Faculty Bibliography

RATIONALE: Previous work has demonstrated a profound effect of N-methyl-D: -aspartic acid receptor (NMDAR) antagonism in the infralimbic cortex (IL) to selectively elevate impulsive responding in a rodent reaction time paradigm. However, the mechanism underlying this effect is unclear. OBJECTIVES: This series of experiments investigated the pharmacological basis of this effect in terms of excitatory and inhibitory neurotransmission. We tested several pharmacological mechanisms that might produce the effect of NMDAR antagonism via disruption or dampening of IL output. METHODS: Drugs known to affect brain GABA or glutamate function were tested in rats pre-trained on a five-choice serial reaction time task (5-CSRTT) following either their systemic administration or direct administration into the IL. RESULTS: Systemic lamotrigine administration (15 mg/kg), which attenuates excess glutamate release, did not counteract the ability of the intra-IL NMDAR antagonist 3-((R)-2-carboxypiperazin-4-yl)-propyl-L: -phosphonic acid ((R)-CPP) to increase premature responding on the 5-CSRTT. Putative elevation of local extracellular glutamate via intra-IL infusions of the selective glutamate reuptake inhibitor DL: -threo-beta-benzyloxyaspartate as well as local alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonism also had no effect on this task. However, intra-IL infusions of the GABA(A) receptor agonist muscimol produced qualitatively but not quantitatively comparable increases in impulsive responding to those elicited by (R)-CPP. Moreover, the GABA(A) receptor antagonist bicuculline blocked the increase in impulsivity produced by (R)-CPP when infused in the IL. CONCLUSIONS: These findings implicate glutamatergic and GABAergic mechanisms in the IL in the expression of impulsivity and suggest that excessive glutamate release may not underlie increased impulsivity induced by local NMDA receptor antagonism.

HYPOTHESIS: Reactivation of herpes simplex virus type 1 (HSV-1) in geniculate ganglion neurons (GGNs) is an etiologic mechanism of Bell's palsy (BP) and delayed facial palsy (DFP) after otologic surgery. BACKGROUND: Several clinical studies, including temporal bone studies, antibody, titers, and intraoperative studies, suggest that reactivation of HSV-1 from latently infected GGNs may lead to both BP and DFP. However, it is difficult to study these processes in humans or live animals. METHODS: Primary cultures of GGNs were latently infected with Patton strain HSV-1 expressing a green fluorescent protein-late lytic gene chimera. Four days later, these cultures were treated with trichostatin A (TSA), a known chemical reactivator of HSV-1 in other neurons. Cultures were monitored daily by fluorescent microscopy. Titers of media from lytic, latent, and latent/TSA treated GGN cultures were obtained using plaque assays on Vero cells. RNA was harvested from latently infected GGN cultures and examined for the presence of viral transcripts using reverse transcription-polymerase chain reaction. RESULTS: Latently infected GGN cultures displayed latency-associated transcripts only, whereas lytically infected and reactivated latent cultures produced other viral transcripts, as well. The GGN cultures displayed a reactivation rate of 65% after treatment with TSA. Media from latently infected cultures contained no detectable infectious HSV-1, whereas infectious virus was observed in both lytically and latently infected/TSA-treated culture media. CONCLUSION: We have shown that cultured GGNs can be latently infected with HSV-1, and HSV-1 in these latently infected neurons can be reactivated using TSA, yielding infectious virus. These results have implications for the cause of both BP and DFP

