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Review 审查

Auditory Brainstem Responses (ABR) of Rats during Experimentally Induced Tinnitus: Literature Review
在实验性诱发的耳鸣过程中,大鼠的听觉脑干反应(ABR):文献综述

Ewa Domarecka , Heidi Olze and Agnieszka J. Szczepek
Ewa Domarecka ,Heidi Olze 和 Agnieszka J. Szczepek
1 Department of Otorhinolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin,
1 柏林自由大学,柏林洪堡大学和柏林健康研究所的耳鼻喉科,头颈外科,夏里特大学医学院
Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin
德国柏林 10117;ewa.domarecka@charite.de(E.D.);Heidi.olze@charite.de(H.O.)
Institute of Health, 10117 Berlin, Germany; ewa.domarecka@charite.de (E.D.); Heidi.olze@charite.de (H.O.)2 Faculty of Medicine and Health Sciences, University of Zielona Gora, 65-046 Zielona Gora, Poland
2 泽洛纳戈拉大学医学与健康科学学院,波兰,65-046 泽洛纳戈拉
* Correspondence: agnes.szczepek@charite.de
* 通讯:agnes.szczepek@charite.de

Received: 20 October 2020; Accepted: 21 November 2020; Published: 24 November 2020
收到日期:2020 年 10 月 20 日;接受日期:2020 年 11 月 21 日;发表日期:2020 年 11 月 24 日

Abstract 摘要

Tinnitus is a subjective phantom sound perceived only by the affected person and a symptom of various auditory and non-auditory conditions. The majority of methods used in clinical and basic research for tinnitus diagnosis are subjective. To better understand tinnitus-associated changes in the auditory system, an objective technique measuring auditory sensitivity-the auditory brainstem responses (ABR)-has been suggested. Therefore, the present review aimed to summarize ABR's features in a rat model during experimentally induced tinnitus. PubMed, Web of Science, Science Direct, and Scopus databanks were searched using Medical Subject Heading (MeSH) terms: auditory brainstem response, tinnitus, rat. The search identified 344 articles, and 36 of them were selected for the full-text analyses. The experimental protocols and results were evaluated, and the gained knowledge was synthesized. A high level of heterogeneity between the studies was found regarding all assessed areas. The most consistent finding of all studies was a reduction in the ABR wave I amplitude following exposure to noise and salicylate. Simultaneously, animals with salicylate-induced but not noise-induced tinnitus had an increased amplitude of wave IV. Furthermore, the present study identified a need to develop a consensus experimental ABR protocol applied in future tinnitus studies using the rat model.
耳鸣是只有患者自己能感知到的主观幻听声音,是各种听觉和非听觉疾病的症状。临床和基础研究中用于耳鸣诊断的大多数方法都是主观的。为了更好地了解听觉系统中与耳鸣相关的变化,提出了一种测量听觉敏感性的客观技术——听觉脑干反应(ABR)。因此,本综述旨在总结在实验性耳鸣大鼠模型中的 ABR 特征。使用医学主题词(MeSH)术语:听觉脑干反应、耳鸣、大鼠,在 PubMed、Web of Science、Science Direct 和 Scopus 数据库中进行了搜索。搜索结果共找到 344 篇文章,其中 36 篇文章被选中进行全文分析。评估了实验方案和结果,并综合了所获得的知识。在所有评估的领域中,研究之间存在较高的异质性。所有研究中最一致的发现是在噪声和水杨酸盐暴露后 ABR 波 I 振幅的降低。 同时,患有水杨酸盐诱导但不是噪声诱导耳鸣的动物的第四波振幅增加。此外,本研究还发现需要制定一致的实验性 ABR 协议,用于未来使用大鼠模型的耳鸣研究。

Keywords: auditory brainstem response (ABR); tinnitus; animal model; rat
关键词:听觉脑干反应(ABR);耳鸣;动物模型;大鼠

1. Introduction 1. 引言

Tinnitus is an auditory phantom perception despite the absence of external sound. Subjective, chronic tinnitus is diagnosed in humans of all ages, affecting about of the adult population and significantly decreasing the life quality of of subjects with severe form [3-5]. Tinnitus may be a symptom of numerous conditions such as Meniere's disease, diabetes, arterial hypertension, intracranial hypertension, or hearing loss. The latter, causative reasons, include exposure to noise or ototoxic drugs (i.e., salicylate, cisplatin, quinine) [6-8] and have been adapted to induce experimental tinnitus in animals.
耳鸣是一种在没有外部声音的情况下产生的听觉幻觉。主观、慢性耳鸣在各个年龄段的人群中都有发现,影响着大约 成年人口的生活质量,并且严重形式的耳鸣会显著降低 受试者的生活质量[3-5]。耳鸣可能是许多疾病的症状,如梅尼埃病、糖尿病、动脉高血压、颅内高压或听力丧失。后者的致病原因包括噪音暴露或耳毒性药物(如水杨酸盐、顺铂、奎宁)[6-8],并已被用于诱导动物实验性耳鸣。
A significant challenge during the tinnitus assessment in patients and animal models is the lack of objective diagnostic methods. To date, the clinical evaluation of tinnitus-induced distress is based on the psychometric scores or visual analog scales (VAS) dedicated to measuring various domains. The audiometric assessment of tinnitus (loudness, pitch, residual inhibition) uses the patient's subjective statement. Similarly, audiometric properties of tinnitus in animals are tested using behavioral paradigms.
在患者和动物模型中进行耳鸣评估时面临的一个重要挑战是缺乏客观的诊断方法。迄今为止,对耳鸣引起的困扰的临床评估是基于心理测量分数或用于测量各个领域的视觉模拟量表(VAS)。耳鸣的听力学评估(响度、音高、残余抑制)使用患者的主观陈述。同样,动物耳鸣的听力学特性是使用行为范例进行测试的。
There are two established tinnitus induction methods used in animal models: overdose of salicylate and noise exposure . Salicylate is known to cause reversible hearing loss and tinnitus in
在动物模型中,有两种已建立的耳鸣诱导方法:水杨酸盐过量和噪声暴露。水杨酸盐被认为会引起可逆性听力损失和耳鸣。Jastreboff 等人的开创性工作证明了高剂量的水杨酸盐会在动物中诱发耳鸣,将水杨酸盐诱导的耳鸣动物模型引入了基础研究。所有暴露于水杨酸盐的动物都会出现可逆性和剂量依赖的全频听力损失,并伴随大约的耳鸣。与水杨酸盐不同,噪声暴露并不总是会引发耳鸣。诱发率从 30 到,耳鸣频率取决于听觉周围的受损部位。尽管水杨酸盐诱导的耳鸣和噪声诱导的耳鸣之间存在许多差异,但它们被认为共享一个机制途径,在内毛细胞-螺旋神经节神经元突触处汇合。

