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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 , whereas two other groups used both systems . Ten articles provided no information about the system used .
两个商业可用的系统-Tucker Davis Technologies (TDT) 和 Intelligent Hearing Systems (IHS)-被用于记录 ABR。大多数组使用了 TDT 系统 。三个研究组使用了系统 ,而另外两个组使用了两个系统 。十篇文章没有提供使用的系统的信息

3.7.2. The Stimulus Signal
3.7.2. 刺激信号

ABR responses were elicited by click and tone burst stimuli . The majority of the research teams used a tone burst ; five groups applied tone bursts of longer duration, 6-10 ms . Fives articles did not provide information about signal . Acoustic stimuli were delivered at [47,65]; 1-45/50 kHz [15,65]; 2.5-40 kHz [45]; 6-16 kHz [29,50]; 8-16 kHz [51]; 4-20 kHz [53]; 4-30 kHz [54]; 2-24 kHz [59]; 4-32 kHz [28,49,66]; 6-20 [44]; [28,49,52]; 8-20 kHz or 8-32 kHz [51,55,58,62-64,67,70,71]; and 10-32 kHz [56,57]. Sound stimuli were presented at a rate of 10-11 [13,55,65,66], 17-19 [50,53], 20-21 [13,28,44,49,51,55,58,59,63], , or bursts/s. Eight articles did not provide information about repetition rate . Sound stimuli were presented directly to the ear canal or in free field . The distance between the speaker and ear were 1 to . Eleven articles provided no information about signal delivering .
ABR 反应是通过点击 和音调爆发刺激 来引发的。大多数研究团队使用了 音调爆发 ;五个组使用了持续时间较长的音调爆发,6-10 毫秒 。五篇文章没有提供有关信号 的信息。声学刺激以 [47,65];1-45/50 千赫 [15,65];2.5-40 千赫 [45];6-16 千赫 [29,50];8-16 千赫 [51];4-20 千赫 [53];4-30 千赫 [54];2-24 千赫 [59];4-32 千赫 [28,49,66];6-20 [44]; [28,49,52];8-20 千赫或 8-32 千赫 [51,55,58,62-64,67,70,71];以及 10-32 千赫 [56,57]进行传递。声音刺激以 10-11 [13,55,65,66]、17-19 [50,53]、20-21 [13,28,44,49,51,55,58,59,63]、 次爆发/秒的速率呈现。八篇文章没有提供有关重复率 的信息。声音刺激直接呈现到耳道 或在自由场中 。扬声器与耳朵之间的距离为 1 到 。十一篇文章没有提供有关信号传递 的信息。

3.7.3. Signal to Noise Ratio and Thresholds
3.7.3. 信噪比和阈值

Original data were averaged to achieve an increase of the signal to noise ratio. To estimate thresholds, the number of averageness was or . When the amplitude and latency were analyzed, it was 64-256 [15,65], 200 [60], 300-400 [45-48,54,69], 512 [53,55,68,70], 600 [49], or 1000-1024 [28,56,57,71]. The sound intensity levels gradually decreased from SPL in 5-10 decrements. Five reports did not provide this information to estimate hearing thresholds [44,61-64]. Click (100 s) was also used to estimate recovery after noise exposure to calculate the correlation factor (corF) . The corF reflects changes in waveform and amplitude before and after noise exposure. High values (around 1) of corF reflect the similarity in a waveform, whereas low values (around 0 ) indicate loss of both waveform similarity and amplitude [15,65].
原始数据被平均以提高信噪比。为了估计阈值,平均次数为 。当分析振幅和潜伏期时,其数值为 64-256 [15,65],200 [60],300-400 [45-48,54,69],512 [53,55,68,70],600 [49],或 1000-1024 [28,56,57,71]。声强级逐渐以 5-10 的递减量从 SPL 降低。五份报告未提供此信息以估计听阈[44,61-64]。点击(100 s)也用于估计噪声暴露后的恢复,以计算相关系数(corF) 。corF 反映了噪声暴露前后波形和振幅的变化。corF 的高值(约为 1)反映了波形的相似性,而低值(约为 0)则表示波形相似性和振幅的丧失[15,65]。

3.7.4. Electrode Placement
3.7.4. 电极放置

In the majority of the studies, three stainless-steel recording electrodes were inserted subcutaneously: one on the mastoid of the tested ear (reference electrode), one on the vertex (active), and one on the contralateral mastoid (ground) . Some research groups placed the ground electrode on the back of animals [15,50,62,65,71], on the occiput [61-64], on the leg , or on the nose [29]. One research group placed electrodes on the vertex and ipsi- and contralateral mastoids [54]. In two studies, four electrodes were located at the vertex (active), mastoids (references), and the ground electrode was located on the nose tip [60] or on the back [28]. In four papers, electrodes were placed atypically [53,56-58]. Two studies have not provided information regarding electrode placement [44,51].
在大多数研究中,插入了三个不锈钢记录电极皮下:一个在被测试耳朵的乳突上(参考电极),一个在顶点(活动电极),一个在对侧乳突上(接地电极)。一些研究小组将接地电极放在动物的背部[15,50,62,65,71],枕部[61-64],腿上或鼻子上[29]。一个研究小组在顶点和同侧、对侧乳突上放置电极[54]。在两项研究中,四个电极位于顶点(活动电极),乳突(参考电极),接地电极位于鼻尖[60]或背部[28]。在四篇论文中,电极的放置位置不典型[53,56-58]。两项研究没有提供有关电极放置的信息[44,51]。

3.7.5. Filters and Polarity
3.7.5. 滤波器和极性

Only a few publications provided information about filters, polarity, and electrode impedance. Averaged ABR waveforms were bandpass-filtered between and [28]; and
只有少数几篇文章提供了有关滤波器、极性和电极阻抗的信息。平均 ABR 波形在 之间进行带通滤波[28];

[13,44,51-53,68,70,71]; [49]; 300-3 kHz [29,45-48,54,56,57,60,69,71]; and [65]; or [66]. The notch filter was or [29,46-49,53,60]. The polarity was alternating .
[13,44,51-53,68,70,71]; [49]; 300-3 kHz [29,45-48,54,56,57,60,69,71]; [65];或 [66]。陷波器是 [29,46-49,53,60]。极性是交替的

3.8. Protocols Used for ABR Recordings
3.8. ABR 记录使用的协议

3.8.1. Anesthesia 3.8.1. 麻醉

Before the ABR measurement, the rats were anesthetized. The majority of the groups used a mixture of ketamine- and xylazine (ratio: 5:1; 9:1; 1:2:21:1; 6:1; 16:1) [15,27,28,45,48,50,56-58,65,66,69-71]. In eight publications, isoflurane ( ) was used . In addition, chloral hydrate was applied in three cases or ) [29,59,60]. In five studies, instead of xylazine, medetomidine was injected [61-64]. In one study, a mixture of Zoletil 50 and Rompun 2% or Zoletil ( xylazine ) were used [51,55]. One research group used only ketamine [52], whereas two groups provided no information about the anesthesia [51,68]. In one study, instead of anesthesia, restraint was used [53].
在进行 ABR 测量之前,大鼠被麻醉。大多数组使用了氯胺酮和异丙酰胺的混合物(比例为 5:1;9:1;1:2:21:1;6:1;16:1)[15,27,28,45,48,50,56-58,65,66,69-71]。在八篇文章中,使用了异氟醚[b1]进行麻醉[b2]。此外,三个案例中使用了氯醛酸酯[b3]或[b4] [29,59,60]。在五项研究中,注射了美托咪定[b5]代替异丙酰胺[61-64]。在一项研究中,使用了 Zoletil 50 和 Rompun 2%或 Zoletil 的混合物[b6](异丙酰胺[b7])[51,55]。一个研究小组仅使用了氯胺酮[52],而两个小组没有提供关于麻醉的信息[51,68]。在一项研究中,使用了约束代替麻醉[53]。