Diffusion-weighted imaging (DWI) involves data acquisitions at multiple b values. In this paper, we presented a method of selecting the b values that maximize estimation precision of the biexponential analysis of renal DWI data. We developed an error propagation factor for the biexponential model, and proposed to optimize the b-value samplings by minimizing the error propagation factor. A prospective study of four healthy human subjects (eight kidneys) was done to verify the feasibility of the proposed protocol and to assess the validity of predicted precision for DWI measures, followed by Monte Carlo simulations of DWI signals based on acquired data from renal lesions of 16 subjects. In healthy subjects, the proposed methods improved precision (P = 0.003) and accuracy (P < 0.001) significantly in region-of-interest based biexponential analysis. In Monte Carlo simulation of renal lesions, the b-sampling optimization lowered estimation error by at least 20-30% compared with uniformly distributed b values, and improved the differentiation between malignant and benign lesions significantly. In conclusion, the proposed method has the potential of maximizing the precision and accuracy of the biexponential analysis of renal DWI. Magn Reson Med, 2011. (c) 2011 Wiley-Liss, Inc

Background: The ability to predict the course of multiple sclerosis (MS) is highly desirable but lacking. Objective: To test whether the MS Severity Scale (MSSS) and global neuronal viability, assessed through the quantification of the whole-brain N-acetylaspartate concentration (WBNAA), concur or complement the assessment of individual patients' disease course. Methods: The MSSS and average WBNAA loss rate (DeltaWBNAA, extrapolated based on one current measurement and the assumption that at disease onset neural sparing was similar to healthy controls, obtained with proton magnetic resonance (MR) spectroscopy and magnetic resonance imaging (MRI)) from 61 patients with MS (18 male and 43 female) with long disease duration (15 years or more) were retrospectively examined. Some 27 patients exhibited a 'benign' disease course, characterized by an Expanded Disability Status Scale score (EDSS) of 3.0 or less, and 34 were 'non-benign': EDSS score higher than 3.0. Results: The two cohorts were indistinguishable in age and disease duration. Benign patients' EDSS and MSSS (2.1 +/- 0.7, 1.15 +/- 0.60) were significantly lower than non-benign (4.6 +/- 1.0, 3.6 +/- 1.2; both p < 10(-4)). Their respective average DeltaWBNAA, 0.10 +/- 0.16 and 0.11 +/- 0.12 mM/year, however, were not significantly different (p > 0.7). While MSSS is both sensitive to (92.6%) and specific for (97.0%) benign MS, DeltaWBNAA is only sensitive (92.6%) but not specific (2.9%). Conclusion: Since the WBNAA loss rate is similar in both phenotypes, the only difference between them is their clinical classification, characterized by MSSS and EDSS. This may indicate that 'benign' MS probably reflects fortuitous sparing of clinically eloquent brain regions and better utilization of brain plasticity

Purpose: To evaluate the ability of magnetization transfer (MT) contrast-prepared magnetic resonance (MR) imaging to help distinguish healthy from cirrhotic liver by using a spectrum of MT pulse frequency offsets. Materials and Methods: This HIPAA-compliant prospective study was approved by the institutional review board. Written informed consent was obtained from all subjects. After optimization of the MT sequence by using agar phantoms with protein concentrations ranging from 0% to 4%, 20 patients with cirrhosis and portal hypertension and 20 healthy volunteers with no known liver disease underwent liver MR imaging that included eight separate breath-hold MT contrast sequences, each performed by using a different MT pulse frequency offset (range, 200-2500 Hz). Regions of interest were then placed to calculate the MT ratio for the liver, fat, and muscle in the volunteer group and for the liver in the cirrhosis group. Results: MT ratio increased with decreasing MT pulse frequency offset for each of the four phantoms and the assessed in vivo tissues, consistent with previous reports. At all frequency offsets, MT ratio increased with increasing phantom protein concentration. In volunteers, at frequency offsets greater than 400 Hz, the MT ratio was significantly greater for muscle (range, 34.4%-54.9%) and significantly lower for subcutaneous fat (range, 10.3%-12.6%), compared with that for the liver (range, 22.8%-46.9%; P < .001 all comparisons). However, the MT ratio was nearly identical between healthy (range, 26.0%-80.0%) and cirrhotic livers (range, 26.7%-81.2%) for all frequency offsets (P = .162-.737), aside from a minimal difference in MT ratio of 1.7% at a frequency offset of 2500 Hz (22.8% in healthy liver vs 24.5% in cirrhotic liver) that was not significant when the Bonferroni correction was applied (P = .015). Conclusion: Findings of this study confirm the ability of the MT contrast-prepared sequence to help distinguish substances of varying protein concentration and suggest that MT imaging is unlikely to be of clinical utility in differentiating healthy and cirrhotic livers. (c) RSNA, 2011

