NEMA NU 1-2018 performance characterization and Monte Carlo model validation of the Cubresa Spark SiPM-based preclinical SPECT scanner.

BACKGROUND: The Cubresa Spark is a novel benchtop silicon-photomultiplier (SiPM)-based preclinical SPECT system. SiPMs in SPECT significantly improve resolution and reduce detector size compared to preclinical cameras with photomultiplier tubes requiring highly magnifying collimators. The NEMA NU 1 Standard for Performance Measurements of Gamma Cameras provides methods that can be readily applied or extended to characterize preclinical cameras with minor modifications. The primary objective of this study is to characterize the Spark according to the NEMA NU 1-2018 standard to gain insight into its nuclear medicine imaging capabilities. The secondary objective is to validate a GATE Monte Carlo simulation model of the Spark for use in preclinical SPECT studies. METHODS: NEMA NU 1-2018 guidelines were applied to characterize the Spark's intrinsic, system, and tomographic performance with single- and multi-pinhole collimators. Phantoms were fabricated according to NEMA specifications with deviations involving high-resolution modifications. GATE was utilized to model the detector head with the single-pinhole collimator, and NEMA measurements were employed to tune and validate the model. Single-pinhole and multi-pinhole SPECT data were reconstructed with the Software for Tomographic Image Reconstruction and HiSPECT, respectively. RESULTS: The limiting intrinsic resolution was measured as 0.85 mm owing to a high-resolution SiPM array combined with a 3 mm-thick scintillation crystal. The average limiting tomographic resolution was 1.37 mm and 1.19 mm for the single- and multi-pinhole collimators, respectively, which have magnification factors near unity at the center of rotation. The maximum observed count rate was 15,400 cps, and planar sensitivities of 34 cps/MBq and 150 cps/MBq were measured at the center of rotation for the single- and multi-pinhole collimators, respectively. All simulated tests agreed well with measurement, where the most considerable deviations were below 7%. CONCLUSIONS: NEMA NU 1-2018 standards determined that a SiPM detector mitigates the need for highly magnifying pinhole collimators while preserving detailed information in projection images. Measured and simulated NEMA results were highly comparable with differences on the order of a few percent, confirming simulation accuracy and validating the GATE model. Of the collimators initially provided with the Spark, the multi-pinhole collimator offers high resolution and sensitivity for organ-specific imaging of small animals, and the single-pinhole collimator enables high-resolution whole-body imaging of small animals.

Concussion susceptibility is mediated by spreading depolarization-induced neurovascular dysfunction.

The mechanisms underlying the complications of mild traumatic brain injury, including post-concussion syndrome, post-impact catastrophic death, and delayed neurodegeneration remain poorly understood. This limited pathophysiological understanding has hindered the development of diagnostic and prognostic biomarkers and has prevented the advancement of treatments for the sequelae of mild traumatic brain injury. We aimed to characterize the early electrophysiological and neurovascular alterations following repetitive mild traumatic brain injury and sought to identify new targets for the diagnosis and treatment of individuals at risk of severe post-impact complications. We combined behavioural, electrophysiological, molecular, and neuroimaging techniques in a rodent model of repetitive mild traumatic brain injury. In humans, we used dynamic contrast-enhanced MRI to quantify blood-brain barrier dysfunction after exposure to sport-related concussive mild traumatic brain injury. Rats could clearly be classified based on their susceptibility to neurological complications, including life-threatening outcomes, following repetitive injury. Susceptible animals showed greater neurological complications and had higher levels of blood-brain barrier dysfunction, transforming growth factor ß (TGFß) signalling, and neuroinflammation compared to resilient animals. Cortical spreading depolarizations were the most common electrophysiological events immediately following mild traumatic brain injury and were associated with longer recovery from impact. Triggering cortical spreading depolarizations in mild traumatic brain injured rats (but not in controls) induced blood-brain barrier dysfunction. Treatment with a selective TGFß receptor inhibitor prevented blood-brain barrier opening and reduced injury complications. Consistent with the rodent model, blood-brain barrier dysfunction was found in a subset of human athletes following concussive mild traumatic brain injury. We provide evidence that cortical spreading depolarization, blood-brain barrier dysfunction, and pro-inflammatory TGFß signalling are associated with severe, potentially life-threatening outcomes following repetitive mild traumatic brain injury. Diagnostic-coupled targeting of TGFß signalling may be a novel strategy in treating mild traumatic brain injury.

