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Objective This proof-of-concept study aimed to demonstrate therapeutic effects of deep brain stimulation (DBS) on noise-induced tinnitus. Study Design Experimental animal study. Methods After Institutional Animal Care and Use Committee approval, nine adult rats were implanted in the caudate nucleus with custom-made electrode array. The rats were exposed to noise to induce tinnitus. Auditory brainstem response was performed to evaluate hearing threshold changes. Noise-induced tinnitus and its suppression by DBS were evaluated using the gap-detection acoustic startle reflex behavioral paradigm and electrophysiological evaluation of modulatory effects on neural correlates of tinnitus. Various stimulation parameters were used to determine the most effective ones in affecting behavioral changes, along with corresponding neural activity in the caudate nucleus. The correlation between the caudate nucleus and auditory cortex also was determined. Analysis of variance with Bonferroni correction was performed to examine DBS-induced effects on behavioral evidence of tinnitus. Results Bursting activity, a neural marker of tinnitus, was noted to decrease compared to baseline in tinnitus (+) animals. After stimulation, spontaneous and bursting activity increased in the tinnitus (+) animals but decreased in the tinnitus (−) animals. Behavioral data suggested suppression of tinnitus after DBS. These effects lasted up to 5 days. To our knowledge, this is the first development of an animal model to test deep brain stimulation of the caudate region for the treatment of tinnitus. Conclusions Deep brain stimulation of the caudate nucleus can modulate tinnitus in a rat model of tinnitus. Level of Evidence NA. Laryngoscope, 2017

Exposure to high-pressure blast shock waves is known to cause tinnitus. Although the underlying mechanisms may involve damage to structures in the ear and/or direct brain impact, which triggers a cascade of neuroplastic changes in both auditory and nonauditory centers, it remains unclear how the induced neuroplasticity manifests neurophysiologically. This study investigates the influence of blast exposure on spontaneous firing rates (SFRs) in the dorsal cochlear nucleus (DCN) and its time course in rats with blast-induced tinnitus. Each rat was exposed to a single blast at 22 psi. Behavioral evidence of tinnitus was measured by using a gap-detection acoustic startle-reflex paradigm. SFRs were measured 1 day, 1 month, and 3 months after blast exposure. The results showed that nine rats with blast-induced tinnitus and hearing loss developed hyperactivity immediately and that the induced hyperactivity persisted in six rats with tinnitus at 1 month after blast exposure. At 3 months after blast exposure, however, the induced hyperactivity of four rats with tinnitus transitioned to hypoactivity. In addition, the 20-30-kHz, and >30-kHz regions in the DCN of rats with and without blast-induced tinnitus were more affected than other frequency regions at different recovery time points after blast exposure. These results demonstrate that the neural mechanisms underlying blast-induced tinnitus are substantially different from those underlying noise-induced tinnitus. © 2014 Wiley Periodicals, Inc. Language: en

In noisy, multipeople talking environments such as a cocktail party, listeners can use various perceptual and/or cognitive cues to improve recognition of target speech against masking, particularly informational masking. Previous studies have shown that temporally prepresented voice cues (voice primes) improve recognition of target speech against speech masking but not noise masking. This study investigated whether static face image primes that have become target-voice associated (i.e., facial images linked through associative learning with voices reciting the target speech) can be used by listeners to unmask speech. The results showed that in 32 normal-hearing younger adults, temporally prepresenting a voice-priming sentence with the same voice reciting the target sentence significantly improved the recognition of target speech that was masked by irrelevant two-talker speech. When a person's face photograph image became associated with the voice reciting the target speech by learning, temporally prepresenting the target-voice-associated face image significantly improved recognition of target speech against speech masking, particularly for the last two keywords in the target sentence. Moreover, speech-recognition performance under the voice-priming condition was significantly correlated to that under the face-priming condition. The results suggest that learned facial information on talker identity plays an important role in identifying the target-talker's voice and facilitating selective attention to the target-speech stream against the masking-speech stream.

Neural electrode devices hold great promise to help people with the restoration of lost functions. However, research is lacking in the biomaterial design of a stable, long-term device. Glial scarring is initiated when a device is inserted into brain tissue and an inflammatory response ensues. Astrocytes become hypertrophic, hyperplastic, and upregulate glial-fibrillary acidic protein. This study was designed to investigate the astrocyte proliferation, viability, morphology, and gene expression to assess the reactive state of the cells on different material surfaces. Although platinum and silicon have been extensively characterized both in vivo and in vitro for their biocompatibility with neuronal cells, this study used the novel usage of PMMA and SU-8 in neural electrodes by comparative analysis of materials' biocompatibility. This study has shown evidence of noncytotoxicity of SU-8. We have also confirmed the biocompatibility of PMMA with astrocytes. Moreover, we have established sound guidelines of which neural implant materials should meet to be depicted biocompatible.