3.8.2. Additional Information
3.8.2. 附加信息

During ABR measurement, animals' body temperature was maintained by either a non-heating pad or a warm blanket [28,45-49]. In one study, the body temperature was controlled by maintaining the temperature of in a sound-proof room [58]. Even though changes in body temperature modulate brainstem functions [90], most articles have not provided information about maintaining body temperature during measurement . Electrode impedance ranged between .
在 ABR 测量过程中,动物的体温通过非加热垫或保暖毯 [28,45-49] 来维持。在一项研究中,通过在隔音房间中维持 的温度来控制体温 [58]。尽管体温的变化会调节脑干功能 [90],但大多数文章没有提供关于测量过程中如何维持体温的信息 。电极阻抗范围为
Detailed information extracted from each publication is presented in Table S2 in the Supplementary Materials.
从每篇出版物中提取的详细信息在附录材料的表格 S2 中呈现。

3.9. ABR Evaluation after Salicylate Treatment
3.9. 水杨酸盐治疗后的 ABR 评估

The ABR was used to study whether salicylate induces long-term changes in the auditory system , to assess the brainstem function following salicylate administration , and to analyze the effect on ABR modulators .
ABR 被用于研究水杨酸盐是否引起听觉系统的长期变化 ,评估水杨酸盐给药后的脑干功能 ,并分析对 ABR 调节剂的影响

3.9.1. Hearing Thresholds after Salicylate Treatment
3.9.1. 水杨酸盐治疗后的听阈

Exposure to salicylate at for seven consecutive days increased hearing thresholds at two tested frequencies ( 8 and ) (on the seventh and eighth day of the experiment). Ten day-long exposure of rats to salicylate at day has not altered the thresholds measured between 2 and compared to the control group [51]. In addition, no changes in hearing thresholds between 6 and were recorded two weeks after the rats' exposure to salicylate ( ) for four consecutive days [52]. The thresholds between 8 and were not affected by a single injection of , two hours after drug administration [51]. Studies comparing hearing thresholds during (1-3 days) and after exposure (4-6 days) demonstrated restoring hearing abilities after salicylate cessation. During and two days after the exposure, hearing thresholds were elevated at 4-32 kHz. On the 6th day of the experiment, the threshold shift recovered (elevation at ) [28].
连续七天接触水杨酸盐(在实验的第七天和第八天)增加了两个测试频率(8和)的听阈。大鼠暴露于水杨酸盐十天(在第天)并未改变在2和之间测量的阈值与对照组相比[51]。此外,大鼠连续四天接触水杨酸盐后两周内()记录到6和之间的听阈没有变化[52]。单次注射后两小时,8和之间的阈值没有受到的影响[51]。比较暴露期间(1-3天)和暴露后(4-6天)的听阈,显示在停止使用水杨酸盐后恢复了听力能力。在暴露期间和暴露后两天,4-32 kHz的听阈升高。在实验的第6天,阈值恢复(升高至)[28]。
Four weeks of exposure to of salicylate/ in water influenced the hearing abilities. A higher mean threshold (at 4-32 dB) was detected in the treated animals compared to the control group, 38 vs. , after salicylate cessation [66].
暴露于水中的水杨酸盐/ 的四周对听力能力产生了影响。与对照组相比,治疗动物中检测到了更高的平均阈值(在 4-32 dB 之间),在水杨酸盐停止后,治疗组为 38 vs. 。
Duron et al. examined changes occurring in auditory function 30-90 min after a single injection of in Sprague-Dawley rats (43). Already 1-1.5 h after injection, thresholds were elevated . The shift was more remarkable at higher frequencies, increasing by about at to at .
Duron 等人研究了 Sprague-Dawley 大鼠注射后 30-90 分钟内听觉功能的变化(43)。注射后 1-1.5 小时,阈值升高了。在较高频率上,这种变化更为显著,增加了约,在到。

3.9.2. Effects of Salicylate on ABR Amplitudes and Latencies
3.9.2. 水杨酸盐对 ABR 振幅和潜伏期的影响

The administration of salicylate ) for eight consecutive days has reduced the ABR amplitudes in all tested frequencies when measured eight days after salicylate cessation. One week later, the reduction of amplitudes lessened [58]. A lower concentration of salicylate applied for ten days has not changed the thresholds, but the reduced amplitude wave I at 2-24 kHz was observed [27]. With a higher concentration of salicylate ( ) applied over three days, the amplitude of wave I was reduced, whereas the changes in amplitudes of waves II and IV were seen only on the first day. Wave V was not affected by salicylate [28].
持续八天给予水杨酸盐( )治疗后,停药八天后在所有测试频率上测量的 ABR 振幅均有所降低。一周后,振幅的降低减轻了[58]。连续十天给予较低浓度的水杨酸盐( )治疗后,未改变阈值,但观察到 2-24 kHz 处波 I 的振幅降低[27]。连续三天给予较高浓度的水杨酸盐( )治疗后,波 I 的振幅降低,而波 II 和波 IV 的振幅变化仅在第一天观察到。波 V 不受水杨酸盐的影响[28]。
In contrast, wave V's amplitude was reduced at after a single salicylate injection for at least three days after injection. The amplitude of wave II was also reduced in a broader range , and ) [53]. Waves IV and I were reduced at after a single dose (150 mg/kg) [50]. The reduced amplitude of wave III after prolonged exposure to salicylate (3 weeks, five days a week) persisted from 3 days to 4 weeks after cessation [49].
相反,在单次水杨酸盐注射后的至少三天内,波 V 的振幅降低了 。波 II 的振幅也在更广范围内降低了 ,并且 )[53]。单次剂量(150 mg/kg)后,波 IV 和波 I 在 处降低[50]。长期暴露于水杨酸盐(每周五天,连续三周)后,波 III 的振幅降低在停药后的 3 天至 4 周内持续存在[49]。
In conclusion, wave I's amplitude decreased, whereas wave IV's amplitude increased after salicylate exposure . The amplitude of wave III was not affected by a short treatment (1-3 days), but prolonged exposure to salicylate caused the amplitude reduction . The decrease of ABR amplitude was seen even though the threshold was not affected [27]. There was a correlation between the presence of tinnitus and decreased amplitude observed in male Wistar rats. In agreement with that, the return of amplitude to the baseline level correlated with subsidence of tinnitus (based on GPIAS) [58].
总之,波I的振幅在水杨酸盐暴露后减小,而波IV的振幅增加 。波III的振幅在短期处理(1-3天)后没有受到影响,但长时间暴露于水杨酸盐会导致振幅降低 。即使阈值没有受到影响,ABR振幅的降低仍然可见[27]。雄性Wistar大鼠中观察到耳鸣与振幅降低之间存在相关性。与此一致的是,振幅恢复到基线水平与耳鸣的减退(基于GPIAS)相关[58]。
A single dose of salicylate affected the latency of wave I and IV. Ninety minutes after salicylate administration, wave I was prolonged at 6,10 , and , whereas the latency of wave IV was reduced (only if measured at ) [50]. Intervals III-IV decreased at after salicylate injection. The changes in latency of wave I were not observed after ten days of exposure to salicylate at the concentration of [27]. The reduced latencies of waves I-IV at 6,16 , and (tested between 4 and ) were observed during treatment and one day after salicylate cessation day for three days). On days 2-4th after cessation, only latency II-IV at was prolonged [28]. Changes in latencies were dose-dependent [27,28,50]. Assessment of individual ABR waves revealed alternations dependent on the stimulus frequencies (Table 4).
水杨酸一次剂量 影响了波 I 和波 IV 的潜伏期。水杨酸给药后 90 分钟,波 I 在 6,10 和 处延长,而波 IV 的潜伏期缩短(仅在 测量时)[50]。水杨酸注射后,III-IV 间隔在 后减小。暴露于浓度为 的水杨酸十天后,波 I 的潜伏期变化不明显[27]。在治疗期间和停药后一天(连续 三天),在 6,16 和 (在 4 和 之间测试)观察到波 I-IV 的潜伏期缩短。停药后的第 2-4 天,仅在 处延长潜伏期[28]。潜伏期的变化与剂量有关[27,28,50]。对个体 ABR 波进行评估发现,其变化取决于刺激频率(表 4)。
Table 4. Salicylate-induced changes in ABR amplitude and latency.
表 4. 水杨酸引起的 ABR 振幅和潜伏期变化。
reduced; increased; _ no changes; prolonged; reduced; SD Sprague-Dawley; Wis Wistar.
减少; 增加;_无变化; 延长; 减少;SD Sprague-Dawley;Wis Wistar。