humans [11]. The pioneering work of Jastreboff et al., demonstrating that high doses of salicylate induce tinnitus in animals [10,12], introduced the salicylate-induced tinnitus animal model to basic research. All animals exposed to salicylate develop reversible and dose-dependent pantonal hearing loss co-occurring with tinnitus measured at roughly . In contrast to salicylate, noise exposure does not always induce tinnitus. The induction rate varies from 30 to , and the tinnitus frequency depends on the injured part of the auditory periphery [14]. Despite many differences between the salicylate- and noise-induced tinnitus, it is supposed that they share a common mechanistic pathway, converging at the inner hair cell-spiral ganglion neuron synapse [15].
The past decades brought progress in defining the objective, neural correlates of tinnitus. Functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) implicated the association of tinnitus with increased neural synchrony, reorganization of tonotopic maps, and increased spontaneous firing rates (SFR) [9,16]. Clinical studies also demonstrated changes in the auditory brainstem responses (ABR), which are possibly associated with tinnitus [17]. ABR is an early-response auditory evoked potential (AEP). During ABR, the electrical potentials consisting of five waves are isolated from the brainstem's entire activity response to a calibrated sound. As a result of its objective nature, ABR is used clinically to estimate hearing thresholds of infants, young children, or adult patients who cannot undergo behavioral testing and is an essential clinical tool for identifying retrocochlear lesions and vestibular schwannomas [20].
过去几十年来,对耳鸣的客观神经相关性的定义取得了进展。功能性磁共振成像(fMRI)和脑电图(EEG)表明耳鸣与神经同步增加、音频地图重组和自发放电率增加(SFR)有关[9,16]。临床研究还表明听觉脑干反应(ABR)发生了变化,这可能与耳鸣有关[17]。ABR是一种早期反应的听觉诱发电位(AEP)。在ABR过程中,从脑干对校准声音的整个活动响应中分离出由五个波组成的电位。由于其客观性质,ABR在临床上用于估计婴儿、幼儿或无法进行行为测试的成年患者的听阈,并且是识别后蜗神经病变和前庭神经瘤的重要临床工具[20]。
Moreover, ABR is applied in basic animal research to study age-related auditory changes, investigate the effect of therapeutic drugs on auditory potentials, and determine the mechanisms of diseases affecting the auditory system [21,22]. In rats, wave I of ABR associates with the activity of the peripheral auditory nerve. In contrast, waves II-V are thought to originate from the ventral cochlear nucleus, superior olivary complex, lateral lemniscus, inferior colliculus, and medial geniculate body [23]. The first ABR response was demonstrated in two-weeks old rats, whereas the mature ABR response consisting of five waves was observed in five-week-old rats [24].
此外,ABR被应用于基础动物研究中,用于研究与年龄相关的听觉变化,调查治疗药物对听觉电位的影响,并确定影响听觉系统的疾病机制[21,22]。在大鼠中,ABR的第一波与外周听觉神经的活动相关。相反,波II-V被认为起源于腹侧耳蜗核、上位耳蜗复合体、侧束、下丘脑和内侧膝状体[23]。第一次ABR反应在两周大的大鼠中得到证明,而包含五个波的成熟ABR反应在五周大的大鼠中观察到[24]。
The ABR amplitudes (II, III, and V wave) provide information about the ABR signal's natural generators or modulators [25], whereas ABR latency (waves I-V) offers evidence about brainstem function [26]. It is supposed that the reduced amplitude of wave I and an increased hearing threshold might reflect the reduced sensory input found in tinnitus. In agreement with that, salicylate administration and acoustic trauma were found to reduce the ABR amplitude in experimental rats [27]. Nevertheless, the reduced amplitude could also reflect both signal reduction and desynchronization [28]. Therefore, the remaining necessary effort is to determine the ABR features that would indicate the presence of tinnitus independent of hearing loss. In agreement with that, ABR is frequently used in animal studies of tinnitus [29].
ABR振幅(II、III和V波)提供了关于ABR信号的自然发生器或调制器的信息[25],而ABR潜伏期(波I-V)则提供了有关脑干功能的证据[26]。据推测,波I的振幅降低和听阈增加可能反映了耳鸣中发现的感觉输入减少。与此一致,实验鼠中水杨酸盐给药和声刺激损伤被发现会降低ABR振幅[27]。然而,振幅降低也可能反映信号减少和非同步[28]。因此,剩下的必要努力是确定能够独立于听力损失指示耳鸣存在的ABR特征。与此一致,ABR在耳鸣的动物研究中经常被使用[29]。
The present literature review attempted to extract and synthesize the knowledge about ABR assessment in rats with experimentally induced tinnitus (salicylate administration, noise, and blast exposures). The main goal was to determine whether there is a consistent impact of salicylate, noise, and blast-induced tinnitus on ABR features such as thresholds, latencies, and amplitudes. In addition, changes in the ABR profile of animals with tinnitus were scrutinized in the context of tinnitus-induction methods.
本文献综述试图提取和综合关于实验性耳鸣(水杨酸盐给药、噪声和爆炸暴露)大鼠ABR评估的知识。主要目标是确定水杨酸盐、噪声和爆炸引起的耳鸣是否对ABR特征(如阈值、潜伏期和幅度)产生一致的影响。此外,还对具有耳鸣的动物的ABR特征进行了详细研究,以了解耳鸣诱导方法的变化。
Our work focused on a rat model, and there were several reasons for this decision. The cochlear physiology and anatomy of humans and rats share similarities (e.g., two and a half cochlear turns) compared to guinea pigs (three and a half turns) [30]. Although the highest audible frequencies at SPL of humans are and of rats 58 to , the lowest audible frequencies are similar ( for humans and for rats) [31]. In contrast to mice, early onset of age-related hearing loss (ARHL) has not been reported for rats. Rats can better tolerate noise exposure and rarely exhibit non-inner ear-related symptoms [32,33]. Auditory afferent periphery, believed to be involved during the process of tinnitus generation, has been much studied in rats more extensively than in any other animal model [34]. Importantly, unlike mice, rats do not develop aggressive behavior following noise exposure or salicylate administration [35]; however, they provide an acknowledged
我们的工作重点是在大鼠模型上进行的,这个决定有几个原因。人类和大鼠的耳蜗生理和解剖学有相似之处(例如,两个半耳蜗转数),相比之下豚鼠有三个半耳蜗转数[30]。虽然人类在 SPL下的最高可听频率为 ,而大鼠为58到 ,但最低可听频率相似(人类为 ,大鼠为 )[31]。与小鼠相比,大鼠没有报道早发性老年性听力损失(ARHL)。大鼠能更好地耐受噪声暴露,并且很少出现非内耳相关的症状[32,33]。听觉传入周围,被认为在耳鸣生成过程中起作用,已在大鼠中进行了比其他动物模型更广泛的研究[34]。重要的是,与小鼠不同,大鼠在噪声暴露或水杨酸盐给药后不会出现攻击行为[35];然而,它们提供了一个被公认的

