at the inversion plane of up to 3.65% in the range of velocities examined, as well as faster relaxation of the arterial label in continuous labeling experiments. The two effects combined can result in inversion efficiency reduction of up to 8.91% in the simulated range of velocities. These effects are strongly dependent on the velocity of the flowing blood, with 10 cm/s yielding the largest loss in efficiency due to magnetization transfer effects. Flowing blood phantom experiments confirmed faster relaxation of the inversion label than that predicted by T 1 decay alone. Copyright © 2007 John Wiley &amp; Sons, Ltd.

The development of biomedical nanoparticulate materials for use in diagnostics is a delicate balance between performance, particle size, shape, and stability. To identify materials that satisfy all of the criteria it is useful to employ automated high-throughput (HT) techniques for the study of these materials. The structure and performance of surfactant templated mesoporous silica is very sensitive to a wide number of variables. Variables, such as the concentration of the structure-directing agent, the cosolvent and dopant ions and also the temperature and concentration of quenching all have an influence on the structure, surface chemistry, and therefore, the performance of the mesoporous silica nanoparticles generated. Using an automated robotic synthetic platform, a technique has been developed for the high-throughput preparation of mesoporous silica and gadolinium-doped silicate (gadoliniosilicate) nanoparticulate MRI contrast agents. Twelve identical repeats of both the mesoporous silica and gadolinosilicate were synthesized to investigate the reproducibility of the HT technique. Very good reproducibility in the production of the mesoporous silica and the gadolinosilcate materials was obtained using the developed method. The performance of the gadolinosilicate materials was comparable as a T(1) agent to the commercial MRI contrast agents. This HT methodology is highly reproducible and an effective tool that can be translated to the discovery of any sol-gel derived nanomaterial.

The rapid and accurate prediction of the need for massive transfusion in bleeding trauma patients remains a challenge. Various models have been proposed to anticipate massive transfusion with variable success. The current study by Mutschler and colleagues proposes four classes of shock as defined by the Shock Index and examines its ability to predict the need for massive transfusion. This model demonstrates promise as a practical tool in acute decision-making for transfusion after injury.

Background To evaluate a new semi‐automated segmentation method for calculating hippocampal volumes and to compare results with standard software tools in a cohort of people with subjective memory complaints (SMC) and mild cognitive impairment (MCI). Methods Data from 58 participants, 39 with SMC (17 male, 22 female, mean age 72.6) and 19 with MCI (6 male, 13 female, mean age 74.3), were analyzed. For each participant, T1‐weighted images were acquired using an MPRAGE sequence on a 3 Tesla MRI system. Hippocampal volumes (left, right, and total) were calculated with a new, age appropriate registration template, based on older people and using the advanced software tool ANTs (Advanced Normalization Tools). The results were compared with manual tracing (seen as the reference standard) and two widely accepted automated software tools (FSL, FreeSurfer). Results The hippocampal volumes, calculated by using the age appropriate registration template were significantly ( P &lt; 0.05) more accurate (mean volume accuracy more than 90%) than those obtained with FreeSurfer and FSL (both less than 70%). Dice coefficients for the hippocampal segmentations with the new template method (75.3%) were slightly, but significantly ( P &lt; 0.05) higher than those from FreeSurfer (72.4%). Conclusion These results suggest that an age appropriate registration template might be a more accurate alternative to calculate hippocampal volumes when manual segmentation is not feasible. J. MAGN. RESON. IMAGING 2015;42:1631–1638.