Post-administration dosimetry in yttrium-90 radioembolization through micro-CT imaging of radiopaque microspheres in a porcine renal model.

The purpose of this study is to perform post-administration dosimetry in yttrium-90 radioembolization through micro-CT imaging of radiopaque microsphere distributions in a porcine renal model and explore the impact of spatial resolution of an imaging system on the extraction of specific dose metrics. Following the administration of radiopaque microspheres to the kidney of a hybrid farm pig, the kidney was explanted and imaged with micro-CT. To produce an activity distribution, 400 MBq of yttrium-90 activity was distributed throughout segmented voxels of the embolized vasculature based on an established linear relationship between microsphere concentration and CT voxel value. This distribution was down-sampled to coarser isotropic grids ranging in voxel size from 2.5 to 15 mm to emulate nominal resolutions comparable to those found in yttrium-90 PET and Bremsstrahlung SPECT imaging. Dose distributions were calculated through the convolution of activity distributions with dose-voxel kernels generated using the GATE Monte Carlo toolkit. Contours were computed to represent normal tissue and target volumes. Dose-volume histograms, dose metrics, and dose profiles were compared to a ground truth dose distribution computed with GATE. The mean dose to the target for all studied voxel sizes was found to be within 5.7% of the ground truth mean dose.D70was shown to be strongly correlated with image voxel size of the dose distribution (r2 = 0.90).D70is cited in the literature as an important dose metric and its dependence on voxel size suggests higher resolution dose distributions may provide new perspectives on dose-response relationships in yttrium-90 radioembolization. This study demonstrates that dose distributions with large voxels incorrectly homogenize the dose by attributing escalated doses to normal tissues and reduced doses in high-dose target regions. High-resolution micro-CT imaging of radiopaque microsphere distributions can provide increased confidence in characterizing the absorbed dose heterogeneity in yttrium-90 radioembolization.

Quantitative MRI cell tracking of immune cell recruitment to tumors and draining lymph nodes in response to anti-PD-1 and a DPX-based immunotherapy.

DPX is a unique T cell activating formulation that generates robust immune responses (both clinically and preclinically) which can be tailored to various cancers via the use of tumor-specific antigens and adjuvants. While DPX-based immunotherapies may act complementary with checkpoint inhibitors, combination therapy is not always easily predictable based on individual therapeutic responses. Optimizing these combinations can be improved by understanding the mechanism of action underlying the individual therapies. Magnetic Resonance Imaging (MRI) allows tracking of cells labeled with superparamagnetic iron oxide (SPIO), which can yield valuable information about the localization of crucial immune cell subsets. In this work, we evaluated the use of a multi-echo, single point MRI pulse sequence, TurboSPI, for tracking and quantifying cytotoxic T lymphocytes (CTLs) and myeloid lineage cells (MLCs). In a subcutaneous cervical cancer model (C3) we compared untreated mice to mice treated with either a single therapy (anti-PD-1 or DPX-R9F) or a combination of both therapies. We were able to detect, using TurboSPI, significant increases in CTL recruitment dynamics in response to combination therapy. We also observed differences in MLC recruitment to therapy-draining (DPX-R9F) lymph nodes in response to treatment with DPX-R9F (alone or in combination with anti-PD-1). We demonstrated that the therapies presented herein induced time-varying changes in cell recruitment. This work establishes that these quantitative molecular MRI techniques can be expanded to study a number of cancer and immunotherapy combinations to improve our understanding of longitudinal immunological changes and mechanisms of action.

Unique depot formed by an oil based vaccine facilitates active antigen uptake and provides effective tumour control.

