Faculty Bibliography

OBJECT: The severity of neurological impairment following traumatic brain injury (TBI) is exacerbated by several endogenous processes, including hyperglycemia, hypotension, and the generation of glutamate. However, in addition to controlling hyperglycemia, insulin has pleiotropic effects on tissue metabolism, which include reducing the concentration of the neurotoxic amino acid glutamate, making it unclear whether insulin's beneficial effects are attributable to the establishment of euglycemia per se. In the present study, the authors asked if reducing glutamate via approaches that do not lower glucose levels would improve neurological outcome following TBI. METHODS: Glucagon activates gluconeogenesis by increasing the hepatic uptake of amino acids such as glutamate and facilitating their conversion to glucose. Glucagon was administered as a single intraperitoneal injection before or after closed head injury (CHI). Neurological function, brain histological features, blood glutamate and glucose levels, and CSF glutamate concentrations were measured. RESULTS: A single intraperitoneal injection of glucagon (25 mug) into mice 10 minutes before or after CHI reduced lesion size by about 60% (p < 0.0001) and accelerated neurological recovery. The neuroprotective effect of glucagon was related to gluconeogenesis by decreasing the concentration of the neuroexcitatory amino acid glutamate in the circulation from 207 +/- 32.1 mumol/L in untreated mice to 101.11 +/- 21.6 mumol/L in treated mice (p < 0.001); a similar effect occurred in the CSF. The neuroprotective effect of glucagon was seen notwithstanding the attendant increase in blood glucose, the final substrate of gluconeogenesis. CONCLUSIONS: Glucagon exerts a marked neuroprotective effect post-TBI by decreasing CNS glutamate. Glucagon was beneficial despite increasing blood glucose. Favorable effects also occurred when glucagon was given prior to TBI, suggesting its involvement in the preconditioning process. Thus, glucagon may be of value in providing neuroprotection when administered after TBI or prior to certain neurosurgical or cardiac interventions in which the incidence of perioperative ischemia is high

Is morphology a discrete and independent element of lexical structure or does it simply reflect a fine-tuning of the system to the statistical correlation that exists among orthographic and semantic properties of words? Hebrew provides a unique opportunity to examine morphological processing in the brain because of its rich morphological system. In an fMRI masked priming experiment, we investigated the neural networks involved in implicit morphological processing in Hebrew. In the lMFG and lIFG, activation was found to be significantly reduced when the primes were morphologically related to the targets. This effect was not influenced by the semantic transparency of the morphological prime, and was not found in the semantic or orthographic condition. Additional morphologically related decrease in activation was found in the lIPL, where activation was significantly modulated by semantic transparency. Our findings regarding implicit morphological processing suggest that morphology is an automatic and distinct aspect of visually processing words. These results also coincide with the behavioral data previously obtained demonstrating the central role of morphological processing in reading Hebrew

The growing uses of deep brain stimulation for various basal ganglia (BG) abnormalities have reinforced the need to better understand its functional circuitry and organization. Here we focus on cortico-basal-ganglia pathways to test the 'parallel, segregated' versus 'funneling, integrated' theories. Using manganese-enhanced MRI (MEMRI) together with principal component spatiotemporal analysis, we previously described two patterns of caudomedial striatum efferent connectivity to the substantia nigra pars reticulata (SNr) that were hypothesized to represent the coexistence of integrated and segregated processes. These patterns corresponded to a direct mono-synaptic projection to the dorsolateral core of the SN and to a di-synaptic projection covering the entire nucleus. In the current study, MEMRI of the rostrolateral striatum was carried out to test whether this coexistence remains in the mirror pathway, by measuring rostrolateral striatum efferent connectivity that is known to connect to the ventromedial SNr. Only one spatiotemporal pattern of manganese accumulation, corresponding to projections from the striatum, was observed. It corresponds to a mono-synaptic projection to the ventromedial SNr covering SNr laminas, but no manganese was observed at the dorsolateral SNr core. Together with our previous findings, this suggests functional asymmetry along the SNr which is consistent with the known anatomical organization of dendrite and axonal 3D arborization. Consequently, the polarized connectivity along the dorsolateral-ventromedial axis implies that funneling and integration occur in the core (dorsolateral SNr) to the lamina (ventromedial SNr) direction, whereas in the other direction, and within other parts of the SNr, segregation predominates

