Optogenetic stimulation of the auditory pathway

Auditory prostheses can partially restore speech comprehension when hearing fails. Sound coding with current prostheses is based on electrical stimulation of auditory neurons and has limited frequency resolution due to broad current spread within the cochlea. In contrast, optical stimulation can be spatially confined, which may improve frequency resolution. Here, we used animal models to characterize optogenetic stimulation, which is the optical stimulation of neurons genetically engineered to express the light-gated ion channel channelrhodopsin-2 (ChR2). Optogenetic stimulation of spiral ganglion neurons (SGNs) activated the auditory pathway, as demonstrated by recordings of single neuron and neuronal population responses. Furthermore, optogenetic stimulation of SGNs restored auditory activity in deaf mice. Approximation of the spatial spread of cochlear excitation by recording local field potentials (LFPs) in the inferior colliculus in response to suprathreshold optical, acoustic, and electrical stimuli indicated that optogenetic stimulation achieves better frequency resolution than monopolar electrical stimulation. Virus-mediated expression of a ChR2 variant with greater light sensitivity in SGNs reduced the amount of light required for responses and allowed neuronal spiking following stimulation up to 60 Hz. Our study demonstrates a strategy for optogenetic stimulation of the auditory pathway in rodents and lays the groundwork for future applications of cochlear optogenetics in auditory research and prosthetics.     

The dorsal auditory pathway is involved in performance of both visual and auditory rhythms

We used functional magnetic resonance imaging to investigate the effect of two factors on the neural control of temporal sequence performance: the modality in which the rhythms had been trained, and the modality of the pacing stimuli preceding performance. The rhythms were trained 1-2 days before scanning. Each participant learned two rhythms: one was presented visually, the other auditorily. During fMRI, the rhythms were performed in blocks. In each block, four beats of a visual or auditory pacing metronome were followed by repetitive self-paced rhythm performance from memory. Data from the self-paced performance phase was analysed in a 2x2 factorial design, with the two factors Training Modality (auditory or visual) and Metronome Modality (auditory or visual), as well as with a conjunction analysis across all active conditions, to identify activations that were independent of both Training Modality and Metronome Modality. We found a significant main effect only for visual versus auditory Metronome Modality, in the left angular gyrus, due to a deactivation of this region after auditory pacing. The conjunction analysis revealed a set of brain areas that included dorsal auditory pathway areas (left temporo-parietal junction area and ventral premotor cortex), dorsal premotor cortex, the supplementary and presupplementary premotor areas, the cerebellum and the basal ganglia. We conclude that these regions are involved in controlling performance of well-learned rhythms, regardless of the modality in which the rhythms are trained and paced. This suggests that after extensive short-term training, all rhythms, even those that were both trained and paced in visual modality, had been transformed into auditory-motor representations. The deactivation of the angular cortex following auditory pacing may represent cross-modal auditory-visual inhibition.     

BOLD fMRI investigation of the rat auditory pathway and tonotopic organization

Rodents share general anatomical, physiological and behavioral features in the central auditory system with humans. In this study, monaural broadband noise and pure tone sounds are presented to normal rats and the resulting hemodynamic responses are measured with blood oxygenation level-dependent (BOLD) fMRI using a standard spin-echo echo planar imaging sequence (without sparse temporal sampling). The cochlear nucleus (CN), superior olivary complex, lateral lemniscus, inferior colliculus (IC), medial geniculate body and primary auditory cortex, all major auditory structures, are activated by broadband stimulation. The CN and IC BOLD signal changes increase monotonically with sound pressure level. Pure tone stimulation with three distinct frequencies (7, 20 and 40 kHz) reveals the tonotopic organization of the IC. The activated regions shift from dorsolateral to ventromedial IC with increasing frequency. These results agree with electrophysiology and immunohistochemistry findings, indicating the feasibility of auditory fMRI in rats. This is the first fMRI study of the rodent ascending auditory pathway.     

