Faculty Bibliography

BACKGROUND:Auditory verbal hallucinations (AVHs) are a core symptom of schizophrenia. Previous reports on neural activity patterns associated with AVHs are inconsistent, arguably owing to the lack of an adequate control group (i.e., patients with similar characteristics but without AVHs) and neglect of the potential confounding effects of medication. METHODS:The current study was conducted in a homogeneous group of patients with schizophrenia to assess whether the presence or absence of AVHs was associated with differential regional cerebral glucose metabolic patterns. We investigated differences between patients with commenting AVHs and patients without AVHs among a group of dextral antipsychotic-naive inpatients with acute first-episode schizophrenia examined with [(18)F]fluoro-deoxyglucose positron emission tomography (FDG-PET) at rest. Univariate and multivariate approaches were used to establish between-group differences. RESULTS:We included 9 patients with AVHs and 7 patients without AVHs in this study. Patients experiencing AVHs during FDG uptake had significantly higher metabolic rates in the left superior and middle temporal cortices, bilateral superior medial frontal cortex and left caudate nucleus (cluster level p < 0.005, family wise error-corrected, and bootstrap ratio > 3.3, respectively). Additionally, the multivariate method identified hippocampal-parahippocampal, cerebellar and parietal relative hypoactivity during AVHs in both hemispheres (bootstrap ratio < -3.3). LIMITATIONS/CONCLUSIONS:The FDG-PET imaging technique does not provide information regarding the temporal course of neural activity. The limited sample size may have increased the risk of false-negative findings. CONCLUSION/CONCLUSIONS:Our results indicate that AVHs in patients with schizophrenia may be mediated by an alteration of neural pathways responsible for normal language function. Our findings also point to the potential role of the dominant caudate nucleus and the parahippocampal gyri in the pathophysiology of AVHs. We discuss the relevance of phenomenology-based grouping in the study of AVHs.

PURPOSE: To develop, and validate in vivo, a robust quantitative first-pass perfusion cardiovascular MR (CMR) method with accurate arterial input function (AIF) and myocardial wall enhancement. MATERIALS AND METHODS: A saturation-recovery (SR) pulse sequence was modified to sequentially acquire multiple slices after a single nonselective saturation pulse at 3 Tesla. In each heartbeat, an AIF image is acquired in the aortic root with a short time delay (TD) (50 ms), followed by the acquisition of myocardial images with longer TD values ( approximately 150-400 ms). Longitudinal relaxation rates (R(1) = 1/T(1) ) were calculated using an ideal saturation recovery equation based on the Bloch equation, and corresponding gadolinium contrast concentrations were calculated assuming fast water exchange condition. The proposed method was validated against a reference multi-point SR method by comparing their respective R(1) measurements in the blood and left ventricular myocardium, before and at multiple time-points following contrast injections, in 7 volunteers. RESULTS: R(1) measurements with the proposed method and reference multi-point method were strongly correlated (r > 0.88, P < 10(-5) ) and in good agreement (mean difference +/-1.96 standard deviation 0.131 +/- 0.317 / 0.018 +/- 0.140 s(-1) for blood/myocardium, respectively). CONCLUSION: The proposed quantitative first-pass perfusion CMR method measured accurate R(1) values for quantification of AIF and myocardial wall contrast agent concentrations in 3 cardiac short-axis slices, in a total acquisition time of 523 ms per heartbeat. J. Magn. Reson. Imaging 2011;. (c) 2011 Wiley-Liss, Inc