3.10. ABR Evaluation after Noise Exposure
3.10. 噪声暴露后的 ABR 评估

ABR was used to assess the capacity of noise injury to induce the auditory threshold shift . To estimate the recovery after noise trauma, ABR Waveform Correlation was used . Following blast exposure, hearing thresholds and wave I amplitude were analyzed [46-48].
使用 ABR 评估噪声损伤诱导听阈移位的能力 。使用 ABR 波形相关性估计噪声创伤后的恢复情况 。在爆炸暴露后,分析听阈和波 I 振幅[46-48]。

3.10.1. Hearing Thresholds after Noise Exposure
3.10.1. 噪声暴露后的听阈

Rats subjected to acoustic trauma had elevated hearing thresholds, and the unilateral noise exposure injured only one side. Observed elevated thresholds depended on the noise parameters. Immediately after unilateral noise exposure ( SPL for ), the hearing thresholds in exposed ears (threshold: 70-90 dB peSPL) were higher than in control. Six weeks later, the thresholds were still elevated (70-90 dB peSPL) [56,57]. Four to six weeks after noise exposure, all rats presented behavior consistent with tinnitus perception (measured by GPIAS) [57]. Unilateral exposure to noise for one hour ( evoked a significant increase in the hearing thresholds at 8-20 kHz in the affected ears (immediately after noise) [61,62]. Simultaneously, five of eight animals tested positive for tinnitus (based on lick suppression task) [62]. Immediately after noise exposure , rats had elevated mean threshold (+30-50 dB at 8-32 kHz) [68].
暴露于声音创伤的老鼠听阈升高,单侧噪声暴露只对一侧造成伤害。观察到的升高阈值取决于噪声参数。单侧噪声暴露后立即( SPL for ),暴露耳朵的听阈(阈值:70-90 dB peSPL)高于对照组。六周后,阈值仍然升高(70-90 dB peSPL)[56,57]。噪声暴露后四到六周,所有老鼠 表现出与听觉幻听感知一致的行为(通过GPIAS测量)[57]。单侧噪声暴露一小时后( ),受影响耳朵的8-20 kHz听阈显著增加(噪声后立即)[61,62]。同时,八只动物中有五只在舔食抑制任务中呈阳性(基于舔食抑制任务)[62]。噪声暴露后立即 ,老鼠的平均阈值升高(8-32 kHz +30-50 dB)[68]。
Following noise exposure (8-16 kHz, for two hours), the thresholds remained higher for one month in the stimulated ears (threshold: 50-60 dB peSPL), which was not observed in the contralateral ears (thresholds: peSPL) [54]. After acoustic trauma, four of six rats developed tinnitus (as per GAP detection) [54]. Shorter acoustic exposure ( induced tinnitus in about of rats (14 animals of 30 ) tested with a conditioned lick suppression task [64]. The thresholds shift recovered six months after the exposure to noise [63,64].
在噪声暴露(8-16 kHz, ,持续两小时)后,刺激的耳朵的阈值在一个月内保持较高(阈值:50-60 dB peSPL),而在对侧耳朵中没有观察到这种情况(阈值: peSPL)[54]。在声音创伤后,六只大鼠中有四只出现耳鸣(根据GAP检测)[54]。较短的声音暴露( )在约 的大鼠中引发耳鸣(30只动物中的14只),通过条件性舔抑制任务进行测试[64]。噪声暴露后六个月,阈值恢复正常[63,64]。
Long-term hearing loss was observed after a single, unilateral exposure to for one hour. The elevated threshold persisted for 14 months [67]. Although the hearing loss was demonstrated in all rats, not all of them developed tinnitus. Nine months after noise exposure, no differences in thresholds were observed between the noise-exposed rats without tinnitus and the control animals [67]. Restoration to baseline levels after single, unilateral noise ( for one hour) was observed 16 weeks after noise exposure [71]. At the same time, 10 of 14 noise-exposed rats developed tinnitus at the frequencies between 24 and , as assessed by GAP detection [91].
单侧暴露于 一小时后,长期听力损失被观察到。这种提高的阈值持续了14个月[67]。虽然所有的大鼠都表现出听力损失,但并非所有大鼠都出现耳鸣。噪声暴露后九个月,没有观察到无耳鸣的噪声暴露大鼠和对照动物之间的阈值差异[67]。单侧暴露于 一小时后,噪声暴露16周后恢复到基线水平[71]。与此同时,通过GAP检测,14只噪声暴露大鼠中有10只在24和 之间的频率上出现耳鸣[91]。
Rats exposed to for two hours had elevated hearing thresholds at frequencies higher than in exposed ears for at least 15 days following noise exposure (frequencies tested: [15]. While there were no differences in hearing thresholds between tinnitus-positive and -negative animals, rats with lesser tinnitus had a slighter reduction in the number of synapses on inner hair cells [15]. The difference in hearing thresholds in rats with and without tinnitus was described by Rüttiger et al. [65]. Rats with noise-induced tinnitus (binaural exposure for one hour, or one and a half hours, SPL) had a significantly larger hearing loss than rats without tinnitus. Six days after one-hour noise exposure, the hearing loss in frequencies above was considerably higher than the tinnitus-free group. Thirty days after noise exposure, an elevated hearing threshold in animals with tinnitus was also significantly greater at low frequencies (tested: ). Tinnitus was determined in five of 15 and five of 17 rats, respectively (the motor task) [65]. The lower intensity of the above noise ( ) did not evoke elevation in hearing thresholds in Wistar rats [65].
暴露于 两小时的老鼠,在噪声暴露后至少15天内,暴露耳朵中高于 频率的听阈升高(测试频率: [15])。虽然耳鸣阳性和阴性动物之间的听阈没有差异,但耳鸣较轻的老鼠内毛细胞突触数量减少较少[15]。耳鸣和无耳鸣老鼠的听阈差异由Rüttiger等人描述[65]。噪声诱发耳鸣的老鼠(双耳暴露一小时或一个半小时, SPL)的听力损失明显大于无耳鸣的老鼠。一小时噪声暴露后的六天内,高于 频率的听力损失明显高于无耳鸣组。 噪声暴露后的三十天内,耳鸣动物的听阈升高在低频(测试频率: )也显著更高。耳鸣在15只老鼠中确定为5只,在17只老鼠中确定为5只(运动任务)[65]。 上述噪声的较低强度( )未引起 Wistar 大鼠听阈升高[65]。
The selected studies detected different patterns of audiometric changes following noise exposure. Two hours after single unilateral noise exposure ( , one-hour exposure), ABR thresholds increased by about at (tested range: ). While some rats developed permanent hearing loss ( weeks), other animals' hearing abilities recovered within three consecutive days. The changes were absent in contralateral ears [44]. The observed differences might be related to the used outbred rat strain (Sprague-Dawley). A different pattern was observed in other studies when acoustic exposure of for two hours, was used [45]. After one week, an increase in hearing thresholds between 2.5 and was observed between SPL 10 and [45].
选定的研究检测到噪声暴露后不同的听力学变化模式。单侧噪声暴露后两小时( ,一小时暴露),ABR 阈值在 (测试范围: )上升约 。虽然一些大鼠出现了永久性听力损失( 周),但其他动物的听力能力在连续三天内恢复。这些变化在对侧耳中不存在[44]。观察到的差异可能与使用的杂交大鼠品系(Sprague-Dawley)有关。在其他研究中,当使用 的声学暴露两小时时,观察到不同的模式[45]。一周后,在 SPL 10 和 之间观察到听阈在 2.5 和 之间的增加[45]。
Turner et al. demonstrated that noise with an intensity below did not evoke changes in the hearing thresholds two hours after exposure [70]. That observation was confirmed by the study of Kim et al. Despite extended noise exposure time (four hours), the next day, no elevated hearing thresholds (8-32 kHz) were determined in the experimental animals [55].
Turner 等人证明,强度低于 的噪声在暴露后两小时内不会引起听阈的变化 [70]。金等人的研究证实了这一观察结果。尽管噪声暴露时间延长(四小时),但实验动物的听阈(8-32 kHz)在第二天没有升高[55]。
The effect of two exposures on behavior consistent with tinnitus perception was demonstrated in Long-Evans rats. Following 1 to 8 weeks after two noise exposures and
在 Long-Evans 大鼠中,两次暴露后 1 至 8 周的行为表现与听觉感知一致的效应得到了证明。在有耳鸣的大鼠中,听力损失范围比没有耳鸣的大鼠更广(分别为 vs. )。18 只大鼠中有 12 只表现出耳鸣(GPIAS)[69]。

