Silun Wang

Temporal Evolution of Ischemic Lesions in Nonhuman Primates: A Diffusion and Perfusion MRI Study

Background and Purpose Diffusion-weighted imaging (DWI) and perfusion MRI were used to examine the spatiotemporal evolution of stroke lesions in adult macaques with ischemic occlusion. Methods Permanent MCA occlusion was induced with silk sutures through an interventional approach via the femoral artery in adult rhesus monkeys (n = 8, 10–21 years old). The stroke lesions were examined with high-resolution DWI and perfusion MRI, and T2-weighted imaging (T2W) on a clinical 3T scanner at 1–6, 48, and 96 hours post occlusion and validated with H&E staining. Results The stroke infarct evolved via a natural logarithmic pattern with the mean infarct growth rate = 1.38 ± 1.32 ml per logarithmic time scale (hours) (n = 7) in the hyperacute phase (1–6 hours). The mean infarct volume after 6 hours post occlusion was 3.6±2.8 ml (n = 7, by DWI) and increased to 3.9±2.9 ml (n = 5, by T2W) after 48 hours, and to 4.7±2.2ml (n = 3, by T2W) after 96 hours post occlusion. The infarct volumes predicted by the natural logarithmic function were correlated significantly with the T2W-derived lesion volumes (n = 5, r = 0.92, p = 0.01) at 48 hours post occlusion. The final infarct volumes derived from T2W were correlated significantly with those from H&E staining (r = 0.999, p < 0.0001, n = 4). In addition, the diffusion-perfusion mismatch was visible generally at 6 hours but nearly diminished at 48 hours post occlusion. Conclusion The infarct evolution follows a natural logarithmic pattern in the hyperacute phase of stroke. The logarithmic pattern of evolution could last up to 48 hours after stroke onset and may be used to predict the infarct volume growth during the acute phase of ischemic stroke. The nonhuman primate model, MRI protocols, and post data processing strategy may provide an excellent platform for characterizing the evolution of acute stroke lesion in mechanistic studies and therapeutic interventions of stroke disease.

Mapping cardiac fiber orientations from high-resolution DTI to high-frequency 3D ultrasound

The orientation of cardiac fibers affects the anatomical, mechanical, and electrophysiological properties of the heart. Although echocardiography is the most common imaging modality in clinical cardiac examination, it can only provide the cardiac geometry or motion information without cardiac fiber orientations. If the patient’s cardiac fiber orientations can be mapped to his/her echocardiography images in clinical examinations, it may provide quantitative measures for diagnosis, personalized modeling, and image-guided cardiac therapies. Therefore, this project addresses the feasibility of mapping personalized cardiac fiber orientations to three-dimensional (3D) ultrasound image volumes. First, the geometry of the heart extracted from the MRI is translated to 3D ultrasound by rigid and deformable registration. Deformation fields between both geometries from MRI and ultrasound are obtained after registration. Three different deformable registration methods were utilized for the MRI-ultrasound registration. Finally, the cardiac fiber orientations imaged by DTI are mapped to ultrasound volumes based on the extracted deformation fields. Moreover, this study also demonstrated the ability to simulate electricity activations during the cardiac resynchronization therapy (CRT) process. The proposed method has been validated in two rat hearts and three canine hearts. After MRI/ultrasound image registration, the Dice similarity scores were more than 90% and the corresponding target errors were less than 0.25 mm. This proposed approach can provide cardiac fiber orientations to ultrasound images and can have a variety of potential applications in cardiac imaging.