Introduction It is known that an interruption of acoustic input in early life will result in abnormal development of the auditory system. Here, we further show that this negative impact actually spans beyond the auditory system to the hippocampus, a system critical for spatial memory. Methods We induced a temporary conductive hearing loss (TCHL) in P14 rats by perforating the eardrum and allowing it to heal. The Morris water maze and Y‐maze tests were deployed to evaluate spatial memory of the rats. Electrophysiological recordings and anatomical analysis were made to evaluate functional and structural changes in the hippocampus following TCHL. Results The rats with the TCHL had nearly normal hearing at P42, but had a decreased performance with the Morris water maze and Y‐maze tests compared with the control group. A functional deficit in the hippocampus of the rats with the TCHL was found as revealed by the depressed long‐term potentiation and the reduced NMDA receptor‐mediated postsynaptic current. A structural deficit in the hippocampus of those animals was also found as revealed the abnormal expression of the NMDA receptors, the decreased number of dendritic spines, the reduced postsynaptic density and the reduced level of neurogenesis. Conclusions Our study demonstrates that even temporary auditory sensory deprivation in early life of rats results in abnormal development of the hippocampus and consequently impairs spatial memory in adulthood.

The reaction mechanism of [CpRu(MeCN)3]PF6-catalyzed cyclization of terminal alkynals 1 to cycloalkenes 2 was investigated by means of density functional methods combined with polarizable continuum models. Calculations indicate that the coordination of the cationic catalyst [CpRu(CH3CN)2]+ to the carbon–carbon triple bond of the substrate 1 enhances the electrophilicity of alkynyl group, and the subsequent nucleophilic attack of the carbonyl oxygen to the electron-deficient alkyne forms ate complex IM2, which would further isomerize into 2H-oxete complex IM3. Then a replacement of MeCN by AcOH occurs, followed by two proton-migrations, which leads to a Fischer-type carbene complex IM6. Finally, a decarbonylation takes place leading to cycloalkene 2. The terminal alkynal is activated by its combination with ruthenium, which leads to a decrease in the natural bond orbital energy of π*(C1C2). The four-membered ring formation is the rate-controlling step. However, AcOH helps proton shift through coordination with metal center and decreases the reaction energy barriers. Throughout the reactions, all the RuII complexes obey the 18-electron-rule. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2009

The complex potential energy surface for the reaction of C3H2 (cyclopropenylidene) with O(3P) was explored computationally using a density functional and ab initio QCISD(T) methods. The geometries of all the stationary points (transition states, intermediates and products) were fully optimized at the B3LYP/6-311++G∗∗ computational level, and the single point calculation including full population analysis was performed by employing QCISD(T). Our results show that the product P1 (C2H+HCO) is the major product, while the products P2 (C2H2+CO) and P3 (HC3O+H) are minor products, as confirmed by experiment. Product P1 could be gained through the path: RIM1IM2P1, and the C3H2+O(3P) reaction was expected to be rapid. So, the C3H2+O(3P) reaction may be an efficient strategy for producing C2H using cyclopropenylidene in atmosphere. The present results can lead us to understand deeply the mechanism of the title reaction.

The reaction mechanism of the palladium(II)-catalyzed addition of urea to dienes to form 1,2-diamine was studied using the B3LYP density functional theory (DFT) method. The results indicate that the first CN σ-bond formation is the rate-determining step, and that the covalent bonds are formed favorably by the terminal carbon atoms of dienes and nitrogen atom. The Pd(NCMe)-catalyst may significantly lower the energy barrier of the rate-determining step from the nonligand Pd(II)-catalyst counterpart. The results are in strong support of a recent experiment. Copyright © 2008 John Wiley & Sons, Ltd.