, rats with tinnitus had broader hearing loss than rats without tinnitus ( vs. , respectively). Tinnitus was demonstrated in 12 of 18 rats (GPIAS) [69].
Bilateral blast (194 dB for ) produced an immediate elevation in hearing thresholds from 39 to about peSPL at frequencies less than [47]. On days 14, 28, and 90, after the blast, thresholds recovered to SPL, SPL, and SPL, respectively [47].
双边爆炸( 处的 194 dB)导致听阈立即从 39 dB 升高到低于 频率的约 peSPL [47]。在爆炸后的第 14、28 和 90 天,阈值分别恢复到 SPL、 SPL 和 SPL [47]。
In another study, 14 days after a single unilateral blast, the hearing level of animals returned to baseline [47]. In contrast, Sprague-Dawley rats, following a unilateral blast, had elevated hearing thresholds between eight and in both ears one day after blast exposure. Three to six weeks later, threshold elevation was still observed but only in the frequencies between 16 and and only in the blast-exposed ears [46].
在另一项研究中,单侧爆炸后的 14 天,动物的听力水平恢复到基线水平 [47]。相比之下,斯普拉格-道利大鼠在单侧爆炸后,爆炸暴露后的第一天,两只耳朵的听阈升高了 8 到 。三到六周后,阈值升高仍然观察到,但仅在 16 到 的频率范围内,且仅在受爆炸影响的耳朵中观察到 [46]。
In the selected studies, not all animals developed tinnitus. Unfortunately, only a few studies performed audiometric analyses of the animals with positive behavioral tests indicative of tinnitus . These analyses demonstrated differences in the hearing thresholds between the animals with and without tinnitus. After the noise exposure, rats with tinnitus had increased hearing thresholds [65] and a broader hearing loss than the noise-exposed animals without tinnitus [69]. Rats with tinnitus had elevated thresholds at , whereas rats without tinnitus had elevated thresholds at (following two noise exposures). Nevertheless, there was no correlation between threshold shift and GPIAS results [69]. In disagreement with the above results, Brozoski et al. [67] observed no differences in hearing thresholds between rats with and without tinnitus.
在所选研究中,并非所有动物都出现了耳鸣。不幸的是,只有少数研究对表现出耳鸣迹象的动物进行了听力分析 。这些分析显示,患有耳鸣的动物与没有耳鸣的动物之间的听阈存在差异。噪声暴露后,患有耳鸣的大鼠听阈增加 [65],听力损失范围比没有耳鸣的噪声暴露动物更广 [69]。患有耳鸣的大鼠在 处阈值升高,而没有耳鸣的大鼠在 处阈值升高(经历两次噪声暴露)。然而,阈值变化与 GPIAS 结果之间没有相关性 [69]。与上述结果不符的是,Brozoski 等人 [67]观察到患有耳鸣和没有耳鸣的大鼠之间的听阈没有差异。

3.10.2. Effects of Noise on ABR Amplitudes and Latencies
3.10.2. 噪声对 ABR 振幅和潜伏期的影响

The influence of noise exposure on the alternation and recovery of the ABR waveform was analyzed by calculating the click-induced ABR waveform correlation factor (CorF) [15,65]. The CorF reflects changes in waveform and amplitude [65] before and after noise exposure. High values (around 1) of corF are indicative of similarities in waveforms, whereas low values (about 0 ) indicate loss of both waveform similarity and amplitude [15,65]. Fifteen days after single noise exposure , two hours, unilateral), the overall ABR amplitude was reduced. Simultaneously, the ABR threshold was elevated at frequencies higher than (assessment of 1-50 kHz) [15]. Moreover, a negative relationship between tinnitus and a number of synaptic contacts on the inner hair cells was observed (tinnitus test: the motor task), as reflected by the ABR wave I [15].
通过计算点击诱发的ABR波形相关系数(CorF)[15,65],分析噪声暴露对ABR波形的变化和恢复的影响。CorF反映了噪声暴露前后波形和幅度的变化[65]。CorF的高值(约为1)表明波形相似性高,而低值(约为0)则表示波形相似性和幅度的丧失[15,65]。单次噪声暴露(双耳,两小时)后的十五天内,整体ABR幅度减小。同时,高于 频率(1-50 kHz评估)的ABR阈值升高[15]。此外,观察到耳鸣与内毛细胞上的突触接触数量之间存在负相关关系(耳鸣测试:运动任务),这反映在ABR波I上[15]。
While the ABR waveform of rats exposed to noise ( for two hours) was restored within two weeks, rats exposed to higher noise intensity ( had distorted ABR waveforms and reduced amplitude two weeks after noise trauma [65]. The overall amplitude reduction was observed in rats 6-30 days after bilateral noise exposure ( or ) [65]. Compared to tinnitus-free rats, rats with tinnitus had a reduced hearing recovery 6 and 30 days after noise trauma [65]
在噪声暴露( 两小时)后的两周内,大鼠的 ABR 波形恢复正常,而暴露于更高噪声强度( )的大鼠在噪声创伤后两周 ABR 波形失真且幅度减小[65]。在双侧噪声暴露( )后的 6-30 天内观察到整体幅度减小[65]。与无耳鸣的大鼠相比,患有耳鸣的大鼠在噪声创伤后的 6 和 30 天内听力恢复减少[65]。
After the unilateral blast, the threshold recovered fully within five weeks , whereas the amplitude of wave I at was still reduced [48]. Tinnitus was determined in eight of 13 animals (GPIAS). There were no differences in ABR between tinnitus and tinnitus-free rats, and the ABR amplitudes were reduced in all exposed rats [48]. In summary, noise exposure induces ABR amplitude reduction. Table 5 summarizes the observed changes.
单侧爆炸后,阈值在五周内完全恢复 ,而 处的波 I 幅度仍然减小[48]。在 13 只动物中,有 8 只被确定为耳鸣(GPIAS)。耳鸣和无耳鸣的大鼠之间的 ABR 没有差异,所有暴露的大鼠的 ABR 幅度都减小[48]。总之,噪声暴露会导致 ABR 幅度减小。表 5 总结了观察到的变化。
Table 5. Changes in amplitude in rats after noise exposure.
表 5. 噪声暴露后大鼠幅度的变化。
Article
Noise
Details
Rats Wave I Wave II Wave III Wave IV Wave V Intervals Threshold
Bing et al.,
,
,
unilateral
female, Wis
Not
tested
Not
tested
Not
tested
Not
tested
at 8-50 kHz
Table 5. Cont. 表 5. 续表
Article
Noise
Details
Rats Wave I Wave II Wave III Wave IV Wave V Intervals Threshold
Singer et al.,
2013 [65]
,
SPL
for ,
binaural
female, Wis
Not
tested
at
Rüttiger et al.,
2013 [65]
1 or ,
binaural
female, Wis
Not
tested
at
Ouyang et al.,
2017 [48]
blast
exposure
(194 dB SPL),
unilateral
male, SD
Not
tested
Not
tested
Not
tested
Not
tested
Not
tested
-
reduced; increased; _ no changes; prolonged; reduced; Wis Wistar rats; SD Sprague-Dawley rats * Despite calculations of corF (which is done with the values of waves I-V), only the amplitudes of wave I and wave IV were provided [15].
减少; 增加; _ 无变化; 延长; 减少; Wis Wistar 大鼠; SD Sprague-Dawley 大鼠 * 尽管计算了 corF(使用波 I-V 的值进行计算),但只提供了波 I 和波 IV 的振幅 [15]。
Some common similarities determined in ABR amplitudes after salicylate and noise exposure are presented in Figure 4.
噪声暴露和水杨酸盐暴露后 ABR 振幅的一些常见相似性见图 4。