Functional activity mapping of rat auditory pathway after intratympanic manganese administration

In the present study, we report a new method of manganese enhanced magnetic resonance imaging (MEMRI) using intratympanic (IT) manganese administration. We explore Mn2? uptake from the middle ear cavity into the cochlea through mechanically gated ion channels of the hair cell and also functional auditory tract tracing without the use of excessive auditory stimuli for a long time period outside the scanner. After manganese administration in animals with normal hearing and unilateral deafness, T1-weighted MR images were obtained for up to 48 h with a 3.0 T MR imager. In normal rats, the mean signal-to-noise ratio (SNR) at each region of interest on the auditory pathway was significantly higher in the IT injection group than in the intraperitoneal (IP) injection group (P<0.05). Furthermore, the cochlea showed Mn2? signal enhancement only in the IT injection group. In unilateral deafness rats, the IT injection of Mn2? into the deaf-side middle ear cavity demonstrated signal enhancement in the cochlea but not in other auditory structures without axonal transport of Mn2? along the auditory pathway. On the other hand, the IT injection of Mn2? into the normal-side middle ear cavity demonstrated that the mean SNRs at the cochlea, cochlear nucleus, superior olivary complex, lateral lemniscus and inferior colliculus were significantly higher in the ipsilateral auditory pathway than in the contralateral pathway (P<0.05). For the IP injection group, the mean SNRs at each auditory structure, except the cochlea, increased bilaterally. In conclusion, the present work demonstrated the potential advantages of a new IT MEMRI over conventional systemic injection strategies in that (i) the functional auditory tract tracing initiated by the hair cell function is possible and (ii) the axonal transport of Mn2? ions by trans-synaptic activity is possible without auditory stimulation for a long time period outside MR scanner.     

脑性瘫痪合并听神经通路损伤的临床研究

目的 调查脑性瘫痪合并听神经通路损伤的发生率，探讨脑性瘫痪合并听神经通路损伤与性别、脑性瘫痪型别及脑性瘫痪高危因素的关系。方法 回顾性调查272例脑性瘫痪患儿的临床资料，了解脑性瘫痪合并听神经通路损伤的发生率，并对脑性瘫痪合并听神经通路损伤发生与性别、脑性瘫痪型别及脑性瘫痪高危因素的关系进行分析。结果 272例脑性瘫痪合并听神经通路损伤的发生率为29．8％，其发生率与性别无关（P〉0．05），与脑性瘫痪型别有关（P〈0．05），其中以手足徐动型和混合型脑性瘫痪合并听神经通路损伤发生率更高（P〈0．0071），病理性黄疸、宫内感染与脑性瘫痪合并听神经通路损伤显著相关。结论 脑性瘫痪合并听神经通路损伤较普遍，以手足徐动型和混合型脑性瘫痪为著，病理性黄疸、宫内感染是脑性瘫痪合并听神经通路损伤的高度危险因素。     

多发性硬化患者中枢听觉传导通路的扩散张量成像

目的 采用扩散张量成像（DTI）和纤维追踪技术探讨有听力损害的多发性硬化（MS）患者听觉中枢传导通路的纤维显微结构改变。方法 收集存在听力损害的MS患者15例（MS组）,其中单侧听力损害8例,双侧7例;另收集健康对照组15名。以MS组和对照组脑干内外侧丘系（LL）、中脑下丘（IC）分别为ROI₁、ROI₂进行DTI;再借助纤维追踪技术观察两侧颞横回（ROI₃）中枢听觉皮层的纤维走行,比较两组不同ROI神经纤维的FA、ADC值,并分析MS组单侧听力损害患者有差异的DTI参数值与临床扩展致残量表（EDSS）评分和病程的相关性。结果 MS组双侧听力损害患者的听觉传导通路ROI₁（P=0.016）、ROI₂（P=0.038）、ROI₃（P=0.007）的FA均低于对照组,ROI₁（P=0.016）、ROI₂（P=0.039）ADC值高于对照组,ROI₃的ADC值与对照组差异无统计学意义（P=0.108）。MS组单侧听力损伤患者的损伤侧仅ROI₁（P=0.022）、ROI₃（P=0.029）FA低于对照组。MS组单侧听力损害患者有差异的DTI参数值与EDSS评分、病程均无相关性。结论 MS患者中枢听觉传导通路DTI参数存在异常,可为临床听力损害提供直接证据。     

Regeneration of the pancreas

Pancreatic beta-cells possess a well-regulated insulin secretory property that maintains systemic glucose homeostasis. Although it has long been thought that differentiated beta-cells are nearly static, recent studies have shown that beta-cell mass dynamically changes throughout the lifetime. The beta-cell mass could be maintained by several mechanisms, including self-replication of pre-existing beta-cells, neogenesis from unidentified stem/progenitor cells, and transdifferentiation from differentiated duct or acinar cells. Recent studies have suggested that self-replication of pre-existing beta-cells is a major source for maintenance of beta-cell mass in adult pancreas. However, regeneration of beta-cells from non-beta-cells does occur under certain conditions, especially in vitro culture systems. In this article, recent progress of regenerative medicine of the pancreas is reviewed.     