Spatio-temporal assessment of the neuroprotective effects of neuregulin-1 on ischemic stroke lesions using MRI

The neuroprotective effects of neuregulin-1 (NRG-1) on stroke lesions were assessed longitudinally in rats with middle cerebral artery occlusion (MCAo) using MRI. Sprague-Dawley rats (n=16, 250±20g) underwent permanent MCAo surgery with cerebral blood flow (CBF) monitored by laser doppler flowmetry at ipsilateral side of bregma for 20min post-occlusion. A single 50μl bolus dose of NRG-1 or vehicle was administered into the left internal carotid artery immediately prior to MCAo. The expansion of the ischemic lesion into the cortex was attenuated by NRG-1 over a 48-hour (h) time span as measured by diffusion weighted imaging (DWI). The final infarct volumes of NRG-1 treated rats were significantly smaller than those of the vehicle treated rats at 48h (264.8±192.1 vs. 533.4±175.5mm(3), p<0.05). The NRG-1 treated rats were further subdivided into 2 subgroups according to their CBF reduction during stroke surgery: mild ischemia (<70% CBF reduction) or severe ischemia (>70% CBF reduction). In particular, ischemic infarction was not usually observed in the cortex of NRG-1 treated rats with mild ischemia at 3 and 48h post-occlusion. Histological results validated the imaging findings and demonstrated that NRG-1 treated rats had fewer injured neurons in peri-infarct areas 48h post-ischemia. In summary, the neuroprotective effect of NRG-1 in the pMCAo stroke model was demonstrated by prevention of ischemic lesion expansion, reduced infarct volume and protection of neurons from ischemic damage.

Simulating cardiac ultrasound image based on MR diffusion tensor imaging.

PURPOSE Cardiac ultrasound simulation can have important applications in the design of ultrasound systems, understanding the interaction effect between ultrasound and tissue and setting the ground truth for validating quantification methods. Current ultrasound simulation methods fail to simulate the myocardial intensity anisotropies. New simulation methods are needed in order to simulate realistic ultrasound images of the heart. METHODS The proposed cardiac ultrasound image simulation method is based on diffusion tensor imaging (DTI) data of the heart. The method utilizes both the cardiac geometry and the fiber orientation information to simulate the anisotropic intensities in B-mode ultrasound images. Before the simulation procedure, the geometry and fiber orientations of the heart are obtained from high-resolution structural MRI and DTI data, respectively. The simulation includes two important steps. First, the backscatter coefficients of the point scatterers inside the myocardium are processed according to the fiber orientations using an anisotropic model. Second, the cardiac ultrasound images are simulated with anisotropic myocardial intensities. The proposed method was also compared with two other nonanisotropic intensity methods using 50 B-mode ultrasound image volumes of five different rat hearts. The simulated images were also compared with the ultrasound images of a diseased rat heart in vivo. A new segmental evaluation method is proposed to validate the simulation results. The average relative errors (AREs) of five parameters, i.e., mean intensity, Rayleigh distribution parameter σ, and first, second, and third quartiles, were utilized as the evaluation metrics. The simulated images were quantitatively compared with real ultrasound images in both ex vivo and in vivo experiments. RESULTS The proposed ultrasound image simulation method can realistically simulate cardiac ultrasound images of the heart using high-resolution MR-DTI data. The AREs of their proposed method are 19% for the mean intensity, 17.7% for the scale parameter of Rayleigh distribution, 36.8% for the first quartile of the image intensities, 25.2% for the second quartile, and 19.9% for the third quartile. In contrast, the errors of the other two methods are generally five times more than those of their proposed method. CONCLUSIONS The proposed simulation method uses MR-DTI data and realistically generates cardiac ultrasound images with anisotropic intensities inside the myocardium. The ultrasound simulation method could provide a tool for many potential research and clinical applications in cardiac ultrasound imaging.

Longitudinal MRI evaluation of neuroprotective effects of pharmacologically induced hypothermia in experimental ischemic stroke