salicylate-induced tinnitus
水杨酸盐引起的耳鸣

determintion of tinnitus (behavioral test, prepuls-gap detection) noise-induced tinnitus
耳鸣的测定(行为测试,前脉-间隙检测)噪声引起的耳鸣
Figure 4. Schematic representation of the ABR profile's similarities and differences between the control rats and animals with tinnitus (created with BioRender.com). Of 36 publications included in this review, four publications regarding noise-induced tinnitus and six publications regarding salicylate-induced tinnitus qualified for the quantitative ABR analyses. The solid black line represents the ABR of the control animals. The dashed blue line represents the ABR of rats with salicylate-induced tinnitus . The red dashed line represents the ABR of rats with noise-induced tinnitus [15,65]. Only the changes consistently reported by two or more studies were taken into account. The changes in latencies are not presented due to inconsistencies between the studies.
图 4. 控制组大鼠和患有耳鸣动物的 ABR 曲线相似性和差异的示意图(使用 BioRender.com 创建)。在本综述中,包括 36 篇文献,其中 4 篇关于噪声引起的耳鸣,6 篇关于水杨酸盐引起的耳鸣,符合定量 ABR 分析的条件。实线黑线代表控制组动物的 ABR。虚线蓝线代表患有水杨酸盐引起的耳鸣的大鼠的 ABR 。红色虚线代表患有噪声引起的耳鸣的大鼠的 ABR [15,65]。只考虑两个或更多研究一致报告的变化。由于研究之间的不一致性,未呈现潜伏期的变化。

4. Discussion 4. 讨论

This review aimed to evaluate the auditory brainstem response changes occurring in rats' auditory systems after experimentally induced-tinnitus. Thirty-six studies published between January 2000 and August 2020 and dedicated to the rat model met the inclusion criteria. Based on the selected studies, we summarize the knowledge of audiometric changes occurring in tinnitus using ABR.
本研究旨在评估实验性耳鸣后大鼠听觉系统中出现的听觉脑干反应变化。符合纳入标准的研究共有 36 篇,发表于 2000 年 1 月至 2020 年 8 月之间,并专注于大鼠模型。根据所选研究,我们总结了使用 ABR 评估耳鸣中听力学变化的知识。
In the selected articles, the principal inducers of tinnitus (noise and salicylate) were used. Rats exposed to salicylate had changes in hearing thresholds and ABR waveforms in specific frequencies [49-51,53,59]. Despite considerable differences between the studies, two consistent parallels were identified. The first similar finding was a consistent reduction in wave I and increased wave IV (Figure 4). The reduction of the wave's I amplitude reflects changes in sensory input. Although there was no significant hair cell loss, a decrease in ribbon synapses was observed . In addition, abnormalities in both presynaptic elements and postsynaptic nerve fibers were observed [27]. Reduced sensory input could have lead to the enhanced auditory midbrain responses such as the increased amplitude of wave IV, reflecting changes in the inferior colliculus [65]. In contrast to the salicylate treatment, the noise has induced a reduction in the amplitude of wave IV [15]. The imbalance in excitation and inhibition occurring on the level of inferior colliculus might contribute to tinnitus development [92].
在选定的文章中,使用了引起耳鸣的主要诱因(噪音和水杨酸盐)。暴露于水杨酸盐的大鼠在特定频率上的听阈和ABR波形发生了变化[49-51,53,59]。尽管研究之间存在相当大的差异,但发现了两个一致的相似之处。第一个相似的发现是波I的一致减少和波IV的增加(图4)。波I幅度的减少反映了感觉输入的变化。虽然没有明显的毛细胞损失,但观察到了缺席突触的减少。此外,还观察到了前突触元件和后突触神经纤维的异常[27]。感觉输入的减少可能导致听觉中脑反应的增强,如波IV的振幅增加,反映了下丘脑的变化[65]。与水杨酸盐治疗相反,噪音引起了波IV振幅的减少[15]。下丘脑水平的兴奋和抑制失衡可能有助于耳鸣的发展[92]。
The relation between behavior consistent with tinnitus and the ABR changes was investigated using the female Sprague-Dawley rats exposed to salicylate day for three days, gavage administration) [28]. There was a correlation between tinnitus behavior and changes in ABR amplitude (waves II-V) and latency (waves II and III) [28]. Such association was observed only for specific frequencies , and ). Nevertheless, upon the return of amplitudes to the baseline level, tinnitus behavior disappeared. There was no association between the amplitude and latency of wave I and hearing thresholds [28]. Fang et al. observed that ABR amplitude was reduced when cochlear sensitivity improved (increased amplitude of the distortion product otoacoustic emissions-DPOAE) [58].
使用暴露于水杨酸盐(三天内,通过灌胃给予)的雌性斯普拉格-道利大鼠,研究了与耳鸣一致行为和ABR变化之间的关系[28]。耳鸣行为与ABR振幅(波II-V)和潜伏期(波II和III)的变化之间存在相关性[28]。这种关联仅在特定频率( )下观察到。然而,当振幅恢复到基线水平时,耳鸣行为消失。波I的振幅和潜伏期与听阈之间没有关联[28]。方等观察到,当耳蜗敏感性改善(失真产品耳声发射的振幅增加)时,ABR振幅减小[58]。
While salicylate evoked tinnitus in all rats, only half of them demonstrated tinnitus after noise exposure [14]. A higher hearing threshold and amplitude reduction were observed in rats subjected to acoustic trauma. After single noise exposure ( , bilateral) and two noise exposures (10 kHz, 118-120 dB peSPL, two hours; then five weeks later for three hours, unilateral), rats with tinnitus had higher hearing thresholds than tinnitus-free animals . This difference was not observed in rats exposed to for one hour [67]. The variance seems to be an effect of different noise parameters and various times of ABR assessment.
水杨酸盐在所有大鼠中引发耳鸣,但只有一半的大鼠在噪声暴露后表现出耳鸣[14]。暴露于声刺激的大鼠观察到更高的听阈和振幅降低。在单次噪声暴露( ,双侧)和两次噪声暴露(10 kHz,118-120 dB peSPL,两小时;然后五周后三小时,单侧)后,患有耳鸣的大鼠的听阈比无耳鸣的动物更高 。这种差异在暴露于 一小时的大鼠中没有观察到[67]。这种差异似乎是不同噪声参数和ABR评估时间的影响。
Some differences were also observed regarding the auditory inner hair cells (IHC) synaptic contacts in rats with and without tinnitus [15]. After noise exposure ( for 1 or , a greater reduction of ribbon synapses in basal and mid-basal turn was observed in rats with tinnitus [65]. No loss of ribbon synapses was seen in the cochlear apical turn after salicylate treatment or noise trauma . Cochlear deafferentation depends on the degree of inner hair cell synaptopathy. Two of the studies included in the present review confirmed the notion about the loss of IHCs ribbon synapses (deafferentation), leading to tinnitus when the ABR was reduced. Upon the restoration of ABR, tinnitus was no longer observed [65], indicating that the degree of IHC ribbon loss might be a crucial factor for the recovery of ABR after acoustic trauma and tinnitus generation [65].
在有和没有耳鸣的大鼠中,还观察到了听觉内毛细胞(IHC)突触接触方面的一些差异[15]。噪声暴露后( 1或 ),耳鸣大鼠的基底和中基底转弯处的缠绕突触减少更为明显[65]。在水杨酸盐治疗或噪声创伤后,耳蜗顶部转弯处没有观察到缠绕突触的损失 。耳蜗去突触化取决于内毛细胞突触病变的程度。本综述中包括的两项研究证实了当ABR减少时,内毛细胞缠绕突触(去突触化)的丧失会导致耳鸣。恢复ABR后,耳鸣不再出现[65],这表明内毛细胞缠绕突触丧失的程度可能是声刺激创伤和耳鸣产生后ABR恢复的关键因素[65]。
In one article, restraint was used during ABR measurement [53]. Restraint applied for four hours was previously shown to impact animals' hearing abilities by inducing stress and the hypothalamus-pituitary-adrenal (HPA) axis, thus increasing the systemic levels of corticosterone, which protected animals from the acoustic trauma [89]. Rats subjected to restraint demonstrated abnormalities in CAP and DPOAE. Interestingly, another type of stress-social stress-induced an increase in IHC ribbon synapses [65]. Furthermore, repeated injections might also be a source of anxiety for animals [93]. In the process of data evaluation, we compared hearing thresholds at baseline
在一篇文章中,ABR 测量过程中使用了约束[53]。之前的研究表明,施加四小时的约束会通过诱导应激和下丘脑-垂体-肾上腺(HPA)轴的作用,增加皮质酮的系统水平,从而保护动物免受声刺激损伤[89]。受到约束的大鼠表现出 CAP 和 DPOAE 的异常。有趣的是,另一种类型的应激-社交应激-会增加 IHC 带状突触[65]。此外,重复注射可能也是动物焦虑的原因之一[93]。在数据评估过程中,我们比较了基线时的听阈值