BACKGROUND: Oil emulsions are commonly used as vaccine delivery platforms to facilitate slow release of antigen by forming a depot at the injection site. Antigen is trapped in the aqueous phase and as the emulsion degrades in vivo the antigen is passively released. DepoVax™ is a unique oil based delivery system that directly suspends the vaccine components in the oil diluent that forces immune cells to actively take up components from the formulation in the absence of passive release. The aim of this study was to use magnetic resonance imaging (MRI) with additional biological markers to evaluate and understand differences in clearance between several different delivery systems used in peptide-based cancer vaccines. METHODS: C57BL/6 mice were implanted with a cervical cancer model and vaccinated 5 days post-implant with either DepoVax (DPX), a water-in-oil emulsion (w/o), a squalene oil-in-water emulsion (squal o/w) or a saponin/liposome emulsion (sap/lip) containing iron oxide-labeled targeted antigen. MRI was then used to monitor antigen clearance, the site of injection, tumour and inguinal lymph node volumes and other gross anatomical changes. HLA-A2 transgenic mice were also vaccinated to evaluate immune responses of human directed peptides. RESULTS: We demonstrated differences in antigen clearance between DPX and w/o both in regard to how quickly the antigen was cleared and the pattern in which it was cleared. We also found differences in lymph node responses between DPX and both squal o/w and sap/lip. CONCLUSIONS: These studies underline the unique mechanism of action of this clinical stage vaccine delivery system.

Using MRI cell tracking to monitor immune cell recruitment in response to a peptide-based cancer vaccine.

PURPOSE: MRI cell tracking can be used to monitor immune cells involved in the immunotherapy response, providing insight into the mechanism of action, temporal progression of tumor growth, and individual potency of therapies. To evaluate whether MRI could be used to track immune cell populations in response to immunotherapy, CD8+ cytotoxic T cells, CD4+ CD25+ FoxP3+ regulatory T cells, and myeloid-derived suppressor cells were labeled with superparamagnetic iron oxide particles. METHODS: Superparamagnetic iron oxide-labeled cells were injected into mice (one cell type/mouse) implanted with a human papillomavirus-based cervical cancer model. Half of these mice were also vaccinated with DepoVaxTM (ImmunoVaccine, Inc., Halifax, Nova Scotia, Canada), a lipid-based vaccine platform that was developed to enhance the potency of peptide-based vaccines. RESULTS: MRI visualization of CD8+ cytotoxic T cells, regulatory T cells, and myeloid-derived suppressor cells was apparent 24 h post-injection, with hypointensities due to iron-labeled cells clearing approximately 72 h post-injection. Vaccination resulted in increased recruitment of CD8+ cytotoxic T cells, and decreased recruitment of myeloid-derived suppressor cells and regulatory T cells to the tumor. We also found that myeloid-derived suppressor cell and regulatory T cell recruitment were positively correlated with final tumor volume. CONCLUSION: This type of analysis can be used to noninvasively study changes in immune cell recruitment in individual mice over time, potentially allowing improved application and combination of immunotherapies. Magn Reson Med 80:304-316, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Characterization of Magneto-Endosymbionts as MRI Cell Labeling and Tracking Agents.

PURPOSE: Magneto-endosymbionts (MEs) show promise as living magnetic resonance imaging (MRI) contrast agents for in vivo cell tracking. Here we characterize the biomedical imaging properties of ME contrast agents, in vitro and in vivo. PROCEDURES: By adapting and engineering magnetotactic bacteria to the intracellular niche, we are creating magneto-endosymbionts (MEs) that offer advantages relative to passive iron-based contrast agents (superparamagnetic iron oxides, SPIOs) for cell tracking. This work presents a biomedical imaging characterization of MEs including: MRI transverse relaxivity (r 2) for MEs and ME-labeled cells (compared to a commercially available iron oxide nanoparticle); microscopic validation of labeling efficiency and subcellular locations; and in vivo imaging of a MDA-MB-231BR (231BR) human breast cancer cells in a mouse brain. RESULTS: At 7T, r 2 relaxivity of bare MEs was higher (250 s-1 mM-1) than that of conventional SPIO (178 s-1 mM-1). Optimized in vitro loading of MEs into 231BR cells yielded 1-4 pg iron/cell (compared to 5-10 pg iron/cell for conventional SPIO). r 2 relaxivity dropped by a factor of ~3 upon loading into cells, and was on the same order of magnitude for ME-loaded cells compared to SPIO-loaded cells. In vivo, ME-labeled cells exhibited strong MR contrast, allowing as few as 100 cells to be detected in mice using an optimized 3D SPGR gradient-echo sequence. CONCLUSIONS: Our results demonstrate the potential of magneto-endosymbionts as living MR contrast agents. They have r 2 relaxivity values comparable to traditional iron oxide nanoparticle contrast agents, and provide strong MR contrast when loaded into cells and implanted in tissue.