Regeneration of the cornea

The cornea is a transparent, colorless tissue that functions as the optical surface of the eye. Transparency is vital for useful vision, which can be compromised by disorders to the corneal epithelium, stroma or endothelium. Transplantation of donor corneas is the standard surgical procedure for irreversible damage to the tissue. However, Japan, as well as many countries across the globe, are suffering from a shortage of donor supplies. Recent developments in bioengineering techniques have opened the way for the possible development of regenerated tissue from cultured progenitor cells. An artificial cornea with all the necessary cell components may become available in the near future.     

Processing abstract auditory features in the human auditory cortex

Using electric and magnetic brain responses we tested whether violations of an abstract auditory regularity are processed in auditory cortex and whether abstract auditory regularities are retained for at least 10 s. The mismatch negativity (MMN) event-related potential and its magnetic counterpart (MMNm) were recorded to infrequent tone pairs of descending pitch (the second tone having a lower frequency than the first one) embedded in a sequence of tone pairs of ascending pitch, whereas the absolute frequency of both ascending and descending tone pairs varied on seven levels. Results showed that the dominant generators of the electromagnetic activity elicited by violations of the pitch-ascension rule lie within auditory cortex. We also found that the memory representation of pitch-ascension is retained for at least 10 s. When short trains of ascending-pitched tone pairs were followed by a silent period of 8-12 s, descending-pitched probe tone pairs elicited the MMN component when a single reminding pair with ascending pitch was presented before the probe. The reactivating effect of the reminder was similar to what has been previously shown for concrete auditory regularities, such as the constancy of tone pitch. The present results support the view that auditory cortical functions can process sensory and categorical information in a similar manner.     

The possible impact of noise-induced Ca2+-dependent activity in the central auditory pathway: a manganese-enhanced MRI study

Noise exposure at high intensities leads to a temporary shift of hearing thresholds (TTS) and is followed by a permanent threshold shift (PTS). Permanent threshold shift is not only associated with cochlear damage as the primary site-of-lesion, but also with subsequent structural and functional changes within the central auditory pathway. The aim of the present study was to monitor neuronal activity within central auditory structures in mice after noise exposure at different time intervals using manganese-enhanced magnetic resonance imaging (MEMRI). The results demonstrate for the first time that calcium-dependent activity patterns are modified in several structures of the central auditory system as the result of a noise-induced hearing loss (NIHL). The MEMRI data demonstrate that temporary threshold shift is correlated with an activity increase in hierarchically lower structures of the auditory pathway. This seems to be indicative of a direct noise impact at the first stage of central auditory processing. However, noise-dependent changes of higher auditory structures were found as well in the phase of PTS. Repeated noise exposure was found to induce an additional elevation of calcium-dependent activity in all investigated auditory structures - without a significant shift in auditory thresholds. Sustained manganese accumulation was present in the auditory brainstem after moderate acoustic stimulation as well without PTS induction. The long-lasting enhancement of MEMRI signals suggests a noise-induced activity increase of various calcium-dependent processes of different origin (such as neuroprotective mechanisms). The present findings could be helpful to better understand the time-course of different symptoms in NIHL and the individual susceptibility to noise.     

Regeneration of the pancreatic beta cell

Type 1 diabetes is the result of an autoimmune attack against the insulin-producing beta cells of the endocrine pancreas. Current treatment for patients with type 1 diabetes typically involves a rigorous and invasive regimen of testing blood glucose levels many times a day along with subcutaneous injections of recombinant DNA-derived insulin. Islet transplantation, even with its substantially improved outcome in recent years, is still not indicated for pediatric patients. However, in light of the fact that some regenerative capabilities of the endocrine pancreas have been documented and recent research has shown that human ES cell lines can be derived in vitro, this review discusses whether it is practical or even possible to combine these lines of research to more effectively treat young diabetic patients.     