model for noise-induced hearing loss [36] and cochlear synaptopathy, which is consistent with hidden hearing loss [37]. Since 1988, rat remains the most prominent species used in tinnitus studies at the behavioral level [38,39]. Moreover, in the pharmacological studies dedicated to developing new tinnitus treatments, rats are a standard animal model [40]. Finally, our laboratory has a long-standing research interest in the effect of stress on the auditory system of rats .
噪声诱发性听力损失[36]和耳蜗突触病变是隐藏性听力损失[37]的一致表现。自 1988 年以来,大鼠一直是行为水平上耳鸣研究中最重要的物种[38,39]。此外,在开发新的耳鸣治疗方法的药理学研究中,大鼠是标准的动物模型[40]。最后,我们实验室长期关注应激对大鼠听觉系统的影响

2. Materials and Methods
2. 材料和方法

For this study, a literature review was performed in August 2020. A search of the following databanks identified the articles:
本研究于 2020 年 8 月进行了文献综述。以下数据库的搜索结果包含了相关文章:
  • Science Direct 科学直接
  • The Search Engine Tool for Scientific (Scopus)
    科学搜索引擎工具(Scopus)
  • US National Library of Medicine National Institutes of Health (PubMed)
    美国国家医学图书馆国立卫生研究院(PubMed)
  • Web of Science
The keywords included the following combination of mesh terms:
包括以下 MeSH 词汇的关键词组合:
  • "auditory evoked potential" AND "tinnitus" AND "rat"
    听觉诱发电位" AND "耳鸣" AND "大鼠
  • "auditory brainstem response" AND "tinnitus" AND "rat"
    听觉脑干反应" AND "耳鸣" AND "大鼠
  • "ototoxicity" AND "tinnitus" AND "rat"
    耳毒性" AND "耳鸣" AND "大鼠
Full-text articles were downloaded when the title, abstract, or keywords suggested that the study is eligible for this review. The cardinal eligibility criterion was the publications in the English language. The further procedure of article selection followed the inclusion and exclusion criteria provided below: Inclusion criteria:
当标题、摘要或关键词表明该研究符合本综述的条件时,下载全文文章。主要的符合条件的标准是以英语语言发表的出版物。进一步的文章选择程序遵循下面提供的包含和排除标准:包含标准:
  • Articles published between January 2000 and August 2020
    2000 年 1 月至 2020 年 8 月间发表的文章
  • Research dedicated to an animal model of tinnitus induced by salicylate administration (When in addition to salicylate, other drugs were applied, only the data related to salicylate were acquired), blast or noise exposure, when the authors used the ABR to measure auditory abilities of animals
    研究针对水杨酸盐诱导的耳鸣动物模型(当除水杨酸盐外,还使用其他药物时,只获取与水杨酸盐相关的数据),爆炸或噪声暴露时,作者使用 ABR 测量动物的听觉能力
  • Using rats 使用大鼠
  • Original research 原始研究
Exclusion criteria 排除标准
  • Literature review, editorials
    文献综述,社论
  • Full text not available
    全文不可用
  • Articles not published in English.
    文章未以英文发布
The search identified 344 studies. After applying the selection criteria, 36 publications were included in the analysis (Figure 1).
搜索结果找到了 344 项研究。在应用筛选标准后,共有 36 篇出版物被纳入分析中(图 1)。
Detailed data extracted from the selected publications are summarized in the Supplementary Tables S1 and S2. The following information was collected:
从所选出版物中提取的详细数据总结在附表 S1 和 S2 中。收集了以下信息:
  • Aim of the article
    文章的目标
  • Age, sex, and strain of rats
    大鼠的年龄、性别和品系
  • Sample size 样本大小
  • Methods used to induce tinnitus (salicylate, noise, blast)
    诱发耳鸣的方法(水杨酸盐、噪音、爆炸)
  • Methods used to determine the presence of tinnitus
    确定耳鸣存在的方法
  • Stimulus and acquisition characteristics of ABR
    ABR 的刺激和获取特征
  • The system used to measure ABR
    用于测量 ABR 的系统
  • Signal intensity 信号强度
  • Rate of signal 信号速率
  • Polarity of signal 信号极性
  • The placement of the electrodes
    电极的放置位置
  • Filters 过滤器
  • ABR protocols ABR 协议
  • ABR outcome. ABR 结果
Records after duplicates removed
删除重复记录后的结果
Figure 1. PRISMA diagram of the study selection process [43]. " " signifies the number of publications.
图 1. 研究选择过程的 PRISMA 图 [43]。" " 表示出版物的数量。
The extracted information was analyzed, and the knowledge was synthesized and presented in the Results section.
提取的信息进行了分析,并在结果部分进行了综合和呈现。