Pharmacologically induced hypothermia (PIH) shows promising neuroprotective effects after stroke insult. However, the dynamic evolution of stroke infarct during the hypothermic therapy has not been understood very well. In the present study, MRI was utilized to longitudinally characterize the infarct evolution in a mouse model of ischemic stroke treated by PIH using the neurotensin agonist HPI201. Adult male C57BL/6 mice underwent permanent occlusion of the right middle cerebra artery (MCA). Each animal received a vehicle or HPI201 intraperitoneal injection. The temporal changes of stroke lesion were examined using T2-weighted imaging and diffusion-weighted imaging (DWI) in the acute phase (1-3h) and 24h post stroke. Significantly reduced infarct and edema volumes were observed in PIH treated stroke mice, in agreement with TTC staining findings. Also, the TUNEL staining results indicated apoptotic cells were widely distributed among the ischemic cortex in control group but limited in PIH treated mice. Dramatically reduced growth rate of infarction was seen in PIH treated stroke mice. These results demonstrate HPI201 has strong neuroprotection effects during acute stroke. In particular, MRI with the numerical modelling of temporal infarct evolution could provide a unique means to examine and predict the dynamic response of the PIH treatment on infarct evolution.

3D in vivo imaging of rat hearts by high frequency ultrasound and its application in myofiber orientation wrapping

Cardiac ultrasound plays an important role in the imaging of hearts in basic cardiovascular research and clinical examinations. 3D ultrasound imaging can provide the geometry or motion information of the heart. Especially, the wrapping of cardiac fiber orientations to the ultrasound volume could supply useful information on the stress distributions and electric action spreading. However, how to acquire 3D ultrasound volumes of the heart of small animals in vivo for cardiac fiber wrapping is still a challenging problem. In this study, we provide an approach to acquire 3D ultrasound volumes of the rat hearts in vivo. The comparison between both in vivo and ex vivo geometries indicated 90.1% Dice similarity. In this preliminary study, the evaluations of the cardiac fiber orientation wrapping errors were 24.7° for the acute angle error and were 22.4° for the inclination angle error. This 3D ultrasound imaging and fiber orientation estimation technique have potential applications in cardiac imaging.

Progressive Assessment of Ischemic Injury to White Matter Using Diffusion Tensor Imaging: A Preliminary Study of a Macaque Model of Stroke

Background: Previous Diffusion Tensor Imaging (DTI) studies have demonstrated the temporal evolution of stroke injury in grey matter and white matter can be characterized by DTI indices. However, it still remains not fully understood how the DTI indices of white matter are altered progressively during the hyperacute (first 6 hours) and acute stage of stroke (≤ 1 week). In the present study, DTI was employed to characterize the temporal evolution of infarction and white matter injury after stroke insult using a macaque model with permanent ischemic occlusion. Methods and materials: Permanent middle cerebral artery (MCA) occlusion was induced in rhesus monkeys (n=4, 10-21 years old). The brain lesion was examined longitudinally with DTI during the hyperacute phase (2-6 hours, n=4), 48 hours (n=4) and 96 hours (n=3) post-occlusion. Results: Cortical infarction was seen in all animals. The Mean Diffusivity (MD) in lesion regions decreased substantially at the first time point (2 hours post stroke) (35%, p <0.05, compared to the contralateral side) and became pseudo-normalized at 96 hours. In contrast, evident FA reduction was seen at 48 hours (39%, p <0.10) post-stroke. MD reduction in white matter bundles of the lesion area was much less than that in the grey matter during the hyper-acute phase but significant change was observed 4 hours (4.2%, p < 0.05) post stroke . Also, MD pseudonormalisation was seen at 96 hours post stroke. There was a significant correlation between the temporal changes of MD in white matter bundles and those in whole lesion areas during the entire study period. Meanwhile, no obvious fractional anisotropy (FA) changes were seen during the hyper-acute phase in either the entire infarct region or white matter bundles. Significant FA alteration was observed in entire lesion areas and injured white matter bundles 48 and 96 hours post stroke. The stroke lesion in grey matter and white matter was validated by pathological findings. Conclusion: The temporal evolution of ischemic injury to the grey matter and white matter from 2 to 96 hours after stroke onset was characterized using a macaque model and DTI. Progressive MD changes in white matter bundles are seen from hyperacute phase to acute phase after permanent MCA occlusion and temporally correlated with the MD changes in entire infarction regions. MD reduction in white matter bundles is mild in comparison with that in the grey matter but significant and progressive, indicating it may be useful to detect early white matter degeneration after stroke.