Abstract Objectives Mapping the neurobiology of meditation using 3 Tesla functional MRI (fMRI) has burgeoned recently. However, limitations in signal quality and neuroanatomical resolution have impacted reliability and precision of extant findings. Although ultra-high strength 7 Tesla MRI overcomes these limitations, investigation of meditation using 7 Tesla fMRI is still in its infancy. Methods In this feasibility study, we scanned 10 individuals who were beginner meditators using 7 Tesla fMRI while they performed focused attention meditation and non-focused rest. We also measured and adjusted the fMRI signal for key physiological differences between meditation and rest. Finally, we explored the 2-week impact of the single fMRI meditation session on mindfulness, anxiety and focused attention attributes. Results Group-level task fMRI analyses revealed significant reductions in activity during meditation relative to rest in Default-mode network hubs, i.e., antero-medial prefrontal and posterior cingulate cortices, precuneus, as well as visual and thalamic regions. These findings survived stringent statistical corrections for fluctuations in physiological responses which demonstrated significant differences (p &lt; 0.05/n, Bonferroni controlled) between meditation and rest. Compared to baseline, State Mindfulness Scale (SMS) scores were significantly elevated (F = 8.16, p&lt;0.05/n, Bonferroni controlled) following the fMRI meditation session, and were closely maintained at 2-week follow up. Conclusions This pilot study establishes the feasibility and utility of investigating focused attention meditation using ultra-high strength (7 Tesla) fMRI, by supporting widespread evidence that focused attention meditation attenuates Default-mode activity responsible for self-referential processing. Future functional neuroimaging studies of meditation should control for physiological confounds and include behavioural assessments.

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.

Polyoxometalates (POMs) incorporating paramagnetic ions, such as gadolinium, show promise as contrast agents for application in magnetic resonance imaging (MRI). Specifically, [Gd(W5O18)2]9- (denoted as GdWO) has been reported to have a higher relaxivity than commercially available contrast agents, but it's clinical utility has been limited by the intrinsic instability of POMs at physiological pH (7.4). In the current report we present a stability study on neat GdWO and nano-assemblies of block copolymers with GdWO in the pH range 5.0-7.4 to assess their suitability as MRI contrast agents. Neat GdWO only maintained structural stability between pH 5.4 and 6.4, and demonstrated poor MRI contrast at pH 7.4. To address this pH instability, GdWO was self-assembled with cationic mPEG brush block copolymers containing 20 or 40 units derived from the cationic monomer, 2-dimethylaminoethyl methacrylate (DMAEMA). Nano-assemblies with different charge ratios were synthesised and characterised according to their size, stability, contrasting properties and toxicity. The longitudinal relaxivity (r1) of the nano-assemblies was found to be dependent on the charge ratio, but not on the length of the cationic polymer block. Further investigation of PDMAEMA20 nano-assemblies demonstrated that they were stable over the pH range 5.0-7.4, exhibiting a higher r1 than either neat GdWO (2.77 s-1 mM-1) or clinical MRI contrast agent Gd-DTPA (4.1 s-1 mM-1) at pH 7.4. Importantly, the nano-assembly with the lowest charge ratio (0.2), showed the highest r1 (12.1 s-1 mM-1) whilst, stabilising GdWO over the pH range studied, eliciting low toxicity with MDA-MB231 cells.

This study aimed to evaluate and validate chemical shift imaging (CSI) for in vivo glutamate (Glu) quantification in patients with supratentorial gliomas. If validated, CSI could become an extremely useful tool to investigate metabolic dysfunction of Glu in excitotoxic neuropathologies. Quantitative CSI estimates of Glu concentrations were compared with known concentrations of Glu in aqueous phantom solutions. Forty-one patients with known or likely supratentorial gliomas underwent preoperative CSI. The spectra obtained were analyzed for Glu concentrations and Glu to creatine (Cr) ratios. These in vivo measurements were correlated against ex vivo Glu content quantified by high performance liquid chromatography (HPLC) measured in 65 resected brain tumor and peritumoral brain specimens. For the phantom solutions the CSI estimates of Glu concentration and the Glu/Cr ratios were highly correlated with known Glu concentration (r2 = 0.95, p = 0.002, and r2 = 0.97, p < 0.0001, respectively). There was a modest, but statistically significant, correlation between the ex vivo measured Glu and in vivo spectroscopic Glu concentration (r2 = 0.22, p = 0.04) and ratios of Glu to Cr (r2 = 0.30, p = 0.002). Quantitative measurement of Glu content is feasible in patients with supratentorial gliomas using CSI. The in vitro and in vivo results suggest that this has the potential to be a reliable quantitative imaging assay for brain tumor patients. This may have wide clinical research applications in a number of neurological disorders where Glu excitotoxicity and metabolic dysfunction are known to play a role in pathogenesis, including tumor associated epilepsy, epilepsy, stroke and neurotrauma. Copyright © 2014 John Wiley & Sons, Ltd.