3. Results 3. 结果

3.1. Study Selection 3.1. 研究选择

Thirty-six studies published between January 2000 and August 2020 met the inclusion criteria. The publication date indicated that during the first decade of the 21st century, the research on that topic was published only sporadically (Figure 2), but the number of publications increased in the second decade.
从 2000 年 1 月到 2020 年 8 月,共有 36 项研究符合纳入标准。出版日期显示,在 21 世纪的第一个十年,该主题的研究仅零星发表(图 2),但在第二个十年中,发表数量增加。
Figure 2. The number of publications regarding auditory brainstem responses (ABR) and rat model of tinnitus per year.
图 2. 每年关于听觉脑干反应(ABR)和耳鸣大鼠模型的出版物数量。

3.2. Strain, Gender, and Age
3.2. 品系、性别和年龄

In the articles selected for this review, Sprague-Dawley rats (both genders) were used in seventeen studies [13,28,44-57]. Wistar rats were used in thirteen [15,27,29,58-65], Long-Evans rats were used in four [66-69], and Fischer rats (FBN) were used in three studies [49,70,71]. One research group used Fischer 344 and Sprague-Dawley rats [49], two studies used both female and male Wistar rats [29,60], and one article did not provide information about the age of rats [45]. All rats were tested during the first few months of their life. No strain-related differences in the hearing thresholds were found [72,73]. However, compared to Sprague-Dawley rats, Wistar rats develop more aggressive behavior after noise exposure and salicylate administration [74]. Summarized data are presented in Table 1.
在本综述所选的文章中,有 17 项研究使用斯普拉格-道利大鼠(两性)[13,28,44-57]。有 13 项研究使用维斯塔大鼠[15,27,29,58-65],有 4 项研究使用长埃文斯大鼠[66-69],有 3 项研究使用费舍尔大鼠(FBN)[49,70,71]。一个研究小组使用费舍尔 344 和斯普拉格-道利大鼠[49],两项研究使用雌雄维斯塔大鼠[29,60],一篇文章没有提供大鼠的年龄信息[45]。所有大鼠在出生后的前几个月进行了测试。没有发现品系相关的听阈差异[72,73]。然而,与斯普拉格-道利大鼠相比,维斯塔大鼠在噪声暴露和水杨酸盐给药后表现出更具攻击性的行为[74]。总结的数据见表 1。
Table 1. Rat strain, gender, and age.
表 1. 大鼠品系、性别和年龄。
Strain
gender
Sprague-Dawley
(Used in 17 Studies)
Wistar (Used in 13 Studies) Long-Evans (Used in 4 Studies)
Fischer FBN;
344 (Used in 3 Studies)
age (range) 1.5-4 months months months months 2-3 months - aths old
In the studies using substance-induced tinnitus, the sample size varied from 4 to 69 animals. Remarkably, only seven of fourteen studies used a control group of animals . In studies using blast- and noise-induced tinnitus, the number of analyzed animals varied from three to 137. Fourteen of the twenty-two studies had a control group [45,48,54,61-65,67-71]. Two articles did not provide information about the experimental and control group [15,45]. In three publications, there was missing data .
在使用物质诱发耳鸣的研究中,样本大小从 4 到 69 只动物不等。值得注意的是,只有 14 项研究中使用了动物对照组 。在使用爆炸和噪声诱发耳鸣的研究中,分析的动物数量从 3 到 137 只不等。其中 22 项研究中有 14 项有对照组[45,48,54,61-65,67-71]。两篇文章没有提供实验组和对照组的信息[15,45]。在三篇出版物中,存在缺失数据