A unique method to map the effect of crusher gradients in space and time on the gradient echo blood oxygen level dependent (BOLD) signal is introduced. Using the Radial Correlation Contrast (RCC) analysis method, amplitude-RCC maps at different time segments and different gradient strengths were obtained. The ratio of amplitude-RCC cluster volumes, with and without crusher gradients, showed a temporal dependency with stronger volume reduction for stimulation-onset versus stimulation-decline. Aside from signal-to-noise ratio reduction in diffusion weighted images, the average temporal patterns were equal. Comparison of the data with and without crushers showed a stronger reduction in local coherence for stimulation-onset times. We hypothesize that the stimulation decline was weighted by extravascular effects originating in expanded veins due to their larger volume and long range susceptibility which couples neighboring voxels. The ratio of amplitude-RCC with and without crushers calculated for each voxel at each time segment yielded a spatial-temporal mapping of the crusher effect. These maps suggest that early stimulation-onset ( approximately 9 s) is weighted by flow; later a dynamic steady-state between intra- and extravascular effects is obtained. Stimulation-decline was dominated by extravascular effects, and at late stimulation decline as well as at early stimulation onset, clusters were small and localized to expected site of neuronal activity

Due to the overall similarity of their brains' structure and physiology to its human counterpart, nonhuman primates provide excellent model systems for the pathogenesis of neurological diseases and their response to treatments. Its much smaller size, 80 versus 1250 cm(3), however, requires proportionally higher spatial resolution to study, nondestructively, as many analogous regions as efficiently as possible in anesthetized animals. The confluence of these requirements underscores the need for the highest sensitivity, spatial coverage, resolution, and exam speed. Accordingly, we demonstrate the feasibility of 3D multi-voxel, proton ((1)H) MRSI at (0.375 cm)(3)=0.05 cm(3) isotropic spatial resolution over 21 cm(3) (approximately 25%) of the anesthetized rhesus macaques brain at 7T in 25 min. These voxels are x10(2)-10(1) times smaller than the 8-1 cm(3) common to (1)H-MRS in humans, retaining similar proportions between the macaque and human brain. The spectra showed a signal-to-noise-ratio (SNR) approximately 9-10 for the major metabolites and the interanimal SNR spatial distribution reproducibility was in the +/-10% range for the standard error of their means (SEMs). Their metabolites' linewidths, 9+/-2 Hz, yield excellent spectral resolution as well. These results indicate that 3D (1)H-MRSI can be integrated into comprehensive MR studies in primates at such high fields

Is morphology a discrete and independent element of lexical structure or does it simply reflect a fine tuning of the system to the statistical correlation that exists among the orthographic and semantic properties of words? Imaging studies in English failed to show unequivocal morphological activation that is distinct from semantic or orthographic activation. Cognitive research in Hebrew has revealed that morphological decomposition is an important component of print processing. In Hebrew, morphological relatedness does not necessarily induce a clear semantic relatedness, thus, Hebrew provides a unique opportunity to investigate the neural substrates of morphological processing. In this functional magnetic resonance imaging study, participants were required to perform judgment tasks of morphological relatedness, semantic relatedness, rhyming, and orthographic similarity. Half of the morphologically related words were semantically related and half were semantically unrelated. This design was chosen to induce explicit morphological processing. We identified two locations involved in morphological processing: the left middle frontal gyrus and the left inferior parietal sulcus. Comparing locations of morphological related activation to the locations of semantic and orthographic related activation, we found that the areas neighbored but only partially overlapped. The similarity in activation between the two morphological conditions eliminates the possibility that morphological activation simply results from the semantic properties of the words. These results demonstrate the important role of morphological processing in reading and suggest that morphological analysis is a distinct process of visual word recognition