Using lymph node swelling as a potential biomarker for successful vaccination.

There is currently a lack of biomarkers to help properly assess novel immunotherapies at both the preclinical and clinical stages of development. Recent work done by our group indicated significant volume changes in the vaccine draining right lymph node (RLN) volumes of mice that had been vaccinated with DepoVaxTM, a lipid-based vaccine platform that was developed to enhance the potency of peptide-based vaccines. These changes in lymph node (LN) volume were unique to vaccinated mice.To better assess the potential of volumetric LN markers for multiple vaccination platforms, we evaluated 100 tumor bearing mice and assessed their response to vaccination with either a DepoVax based vaccine (DPX) or a water-in-oil emulsion (w/o), and compared them to untreated controls. MRI was used to longitudinally monitor LN and tumor volumes weekly over 4 weeks. We then evaluated changes in LN volumes occurring in response to therapy as a potential predictive biomarker for treatment success.We found that for both vaccine types, DPX and w/o, the %RLN volumetric increase over baseline and the ratio of RLN/LLN were strong predictors of successful tumor suppression (LLN is left inguinal LN). The area under the curve (AUC) was greatest, between 0.75-0.85, two (%RLN) or three (RLN/LLN) weeks post-vaccination. For optimized critical thresholds we found these biomarkers consistently had sensitivity >90% and specificity >70% indicating strong prognostic potential. Vaccination with DepoVax had a more pronounced effect on draining lymph nodes than w/o emulsion vaccines, which correlated with a higher anti-tumor activity in DPX-treated mice.

Molecular Magnetic Resonance Imaging of Tumor Response to Therapy.

Personalized cancer medicine requires measurement of therapeutic efficacy as early as possible, which is optimally achieved by three-dimensional imaging given the heterogeneity of cancer. Magnetic resonance imaging (MRI) can obtain images of both anatomy and cellular responses, if acquired with a molecular imaging contrast agent. The poor sensitivity of MRI has limited the development of activatable molecular MR contrast agents. To overcome this limitation of molecular MRI, a novel implementation of our caspase-3-sensitive nanoaggregation MRI (C-SNAM) contrast agent is reported. C-SNAM is triggered to self-assemble into nanoparticles in apoptotic tumor cells, and effectively amplifies molecular level changes through nanoaggregation, enhancing tissue retention and spin-lattice relaxivity. At one-tenth the current clinical dose of contrast agent, and following a single imaging session, C-SNAM MRI accurately measured the response of tumors to either metronomic chemotherapy or radiation therapy, where the degree of signal enhancement is prognostic of long-term therapeutic efficacy. Importantly, C-SNAM is inert to immune activation, permitting radiation therapy monitoring.

Using MRI to evaluate and predict therapeutic success from depot-based cancer vaccines.

In the preclinical development of immunotherapy candidates, understanding the mechanism of action and determining biomarkers that accurately characterize the induced host immune responses is critical to improving their clinical interpretation. Magnetic resonance imaging (MRI) was used to evaluate in vivo changes in lymph node size in response to a peptide-based cancer vaccine therapy, formulated using DepoVax (DPX). DPX is a novel adjuvant lipid-in-oil-based formulation that facilitates enhanced immune responses by retaining antigens at the injection site for extended latencies, promoting increased potentiation of immune cells. C57BL/6 mice were implanted with C3 (HPV) tumor cells and received either DPX or control treatments, 5 days post-implantation. Complete tumor eradication occurred in DPX-vaccinated animals and large volumetric increases were observed in the vaccine-draining right inguinal lymph node (VRILN) in DPX mice, likely corresponding to increased localized immune response to the vaccine. Upon evaluating the relative measure of vaccine-potentiated immune activation to tumor-induced immune response (VRILN/VLILN), receiver-operating characteristic (ROC) curves revealed an area under the curve (AUC) of 0.90 (±0.07), indicating high specificity and sensitivity as a predictive biomarker of vaccine efficacy. We have determined that for this tumor model, early MRI lymph node volumetric changes are predictive of depot immunotherapeutic success.

