Animal MRI/MRS Methodological Development for Drug Addiction Applications

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1. Registering and Analyzing Rat fMRI Data in the Stereotaxic Framework by Exploiting Intrinsic Anatomical Features The value of analyzing neuroimaging data on a group level in a common space has been well established in human studies. However, there has been no standard procedure for registering and analyzing rodent functional magnetic resonance imaging (fMRI) data in a common space. An approach for performing rat imaging data analysis in the stereotaxic framework is presented. This method is rooted in the biological observation that the skull shape and size of rat brain are essentially the same as long as their weights are within certain range. Registration was performed using rigid-body transformations without scaling or shearing, preserving the unique properties of the stable shape and size inherent in rat brain structure. It also does not require brain tissue masking, and is not biased towards surface coil sensitivity profile. A standard rat brain atlas was used to facilitate the identification of activated areas in common space, allowing accurate region-of-interest (ROI) analysis. This technique was evaluated from a group of rats (n = 11) undergoing routine scans. On average, the registration accuracy is estimated to be within 400 m. The utility of this technique is demonstrated in the analysis of fMRI data acquired with an electrical forepaw stimulation model. The method is implemented in the AFNI framework and can be readily extended to other studies. (Magn Reson Imaging, in press) 2. Physiologically evoked neuronal current MRI in a bloodless turtle brain: detectable or not? Contradictory reports regarding the detection of neuronal currents have left the feasibility of neuronal current MRI (ncMRI) an open question. Most previous ncMRI studies in human subjects are suspect due to their inability to separate or eliminate hemodynamic effects. In this study, we used a bloodless turtle brain preparation that eliminates hemodynamic effects, to explore the feasibility of detecting visually-evoked ncMRI signals at 9.4 T. Intact turtle brains, with eyes attached, were dissected from the cranium and placed in artificial cerebral spinal fluid. Light flashes were delivered to the eyes to evoke neuronal activity. Local field potential (LFP) and MRI signals were measured in an interleaved fashion. Robust visually-evoked LFP signals were observed in turtle brains, but no significant signal changes synchronized with neuronal currents were found in the ncMRI images. In this study, detection thresholds of 0.1% and 0.1 degrees were set for MRI magnitude and phase signal changes, respectively. The absence of significant signal changes in the MRI images suggests that visually-evoked ncMRI signals in the turtle brain are below these detectable levels. (NeuroImage 47:1268-1276, 2009) 3. Perfusion Imaging of the Entire Rat Brain Using Continuous Arterial Spin Labeling (CASL) at 9.4T In quantitative perfusion imaging, variable arterial transit times and post-labeling delays are two confounding factors that have been well documented. In the present study, we implement a three-coil CASL technique and demonstrate that, by increasing the labeling duration to 6.4 sec, the confounds resulting from variable post-labeling delays have been essentially eliminated, the ASL signal acquired in multi-slice ASL is virtually the same as that acquired in single slice ASL; we further suggest that combining long labeling duration with a post-labeling delay of 0.8 sec could dramatically reducing confounds resulting from variable arterial transit times while maintaining reasonable sensitivity (Fig. 4), permitting quantitative perfusion imaging of the entire rat brain. (Proceedings of 17th Annual Meeting ISMRM, 2009) 4. Temporary Disruption of the Rat Blood-Brain Barrier with a Monoclonal Antibody: A Novel Method for Dynamic Manganese-Enhanced MRI Manganese-enhanced magnetic resonance imaging (ME-MRI) has evolved into a promising neuroimaging tool. However, manganese hs limited permeability through the blood-brain barrier (BBB). Opening the BBB such that a sufficient amount of Mn2+ enters the extracellular space is a critical step for dynamic manganese-enhanced MRI (ME-MRI) experiments. Traditional BBB opening method through intracarotid hyperosmolar stress involves suboptimal BBB opening outcome, substantial surgical trauma, and practically limits to nonsurvival experiments. In the present study, we studied the feasibility of ME-MRI with the BBB opened by an antibody that targets the endothelial barrier antigen (EBA) specifically expressed by the endothelial cells of rat BBB. Results demonstrate that intravenous infusion of anti-EBA agent leads to BBB disruption of the whole brain as detected by ME-MRI. This method is straightforward and obviates technical difficulties associated with BBB disruption through intracarotid hyperosmolar stress, opening new possibilities for in-vivo neuroimaging with ME-MRI. (Proceedings of 17th Annual Meeting ISMRM, 2009) 5. Morphological changes of rhesus monkey brain induced by early life stress using deformation-based morphometry (DBM) with unbiased group registration DBM is an automatic computational method to detect voxel-wise anatomical differences between populations by examining deformation fields generated from registering their images. It has been used for detecting brain structural changes during development, aging and in various neuropathological states. We used DBM with an unbiased group-wise image registration method, which provides more accurate results, to analyze the morphological changes due to early life stress. The DBM analysis confirms our previous findings of enlarged dorsomedial prefrontal, dorsal anterior cingulated and vermis volumes. It also suggests that early life stress induces morphological abnormalities of the cortico-striato-pallidal system. (Proceedings of 17th Annual Meeting ISMRM, 2009) 6. MRI Indices Monitoring Stroke Recovery and Drug Intervention To investigate the feasibility of MRI-related techniques in detecting the evolution of the stroke model in rats with reperfusional injury, we used diffusion-weighted images (DWI) and arterial-spin lebeling (ASL) to investigate whether the lesion core and the penumbra areas could be differentiated at acute stage after stroke onset. To generate a reperfusional injury in rat stroke, a bilateral common carotids were ligated with nontraumatic arterial clips first and the right MCA was ligated with a 10-O suture to generate focal infarction in the cerebral cortex. The ligature and clips were then removed after 60-min ischemia. Five time points were applied in the longitudinal MRI follow-up study: two hours, two days, one week, two weeks and twelve weeks after stroke onset. A region of interest (ROI) for the lesion core area was determined by the lesion size shown at the hyperacute stage (two hours after stroke onset) and the difference between the ischemic lesion areas acquired at 2h and 2 days after stroke onset is referred to as the penumbra area. In our preliminary analysis, both DWI and ASL techniques are feasible in detecting the difference between the lesion core and the penumbra areas at acute stage, but there is no difference at chronic stage. The evolution of the present reperfusion stroke model in rats without any medicine treatment can be clearly characterized by using DWI and ASL techniques. The information from this study may help to clarify the treatment effects of anti-stroke agents.