3.3. Methods Used for Tinnitus Induction
3.3. 用于诱发耳鸣的方法

For the induction of tinnitus, three methods were used (Figure 3). In 14 articles, tinnitus was induced with salicylate . Nineteen reports analyzed tinnitus after noise exposure [15,44,45,54-57,61-65,67-71] and three analyzed tinnitus after blast injury [46-48].
为了诱发耳鸣,使用了三种方法(图 3)。在 14 篇文章中,使用水杨酸盐诱发耳鸣 。19 篇报告分析了噪声暴露后的耳鸣[15,44,45,54-57,61-65,67-71],而 3 篇分析了爆炸伤害后的耳鸣[46-48]。
These publications were analyzed in one group because of the similarity in the blast- and noise-induced tinnitus mechanisms. They will be referred to as "noise-induced" throughout the rest of this review [75].
由于爆炸和噪声引起的耳鸣机制的相似性,这些出版物被归为一组进行分析。在本综述的其余部分中,它们将被称为“噪声诱发”[75]。

METHODS USED TO INDUCE TINNITUS IN RATS
用于诱发大鼠耳鸣的方法

Figure 3. Methods used to induce tinnitus in the selected articles .
选择的文章中用于诱发耳鸣的方法

3.4. Methods Used to Determine the Presence of Tinnitus
3.4. 用于确定耳鸣存在的方法

The tinnitus-induction rate in rats exposed to salicylate was , whereas the noise exposure resulted in a tinnitus-induction rate that varied from 30 to [14].
暴露于水杨酸盐的大鼠中耳鸣诱发率为 ,而噪声暴露导致的耳鸣诱发率在 30 到 之间变化[14]。
Different methods were used to determine if animals have tinnitus. In studies with substanceinduced tinnitus, the primary tinnitus-detection method was the gap-prepulse inhibition of the acoustic startle (GPIAS) [13,27,51,52,58-60]. GPIAS is based on a hypothesis that assumes that the animals experiencing tinnitus have a fundamental deficit in hearing the silence. Therefore, unlike tinnitus-free animals, animals with tinnitus will not get startled when a sound is played after a short period of silence [44]. In comparison to an operant conditioned procedure, GPIAS does not require training [70]. The operant conditioned procedures require training, e.g., pressing a lever. That type of operant was successfully applied by one study to detect tinnitus [28]. However, six other studies could not determine tinnitus in rats using that method . Another operant conditioned procedure was "conditioned lick suppression". During the conditioned leak suppression, the animals choose between the drinking water source: one is a standard bottle, and the other is a spout. Rats are trained to drink from a spout during silence and suppress drinking from a spout during the sound presentation. A light electric shock is used to train the suppressive behavior of rats. If the rats develop tinnitus, they show suppressive behavior and do not use a spout for drinking. This method was used in six studies about noise-induced tinnitus . In ten further studies, GPIAS was used [44-48,54-57,69,70]. The last operant-conditioned procedure used to determine tinnitus was a motor task (foraging behavior for sugar water) that was used in three studies [15,65], where animals with tinnitus actively execute the motor task even in the absence of external sound. Rats were trained 3-4 months before the noise exposure [65]. The ratio of activity during an external sound and during periods of silence was used to quantify the motor task [65].
使用不同的方法来确定动物是否患有耳鸣。在药物诱发耳鸣的研究中,主要的耳鸣检测方法是声音惊跳的间隙-前脉冲抑制(GPIAS)[13,27,51,52,58-60]。GPIAS基于一个假设,认为患有耳鸣的动物在听到寂静时存在基本的听觉缺陷。因此,与没有耳鸣的动物不同,患有耳鸣的动物在短暂的寂静后播放声音时不会感到惊吓[44]。与操作性条件程序相比,GPIAS不需要训练[70]。操作性条件程序需要训练,例如按下一个杠杆。一项研究成功地应用了这种类型的操作性条件程序来检测耳鸣[28]。然而,另外六项研究无法通过这种方法确定大鼠是否患有耳鸣。另一种操作性条件程序是“条件性舔抑制”。在条件性舔抑制中,动物可以选择饮水源:一个是标准瓶子,另一个是喷嘴。大鼠在寂静时被训练从喷嘴饮水,并在声音出现时抑制从喷嘴饮水。 使用轻微的电击来训练大鼠的抑制行为。如果大鼠出现耳鸣,它们会表现出抑制行为,不会使用喷嘴饮水。这种方法在六项关于噪声诱发耳鸣的研究中使用过 。在另外十项研究中,使用了 GPIAS [44-48,54-57,69,70]。最后一种用于确定耳鸣的操作条件是一项运动任务(寻找糖水的觅食行为),在三项研究中使用过 [15,65],在这些研究中,即使在没有外部声音的情况下,患有耳鸣的动物也会积极执行这项运动任务。大鼠在噪声暴露前接受了 3-4 个月的训练 [65]。使用在外部声音和静默期间的活动比率来量化这项运动任务 [65]。

