Christian Beaulieu - US grants

technology /technique development; radiology; magnetic resonance imaging; nervous system; biomedical resource; bioengineering /biomedical engineering;

Introduction: Diffusion- (DWI) and perfusion-weighted (PWI) magnetic resonance imaging are powerful tools for the evaluation of therapeutic drugs for stroke. The temporal progression of the ischemic lesion can be monitored by DWI whereas PWI can be used to follow the underlying hemodynamics. The purpose of this study was to evaluate the efficacy of a novel intra-vascular compound, polynitroxyl albumin (PNA) (SynZyme Technologies), in a transient focal cerebral ischemia model in the rat. Methods: Anesthetized Sprague-Dawley rats underwent 2 hours of middle cerebral artery occlusion (MCAO) by an intraluminal suture. Three treatment groups (N=6 per group) were studied: i) saline and ii) albumin as controls, and iii) PNA. PNA, albumin, or saline was injected i.v. at 0.5, 2, and 4 h post-MCAO (total dose = 1% body weight). DWI and PWI (bolus tracking) were performed on a GE CSI 2 T spectrometer at 0.25 (before first drug treatment), 1, 1.7, 2.3, 3, and 4 h post-MCAO. At 24 h, brain sections were stained with 2,3,5-triphenyltetrazolium chloride (TTC) to obtain an MRI-independent measure of ischemic injury. Results and Conclusion: The ability of DWI to monitor the ischemic region over time revealed different evolution patterns. Lesion volumes increased significantly for both the saline- and albumin groups, whereas the growth of the lesion was suppressed in the PNA group. The lesion volume (4 h DWI) in the PNA group was reduced by 63% compared to the saline group (p=0.003) and by 52% compared to the albumin group (p = 0.006). The TTC-derived lesion volumes at 24 h are in reasonable agreement with the DWI at 4 h. The perfusion measurements suggest that improved blood flow pre- and post-reperfusion may be responsible for the beneficial effect of PNA.

Introduction: The apparent diffusion coefficient (ADC) of water in gray and white matter decreases significantly (~35%) after global ischemia. However, the effects of ischemia on water diffusion and its anisotropy in nerve are unknown. The purpose of this study was to measure water diffusion and its anisotropy in the optic and trigeminal nerve after cardiac arrest in the rat. Methods: Cardiac arrest was induced in anesthetized Sprague-Dawley rats (n=7) by an i.v. injection of potassium chloride. Core temperature was maintained at 3711!C by warm air circulation. MRI diffusion measurements were performed on a GE CSI 2 T spectrometer prior to cardiac arrest and at 20, 40, 60, and 90 min after cardiac arrest. In order to investigate anisotropic diffusion and since the nerves are in approximate alignment with the Z direction, the ADC values parallel (//) and perpendicular (^) to the length of the nerve were obtained with the diffusion gradients applied along Z and X (or Y), respectively. Results and Conclusion: ADC(//) and ADC(^) decreased by 44 and 46%, respectively, in the optic nerve, and by 24 and 26%, respectively, in the trigeminal nerve at 90 min post cardiac arrest, relative to the ADCs prior to cardiac arrest. Interestingly, the rate of approach to the minimum ADC was slower than in the cortex. This is in agreement with the slower decrease of the ADC in white matter relative to gray matter after cardiac arrest. Despite the absolute reductions in ADC, anisotropy {ADC(//)/ADC(^)} was preserved throughout the 90 min after cardiac arrest and it remained at ~2.9 for both the optic and trigeminal nerves. Therefore, changes in diffusional anisotropy would not be expected at the acute stage of ischemia.