between mock-injected and non-injected animals and found that the injected rats had higher hearing thresholds by about 10-20 dB [61-64], which has so far not been reported.
与未注射动物进行了对比,发现注射的大鼠听阈值较高,约为 10-20 dB [61-64],这是迄今为止未报道的。
It has been suggested that tinnitus can internally mask the ABR [94]. Therefore, ABR with a forward masker is supposed to be an objective indicator of tinnitus and was used after salicylate treatment in female and male Wistar rats. The forward masker and the probe were presented to both ears. After the above stimulation, rats had a reduction in ABR amplitude and prolonged latencies (I-V). This was not observed in rats treated with salicylate [29,60]. Additional experiments with a larger sample size should be performed to address this exciting issue.
已经有人提出耳鸣可能会在内部掩盖 ABR [94]。因此,ABR 与前向屏蔽器被认为是耳鸣的客观指标,并在雌性和雄性 Wistar 大鼠的水杨酸盐治疗后使用。前向屏蔽器和探针都被呈现给两只耳朵。在上述刺激后,大鼠的 ABR 幅度减小,潜伏期延长(I-V)。这在接受水杨酸盐治疗的大鼠中没有观察到[29,60]。应进行更大样本量的额外实验来解决这个令人兴奋的问题。
The data extracted and analyzed in the present review suggest that a loss of cochlear inner hair cell ribbon synapses could contribute to the development of tinnitus reflected by reducing the amplitude of wave I, which was also observed in human studies [17]. Some studies suggest measuring abnormalities in wave V's latency to indicate cochlear synaptopathy in humans after noise exposure [95]. The term "cochlear synaptopathy" was proposed to describe damage at the cochlear synapse without any loss of hair cells, resulting in "hidden hearing loss" [96].
本次综述中提取和分析的数据表明,耳蜗内毛细胞带状突触的丧失可能会导致耳鸣的发展,表现为波 I 幅度降低,这也在人类研究中观察到[17]。一些研究表明,测量波 V 的潜伏期异常可以指示噪声暴露后人类的耳蜗突触病变[95]。术语“耳蜗突触病变”被提出来描述耳蜗突触的损伤,而没有任何毛细胞的丧失,导致“隐性听力损失”[96]。
The eardrum perforation is one of the most frequent injuries after blast exposure [91]. Despite the middle ear's known impact on ABR response, none of the articles dedicated to the blast injury provided information about the middle ear status after blast [46-48].
鼓膜穿孔是爆炸暴露后最常见的伤害之一[91]。尽管已知中耳对 ABR 反应有影响,但没有一篇关于爆炸伤害的文章提供了关于爆炸后中耳状况的信息[46-48]。
The factors that could affect ABR are summarized in Table 6. It is our recommendation to use this summary as a template for the experimental outlines.
影响 ABR 的因素总结如表 6 所示。我们建议将此摘要用作实验大纲的模板。
Several limitations were identified in the data collected. The first limitation was a lack of precise information about the experimental protocol during ABR measurements such as animals' body temperature or anesthesia. Both of these factors could influence the ABR recordings. Each decrement at of the body temperature may significantly alter ABR latencies and amplitudes [105,106]. What is more, rats anaesthetized with isoflurane have higher hearing thresholds in comparison to thresholds after an administration of ketamine + xylazine . One study reported a lack of amplitude differences after blast exposure between the rats anesthetized with isoflurane (4%) or ketamine. However, other researchers observed poorer ABR responses after isoflurane (dose not known) [48,70]. What is more, there are no studies on the impact of anesthesia on substance-induced tinnitus.
在收集的数据中发现了几个限制。第一个限制是在 ABR 测量期间实验方案的精确信息不足,例如动物的体温或麻醉情况。这两个因素都可能影响 ABR 记录。体温每下降一个单位可能会显著改变 ABR 潜伏期和振幅[105,106]。此外,用异氟醚麻醉的大鼠与使用氯胺酮+异丙酰苯胺麻醉后的听阈相比,听阈更高[b1]。一项研究报告称,在爆炸暴露后,异氟醚(4%)或氯胺酮麻醉的大鼠之间没有振幅差异。然而,其他研究人员观察到异氟醚(剂量未知)后 ABR 反应较差[48,70]。此外,还没有关于麻醉对物质诱发性耳鸣的影响的研究。
The second limitation was a variation in the frequencies tested by ABR. While the standard testing range includes to , some selected papers provide information only for single frequencies [97].
第二个限制是 ABR 测试中测试的频率变化。虽然标准测试范围包括[b0]到[b1],但一些选定的论文只提供单一频率的信息[97]。
The third pitfall is various techniques used for ABR recording, such as signal delivery. Acoustic stimuli were delivered directly to the ear or in the free field. These different conditions may also contribute to the differences in latencies and amplitudes reported.
第三个限制是 ABR 记录中使用的各种技术,例如信号传递。声学刺激直接传递到耳朵或自由场中。这些不同条件可能也导致了报告的潜伏期和幅度的差异。
The fourth limitation was a high sample size variation, which might have impacted the results (e.g., reduction, improvement vs. no changes in amplitude of wave II, III, and V) in rats following salicylate . Nevertheless, the sample size was not used as an exclusion criterion because of our review's character.
第四个限制是高样本大小的变异,这可能会影响结果(例如,在水杨酸盐引起的大鼠中,波 II、III 和 V 的幅度的减少、改善或无变化)。然而,由于我们的回顾性研究的性质,样本大小并未被用作排除标准。
The fifth limitation is not reporting whether the gender differences influenced rats' hearing abilities [29,60]. Older male rats (8-24 months old) had higher ABR thresholds and overall smaller amplitude than female rats. Despite the lack of ABR differences between young female and male rats, adult female rats had shorter latencies (I-IV) than the male rats . Various studies also demonstrated a link between hearing thresholds and the menstrual cycle [111,112], suggesting that the estrous cycle phase should be considered when using female rats.
第五个限制是没有报告性别差异是否影响大鼠的听力能力[29,60]。老年雄性大鼠(8-24 个月)的 ABR 阈值较高,整体幅度较小。尽管年轻雌性和雄性大鼠之间没有 ABR 差异,但成年雌性大鼠的潜伏期(I-IV)较短。各种研究还表明听阈与月经周期之间存在联系[111,112],这表明在使用雌性大鼠时应考虑发情周期阶段。
The sixth limitation is the variety of methods used to determine the presence of tinnitus in rats.
第六个限制是用于确定大鼠耳鸣存在的方法的多样性。
Table 6. Factors possibly influencing ABR response.
表 6. 可能影响 ABR 反应的因素。
Factor Influence on ABR
Suggestions Based on
ABR User Guide [97]
Additional
Recommendations
Experimental area
Cables, noise generators might
generate electrical noise
A sound
attenuating chamber
with a built-in
Faraday cage
Before starting
experiments, conduct a
saline test (to determine
the noise floor)
Speaker placement Affect the stimulus level
The speaker should be
on the same plane as the
tested ear and set at an
angle from the sides of
the enclosure
Place the speaker in a
distance of away
from the animal
Electrode placement Incorrect recording
Vertex (active); reference
(ipsilateral ear); ground
(contralateral ear or hind
hip or base of tail)
Write the lot number of
electrodes in the protocol
Electrode impedance
, lower artifacts suppression,
low quality of ABR recording
If the repetition rate increases,
latency increases, too With
increased stimulus rates (click,
to , aged Fischer 344 rats
demonstrated an increase in
latencies wave IV and V and
Repetition rate
overall amplitude reduction (I-V)
A similar result was observed
in young Sprague-Dawley rats in
response to click and
pure tones [100]
The rate minimizes
the effects of noise from
the cycle of
mains power
Increasing the repetition rate
shortens the recovery time, but it
also reduces ABR measurement
times and shortens the time of
anesthesia [87]
Hearing range tested
Standard Testing Range:
to