We report results of 1H NMR transverse relaxation experiments on human and porcine eye lenses. Several authors have reported that transverse relaxation is not mono-exponential when observed by the Carr-Purcell-Meiboom-Gill (CPMG) sequence and have interpreted the results by postulating the presence of "pools" of water molecules in different binding environments that do not exchange rapidly on the NMR timescale. We have compared CPMG data for intact lenses with results for lens homogenates and have combined a CPMG spectroscopic pulse train with NMR micro-imaging to study the nature of the transverse relaxation process in human and porcine lenses. Fast exchange of water protons with the lens proteins (crystallins) leads to an enhanced transverse relaxation rate that varies linearly with protein concentration. At the resolution of NMR micro-imaging the transverse relaxation process is mono-exponential. The results show that the multi-exponential CPMG data observed spectroscopically for whole lenses reflect spatial variations in crystallin content through the lens rather than the presence of distinct "bound" and "free" water pools.

Bimodal radioiodine/Gd labelled polymeric nanoparticles prepared using a versatile one-step three-component click reaction.

Enhanced T1 MRI contrast was observed in mesoporous gadolinosilicates co-doped with aluminium. The effect of gadolinium and aluminium dopant concentration was explored using a high-throughput workflow. The T1 relaxivity increases with lower gadolinium and higher aluminium loadings.

Abstract Performing voluntary movements involves many regions of the brain, but it is unknown how they work together to plan and execute specific movements. We recorded high‐resolution ultra‐high‐field blood‐oxygen‐level‐dependent signal during a cued ankle‐dorsiflexion task. The spatiotemporal dynamics and the patterns of task‐relevant information flow across the dorsal motor network were investigated. We show that task‐relevant information appears and decays earlier in the higher order areas of the dorsal motor network then in the primary motor cortex. Furthermore, the results show that task‐relevant information is encoded in general initially, and then selective goals are subsequently encoded in specifics subregions across the network. Importantly, the patterns of recurrent information flow across the network vary across different subregions depending on the goal. Recurrent information flow was observed across all higher order areas of the dorsal motor network in the subregions encoding for the current goal. In contrast, only the top–down information flow from the supplementary motor cortex to the frontoparietal regions, with weakened recurrent information flow between the frontoparietal regions and bottom–up information flow from the frontoparietal regions to the supplementary cortex were observed in the subregions encoding for the opposing goal. We conclude that selective motor goal encoding and execution rely on goal‐dependent differences in subregional recurrent information flow patterns across the long‐range dorsal motor network areas that exhibit graded functional specialization.

INTRODUCTION: 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 standardised protocols for fMRI exists at present. Here we present a novel, online available fMRI task that could be used to assess the in vivo pathology of tremor. OBJECTIVE: 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. METHODS: 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 conditions: WATCH (look at the game without moving joystick), MOVE (rhythmic left/right movement of joystick without game), and PLAY (playing the game). Task fMRI was analysed using FSL FEAT to determine clusters of activation during the different conditions. Maximum activation within the clusters was used to assess the ability to control for task related activation and reproducibility. Four tremor patients have been included to test ecological and construct validity of the joystick task by assessing tremor frequencies captured by the joystick. RESULTS: In HCs the game activated areas corresponding to motor, attention and visual areas. Most areas of activation by our game showed moderate to good reproducibility (intraclass correlation coefficient (ICC) 0.531 to 0.906) with only inferior parietal lobe activation showing poor reproducibility (ICC 0.446). Furthermore, the joystick captured significantly more tremulous movement in tremor patients compared to HCs (p=0.01) during PLAY, but not during MOVE. CONCLUSION: Validation of our novel task confirmed tremor-evoking potential and reproducibility analyses yielded acceptable results to continue further investigations into the pathophysiology of tremor. The use of this technique in studies with tremor patient will no doubt provide significant insights into the treatment options.