PURPOSE: To measure intra- and inter-hemispheric connectivity within the basal ganglia (BG) nuclei in healthy and in unilateral 6-hydroxydopamine (6-OHDA) Parkinson disease rat model in order to test the BG interhemispheric connectivity hypothesis. MATERIAL AND METHODS: The manganese-enhanced MRI (MEMRI) method with direct injection of manganese chloride into the entopeduncular (EP), substantia nigra (SN), and the Habenula nuclei in unilateral 6-OHDA (N = 22) and sham-operated (N = 16) rat groups was used. MEMRI measurements were applied before, 3, 24, and 48 hours post-manganese injection. Signal enhancements in T1-weighted images were compared between groups. RESULTS: Manganese injection into the EP nucleus resulted with bihemispheric signal enhancements in the habenular complex (Hab) at both groups with stronger enhancements in the 6-OHDA group. It also exhibited lower sensorimotor cortex signal enhancement in the 6-OHDA rat group. SN manganese injection caused enhanced anteroventral thalamic and habenular nuclei signals in the 6-OHDA rat group. Manganese habenula injection revealed enhanced interpeduncular (IP) and raphe nuclei signals of the 6-OHDA rat group. CONCLUSION: Modulations in the effective intra- and interhemispheric BG connectivity in unilateral 6-OHDA Parkinson's disease (PD) rat model support the BG interhemispheric connectivity hypothesis and suggest a linkage between the dopaminergic and serotonergic systems in PD, in line with clinical symptoms

A statistical framework for the amplitude radial correlation contrast (RCC) method, which integrates a conventional pixel threshold approach with cluster-size statistics, is presented. The RCC method uses functional MRI (fMRI) data to group neighboring voxels in terms of their degree of temporal cross correlation and compares coherences in different brain states (e.g., stimulation OFF vs. ON). By defining the RCC correlation map as the difference between two RCC images, the map distribution of two OFF states is shown to be normal, enabling the definition of the pixel cutoff. The empirical cluster-size null distribution obtained after the application of the pixel cutoff is used to define a cluster-size cutoff that allows 5% false positives. Assuming that the fMRI signal equals the task-induced response plus noise, an analytical expression of amplitude-RCC dependency on noise is obtained and used to define the pixel threshold. In vivo and ex vivo data obtained during rat forepaw electric stimulation are used to fine-tune this threshold. Calculating the spatial coherences within in vivo and ex vivo images shows enhanced coherence in the in vivo data, but no dependency on the anesthesia method, magnetic field strength, or depth of anesthesia, strengthening the generality of the proposed cutoffs

Ras proteins play a role in receptor-mediated signaling pathways and are activated after traumatic brain injury. S-trans-trans-farnesylthiosalicylic acid (FTS), a synthetic Ras inhibitor, acts primarily on the active, GTP-bound form of Ras and was shown to improve neurobehavioral outcome after closed head injury (CHI) in mice. To gain a better understanding of the neuroprotective mechanism of FTS, we used diffusion-weighted imaging (DWI) in a rat model of CHI. Apparent diffusion coefficients (ADC) and transverse relaxation times (T2) were measured in injured rat brains after treatment with vehicle or FTS (5 mg/kg). Neuroprotection by FTS was also assessed in terms of the neurological severity score. One week after injury, significantly better recovery was observed in the FTS-treated rats than in the controls (p = 0.0191). T2 analysis of the magnetic resonance images revealed no differences between the two groups. In contrast, they differed significantly in ADC, particularly at 24 h post-CHI (p < 0.05): in the vehicle-treated rats ADC had decreased to approximately 26% below baseline, whereas it had increased to about 10% above baseline in the FTS-treated rats. As the magnitude of ADC reduction is strongly linked to blood perfusion deficit, these results suggest that the neuroprotective mechanism of FTS might be related to an improvement in cerebral perfusion. We propose that FTS, which is currently being tested in humans for anti-cancer indications, should also be considered as a new strategy for the management of head injury

Proton MR spectroscopic imaging (MRSI) at higher magnetic fields (B(0)) suffers metabolite localization errors from different chemical-shift displacements (CSDs) if spatially-selective excitation is used. This phenomenon is exacerbated by the decreasing radiofrequency (RF) field strength, B(1), at higher B(0)s, precluding its suppression with stronger gradients. To address this, two new methods are proposed: 1) segmenting the volume-of-interest (VOI) into several slabs, allowing proportionally stronger slice-select gradients; and 2) sequentially cascading rather than superposing the components of the Hadamard selective pulses used for reasons of better point-spread function (PSF) to localize the few slices within each slab. This can reduce the peak B(1) to that of a single slice. Combining these approaches permits us to increase the selective gradient four- to eightfold per given B(1), to 12 or 18mT/m for 4- or 2-cm VOIs. This 'brute force' approach reduces the CSD to under 0.05 cm/ppm at 7T, or less than half that at 3T