Type of stimulus Data not available
Click: , pure tone:
-
Number of averages
Impact on signal/noise ratio.
Rats with hearing loss require
more averages than rats with
normal hearing
512 averages
512 ensures a balance
between the signal
quality and
minimalization of the
time to complete testing
Polarity
Data not available
Rats following isoflurane ;
Alternating -
Anesthesia
administration have higher
hearing thresholds in comparison
to ketamine + xylazine
) [101,102] In addition,
isoflurane significantly impairs
DPOAEs, whereas a normal dose
of ketamine + xylazine
in Sprague-Dawley
rats does not
A mixture of ketamine
+ xylazine
(a weight-dependent
dosage)
Ketamine can be used to
keep the subject
anesthetized longer than
Monitor rats
under anesthesia
Tympanic membrane
evaluation
Properly functioning ossicular
chain conduction is a prerequisite
for ABR recording
Evaluate tympanic
membrane using
otoscope before the start
of the experiment
See picture in [104]
Body temperature of rats
Temperature decreasing by
or more degrees may significantly
alter ABR latencies and
amplitudes
Heating pads should be
used to maintain body
temperature or
control the temperature
in the experimental room
Monitor the body
temperature with a rectal
probe throughout the
recording
Table 6. Cont. 表 6. 续。
Factor Influence on ABR
Suggestions Based on
ABR User Guide [97]
Additional
Recommendations
Gender
There were no significant
gender-dependent differences in
amplitudes or latencies between
the ages of 14 and 70 days in
Sprague-Dawley rats [100]
However, adult female rats had
shorter latencies (I-IV) than male
rats [100,107]
-
In female rats weeks
old, the estrous cycle
should be
controlled [108]
Age
Immature auditory response of rat
pups [109]
Age-related effects on hearing
-
Write the age and the
body weight
in the protocol
Strain
The hearing range of laboratory
subjects varies across different
strains (95)
Day-night cycle
The sensitivity to noise varies at
different daytimes. Two weeks
after noise trauma (during the
night 9 PM) ABR thresholds were
elevated, whereas in mice exposed
to noise at 9 AM (6-12 kHz,
SPL for
-
Note the time of
experiments
Handling rats
Handling is a well-known source
of stress-induced variation in
animal studies [98]
-
Housing rats
Disruption in factors below evokes
stress reactions in rats, which
mediates hearing abilities in rats.
Factors:
Maintaining a stable temperature,
humidity, and light-dark cycle in
the facility, free access to water
and chow
-
Maintaining a stable
temperature and
humidity in the facility;
Standard chow and
water ad libitum;
acclimatization one week
before running the
experiment; providing
an enriched environment
The studies using ABR for the evaluation of experimentally induced tinnitus in the rat model demonstrated differences in hearing abilities after tinnitus induction. Observed changes depended on the drug dose, noise intensity, time point of audiometric measurement, and frequency used during ABR measurement. Differences in results were also observed even if the experiments were conducted by the same research group .
使用 ABR 评估实验性诱发大鼠耳鸣的研究表明,在诱发耳鸣后听力能力存在差异。观察到的变化取决于药物剂量、噪声强度、听力测量时间点以及 ABR 测量中使用的频率。即使是同一研究小组进行的实验,也观察到了结果的差异。
All the above limitations indicate a great need to create a universal protocol, at least for each research group, if not for all of them. Nevertheless, the most consistent finding across all studies was a general reduction of ABR amplitudes in the animals experiencing noise-induced tinnitus. In contrast, In rats with salicylate-induced tinnitus, the amplitude of wave I was also reduced, but the amplitude of wave IV increased.
所有上述限制表明,有必要创建一个通用的协议,至少对于每个研究小组,如果不是所有研究小组。然而,所有研究中最一致的发现是在经历噪声诱发耳鸣的动物中 ABR 幅度普遍降低。相反,在水杨酸盐诱发耳鸣的大鼠中,波 I 的幅度也降低,但波 IV 的幅度增加。
Clinical studies in tinnitus patients with normal hearing (frequency ) demonstrated reduced amplitude of wave I at high intensities (80-90 dB SPL). The amplitude of wave V was not affected compared to the control group [113]. Despite the reduction of wave I, a normal wave V, might be an effect of increased neural responsiveness in the central auditory system to compensate for the reduced activity of the auditory nerve [113]. No differences in the amplitude of wave V in tinnitus patients and an average hearing threshold were also described in the study of Kehrle et al. [114]. In contrast, Gu et al. observed a higher amplitude of wave V in patients with tinnitus [115]. The authors suggested that wave's higher amplitude is an artifact induced by a lower frequency filter cutoff [115]. To sum up, ABR amplitude changes were determined in patients with tinnitus and normal hearing thresholds (based on pure tone audiometry). Reduction in the amplitude of wave I likely indicates a cochlear synaptopathy, whereas the unchanged or elevated amplitude of wave V could reflect central regions' compensated responses [17].
正常听力的耳鸣患者(频率 )的临床研究表明,在高强度(80-90 dB SPL)下,波I的振幅减小。与对照组相比,波V的振幅没有受到影响[113]。尽管波I减小,但正常的波V可能是中枢听觉系统对听神经活动减少的补偿效应[113]。Kehrle等人的研究中也描述了耳鸣患者和平均听阈之间波V振幅的无差异[114]。相反,Gu等人观察到耳鸣患者的波V振幅较高[115]。作者认为,波的 较高振幅是由较低频率滤波器截止引起的伪迹[115]。总之,耳鸣患者和正常听阈(基于纯音听力学)的ABR振幅变化被确定。波I振幅的减小可能表明耳蜗突触病变,而波V振幅的不变或升高可能反映了中枢区域的补偿反应[17]。
Studies in patients with tinnitus and high-frequency hearing loss demonstrated greater amplitude of wave III than in the control group without tinnitus (threshold-, sex-, and age-matched) [116]. Interestingly, such differences were not observed in a previous study published by the same group. Nevertheless, the mean ABR amplitudes tended to be reduced [117].
患有耳鸣和高频听力损失的患者研究表明,波 III 的振幅比没有耳鸣的对照组(阈值、性别和年龄匹配)更大[116]。有趣的是,同一研究小组发表的先前研究中并未观察到这种差异。然而,平均 ABR 振幅倾向于降低[117]。
In 2017, a review dedicated to studying changes in the ABR of patients with tinnitus was published [17]. The results indicated a high level of heterogeneity between the clinical studies. This heterogeneity was attributed to different etiologies of tinnitus, gender, age, and various protocols used for ABR recording. Similar diverseness was observed in our review. Interestingly, similar to ABR's study in individuals with tinnitus, animal studies' most consistent finding was a reduced amplitude of wave I. Despite the similar methods for tinnitus induction in animal studies, there is still a considerable heterogeneity of results suggesting a possible intrinsic heterogeneity of tinnitus and the importance of using a standardized universal protocol to perform the experiments.
2017 年,发表了一篇专门研究耳鸣患者 ABR 变化的综述文章[17]。结果显示临床研究之间存在较高的异质性。这种异质性归因于耳鸣的不同病因、性别、年龄以及用于 ABR 记录的各种协议。我们的综述中也观察到类似的多样性。有趣的是,与耳鸣患者的 ABR 研究类似,动物研究中最一致的发现是波 I 的振幅降低。尽管动物研究中使用了类似的耳鸣诱导方法,但结果仍然存在相当大的异质性,这表明耳鸣可能存在内在的异质性,并且使用标准化的通用协议进行实验非常重要。