Exploring auditory neglect: Anatomo-clinical correlations of auditory extinction

BackgroundThe key symptoms of auditory neglect include left extinction on tasks of dichotic and/or diotic listening and rightward shift in locating sounds. The anatomical correlates of the latter are relatively well understood, but no systematic studies have examined auditory extinction. Here, we performed a systematic study of anatomo-clinical correlates of extinction by using dichotic and/or diotic listening tasks.MethodsIn total, 20 patients with right hemispheric damage (RHD) and 19 with left hemispheric damage (LHD) performed dichotic and diotic listening tasks. Either task consists of the simultaneous presentation of word pairs; in the dichotic task, 1 word is presented to each ear, and in the diotic task, each word is lateralized by means of interaural time differences and presented to one side.Results and conclusionRHD was associated with exclusively contralesional extinction in dichotic or diotic listening, whereas in selected cases, LHD led to contra- or ipsilesional extinction. Bilateral symmetrical extinction occurred in RHD or LHD, with dichotic or diotic listening. The anatomical correlates of these extinction profiles offer an insight into the organisation of the auditory and attentional systems. First, left extinction in dichotic versus diotic listening involves different parts of the right hemisphere, which explains the double dissociation between these 2 neglect symptoms. Second, contralesional extinction in the dichotic task relies on homologous regions in either hemisphere. Third, ipsilesional extinction in dichotic listening after LHD was associated with lesions of the intrahemispheric white matter, interrupting callosal fibres outside their midsagittal or periventricular trajectory. Fourth, bilateral symmetrical extinction was associated with large parieto-fronto-temporal LHD or smaller parieto-temporal RHD, which suggests that divided attention, supported by the right hemisphere, and auditory streaming, supported by the left, likely play a critical role.     

多频稳态听觉反应与听性脑干反应测定成人感音神经性聋听阈的相关性

背景：多频稳态听觉反应是近年兴起的一种听觉电生理学检测方法,在儿童客观听阈评估方面应用很多,而在成人耳聋患者应用较少。目的：探讨成人感音神经性聋患者听性脑干反应和多频稳态听觉反应的关系,明确多频稳态听觉反应临床应用价值。设计、时间及地点：单一样本观察,对比分析,于2006-01/2008-03在南京医科大学附属南京第一医院耳鼻喉科听力研究室完成。对象：感音神经性耳聋患者30例（60耳）,磁共振检查排除内听道占位病变。方法：所有受试者采用美国Intelligent Hearing诱发电位仪先行听性脑干反应,再行多频稳态听觉反应测试,分别以降10升5法得出二者的反应阈。多频稳态听觉反应和听性脑干反应测试软件分别为Smart ASSR和Smart EP。主要观察指标：比较多频稳态听觉反应阈值和传统听性脑干反应方法检测所得阈值及波形引出情况。结果：多频稳态听觉反应的1,2,4kHz阈值和听性脑干反应短声反应阈之间有较好的相关性,相关系数分别为0.894,0.912和0.901,同时多频稳态听觉反应能检测到听性脑干反应不能引出的波形。结论：多频稳态听觉反应和听性脑干反应有很大的相关性,在波形引出方面优于听性脑干反应,因此多频稳态听觉反应在成人感音神经性聋的诊断中有重要应用价值。     

Intradermal nevus of the external auditory canal

Melanocytic nevus is a benign melanocytic neoplasm and the most common type of skin tumor. Melanocytic nevus in the external auditory canal (EAC) is rare. Surgical excision and pathologic confirmation should be considered in large lesions, which could occlude the EAC, or atypical lesions that are suspicious for malignancy.     

Event-related fMRI of the auditory cortex.

An event-related protocol was designed to permit auditory fMRI studies minimally affected by the echo-planar noise artifact; a long time interval (TR = 10 s) between each cerebral volume acquisition was combined with stroboscopic data acquisition, and event-related curves were reconstructed with a 1-s resolution. The cerebral hemodynamic-response time course to a target auditory stimulus was measured in five individual subjects using this method. Clear bell-shaped event-related responses were observed bilaterally in all individuals in primary auditory cortex (A1) as well as in laterally extending secondary cortical fields. Group-average event-related curves attained their maxima (0.5-0.7%) 3 s after stimulus onset in A1 (4 s for more anterior and lateral regions of auditory cortex), and signal had returned to near-baseline level 6 s after stimulus onset. The stroboscopic event-related method appeared effective in minimizing effects of the interaction between scanning noise and experimental auditory stimulation; it adds useful temporal information to the spatial resolution afforded by fMRI in studies of human auditory function, while allowing presentation of auditory stimuli on a silent background.     

Concrete impaction of the external auditory canal

A case of accidental impaction of the external auditory canal by concrete in a construction worker seen at Orlando Regional Medical Center is reported. A general discussion of the pathophysiology of concrete-related injuries is included. Recommendations are made for the optimal emergency management of these type injuries.     

Regeneration of articular cartilage

Articular cartilage has very limited healing potential. Although there are several treatment options for cartilage defect, no treatment has been established as a gold standard procedure. Recently, a tissue-engineering technique has made great progress, and repair of cartilage has been given much attention in regenerative medicine. Since 1996, we have been performing transplantation of tissue-engineered cartilage made ex vivo for the treatment of human cartilage defect of the joint. This paper will summarize our procedure of articular cartilage repair and our novel stem cell delivery system using magnetic field.