Clearance of depot vaccine SPIO-labeled antigen and substrate visualized using MRI.

Immunotherapies, including peptide-based vaccines, are a growing area of cancer research, and understanding their mechanism of action is crucial for their continued development and clinical application. Exploring the biodistribution of vaccine components may be key to understanding this action. This work used magnetic resonance imaging (MRI) to characterize the in vivo biodistribution of the antigen and oil substrate of the vaccine delivery system known as DepoVax(TM). DepoVax uses a novel adjuvanted lipid-in-oil based formulation to solubilise antigens and promote a depot effect. In this study, antigen or oil were tagged with superparamagnetic iron oxide (SPIO), making them visible on MR images. This enables tracking of individual vaccine components to determine changes in biodistribution. Mice were injected with SPIO-labeled antigen or SPIO-labeled oil, and imaged to examine clearance of labeled components from the vaccine site. The SPIO-antigen was steadily cleared, with nearly half cleared within two months post-vaccination. In contrast, the SPIO-oil remained relatively unchanged. The biodistribution of the SPIO-antigen component within the vaccine site was heterogeneous, indicating the presence of active clearance mechanisms, rather than passive diffusion or drainage. Mice injected with SPIO-antigen also showed MRI contrast for several weeks post-vaccination in the draining inguinal lymph node. These results indicate that MRI can visualize the in vivo longitudinal biodistribution of vaccine components. The sustained clearance is consistent with antigen up-take and trafficking by immune cells, leading to accumulation in the draining lymph node, which corresponds to the sustained immune responses and reduced tumor burden observed in vaccinated mice.

Caspase-responsive smart gadolinium-based contrast agent for magnetic resonance imaging of drug-induced apoptosis.

Non-invasive detection of caspase-3/7 activity in vivo has provided invaluable predictive information regarding tumor therapeutic efficacy and anti-tumor drug selection. Although a number of caspase-3/7 targeted fluorescence and positron emission tomography (PET) imaging probes have been developed, there is still a lack of gadolinium (Gd)-based magnetic resonance imaging (MRI) probes that enable high spatial resolution detection of caspase-3/7 activity in vivo. Here we employ a self-assembly approach and develop a caspase-3/7 activatable Gd-based MRI probe for monitoring tumor apoptosis in mice. Upon reduction and caspase-3/7 activation, the caspase-sensitive nano-aggregation MR probe (C-SNAM: 1) undergoes biocompatible intramolecular cyclization and subsequent self-assembly into Gd-nanoparticles (GdNPs). This results in enhanced r1 relaxivity-19.0 (post-activation) vs. 10.2 mM-1 s-1 (pre-activation) at 1 T in solution-and prolonged accumulation in chemotherapy-induced apoptotic cells and tumors that express active caspase-3/7. We demonstrate that C-SNAM reports caspase-3/7 activity by generating a significantly brighter T1-weighted MR signal compared to non-treated tumors following intravenous administration of C-SNAM, providing great potential for high-resolution imaging of tumor apoptosis in vivo.

Signal displacement in spiral-in acquisitions: simulations and implications for imaging in SFG regions.

