Faculty Bibliography

Neuronal activity evokes changes in local CBF and CBV, whose spatial differences are not fully known. We use the Radial Correlation Contrast (RCC) analysis method with high spatial resolution 100 x 100 x 1000 microm3 data collected with an 11.7 T magnet to differentiate two spatial-temporal BOLD clusters during sensory rat forepaw stimulation and hypothesize that each corresponds to either the CBF or the CBV processes. One cluster, obtained during the time segment of stimulation onset, is characterized by a high positive BOLD signal whereas the other, obtained during the simulation decline time segment, is characterized by a lower positive signal and strong post stimulus undershoot. The average volume of stimulation onset clusters is embedded in the stimulation decline clusters with the latter significantly larger and shifted towards deeper cortical layers. Comparison of amplitude-RCC and cross-correlation analyses performed on equivalent time segments (30 s, 40 images) revealed no differences in cluster size or location, demonstrating that temporal locality is more important than spatial locality in distinguishing between stimulation onset and stimulation decline clusters. We hypothesize that clusters characterized by stimulation onset are highly weighted by local changes in CBF whereas clusters characterized by stimulation decline are more CBV weighted. Moreover, the data suggest that the locations of the highest CBF changes are distinct from the locations of the highest CBV changes. While the former located within stimulation decline clusters and its weight is gradually reduced towards cluster's periphery (mainly ventrally), the highest changes in CBV occur in the cluster's periphery with only modest changes towards its center

A new strategy to yield information from the maximum number of voxels, each at the optimum signal-to-noise ratio (SNR) per unit time, in MR spectroscopic imaging (MRSI) is introduced. In the past, maximum acquisition duty-cycle was obtained by multiplexing in time several single slices each repetition time (TR), while optimal SNR was achieved by encoding the entire volume of interest (VOI) each TR. We show that optimal SNR and acquisition efficiency can both be achieved simultaneously by multiplexing in space and time several slabs of several slices, each. Since coverage of common VOIs in 3D proton MRSI in the human brain typically requires eight or more slices, at 3 T or higher magnetic fields, two or more slabs can fit into the optimum TR (approximately 1.6 s). Since typically four or less slices would then fit into each slab, Hadamard encoding is favored in that direction for slice profile reasons. It is demonstrated that per fixed examination length, the new method gives, at 3 T, twice as many voxels, each of the same SNR and size, compared with current 3D chemical shift imaging techniques. It is shown that this gain will increase for more extensive spatial coverage or higher fields

The point spread function (PSF) of Hadamard encoding deviates from its ideal profile due to practical (as opposed to intrinsic) reasons. Finite radiofrequency (RF) pulse length and gradient strength cause slice profile imperfections that lead to cross-talk ('voxel bleed') as large as 17% for a 1-KHz bandwidth, 5.12-ms RF pulse under 3 mT/m. This could adversely affect localization and quantification, and consequently clinical usefulness. A simple modification of the Hadamard RF pulse synthesis that exploits its unique ability to encode noncontiguous slices is proposed and shown to markedly improve the PSF. Computer simulation, in vitro and in vivo experiments confirm the theoretical derivation of voxel bleed reduction from approximately 17% to below 5% per Hadamard-encoded direction

The present study tested the hypothesis that lesion to the rat globus pallidus (GP) can 'normalize' the functioning of the basal ganglia-thalamocortical circuits in striatal-lesioned rats by assessing the functional connectivity of these regions using functional magnetic resonance imaging (fMRI). Changes in brain activation following systemic administration of amphetamine were assessed in (1) rats sustaining a unilateral lesion to the striatum, (2) rats sustaining a combined striatal and pallidal lesion, and (3) control rats. Striatal-lesioned rats showed attenuated cortical activation following amphetamine administration and lower correlations between the responses to amphetamine in different brain regions compared to control rats. Although the addition of an excitotoxic GP lesion failed to prevent striatal lesion-induced attenuation of cortical activation by amphetamine, it was effective in 'normalizing' the correlations between the responses to amphetamine in the different areas. These results suggest that, although the GP lesion is ineffective in correcting the global changes in activity caused by the striatal lesion, it may have the capacity to partially restore alterations in functional connectivity resulting from the striatal lesion. These results are further discussed in view of our previous demonstration that lesions to the GP can reverse several behavioral deficits produced by a striatal lesion

Functional neuro-imaging studies of Parkinson's disease (PD) patients and animal models show inconsistent cortical responses to sensory stimulation: some present increased sensorimotor cortex activation contradicting classical basal ganglia-cortex circuitry models, whereas others show decreased activation. As functional neuro-imaging activation is defined as the signal difference between stimulation ON and stimulation OFF, reduced 'activation' can point to either increased neuronal activity during stimulation ON or to decreased basal neuronal activity during stimulation OFF. A unique non-invasive method that uses the temporal and the spatial variances of functional magnetic resonance imaging signal is employed here to compare basal neuronal activity levels and 'functional homogeneity' between groups. Based on the assumption that the temporal variance reflects average neuronal activity, the variance of activity within a predefined region is defined as the region's 'functional homogeneity', which is assumed to estimate neuronal synchronization. Comparison of temporal and spatial variances of the sensorimotor cortex and the striatum in the 6-hydroxydopamine (6-OHDA) PD rat model and a control rat group show bilaterally decreased temporal and spatial variances in the 6-OHDA rat group, suggesting bilateral reduction of basal neuronal activity levels together with an increase in local neuronal synchronization in line with classical basal ganglia-cortex circuit models