The longitudinal repeatability of proton MR spectroscopy ((1) H-MRS) in the healthy human brain at high fields over long periods is not established. Therefore, we assessed the inter- and intra-subject repeatability of (1) H-MRS in an approach suited for diffuse pathologies in 10 individuals, at 3T, annually for 3 years. Spectra from 480 voxels over 360 cm(3) ( approximately 30%) of the brain, were individually phased, frequency-aligned, and summed into one average spectrum. This dramatically increases metabolites' signal-to-noise-ratios while maintaining narrow linewidths that improve quantification precision. The resulting concentrations of the N-acetylaspartate, creatine, choline, and myo-inositol are: 8.9 +/- 0.8, 5.9 +/- 0.6, 1.4 +/- 0.1, and 4.5 +/- 0.5 mM (mean +/- standard-deviation). the inter-subject coefficients of variation are 8.7%, 10.2%, 10.7%, and 11.8%; and the longitudinal (intra-subject) coefficients of variation are lower still: 6.6%, 6.8%, 6.8%, and 10%, much better than the 35%, 44%, 55%, and 62% intra-voxel coefficients of variation. The biological and nonbiological components of the summed spectra coefficients of variation had similar contributions to the overall variance. Magn Reson Med, 2011. (c) 2011 Wiley-Liss, Inc

Introduction: Recent work has demonstrated head motion contributes to artifactual differences in resting-state fMRI (R-fMRI) measures (Power et al., 2012a;Satterthwaite et al., 2012;Van Dijk et al., 2012). Here we explored how a broad array of R-fMRIbased intrinsic brain function measures are affected by head motion, and how such sensitivities and their test-retest (TRT) reliabilities are impacted by various motion correction strategies. Methods: After preprocessing publicly released developmental, young adult and TRT datasets, the following strategies were applied to correct head motion effects: regressing out 6 head motion parameters (Traditional 6), regressing out autoregressive models (Friston et al., 1996) (Friston 24), regressing out voxelspecific head motion regressors (Voxel-Specific 12), and data scrubbing at framewise displacement (FD) > 0.2 or 0.5mm. We then explored head motion effects and TRT reliability on amplitude of low frequency fluctuation (ALFF), fractional ALFF (fALFF), regional homogeneity, voxel-mirrored homotopic connectivity, and functional connectivity of medial prefrontal cortex. Results: As previously suggested, head motion effects are stronger in developmental than adult data (Fig. 1 vs. Fig. 2). Among the measures, fALFF is least affected by head motion. Among head motion correction strategies, scrubbing at FD > 0.2 mm (Power et al., 2012b) cleared the most motion effect while creating artificial head motion effect in fALFF due to destruction of temporal structure. Scrubbing at FD > 0.2mm also diminished TRT reliability dramatically (Fig. 3); some subjects varied markedly in the number of time points excluded across sessions (e.g., (Figure Presented) 150 vs. 37). Importantly, head motion effects remained after all correction strategies (Figs. 1, 2) suggesting taking subject head motion into account at the group level is still necessary. Regressing out mean FD slightly decreased TRT reliability but preserved its structure (Fig. 4). Conclusion: Results suggest that head motion effects extend to all metrics when studying hyperkinetic populations. We suggest caution when using stringent scrubbing (e.g. FD > 0.2mm as recommend by Power et al. 2012b), as test-retest reliability can be compromised and frequency metrics made immeasurable. Correction for inter-individual differences in motion at the grouplevel appears to be necessary regardless of individual subject correction strategy