3.5. Salicylate-Induced Tinnitus
3.5. 水杨酸盐诱发的耳鸣

Salicylate is commonly used to induce tinnitus in rats [38]. In addition to salicylate, quinine or cisplatin were used to study tinnitus in animals [76]. Despite the similarity in inducing tinnitus-like
水杨酸盐常用于诱发大鼠的耳鸣 [38]。除了水杨酸盐外,奎宁或顺铂也被用于动物耳鸣的研究 [76]。尽管在诱发类似耳鸣的情况下存在相似之处

behavior in rats, the mechanisms behind salicylate- and quinine-induced salicylate are different [13]. Salicylate acts by changing the membrane potential and membrane properties [77]. It is a competitive antagonist for the chloride anion-binding site of prestin [78]-a motor protein of outer hair cells [79]. Additionally, salicylate may impact cochlear fast synaptic transmission via the activation of -methyl-D-aspartate (NMDA) glutamate receptors, accounting for the occurrence of tinnitus [80] and, when administered systemically, it can directly affect the auditory cortex by reversibly depressing the inhibitory, -aminobutyric acid (GABA)-ergic neurons [81]. In contrast, quinine acts by altering the cochlear blood flow and the interaction with calcium channels and calcium-dependent potassium channels [77].
大鼠行为中,水杨酸盐和奎宁引起耳鸣的机制不同[13]。水杨酸盐通过改变细胞膜电位和膜特性起作用[77]。它是外毛细胞马达蛋白prestin氯离子结合位点的竞争性拮抗剂[78],此外,水杨酸盐可能通过激活N-甲基-D-天门冬氨酸(NMDA)谷氨酸受体影响耳蜗快速突触传递,解释了耳鸣的发生[80],当系统给药时,它可以通过可逆地抑制抑制性-γ-氨基丁酸(GABA)能神经元直接影响听觉皮层[81]。相比之下,奎宁通过改变耳蜗血流和与钙通道和钙依赖性钾通道的相互作用起作用[77]。
Nevertheless, the most commonly used substance in animal studies is a salicylate [38]. A high dose of sodium salicylate induces short-term, reversible tinnitus in rats, as demonstrated by Jastreboff . The minimum dose needed to cause tinnitus in rats is [12]. Salicylate evokes changes in the peripheral and central auditory system . In the auditory periphery, high doses of salicylate suppress the electromotility of the auditory outher hair cells (OHC) [78]. However, salicylate's long-term administration increases the prestin expression in the OHCs [49].
然而,在动物研究中最常用的物质是水杨酸盐[38]。高剂量的水杨酸钠会在大鼠中引起短期可逆性耳鸣,如 Jastreboff 所示 。在大鼠中引起耳鸣所需的最小剂量是 [12]。水杨酸盐会引起外周和中枢听觉系统的变化 。在听觉外周,高剂量的水杨酸盐会抑制听觉外毛细胞(OHC)的电动力[78]。然而,长期使用水杨酸盐会增加 OHC 中的 prestin 表达[49]。
In addition, salicylate reduces the amplitude of compound action potentials (CAP) and impacts ABR modulators [82]. The reduced CAP amplitudes in the rats following chronic salicylate treatment indicate long-term functional or structural damage to spiral ganglion neurons (SGN) [49]. The changes are also reflected by the ABR response (reduced amplitude). Nevertheless, the full mechanism of salicylate-induced tinnitus is still unclear.
此外,水杨酸盐会降低复合动作电位(CAP)的幅度,并影响 ABR 调节因子[82]。慢性水杨酸盐治疗后,大鼠的 CAP 幅度降低,表明螺旋神经节神经元(SGN)存在长期的功能或结构损伤[49]。这些变化也反映在 ABR 响应中(幅度降低)。然而,水杨酸盐引起耳鸣的完整机制仍不清楚。
In the selected studies, both acute and chronic treatments were used (Table 2). Of 14 selected studies, four used ABRs to determine the presence of tinnitus [28,29,50,60]. Two of them focused on developing a diagnostic method by joining ABR with a forward masker of tinnitus. Forward masking results from one stimulus producing temporal inhibition, thus suppressing the subsequent stimulus [28]. Forward masking can create an unmasking effect that results in a recovery of the suppressed ABR and could potentially be used as an objective indicator of tinnitus [29,60]. The method's usefulness was demonstrated after a single injection of salicylate . In four other studies, a correlation between acoustic startle response (ASR) and ABR was examined in rats injected with a single dose of salicylate, [50]. In the last study, electrophysiological changes in auditory evoked potentials were analyzed after a 3-day treatment with day [28].
在所选的研究中,使用了急性和慢性治疗(表2)。在14项选定的研究中,有四项使用ABR来确定耳鸣的存在[28,29,50,60]。其中两项着重于通过将ABR与耳鸣的前向屏蔽器结合来开发一种诊断方法。前向屏蔽是由一个刺激产生的时间性抑制,从而抑制后续的刺激[28]。前向屏蔽可以产生一个解屏效应,导致被抑制的ABR恢复,并有可能用作耳鸣的客观指标[29,60]。该方法的有用性在单次水杨酸盐注射后得到了证明。在另外四项研究中,研究了注射单剂水杨酸盐的大鼠中声音惊跳反应(ASR)与ABR之间的相关性[50]。在最后一项研究中,分析了经过3天治疗后听觉诱发电位的电生理变化[28]。
The mechanism of salicylate-induced tinnitus was studied in rats exposed to of salicylate/ day for three weeks ( 5 days a week) [49]. The effect of salicylate on ribbon synapses was assessed in rats treated with of salicylate/ day for ten consecutive days [27]. Changes in the II wave of ABR (representing ventral cochlear nucleus VCN) were examined after four and eight days of salicylate injection at day [58].
暴露于水杨酸盐/天的大鼠中研究了水杨酸盐引起的耳鸣机制(每周 5 天,连续 3 周)[49]。在连续十天内以水杨酸盐/天治疗的大鼠中评估了水杨酸盐对缠绕突触的影响[27]。在注射水杨酸盐后的第四天和第八天,检测了 ABR 的 II 波(代表腹侧耳蜗核 VCN)的变化[58]。