Susceptibility field gradients (SFGs) cause problems for functional magnetic resonance imaging (fMRI) in regions like the orbital frontal lobes, leading to signal loss and image artifacts (signal displacement and "pile-up"). Pulse sequences with spiral-in k-space trajectories are often used when acquiring fMRI in SFG regions such as inferior/medial temporal cortex because it is believed that they have improved signal recovery and decreased signal displacement properties. Previously postulated theories explain differing reasons why spiral-in appears to perform better than spiral-out; however it is clear that multiple mechanisms are occurring in parallel. This study explores differences in spiral-in and spiral-out images using human and phantom empirical data, as well as simulations consistent with the phantom model. Using image simulations, the displacement of signal was characterized using point spread functions (PSFs) and target maps, the latter of which are conceptually inverse PSFs describing which spatial locations contribute signal to a particular voxel. The magnitude of both PSFs and target maps was found to be identical for spiral-out and spiral-in acquisitions, with signal in target maps being displaced from distant regions in both cases. However, differences in the phase of the signal displacement patterns that consequently lead to changes in the intervoxel phase coherence were found to be a significant mechanism explaining differences between the spiral sequences. The results demonstrate that spiral-in trajectories do preserve more total signal in SFG regions than spiral-out; however, spiral-in does not in fact exhibit decreased signal displacement. Given that this signal can be displaced by significant distances, its recovery may not be preferable for all fMRI applications.

Quantification of superparamagnetic iron oxide with large dynamic range using TurboSPI.

This work proposes the use of TurboSPI, a multi-echo single point imaging sequence, for the quantification of labeled cells containing moderate to high concentrations of iron oxide contrast agent. At each k-space location, TurboSPI acquires several hundred time points during a spin echo, permitting reliable relaxation rate mapping of large-R(2)(∗) materials. An automatic calibration routine optimizes image quality by promoting coherent alignment of spin and stimulated echoes throughout the multi-echo train, and this calibration is sufficiently robust for in vivo applications. In vitro relaxation rate measurements of SPIO-loaded cervical cancer cells exhibit behavior consistent with theoretical predictions of the static dephasing regime in the spin echo case; the relaxivity measured with TurboSPI was 10.47±2.3 s(-1)/mG, comparable to the theoretical value of 10.78 s(-1)/mG. Similar measurements of micron-sized iron oxide particles (0.96 µm and 1.63 µm diameter) show a reduced relaxivity of 8.06±0.68 s(-1)/mG and 7.13±0.31 s(-1)/mG respectively, indicating that the static dephasing criterion was not met. Nonetheless, accurate quantification of such particles is demonstrated up to R(2)(∗)=900 s(-1), with a potentially higher upper limit for loaded cells having a more favorable R(2)('):R(2) ratio. Based on the cells used in this study, reliable quantification of cells loaded with 10 pg of iron per cell should be possible up to a density of 27 million cells/mL. Such quantification will be of crucial importance to the development of longitudinal monitoring for cellular therapy and other procedures using iron-labeled cells.

Functional mapping in the corpus callosum: a 4T fMRI study of white matter.

INTRODUCTION: The idea of fMRI activation in white matter (WM) is controversial. Our recent work has used two different approaches to investigate whether there is evidence for WM fMRI. The first approach used words and faces to elicit interhemispheric transfer activation in the posterior corpus callosum (Sperry task). The second approach used checkerboard stimuli to elicit similar activation in the anterior corpus callosum (Poffenberger task). Using these different tasks, it has been possible to detect WM activation in different regions. In the current study, we report the results of a critical experiment: demonstrating that callosal activation can be experimentally manipulated within the same set of individuals. METHODS: All subjects completed both the Sperry and Poffenberger tasks. Functional MRI data were acquired at 4T, using an asymmetric spin echo spiral sequence. Data were analyzed with FSL using a model-based approach. Analyses focused on group and individual activations in WM. RESULTS AND DISCUSSION: Corpus callosum activation was elicited for both tasks, with activation varying according to task type. A statistical contrast of the two tasks revealed posterior callosal activation for the Sperry task and anterior callosal activation for the Poffenberger task. The Sperry task showed activation in the isthmus and middle body of the corpus callosum at the group level and in 100% of subjects. The Poffenberger task showed activation in the genu and middle body of the corpus callosum at the group level and in 94% of subjects. The WM activation replicated prior results, with the additional strength of functional mapping within the same group of individuals.

Confirming white matter fMRI activation in the corpus callosum: co-localization with DTI tractography.