Advanced magnetic resonance imaging (MRI) techniques, such as magnetic resonance spectroscopy, diffusion MRI, and perfusion MRI, allow for a diverse range of multidimensional information regarding brain tumor physiology to be obtained in addition to the traditional anatomic images. Although it is well documented that MRI of rodent brain tumor models plays an important role in the basic research and drug discovery process of new brain tumor therapies, the role that animal models have played in translating these methodologies is rarely discussed in such articles. Even in consensus reports outlining the pathway to validation of these techniques, the use of animal models is given scant regard. This is despite that the use of rodent cancer models to test advanced MRI techniques predates and was integral to the development of clinical MRI. This article highlights just how integral preclinical imaging is to the discovery, development, and validation of advanced MRI techniques for imaging brain neoplasms.

Purpose Fast bi‐exponential transverse signal decay compounds sodium image quality. This work aims at enhancing image characteristics using a special case of ramped hybrid encoding (RHE). Zero‐gradient‐excitation (zG RF )‐RHE provides (1) gradient‐free excitation for high flip angle, artifact‐free excitation profiles and (2) gradient ramping during dead‐time for the optimization of encoding time (t enc ) to reduce T 2 * signal decay influence during acquisition. Methods Radial zG RF ‐RHE and standard radial UTE were investigated over a range of receiver bandwidths in simulations, phantom and in vivo brain experiments. Central k‐space in zG RF ‐RHE was acquired through single point measurements at the minimum achievable TE. T 2 * blurring artifacts and image SNR and CNR were assessed. Results zG RF ‐RHE enabled 90° flip angle artifact‐free excitation, whereas gradient pre‐ramping provided greater t enc efficiency for any readout bandwidths. Experiments confirmed simulation results, revealing sharper edge characteristics particularly at short readout durations (T RO ). Significant SNR improvements of up to 4.8% were observed for longer T RO . Conclusion zG RF ‐RHE allows for artifact‐free high flip angle excitation with time‐efficient encoding improving on image characteristics. This hybrid encoding concept with gradient pre‐ramping is trajectory independent and can be introduced in any center‐out UTE trajectory design.

Background Recent evidence suggests that exercise plays a role in cognition and that the posterior cingulate cortex (PCC) can be divided into dorsal and ventral subregions based on distinct connectivity patterns. Aims To examine the effect of physical activity and division of the PCC on brain functional connectivity measures in subjective memory complainers (SMC) carrying the epsilon 4 allele of apolipoprotein E (APOE 4) allele. Method Participants were 22 SMC carrying the APOE ɛ4 allele (ɛ4+; mean age 72.18 years) and 58 SMC non-carriers (ɛ4–; mean age 72.79 years). Connectivity of four dorsal and ventral seeds was examined. Relationships between PCC connectivity and physical activity measures were explored. Results ɛ4+ individuals showed increased connectivity between the dorsal PCC and dorsolateral prefrontal cortex, and the ventral PCC and supplementary motor area (SMA). Greater levels of physical activity correlated with the magnitude of ventral PCC–SMA connectivity. Conclusions The results provide the first evidence that ɛ4+ individuals at increased risk of cognitive decline show distinct alterations in dorsal and ventral PCC functional connectivity.

Abstract Invasive Brain-Computer Interfaces (BCIs) require surgeries with high health-risks. The risk-to-benefit ratio of the procedure could potentially be improved by pre-surgically identifying the ideal locations for mental strategy classification. We recorded high-spatiotemporal resolution blood-oxygenation-level-dependent (BOLD) signals using functional MRI at 7 Tesla in eleven healthy participants during two motor imagery tasks. BCI diagnostic task isolated the intent to imagine movements, while BCI simulation task simulated the neural states that may be yielded in a real-life BCI-operation scenario. Imagination of movements were classified from the BOLD signals in sub-regions of activation within a single or multiple dorsal motor network regions. Then, the participant’s decoding performance during the BCI simulation task was predicted from the BCI diagnostic task. The results revealed that drawing information from multiple regions compared to a single region increased the classification accuracy of imagined movements. Importantly, systematic unimodal and multimodal classification revealed the ideal combination of regions that yielded the best classification accuracy at the individual-level. Lastly, a given participant’s decoding performance achieved during the BCI simulation task could be predicted from the BCI diagnostic task. These results show the feasibility of 7T-fMRI with unimodal and multimodal classification being utilized for identifying ideal sites for mental strategy classification.