3.6. Noise-Induced Tinnitus
3.6. 噪声诱发耳鸣

The degree of noise-induced hearing loss depends on the noise intensity, exposure duration, distance from the noise source, spectrum, and interval length [83]. Only about half of noise-exposed animals developed tinnitus in the research selected for this review [54,64,65]. Despite that, only five of the 22 publications divided the rats into groups with and without tinnitus . The effect of noise can be mechanical or metabolic [32]. The mechanical effects of noise include loss of either tip links between hair cells or disruption of actin organization in stereocilia. The metabolic impact involves the generation of oxidative stress that may interfere with hair cell function and neurotransmitter release [32].
噪声诱发的听力损失程度取决于噪声强度、暴露时间、距离噪声源的距离、频谱和间隔长度[83]。在本次回顾中选择的研究中,只有大约一半的受噪声暴露的动物出现了耳鸣[54,64,65]。尽管如此,只有 22 篇文章中的五篇将大鼠分为有耳鸣和无耳鸣的组别。噪声的影响可以是机械的或代谢的[32]。噪声的机械效应包括毛细胞之间的顶链丢失或毛细胞立毛的肌动蛋白组织紊乱。代谢影响涉及产生氧化应激,可能干扰毛细胞功能和神经递质释放[32]。

The Noise Characteristics
噪声特征

The parameters of noise in the animal model are variable. Typically, rats are subjected to high-level noise for 1 to , binaural or unilateral (when plugged contralateral ear). Mainly, noise characteristics involved SPL [45,54-57,61-64,67,68]. In three studies, narrow-band noise consisted
动物模型中的噪声参数是可变的。通常,大鼠在高强度噪声下暴露 1 到 ,双耳或单耳(当对侧耳塞)。主要涉及噪声特征 SPL [45,54-57,61-64,67,68]。在三项研究中,窄带噪声包括