Recently, functional magnetic resonance imaging (fMRI) activation has been detected in white matter, despite the widely-held belief that fMRI activation is restricted to gray matter. The objective of the current study was to determine whether the regions of white matter fMRI activation were structurally connected to the functional network in gray matter. To do this, we used fMRI-guided tractography to evaluate whether tracts connecting regions of gray matter fMRI activation were co-localized with white matter fMRI activation. An established interhemispheric transfer task was employed to elicit activation in the corpus callosum. Diffusion tensor imaging (DTI) tractography was used to determine the existence of tracts that connected regions of gray matter fMRI activation to regions of activation in the corpus callosum. Corpus callosum activation was detected in the majority of participants. While there was individual variability in the location of corpus callosum activation, activation was commonly observed in the callosal mid-body, isthmus/splenium, or both. Despite the variability, gray matter fMRI-guided tractography identified tracts that were co-localized with corpus callosum fMRI activation in all instances. In addition, callosal activation had tracts to bilateral gray matter fMRI activation for 7/8 participants. The results confirmed that the activated regions of the corpus callosum were structurally connected to the functional network of gray matter regions involved in the task. These findings are an important step towards establishing the functional significance of white matter fMRI, and provide the foundation for future work combining white matter fMRI and DTI tractography to study brain connectivity.

Asymmetric spin-echo (ASE) spiral improves BOLD fMRI in inhomogeneous regions.

Functional MRI (fMRI) is of limited use in areas such as the orbitofrontal and inferior temporal lobes due to the presence of local susceptibility-induced field gradients (SFGs), which result in severe image artifacts. Several techniques have been developed to reduce these artifacts, the most common being the dual-echo spiral sequences (spiral-in/out and spiral-in/in). In this study, a new multiple spiral acquisition technique was developed, in which the later spiral acquisitions are acquired asymmetrically with the peak of a spin-echo causing increased R(2)-weighting but matched R(2)'-weighting. This sequence, called asymmetric spin-echo (ASE) spiral, has demonstrated significant improvements in minimizing the signal loss and increasing the image quality as well as optimal blood-oxygen-level-dependent (BOLD)-weighting. The ASE spiral is compared to conventional spiral-out using both signal-to-noise ratio (SNR) and whole brain fMRI activation volumes from a breath-hold task acquired at 4 Tesla. The ASE dual spiral has exhibited SNR increases of up to 300% in areas where strong SFGs are present. As a result, the ASE spiral is highly efficient for recovering lost activation in areas of SFGs, as demonstrated by a 16% increase in the total number of activated voxels over the whole brain. Post spin-echo ASE spiral images have decreasing SNR due to R(2) signal losses, however the increase in R(2)-weighting leads to a higher percentage of signal changes producing ASE spiral images with equivalent contrast-to-noise ratio (CNR) for each echo. The use of this sequence allows for recovery of BOLD activation in areas of SFG without sacrificing the CNR over the whole brain.

Optimizing the detection of white matter fMRI using asymmetric spin echo spiral.

The majority of functional magnetic resonance imaging (fMRI) studies restrict their focus to gray matter regions because this tissue is highly perfused relative to white matter. However, an increasing number of studies are reporting fMRI activation in white matter. The current study had two objectives: 1) to evaluate whether it is possible to detect white matter fMRI activation and 2) to determine whether certain MRI contrast mechanisms are more sensitive to white matter activation (i.e., BOLD contrast- versus T(2)-weighting). Data were acquired from a 4 T MRI using an asymmetric spin echo spiral sequence (ASE spiral). This technique collected three images with equal BOLD contrast weighting and increasing T(2)-weighting. An interhemispheric transfer task was used to elicit activation in the corpus callosum. White matter fMRI activation was examined for the averaged ASE spiral data and for each image separately. Callosal activation was present in all subjects as well as in the group analysis. Analyses revealed that increasing T(2) contrast improved sensitivity as measured by percent signal change. The results suggest that it is possible to detect white matter activation in fMRI and that ASE spiral showed increasing sensitivity to this activation as a function of T(2)-weighting. The findings provide further support for the investigation of white matter fMRI.