We investigated the correlation between the circulating and imaging biomarkers of tumour vascularity, and examined whether they are prognostic of outcomes in patients with glioblastoma multiforme (GBM). Despite the increasing use of anti-angiogenic agents within neuro-oncology, there are still no validated biomarkers to monitor for a treatment response or relapse. The pre- and postoperative circulating endothelial cell (CEC) and progenitor cell (CEP) levels were assessed. Preoperative perfusion-weighted MRI (PWI) was also performed, and the relative cerebral blood volume (rCBV) histogram statistics of the contrast-enhancing tumour were analysed. A novel PWI parameter (rCBVload) was developed to estimate the total volume of perfused tumour vessels, and it was hypothesised that this parameter would correlate with CEC and CEP concentrations. In total, 24 GBM patients were included. The mean preoperative CEC concentration was significantly higher in GBM patients than the controls (p=0.019), and it then declined significantly postoperatively (p=0.009). The preoperative CEP levels were significantly correlated with the median tumour rCBV (Spearman rank-order coefficient=0.526; p=0.039). Neither CEC nor CEP was correlated with the total tumour vessel volume, as measured by rCBVload. None of the biomarkers that were investigated showed a significant correlation with progression-free or overall survival. We conclude that CEC are potentially useful biomarkers to monitor GBM patients during treatment. We found that CEC are increased in the presence of GBM, and that CEP levels appear to be proportional to tumour vascularity, as measured on PWI. However, in this study, none of the biomarkers of GBM vascularity were highly prognostic of patient outcomes.

Missed injuries during the initial assessment are a major cause of morbidity after trauma. The tertiary survey is a head-to-toe exam designed to identify any injuries missed after initial resuscitation. We designed a novel mobile device application (Physician Assist Trauma Software [PATS]) to standardize performance and documentation of the tertiary survey. This study was undertaken to assess the feasibility of introducing PATS into routine clinical practice, as well as its capacity to reduce missed injuries.Prior to implementation of PATS, the missed injury rates at a higher-volume and a medium-volume level I trauma center were assessed. The PATS program was implemented simultaneously at both centers. Missed injuries were tracked during the study period. Compliance and tertiary survey completion rates were evaluated as a marker of feasibility.At the higher-volume trauma center, the missed injury rated decreased from 1% to 0% with the introduction of the PATS program (p = 0.04). At the medium-volume trauma center, the missed injury rate decreased from 9% to 1% (p < 0.001). Compliance and documentation increased from 68% to 100%, and from no formal documentation to 60% compliance at the higher- and medium-volume centers respectively.The implementation of a mobile tertiary survey application significantly reduced missed injuries at both a higher- and medium-volume trauma center. The use of this application resulted in a significant improvement in compliance with documentation of the tertiary survey.

Background Treatment of tremor in MS is an unmet need. OnabotulinumtoxinA (BoNT-A) has shown promising results; however, little is known regarding its effects on the brain. The clinical presentation of tremor MS is shown to depend on subcortical neural damage and cortical neural plasticity. This study aimed to identify effects of onabotulinumtoxinA (BoNT-A) on brain activation in MS and upper-limb tremor using functional MRI. Methods Forty-three MS participants with tremor were randomized to receive intramuscular injections of placebo (n = 22) or BoNT-A (n = 21). Tremor was quantified using the Bain score (0–10) for severity, handwriting and Archimedes drawing at baseline, 6 weeks and 12 weeks. Functional MRI activation within two previously identified clusters, ipsilateral inferior parietal cortex (IPL) and premotor/supplementary motor cortex (SMC) of compensatory activity, was measured at baseline and 6 weeks. Results Treatment with BoNT-A resulted in improved handwriting tremor at 6 weeks (p = 0.049) and 12 weeks (p = 0.014), and tremor severity -0.79 (p = 0.007) at 12 weeks. Furthermore, the patients that received BoNT-A showed a reduction in activation within the IPL (p = 0.034), but not in the SMC. The change in IPL activation correlated with the reduction in tremor severity from baseline to 12 weeks (β = 0.608; p = 0.015) in the BoNT-A group. No tremor and fMRI changes were seen in the placebo treated group. Conclusion We have shown that reduction in MS-tremor severity after intramuscular injection with BoNT-A is associated with changes in brain activity in sensorimotor integration regions.