Objectives/Hypothesis: The purpose of the study was to determine the effect of electrical stimulation of the auditory cortex in patients with tinnitus. Study Design: Nonrandomized clinical trial. Methods: Two patients with debilitating tinnitus refractory to conventional therapies were treated. Patients were evaluated with validated questionnaires and psychoacoustic measures to determine the frequency and pitch of their tinnitus. Tones at these frequencies were then presented to the first patient (RP) under magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) to determine the tonotopic map for these frequencies in Heschl's gyrus. These tonotopic sites were targeted for implant with a quadripolar electrode. In the second patient (MV), only the fMRI tonotopic map was performed. These fMRI results detected an area of increased activity, which was selected as the site for the implanted bipolar electrode. Results: Patient RP (bilateral tinnitus for 2 years) has experienced a sustained reduction to near elimination of tinnitus with intracerebral implanted electrodes, whereas patient MV (unilateral tinnitus for 7 years) had an unsustained reduction in her tinnitus. Conclusion: These findings suggest that the perception and annoyance of tinnitus may be modulated or reduced through electrical stimulation of the auditory cortex. These unsustained effects for patient MV may have been influenced by the longstanding nature of her tinnitus or by another reason as yet undetermined.

By means of density functional theory (DFT), the regio- and diastereoselective mechanism for the synthesis of 2,5-disubstituted tetrahydrofuran from a donor–acceptor (D–A) cyclopropane cycloaddition reaction with benzaldehyde catalyzed by Sn(OTf)2 was investigated. As demonstrated, the overall reaction includes the activation of the D–A cyclopropane (S)-1, an unusual SN2 attack on the activated cyclopropane, the formation of the tetrahydrofuran coordination complex and the regeneration of the catalyst. The D–A cyclopropane is activated by its combination with Sn(OTf)2, which leads to a decrease in the natural bond orbital (NBO) energy ofσ*(C1–C2) and an increase in the dipole moment and angular deviation of the bent bond σ(C1–C2). Two nucleophilic reactions generates two chiral carbon centres, and the first one is rate controlling. In the SN2 reaction, one molecule of trifluoromethane sulfonate forms a hydrogen-bond H(CHO)···O(OTf), which can control the stretching direction of the benzaldehyde. On the whole, the solvation energies of the species increase with increases in the molecular dipole moments, and the solvent effects increase the reaction barriers. The theoretically predicted dominant product is cis-(2R,5R)-tetrahydrofuran. So these can satisfactorily account for the experimental observations.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Aim: Hepatic stellate cells (HSCs) play a key role in liver fibrosis. CCAAT/enhancer-binding proteins-alpha (C/EBP-α) can inhibit HSCs activation in vitro, as described in our previous study. However, little is known about the in vivo effect of C/EBP-α gene in hepatic fibrosis. Methods: Male BALB/c mice were injected by hydrodynamic protocol with pIRES2-EGFP-C/EBPα expression vector from the first to the fourth week (early intervention) or from the ninth to the 12th week (late intervention) after CCl4 injection, respectively. Successful transfection of vector and the expression of C/EBP-α were confirmed with the appearance of green fluorescence in liver cells, immunohistochemical staining and the western blot. Results: High expression of C/EBP-α gene in liver cells, especially in non-parenchymal cells, could reduce the content of collagens by 82.5% and 72.3% (Sirius red staining + image analysis) and the content of hydroxyproline by 56.3% and 51.6%, respectively, in the early and late intervention experiments. Conclusion: It is evident that exogenous C/EBP-α gene has an early and late intervention role in mice liver fibrosis.

The PtCl2-catalyzed asymmetric cycloisomerization reaction of hydroxylated enynes was studied using density functional theory (DFT). All structures have been optimized completely at the B3LYP/6-311G(d,p) level. As shown, the cycloisomerization reaction is exothermic. The cycloisomerization reaction mainly undergoes the formation of catalyst-hydroxylated enzyme coordination, the asymmetric cyclopropyl platinum carbene, catalyst–cyclopropyl enol coordination, and catalyst–cyclopropyl ketone coordination. The chirality-limiting step for the asymmetric cycloisomerization reaction is the formation of the asymmetric cyclopropyl platinum carbene, and the rate-determining step for this reaction is the formation of the catalyst–cyclopropyl ketone coordination. The dominant products predicted theoretically are (R,S) -syn_5a, in agreement with the experiment. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2006