Purpose: To assess prospectively the ability of quantitative low-dose three-dimensional magnetic resonance (MR) renography to help identify the cause of acute graft dysfunction. Materials and Methods: This HIPAA-compliant study was approved by the institutional review board, and written informed consent was obtained. Between December 2001 and May 2009, sixty patients with transplanted kidneys (41 men and 19 women; mean age, 49 years; age range, 22-71 years) were included. Thirty-one patients had normal function and 29 had acute dysfunction due to acute rejection (n = 12), acute tubular necrosis (ATN) (n = 8), chronic rejection (n = 6), or drug toxicity (n = 3). MR renography was performed at 1.5 T with three-dimensional gradient-echo imaging. With use of a multicompartment renal model, the glomerular filtration rate (GFR) and the mean transit time (MTT) of the tracer for the vascular compartment (MTT(A)), the tubular compartment (MTT(T)), and the collecting system compartment (MTT(C)) were calculated. Also derived was MTT for the whole kidney (MTT(K) = MTT(A) + MTT(T) + MTT(C)) and fractional MTT of each compartment (MTT(A/K) = MTT(A)/MTT(K), MTT(T/K) = MTT(T)/MTT(K), MTT(C/K) = MTT(C)/MTT(K)). These parameters were compared in patients in the different study groups. Statistical analysis was performed by using analysis of covariance. Results: There were significant differences in GFR and MTT(K) between the acute dysfunction group (36.4 mL/min +/- 20.8 [standard deviation] and 177.1 seconds +/- 46.8, respectively) and the normal function group (65.9 mL/min +/- 27.6 and 140.5 seconds +/- 51.8, respectively) (P < .001 and P = .004). The MTT(A/K) was significantly higher in the acute rejection group (mean, 12.7% +/- 2.9) than in the normal function group (mean, 8.3% +/- 2.2; P < .001) or in the ATN group (mean, 7.1% +/- 1.4; P < .001). The MTT(T/K) was significantly higher in the ATN group (mean, 83.2% +/- 9.2) than in the normal function group (mean, 72.4% +/- 10.2; P = .031) or in the acute rejection group (mean, 69.2% +/- 6.1; P = .003). Conclusion: Low-dose MR renography analyzed by using a multicompartmental tracer kinetic renal model may help to differentiate noninvasively between acute rejection and ATN after kidney transplantation. (c) RSNA, 2011

Cancers often cause excruciating pain and rapid weight loss, severely reducing quality of life in cancer patients. Cancer-induced pain and cachexia are often studied and treated independently, although both symptoms are strongly linked with chronic inflammation and sustained production of proinflammatory cytokines. Because nerve growth factor (NGF) plays a cardinal role in inflammation and pain, and because it interacts with multiple proinflammatory cytokines, we hypothesized that NGF acts as a key endogenous molecule involved in the orchestration of cancer-related inflammation. NGF might be a molecule common to the mechanisms responsible for clinically distinctive cancer symptoms such as pain and cachexia as well as cancer progression. Here we reported that NGF was highly elevated in human oral squamous cell carcinoma tumors and cell cultures. Using two validated mouse cancer models, we further showed that NGF blockade decreased tumor proliferation, nociception, and weight loss by orchestrating proinflammatory cytokines and leptin production. NGF blockade also decreased expression levels of nociceptive receptors TRPV1, TRPA1, and PAR-2. Together, these results identified NGF as a common link among proliferation, pain, and cachexia in oral cancer. Anti-NGF could be an important mechanism-based therapy for oral cancer and its related symptoms

Neurofibrillary tangles (NFTs) are one of the pathological hallmarks of Alzheimer's disease (AD) and are primarily composed of aggregates of hyperphosphorylated forms of the microtubule associated protein tau. It is likely that an imbalance of kinase and phosphatase activities leads to the abnormal phosphorylation of tau and subsequent aggregation. The wide ranging therapeutic approaches that are being developed include to inhibit tau kinases, to enhance phosphatase activity, to promote microtubule stability, and to reduce tau aggregate formation and/or enhance their clearance with small molecule drugs or by immunotherapeutic means. Most of these promising approaches are still in preclinical development whilst some have progressed to Phase II clinical trials. By pursuing these lines of study, a viable therapy for AD and related tauopathies may be obtained

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, Huntington's disease (HD) or amyotrophic lateral sclerosis (ALS) are all characterized histologically by the presence of deposits of misfolded proteins, tau and amyloid, -synuclein, huntingtin or superoxide dismutase respectively. Currently these illnesses do not have any disease modifying treatment options. A novel therapeutic strategy that is being pursued is immunomodulation, which is using the body's immune system to target the self proteins that are deposited. Most of these promising approaches are still in preclinical development whilst some have progressed to Phase III clinical trials. As new insights are gained, it is hoped that these immunotherapies will be effective tools at slowing the progression of these debilitating diseases