A facile sonochemical method to fabricate magnetic tryptophan-iron oxide nanoparticles for biomedical applications.

Abstract BACKGROUND The O-(2-[18F]-fluoroethyl)-L-tyrosine positron emission tomography (FET-PET) in Glioblastoma (FIG) study is a prospective study evaluating the management impact of FET-PET imaging in up to 210 newly diagnosed adult glioblastoma patients across 10 Australian sites. Patients undergo contrast MRI and FET-PET at 3 timepoints: pre-chemoradiotherapy (CRT), one-month post-CRT and at suspected progression. MRI QA programme components, approach and integrated workflows are described here. MATERIAL AND METHODS The FIG MRI protocol comprised 3D-T1, 3D-FLAIR, Axial 2D DWI (including derived ADC map), DCE (including T1 mapping), DSC, Axial T2 and 3D T1-post-contrast (T1C) sequences, with SWI and 3D DIR sequences optional. QA components included data acquisition quality and completeness (standard and advanced), motion artefact, low contrast to noise or signal to noise, series description and susceptibility artifacts. Suitability of T1/T1C using modified RANO (mRANO) criteria was assessed. An optimised workflow involved site upload from local PACS systems to centralised database via TROG Central Quality Management System (CQMS) platform and collation into a central imaging database utilising MIM software. The MRI QA workflow encompassed automated anonymisation of DICOM data, data completeness and reconstruction evaluation, then review by two expert neuroimaging analysts. Sites received feedback with request for resubmission where required. RESULTS Between December 2021 and February 2023, MRI data in 74 patients across 9 sites with median of 6 patients (range 2-17) per site was submitted. A total of 141 MRI datasets across all timepoints were collected (per site range:4-35, median:13), with 43 imaging time-points selected for QA (per site range:3-12, median: 4). Importantly, 41/43 (95%) of initial datasets were deemed suitable for mRANO assessment, but only 13/43 (30%) were suitable for advanced MRI analysis. Very few datasets had motion or susceptibility artifacts, low contrast to noise or signal to noise, or incorrect series description. Technical issues identified included incomplete data (DCE - missing T1 maps, DWI - missing ADC maps), incorrect sequence reconstruction (DCE split series and Axial/Sagittal/Coronal reformats for 3D images) and lack of non-mandatory SWI sequences. Feedback to sites resulted in improvements in DCE sequence acquisition from split series in 11/45 (24%) to preferred single series in 18/24 (75%) and similar increases in T1 maps completeness from 7/19 (37%) to 7/7 (100%). CONCLUSION Despite challenges in multisite workflow and substantial multi-modality site and central data management, a robust MRI QA program has confirmed 95% compliance for mRANO assessment. Site specific feedback resulted in increased compliance with advanced MRI sequences to enable detailed future analysis.