of and sound level (80-120 dB SPL), and a duration between 1 and . Two researchers' groups subjected rats for one hour to 116-120 dB SPL and 12 or [44,71].
和声音水平(80-120 dB SPL)之间的频率和持续时间为 1 到 。两个研究小组将大鼠暴露在 116-120 dB SPL 和 12 或 [44,71]之间的声音中一小时。
Table 2. Features of experiments with salicylate-induced tinnitus.
表 2. 水杨酸盐诱发耳鸣实验的特点。
Binaural exposure to a for led to tinnitus when the sound level was SPL but not 80-110 dB SPL [65]. The characteristics of noise used to induce tinnitus are summarized in Table 3.
当声音水平为 SPL 而不是 80-110 dB SPL 时,双耳暴露于 持续 会导致耳鸣[65]。用于诱发耳鸣的噪音特征总结在表 3 中。
The frequency used for acoustic exposure impacts the distribution of noise-induced effects along the cochlea and within the brain [84]. The most significant influence of narrow-band noise was often observed above the noise used [32]. The hearing loss accompanying tinnitus was located in the high-frequency range. The hearing loss, hair cell loss, and changes in the central auditory system are less predictable when using broad-band noise than narrow-band noise [38]. Occurred changes also depend on the sound pressure level (SPL) and the experiment duration [85]. It was demonstrated that only rats subjected to SPL for two hours demonstrated elevated hearing thresholds (tested: 0.5 to , and SPL, octave band noise (OBN)) [70].
用于声学暴露的频率会影响噪声引起的效应在耳蜗和大脑内的分布[84]。狭带噪声的最显著影响通常在使用的噪声之上观察到[32]。伴随耳鸣的听力损失位于高频范围内。与狭带噪声相比,使用宽带噪声时的听力损失、毛细胞损失和中枢听觉系统的变化较不可预测[38]。发生的变化还取决于声压级(SPL)和实验持续时间[85]。实验证明,只有在两小时内受到 SPL 的大鼠才表现出升高的听阈(测试范围:0.5 到 ,以及 SPL, 八度带噪声(OBN))[70]。
Unlike the others, one research group used more than one unilateral acoustic trauma, the first being peak SPL for two hours, and the second (5 weeks later) of identical characteristics, but applied for three hours [69]. In the research regarding blast-induced tinnitus, a single or three consecutive blasts exposures (194 dB), unilateral and bilateral, were used [46-48]
与其他研究不同,一个研究小组使用了一个以上的单侧声音创伤,第一个是 峰值 SPL,持续两小时,第二个(5 周后)具有相同特征,但持续三小时[69]。在关于爆炸引起的耳鸣的研究中,使用了单次或连续三次爆炸暴露(194 dB),单侧和双侧[46-48]。
ABR in the selected studies was used to assess hearing loss after noise trauma, determine shortand long-term changes in ABR after the noise, and study the efficacy of drugs for hearing loss.
选择的研究中使用 ABR 来评估噪声损伤后的听力损失,确定噪声后 ABR 的短期和长期变化,并研究治疗听力损失的药物的疗效。
During most studies using noise and blast exposure, rats were anesthetized. However, there were two exceptions . In the first work, rats were held in a slowly rotating hardware cloth cage . In the second study, rats were subjected to two noise exposures (51). To avoid the protective effect of isoflurane against hearing loss [86], rats were awake during the second exposure (51). Two articles did not provide information about anesthesia during noise exposure .
在大多数使用噪声和爆炸暴露的研究中,大鼠被麻醉。然而,有两个例外情况。在第一项工作中,大鼠被放置在一个缓慢旋转的金属网笼中。在第二项研究中,大鼠经历了两次噪声暴露。为了避免异氟醚对听力损失的保护作用[86],大鼠在第二次暴露时是清醒的。有两篇文章没有提供噪声暴露期间的麻醉信息。
Table 3. Features of experiments with noise-induced tinnitus.
表 3. 噪声诱发耳鸣实验的特点。
Article
Laterality of Noise
Application
Noise Intensity Noise Duration
Anesthetic Used during
Noise Exposure
Determination of Tinnitus
in Rats/Sample Size
Timepoint of Tinnitus
Determination
Kim et al., 2020 [55] Bilateral Data not available Data not available (GPIAS)
One day after the noise and 1
and 10 days after completing
DEX administration
Brozoski et al., 2019 [67]
Unilateral (contralateral
ear-plugged)
SPL Isoflurane
Not all (an operant
conditioned-suppression
procedure)
3 and 9 months after noise
van Zwieten et al., 2019 [57]
Unilateral (contralateral
ear-plugged)
Ketamine
Xylazine
11/11 (GPIAS) 4-6 weeks after noise
van Zwieten et al., 2019 [56]
Unilateral (contralateral
ear-plugged)
SPL
Ketamine
Xylazine
(Data not available
GPIAS)
4-6 weeks after noise
Ahsan et al., 2018 [54]
Unilateral (contralateral
ear-plugged)
Isoflurane (GPIAS) After noise (no details)
Turner and Larsen, 2016 [70]
Unilateral (contralateral
ear-not announced)
or 122
or or
BBN, SPL
, or
Ketamine + Xylazine
(doses-not announced)
Data not available (GPIAS)
On Day after
noise exposure and monthly
thereafter over until 1 year
Bing et al., 2015 [15]
Unilateral (contralateral
ear-plugged)
Medetomidine hydrochloride
Data not available
(the motor task)
3 and 10 days after noise
Zheng et al., 2015 [64]
Unilateral (contralateral
ear-plugged)
Fentanyl
Medetomidine hydrochloride
14/30 (a conditioned lick
suppression task)
1 month after noise
Zheng, McPherson and
Smith, 2014 [63]
Unilateral (contralateral
ear-plugged)
,
Medetomidine hydrochloride
Data not available
(a conditioned lick
suppression task)
2 weeks and then at 10 and
17.5 weeks after noise
Laundrie and Sun, 2014 [44]
Unilateral (contralateral
ear-plugged)
SPL Isoflurane Data not available GPIAS) after noise
Ropp et al., 2014 [45]
Unilateral (contralateral
ear-plugged)
SPL
Unanesthetized (rat was held
in a slowly rotating hardware
cloth cage)
Data not available (GPIAS)
At various delays after noise
(2-3 times a week
for months)
Rüttiger et al., 2013 [87] Binaural SPL or
Ketamine
Xylazine hydrochloride
5/15 and 5/17.
(the motor task)
Before and at 6 day or
30 days after noise
Pace and Zhang, 2013 [69]
Unilateral (contralateral
ear-plugged)
peak SPL
Two hours, five
weeks later, the 2 nd
exposure for
First: Isoflurane ; second:
while rats awake
12/18 (GPIAS)
One day after the 1st noise
and two times a week until
six weeks after the 2nd noise
Singer et al., 2013 [65] Binaural
, or
Ketamine hydrochloride
Xylazine
hydrohloride
Only rats subjected to
demonstrated tinnitus
(the motor task)
6-14 days after
noise exposure
Brozoski et al., 2012 [68]
Unilateral (contralateral
ear-plugged)
Data not available
Data not available
(an operant
conditioned-suppression)
Immediately after noise
Zheng et al., 2012 [62]
Unilateral (contralateral
ear-plugged)
Ketamine hydrochloride
Medetomidine
hydrochloride
5/8 (a conditioned lick
suppression task)
After noise (no details)
Table 3. Cont. 表 3. 续表
Article
Laterality of Noise
Application
Noise Intensity Noise Duration
Anesthetic Used during
Noise Exposure
Determination of Tinnitus
in Rats/Sample Size
Timepoint of Tinnitus
Determination
Zheng et al., 2012 [62]
Unilateral (contralateral
ear-plugged)
Ketamine hydrochloride
Medetomidine
hydrochloride
Data not available
(a conditioned lick
suppression task)
Two weeks after noise
Zheng et al., 2011 [61]
Unilateral (contralateral
ear-plugged)
Ketamine hydrochloride
Medetomidine
hydrochloride
Data not available
(a conditioned lick
suppression task)
2 weeks and 10 months
after noise
Wang et al., 2009 [88]
Unilateral (contralateral
ear-plugged)
SPL
Ketamine hydrochloride
Xylazine
10/14 (GPIAS)
20 days after noise every
2 weeks up to 16 weeks
Ouyang 2017 [48]
Unilateral (contralateral
ear-plugged)
SPL Single blast exposure
Isoflurane or Ketamine
Xylazine
8/13 (GPIAS) After blast (2 times per week)
Mahmood et al., 2014 [46]
Unilateral (contralateral
ear-plugged)
Data not available
3 consecutive
blast exposure
Isoflurane
Data not available
(GPIAS)
after the last blast and for
8 weeks afterward
Mao et al., 2012 [47] Bilateral SPL
Single blast
exposure
Ketamine
Xylazine
Data not available
(GPIAS)
, and 90 days
after blast

3.7. Methods of ABR Measurement
3.7. ABR 测量方法

3.7.1. ABR Recording Systems
3.7.1. ABR 记录系统

Two commercially available systems-Tucker Davis Technologies (TDT) and Intelligent Hearing Systems (IHS)-were used to record ABR. The majority of the groups used the TDT system . Three research groups used the system