A functional connectivity MRI method that groups neighboring voxels in relation to their degree of temporal cross-correlation between their time courses is presented. This grouping generates a vector field, which is assumed to provide insights into the local organization of neuronal activity. Application with high spatial resolution fMRI rat data subjected to electric forepaw sensory stimulation (156 . 156 . 1000 micron1) shows a significant localized increase of the vector field amplitude in cortical layers 4 and 2/3 of the primary sensory cortex and in layer 2/3 of the primary motor cortex, suggesting a strong correlation with local neuronal communication. Vector field phases exhibit a transition with neuronal activation from random-like orientations during rest to clusters of common orientations. Cluster size is shown to be weakly dependent on the radii of the vector field calculation, and shuffling voxel position within clusters generates a random-like vector orientation instead. This suggests that changes in vector orientations upon activation represent changes in the internal correlation between voxels that is interpreted as a change in the internal neuronal communication

Significantly higher temporal fluctuations of the blood oxygenation level-dependent (BOLD) signal in the living rat group compared to that in the dead rat group were observed in the cortex, suggesting the existence of physiological information in the signal fluctuations. A similar analysis shows significantly different fluctuations between visual cortical layers. The highest fluctuations were observed in layers 4 and 5 and the lowest in layer 1. Given the consistency with published electrophysiology studies anticipating high spontaneous activity in the deeper layers (particularly layer 4), and low activity in superficial layers, we hypothesize that the BOLD signal temporal fluctuations may reflect cortical neuronal activity. Temporal fluctuations in ultrahigh spatial resolution data of the rat brain were measured in two ways. In the first, analyses were performed according to known layer widths, and in the second equal lines of 117 micro along the cortex were selected. The second approach yielded temporal fluctuations along the cortex that resemble known neuronal density distributions including the intralayer structure, particularly within layer 5

Eleven cats with signs of cerebellar dysfunction, developed on recovery from a brief and uneventful general anesthesia, were examined at the Koret School of Veterinary Medicine Teaching Hospital (KSVMTH) between 1998 and 2002. Neurological signs included mild to severe ataxia of all 4 limbs, intentional tremor, lack of menace response, and delayed hopping. The cats were of different ages when anesthetized and none had shown any prior signs of neural disease. They were examined 1 day to 4 years after onset of clinical signs, and the neurological deficits remained unchanged in a follow-up period of 6 months to 8 years. Medical and anesthetic records showed that all were Persian cross cats, 7 of them originating in the same city in Israel. Ketamine was the only anesthetic drug that had been used with all cats. It might be that a genetic component predisposes Persian cross cats to nonreversible cerebellar damage after exposure to an anesthetic dose of ketamine

To gain insight into neovascularization of adult organs and to uncover inherent obstacles in vascular endothelial growth factor (VEGF)-based therapeutic angiogenesis, a transgenic system for conditional switching of VEGF expression was devised. The system allows for a reversible induction of VEGF specifically in the heart muscle or liver at any selected schedule, thereby circumventing embryonic lethality due to developmental misexpression of VEGF. Using this system, we demonstrate a progressive, unlimited ramification of the existing vasculature. In the absence of spatial cues, however, abnormal vascular trees were produced, a consequence of chaotic connections with the existing network and formation of irregularly shaped sac-like vessels. VEGF also caused a massive and highly disruptive edema. Importantly, premature cessation of the VEGF stimulus led to regression of most acquired vessels, thus challenging the utility of therapeutic approaches relying on short stimulus duration. A critical transition point was defined beyond which remodeled new vessels persisted for months after withdrawing VEGF, conferring a long-term improvement in organ perfusion. This novel genetic system thus highlights remaining problems in the implementation of pro-angiogenic therapy

Functional magnetic resonance imaging (fMRI) is used to investigate the basal ganglia (BG)-cortex circuit using a rat model of Parkinson's disease (PD). The model involves a unilateral destruction of the right substantia nigra by intranigral injection of the dopaminergic neurotoxin 6-hydroxydopamine. Volume of cortical activity was measured by the blood oxygenation level-dependent contrast method while applying electrical forepaw stimulation. The main findings are the following. (i) Contrary to the predictions of the classic model but in line with recent experimental results (positron emission tomography, fMRI and electrophysiology), an increased cortical activity in the sensorimotor cortex of PD rats compared with sham-operated or normal rats was found. (ii) A diffuse neuronal activity at large cortical areas that were not related directly to the stimulation used, was observed. (iii) No difference was found between the lesion and the nonlesion hemispheres when the left or the right forepaw was stimulated; both cortices show significant overactivation of the sensorimotor cortices in addition to diffuse cortical activation. The last finding could be explained by either corticocortical connections or by bilateral BG-cortex connections. These finding suggest that the mutual influence of the two hemispheres is important in the pathophysiology of the BG-cortex circuit and might be crucial in predicting treatments