The cerebellum is a highly organized structure partitioned into lobules along the anterior-posterior (A-P) axis and into striped molecular domains along the medial-lateral (M-L) axis. The Engrailed (En) homeobox genes are required for patterning the morphological and molecular domains along both axes, as well as for the establishment of the normal afferent topography required to generate a fully functional cerebellum. As a means to understand how the En genes regulate multiple levels of cerebellum construction, we characterized En1 and En2 expression around birth and at postnatal day (P) 21 during the period when the cerebellum undergoes a remarkable transformation from a smooth ovoid structure to a highly foliated structure. We show that both En1 and En2 are expressed in many neuronal cell types in the cerebellum, and expression persists until at least P21. En1 and En2 expression, however, undergoes profound changes in their cellular and spatial distributions between embryonic stages and P21, and their expression domains become largely distinct. Comparison of the distribution of En-expressing Purkinje cells relative to early- and late-onset Purkinje cell M-L stripe proteins revealed that although En1- and En2-expressing Purkinje cell domains do not strictly align with those of ZEBRINII at P21, a clear pattern exists that is most evident at E17.5 by an inverse correlation between the level of En2 expression and PLCss4 and EPHA4

The nervous system must dynamically represent sensory information in order for animals to perceive and operate within a complex, changing environment. Receptive field plasticity in the auditory cortex allows cortical networks to organize around salient features of the sensory environment during postnatal development, and then subsequently refine these representations depending on behavioral context later in life. Here we review the major features of auditory cortical receptive field plasticity in young and adult animals, focusing on modifications to frequency tuning of synaptic inputs. Alteration in the patterns of acoustic input, including sensory deprivation and tonal exposure, leads to rapid adjustments of excitatory and inhibitory strengths that collectively determine the suprathreshold tuning curves of cortical neurons. Long-term cortical plasticity also requires co-activation of subcortical neuromodulatory control nuclei such as the cholinergic nucleus basalis, particularly in adults. Regardless of developmental stage, regulation of inhibition seems to be a general mechanism by which changes in sensory experience and neuromodulatory state can remodel cortical receptive fields. We discuss recent findings suggesting that the microdynamics of synaptic receptive field plasticity unfold as a multi-phase set of distinct phenomena, initiated by disrupting the balance between excitation and inhibition, and eventually leading to wide-scale changes to many synapses throughout the cortex. These changes are coordinated to enhance the representations of newly-significant stimuli, possibly for improved signal processing and language learning in humans

J. Neurochem. (2011) 118, 721-736. ABSTRACT: ATP-sensitive K(+) (K(ATP) ) channels are composed of pore-forming subunits, typically Kir6.2 in neurons, and regulatory sulfonylurea receptor subunits. In dorsal striatum, activity-dependent H(2) O(2) produced from glutamate receptor activation inhibits dopamine release via K(ATP) channels. Sources of modulatory H(2) O(2) include striatal medium spiny neurons, but not dopaminergic axons. Using fast-scan cyclic voltammetry in guinea-pig striatal slices and immunohistochemistry, we determined the time window for H(2) O(2) /K(ATP) -channel-mediated inhibition and assessed whether modulatory K(ATP) channels are on dopaminergic axons. Comparison of paired-pulse suppression of dopamine release in the absence and presence of glibenclamide, a K(ATP) -channel blocker, or mercaptosuccinate, a glutathione peroxidase inhibitor that enhances endogenous H(2) O(2) levels, revealed a time window for inhibition of 500-1000 ms after stimulation. Immunohistochemistry demonstrated localization of Kir6.2 K(ATP) -channel subunits on dopaminergic axons. Consistent with the presence of functional K(ATP) channels on dopaminergic axons, K(ATP) -channel openers, diazoxide and cromakalim, suppressed single-pulse evoked dopamine release. Although cholinergic interneurons that tonically regulate dopamine release also express K(ATP) channels, diazoxide did not induce the enhanced frequency responsiveness of dopamine release seen with nicotinic-receptor blockade. Together, these studies reveal subsecond regulation of striatal dopamine release by endogenous H(2) O(2) acting at K(ATP) channels on dopaminergic axons, including a role in paired-pulse suppression