Amyloid-related imaging abnormalities in an aged squirrel monkey with cerebral amyloid angiopathy

Amyloid-related imaging abnormalities (ARIA) in magnetic resonance imaging scans have emerged as indicators of potentially serious side effects in clinical trials of therapeutics for Alzheimers disease. These anomalies include an edematous type (ARIA-E) that appears as hyperintense (bright) regions by T2-weighted MRI, and a type characterized by the deposition of hemosiderin (ARIA-H) that elicits a hypointense signal, especially in T2* susceptibility weighted images. ARIA in general has been linked to the presence of amyloid-β (Aβ)-type cerebral amyloid angiopathy, an accumulation of misfolded Aβ protein in the vascular wall that impairs the integrity of brain blood vessels. However, the pathobiology of ARIA remains poorly understood, in part due to the absence of an animal model of the disorder that would enable a contemporaneous analysis of tissue integrity in the affected region. Here we describe both ARIA-E and ARIA-H in an aged squirrel monkey (Saimiri sciureus), a nonhuman primate model of naturally occurring cerebral amyloid angiopathy. Histopathologic examination of the anomalous region revealed reactive astrocytosis and microgliosis, infiltration of systemic inflammatory/immune cells, damage to axons and myelin, and hemosiderin deposition. The disruption of axons in particular suggests that ARIA-E could have functional consequences for affected regions. The squirrel monkey model can be useful for studying the pathogenesis and long-term effects of ARIA, and for testing the safety and efficacy of emerging therapies for Alzheimers disease.

Determining Cardiac Fiber Orientation Using FSL and Registered Ultrasound/DTI volumes.

Accurate extraction of cardiac fiber orientation from diffusion tensor imaging is important for determining heart structure and function. However, the acquisition of magnetic resonance (MR) diffusion tensor images is costly and time consuming. By comparison, cardiac ultrasound imaging is rapid and relatively inexpensive, but it lacks the capability to directly measure fiber orientations. In order to create a detailed heart model from ultrasound data, a three-dimensional (3D) diffusion tensor imaging (DTI) with known fiber orientations can be registered to an ultrasound volume through a geometric mask. After registration, the cardiac orientations from the template DTI can be mapped to the heart using a deformable transformation field. This process depends heavily on accurate fiber orientation extraction from the DTI. In this study, we use the FMRIB Software Library (FSL) to determine cardiac fiber orientations in diffusion weighted images. For the registration between ultrasound and MRI volumes, we achieved an average Dice similarity coefficient (DSC) of 81.6±2.1%. For the estimation of fiber orientations from the proposed method, we achieved an acute angle error (AAE) of 22.7±3.1° as compared to the direct measurements from DTI. This work provides a new approach to generate cardiac fiber orientation that may be used for many cardiac applications.

Register cardiac fiber orientations from 3D DTI volume to 2D ultrasound image of rat hearts.

Two-dimensional (2D) ultrasound or echocardiography is one of the most widely used examinations for the diagnosis of cardiac diseases. However, it only supplies the geometric and structural information of the myocardium. In order to supply more detailed microstructure information of the myocardium, this paper proposes a registration method to map cardiac fiber orientations from three-dimensional (3D) magnetic resonance diffusion tensor imaging (MR-DTI) volume to the 2D ultrasound image. It utilizes a 2D/3D intensity based registration procedure including rigid, log-demons, and affine transformations to search the best similar slice from the template volume. After registration, the cardiac fiber orientations are mapped to the 2D ultrasound image via fiber relocations and reorientations. This method was validated by six images of rat hearts ex vivo. The evaluation results indicated that the final Dice similarity coefficient (DSC) achieved more than 90% after geometric registrations; and the inclination angle errors (IAE) between the mapped fiber orientations and the gold standards were less than 15 degree. This method may provide a practical tool for cardiologists to examine cardiac fiber orientations on ultrasound images and have the potential to supply additional information for diagnosis of cardiac diseases.