5. Future Directions 5. 未来的方向

For future studies, we acknowledge using the rat model as offering three significant advantages: (i) the presence of similarities in the phantom character of tinnitus between rats and humans; (ii) the ability to perform the audiometric measurements before and after tinnitus onset; and (iii) the possibility to control and modify experimental factors influencing tinnitus. However, in future investigations, sufficient details regarding the tinnitus induction and ABR protocols (factors listed in Table 6) should ensure the data reproducibility and facilitate future work.
对于未来的研究,我们承认使用大鼠模型具有三个重要优势:(i)大鼠和人类之间的耳鸣幻像特征的相似性;(ii)在耳鸣发生前后进行听力测量的能力;以及(iii)控制和修改影响耳鸣的实验因素的可能性。然而,在未来的研究中,关于耳鸣诱导和 ABR 协议(表 6 中列出的因素)的充分细节应确保数据的可重复性并促进未来的工作。

6. Conclusions 6. 结论

The publications included in the present review provided audiometric characteristics of hearing loss and contributed to a better understanding of tinnitus in the rat model. In animals with salicylate-induced tinnitus, ABR waves had a shorter latency as in the control animals, reduced amplitude of wave I, and increased amplitude of wave IV. In contrast, in animals with noise-induced tinnitus, all ABR waves had reduced amplitudes, implicating that salicylate and noise induce different changes in the auditory brainstem which still result in the tinnitus percept. Contrasting changes in the amplitude of wave IV could reflect fluctuations in the auditory processing that are not related to tinnitus but might be associated with the cause of tinnitus. The overall evidence collected in the present work urges to establish a universal protocol for electrophysiological recording and animal handling in future animal studies on tinnitus.
本次综述中包含的出版物提供了听力损失的听觉特征,并有助于更好地理解大鼠模型中的耳鸣。在水杨酸盐诱导的耳鸣动物中,ABR 波的潜伏期较控制动物短,波 I 的振幅减小,波 IV 的振幅增加。相比之下,噪声诱导的耳鸣动物中,所有 ABR 波的振幅都减小,这意味着水杨酸盐和噪声在听觉脑干中引起了不同的变化,但仍导致耳鸣感知。波 IV 振幅的对比变化可能反映了与耳鸣无关的听觉处理波动,但可能与耳鸣的原因有关。本研究收集的整体证据迫使我们在未来的动物耳鸣研究中建立一个通用的电生理记录和动物处理方案。
Supplementary Materials: The following are available online at http://www.mdpi.com/2076-3425/10/12/901/s1, Table S1: Extracted data regarding tinnitus characteristics and tinnitus-relevant changes in ABR, Table S2: Extracted data regarding ABR setups.
补充材料:在线提供以下内容:http://www.mdpi.com/2076-3425/10/12/901/s1,表 S1:关于耳鸣特征和与耳鸣相关的 ABR 变化的提取数据,表 S2:关于 ABR 设置的提取数据。
Author Contributions: Conceptualization, E.D. and A.J.S.; methodology, E.D. and A.J.S.; validation, E.D. and A.J.S.; formal analysis, E.D. and A.J.S.; investigation, E.D.; resources, A.J.S.; data curation, E.D. and A.J.S.; writing—original draft preparation E.D.; writing—review and editing, E.D., H.O. and A.J.S.; visualization, E.D. and A.J.S.; supervision, H.O. and A.J.S.; project administration, A.J.S.; funding acquisition, A.J.S. All authors have read and agreed to the published version of the manuscript.
作者贡献:概念化,E.D. 和 A.J.S.;方法论,E.D. 和 A.J.S.;验证,E.D. 和 A.J.S.;形式分析,E.D. 和 A.J.S.;调查,E.D.;资源,A.J.S.;数据整理,E.D. 和 A.J.S.;原始草稿撰写,E.D.;审查和编辑,E.D.,H.O. 和 A.J.S.;可视化,E.D. 和 A.J.S.;监督,H.O. 和 A.J.S.;项目管理,A.J.S.;资金获取,A.J.S. 所有作者已阅读并同意发表版本的手稿。
Funding: This research was funded by European Commission Action HORIZON 2020, TIN-ACT (Research School for TINnitus Assessment, Causes and Treatments) grant number 764604/ESR11.
资金支持:本研究由欧洲委员会行动 HORIZON 2020 资助,TIN-ACT(TINnitus 评估、原因和治疗研究学校)资助号 764604/ESR11。
Conflicts of Interest: The authors declare no conflict of interest.
利益冲突:作者声明无利益冲突。

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