Mapping the neurobiology of meditation has been bolstered by functional MRI (fMRI) research, with advancements in ultra-high field 7 Tesla fMRI further enhancing signal quality and neuroanatomical resolution. Here, we utilize 7 Tesla fMRI to examine the neural substrates of meditation and replicate existing widespread findings, after accounting for relevant physiological confounds.In this feasibility study, we scanned 10 beginner meditators (N = 10) while they either attended to breathing (focused attention meditation) or engaged in restful thinking (non-focused rest). We also measured and adjusted the fMRI signal for key physiological differences between meditation and rest. Finally, we explored changes in state mindfulness, state anxiety and focused attention attributes for up to 2 weeks following the single fMRI meditation session.Group-level task fMRI analyses revealed significant reductions in activity during meditation relative to rest in default-mode network hubs, i.e., antero-medial prefrontal and posterior cingulate cortices, precuneus, as well as visual and thalamic regions. These findings survived stringent statistical corrections for fluctuations in physiological responses which demonstrated significant differences (p < 0.05/n, Bonferroni controlled) between meditation and rest. Compared to baseline, State Mindfulness Scale (SMS) scores were significantly elevated (F(3,9) = 8.16, p < 0.05/n, Bonferroni controlled) following the fMRI meditation session, and were closely maintained at 2-week follow up.This pilot study establishes the feasibility and utility of investigating focused attention meditation using ultra-high field (7 Tesla) fMRI, by supporting widespread evidence that focused attention meditation attenuates default-mode activity responsible for self-referential processing. Future functional neuroimaging studies of meditation should control for physiological confounds and include behavioural assessments.

A metric, referred to as the Normalized Performance Ratio (NPR), is defined. The NPR measures a quality of the man-machine interface (MMI) which profoundly influences its value to the human operator of the associated man-machine system. The value of an MMI's NPR is equal to the mean of the periods of time required by a group of people, varying in their familiarity with the interface's operation, to complete an identical processing task with the system (the mean of the completion times), divided by the sample standard deviation of those completion times. The potential variability among MMIs is infinite. However, all MMIs share a common operational objective, which is to facilitate an operator's ability to manipulate the MMI's associated processor. The value of an MMI's NPR is a measure of the degree to which that MMI satisfies that operational objective. It is asserted that the value of an MMI's NPR is independent of the complexity of the processing task(s) used for its measurement, and of the complexity of the MMI-processor system. The NPR would thus provide the basis for the unbiased comparison of all MMIs. A detailed description of the methodology with which an MMI's NPR may be measured is provided, along with illustrations of that methodology which are based on the analyses of the MMIs of actual man-machine systems. Existing MMI-evaluation methods are critically reviewed.

Vision-based navigation technologies are currently under development in order to support future planetary exploration missions to the Moon, Mars and small bodies. By tracking landmarks and local features on the surface of celestial bodies, these technologies will provide GPS-like spacecraft localization capabilities and enable precision orbiting and/or landing toward known targets of interest. In order to contribute to the development roadmap of these technologies, this paper will present the Simulation Infrastructure for Autonomous Navigation technologies (SIAN) aiming at simulating with hardware-in-the-loop and high repeatability vision-based terrain relative navigation algorithms. This scaled simulation infrastructure aims at bridging the gap between pure software simulations and expensive helicopter or rocket-based flight tests. This paper will present the main objectives of this innovative and unique simulation infrastructure and report its conceptual and detailed design.

Abstract Aim 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. Methods 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. Results 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 &lt; 0.001). Responses were documented more frequently by sites ( n = 16, 18%) than centrally ( n = 11, 12%). Seven of 120 patients continued on trial without site‐determined progression for more than 6 months beyond the central review determination of progression. Of scans reviewed by all three central reviewers, 33% were fully concordant for progression date. Conclusion While the difference between site and central PFS dates was statistically significant, the 0.3‐month median difference is small. The variability within central review is consistent with previous studies, highlighting the challenges in MRI interpretation in this context. A small proportion of patients benefited from treatment well beyond the centrally determined progression date, reinforcing that clinical status together with radiology results are important determinants of whether a therapy is effective for an individual.

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 (V T ) was able to statistically discriminate (P&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&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]

# Traumatic brain injury is not associated with hyper-fibrinolysis. {#article-title-2} Hyperfibrinolysis (HF) is uncommon after trauma but carries a high mortality. In practice, thromboelastometry (i.e., ROTEM) is the only test capable of diagnosing HF during initial resuscitation. We used ROTEM to

# Outcomes and opportunities for improvement in self-inflicted blunt and penetrating trauma {#article-title-2} Self-inflicted trauma (SIT) is a public health issue ranking 4th as leading cause of death and disability in young adults. Retrospective descriptive analysis of patients admitted to a

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.