Introduction: Diffusion-weighted MRI (DWI) can detect transient declines of the apparent diffusion coefficient (ADC) that represent spreading depression (SD) associated disturbances of the ion homeostasis and the concomitant extra- to intracellular water shift in the periinfarct tissue. We investigated the dynamics of the initial SD-related ADC transients in hyper- and normoglycemic rats after remote middle cerebral artery occlusion (MCAO) to test the hypothesis that an increased blood glucose level should result in a faster recovery of SD like transients in the periinfarct tissue. Methods: Six rats were rendered hyperglycemic by i.p. injection of streptozotocin 36 hours before induction of focal cerebral ischemia using the remote suture model. Periinfarct SD was monitored during the initial 15 minutes after remotely induced middle cerebral artery occlusion (MCAO) using serial ultrafast. Data for each ADC calculation was acquired in 16s. Perfusion imaging was performed immediately after the DWI using the same multi-slice EPI technique to follow a bolus injection of 0.3 mmol/kg Gd-DTPA. Multiple adjacent ROIs were defined in the ADC maps. The latency time from MCAO to the onset of the ADC decrease (LT), the time from the start of the ADC decrease to the maximal ADC decline (= T FADC), the time from the start of the ADC decrease to the ADC recovery and the maximal ADC change (F ADC) were defined in order to characterize the temporal evolution of the ADC. Results: The ischemic core in hyperglycemic rats had a significant prolongation of LT as compared to normoglycemic control rats. Furthermore, T FADC was significantly increased in the ischemic core of hyperglycemic rats. Transient ADC decreases during SD occurred in the periinfarct tissue of both experimental groups. Hyperglycemic rats showed a significantly faster recovery of transient ADC declines in ROIs 2 and 3 adjacent to the ischemic core (5.610.6 min. vs. 10.111.6 min. in controls, p=0.03). Tissue perfusion did not reveal significant differences between the two groups. Conclusion: We conclude that hyperglycemia delays the terminal depolarization in the ischemic core and supports a faster repolarization in severely mal-perfused pen-umbral tissue after SD, which reflects the increased availability of energy substrate in the state of hyper-glycemia.

Introduction: The objective of this work was to design and utilize a flexible imaging sequence for ultra-fast, breath-held contrast-enhanced MR Angiography. Methods: Using the current generation of high speed imaging gradients it is possible to achieve sequence repetition times of 4 ms or less. This make it possible to obtain high resolution (512 x 512 x 64) images in under 30 seconds. The versatility of this technique will be demonstrated with applications including imaging of aortic dissection, thoracic and abdominal aortic aneurysm, pulmonary embolus, carotid stenosis, and peripheral vascular disease. We will discuss how the administration of contrast must be tailored to the vascular anatomy under examination to avoid venous enhancement. The rapid data acquisition times can be used to image multiple temporal phases or multiple spatial locations. Results/Conclusions: With this technique and the administration of a T1 shortening contrast agent, high quality MRA examinations can be routinely performed in a variety of vascular regions.

Introduction: An important aspect of thought is the ability to solve novel problems. Very little is understood about the brain basis of fluid reasoning. fMRI was used to identify which brain regions are important for fluid reasoning. We further examined whether there were separable brain region involved in abstract or analytic reasoning versus figural or visuospatial reasoning. We therefore examined brain activation while subjects solved problems from the Raven's Progressive Matrices Test. Methods: Activation was examined in seven, normal right-handed subjects (3 men, 4 woman, aged 23-30 years) with fMRI using blood-oxygen level-dependent contrast measured by a gradient echo spiral sequence. Each subject performed three scans that included (1) analytic reasoning, (2) figural reasoning, and (3) a baseline condition that controlled for perceptual and motor aspects of test performance but did not involve any reasoning. Results: Figural (visuospatial) reasoning activated right frontal and bilateral parietal areas. In addition to those areas, analytic reasoning activated bilateral frontal, and left parietal, occipital, and temporal areas. Further analyses showed that figural and analytic reasoning were disproportionately mediated by right and left hemisphere, respectively, but that both hemispheres contributed to both kinds of reasoning. Also, frontal areas contributed disproportionately relative to posterior cortical areas for analytic reasoning. Thus, reasoning activated an extensive, but specific, network of cortical regions. Therefore, it appears that reasoning on a novel problem activates all kinds of working memory capacities that may maintain a wide variety of relevant information in mind as subjects reason about a difficult problem. Conclusions: These findings constitute the most specific information about the brain basis of fluid reasoning abilities that people use to solve novel problems. Impairments in reasoning are prominent in several disease, including Alzheimer's disease and schizophrenia. Fluid reasoning also declines modestly but steadily in normal aging. Further studies will aim to better understand how age-related or disease-related changes in reasoning relate to changes in brain functions.