Background/Purpose: The objective was to compare the efficiencies of the 595 nm pulsed dye and the 1320 nm Nd : YAG laser non-ablative rejuvenation. Methods: KM mice were irradiated with the 595 nm pulsed dye and the 1320 nm Nd : YAG lasers. Histological changes were evaluated immediately, 1, 7, 21, 30 and 60 days after the two laser treatments. Skin hydration and hydroxyproline content were measured to quantify the degree of improvement of the skin's water-holding capacity and the rate of hydroxyproline synthesis. Results: Although not statistically significant, the 1320 nm Nd : YAG laser treatment induced 9.7% greater improvement of skin hydration than the 595 nm laser while the 595 nm pulsed dye laser treatment led to a thicker dermis and 8.7% greater increase of hydroxyproline than the 1320 nm laser. More than 50% increase of collagen type I was observed in 75% of 595 nm laser-treated sites and 42% of 1320 nm laser-treated sites, and more than 25% increase of collagen type III was observed in 75% of 595 nm laser-treated sites and 50% of 1320 nm laser-treated sites. The 595 nm laser treatment was better in increasing the amount of collagen fibers, especially collagen type I (P

We investigated the use of optical imaging for observing the spatial patterns of neural activation in the dorsal cochlear nucleus (DCN) of hamsters during tonal stimulation. The patterns of activation were studied in the DCN, in vivo, following application of a voltage sensitive dye, Di-2-ANEPEQ, to the DCN surface. Beginning 60-90 min following dye application, tones were presented to the ipsilateral ear. Electrophysiological recordings after dye application revealed no significant toxicity of Di-2-ANEPEQ that affected the frequency-tuning properties of DCN neurons. We examined areas of activation in response to each of a series of test stimuli consisting of pure tones ranging in frequency from 2 to 20 kHz. For each stimulus condition, images were collected over a stimulus interval of 400 msec and averaged over 32 stimulus repetitions. These images revealed areas of activation with definable epicenters. The epicenters shifted from lateral to more medial locations on the DCN surface with increases in stimulus frequency. Comparison with electrophysiological data indicated a close parallel between the tonotopic gradient defined by optical imaging and that defined by the distribution of characteristic frequencies. The principal temporal and spatial features of these optical responses are described.

BACKGROUND/AIM In hepatic stellate cells isolated from rat fibrotic livers, the amount of retinoid X receptor-alpha (RXR-alpha) mRNA is greatly reduced. However, the effectiveness of retinoids in the treatment of liver fibrosis is controversial. We hypothesized that increasing the expression levels of RXR-alpha in livers will improve the response of liver fibrosis to retinoids treatment. METHODS pTracer-CMV2 vector harboring both green fluorescent protein and RXR-alpha genes was given to mice with carbon tetrachloride (CCl(4))-induced liver fibrosis, by hydrodynamic-based in vivo transfection. Vitamin A was simultaneously administered to the mice. Sirius red staining and measurement of hydroxyproline content were performed to evaluate liver fibrosis. The incorporation of 5-bromo-2-deoxyribouridine (BrdU) was carried out to determine liver cell proliferation. RESULTS Successful transfection and expression of exogenous RXR-alpha gene in the liver was determined by observance of green fluorescence under a confocal microscope, and detection of RXR-alpha protein by immunohistochemistry. Hepatic fibrosis, evaluated by both Sirius red staining with image analysis and quantity of hydroxyproline in livers of RXR-alpha-transfected group, tapered off remarkably. The hydroxyproline content and Sirius red-positive staining area on liver sections from RXR-alpha-transfected mice decreased by 34.3% and 54.63%, respectively, compared with the control group receiving empty vector. The labeling index of BrdU in non-parenchymal cells was much lower in livers from the RXR-alpha-transfected group than that of empty vector-transfected group. CONCLUSIONS Hydrodynamic-based in vivo transfection of the RXR-alpha gene can enhance the vitamin A-induced attenuation of liver fibrosis in mice. One of the possible mechanisms of action for this gene treatment is inhibition of non-parenchymal cell proliferation mainly composed of hepatic stellate cells in fibrotic livers.

We used the hamster as a model for identifying frequency specific loci in the dorsal cochlear nucleus (DCN) using c-fos immunocytochemistry. Animals were divided into three groups. The animals in the first group were stimulated with tone bursts at a frequency of 5kHz, those in the second group at 10kHz, and those in the third at 17kHz. The bursts were 50 msecs in duration and were presented for 1 hour at 67 dB SPL (4/sec). Brain tissue was obtained and procedures for c-fos assay were performed. Following stimulation distinct clusters of immunolabeled nuclei were found within the DCN. Cluster locations varied as a function of frequency. For the 5 kHz stimulus group, clusters were found at a mean position of 33% of the distance from the lateral to the medial extremities of the DCN. For exposures of 10 kHz, the bands were positioned approximately 50% of this distance, and for 17 kHz at approximately 67% of the lateral to medial distance. These results are consistent with the pattern of tonotopic organization which has been demonstrated in the DCN using electrophysiological procedures.