第一部分：慢性主观性耳鸣患者的临床特征分析

第一节：成人慢性主观性耳鸣出现失代偿的危险因素分析

目的：本部分研究旨在探讨成人慢性主观性耳鸣发生失代偿的危险因素，及不同影响因素间的相互作用。

方法：回顾性研究了2019年9月至2020年11月在国内5家临床研究中心就诊的慢性主观性耳鸣患者的临床资料，采集包括人口学特征、听力学和耳鸣检测结果的信息，使用耳鸣残障量表（tinnitus handicap inventory，THI）、医院焦虑抑郁量表（hospital anxiety depression scale，HADS)、匹兹堡睡眠质量指数（Pittsburgh sleep quality index, PSQI）、耳鸣响度和烦恼程度视觉模拟评分量表（visual analogue scale，VAS）来评估患者耳鸣的严重程度、睡眠和心理状况。以THI≥58分代表失代偿性耳鸣。

结果：共纳入338名患者，其中男性占53.3%，女性占46.7%。失代偿组患者共有99（29.3%）名，代偿组患者239（70.7%）名。失代偿性耳鸣组与代偿性耳鸣组患者相比，平均年龄更大，耳鸣相关性睡眠障碍发生率更高，平均听阈、耳鸣响度和最小掩蔽级更高，THI、PSQI、HADS、VAS_耳鸣响度和VAS_耳鸣烦恼评分更高（p＜0.05）。二元logistic回归分析结果示睡眠问题和焦虑是耳鸣发生失代偿的危险因素。进一步研究发现睡眠问题和焦虑在失代偿性耳鸣患者中具有相加交互作用（RERI=10.96，S=18.22，AP=0.87）。

结论：焦虑和睡眠障碍是耳鸣出现失代偿的危险因素。睡眠问题和焦虑对耳鸣产生的叠加作用比两者单独存在时产生的作用更大。

第二节：影响慢性主观性耳鸣严重程度的关键因素分析：基于复杂网络分析的研究

目的：通过构建复杂网络探讨影响慢性主观性耳鸣严重程度的关键因素，并分析不同影响因素之间的相关性。

方法：研究人群及采集资料同第一节。将人口学特征、听力学特点（平均听阈、听力曲线分型）及耳鸣相关检查（频率、响度、最小掩蔽级及残余抑制实验）、THI量表、HADS量表、PSQI量表、VAS_耳鸣响度和VAS_耳鸣烦恼得分作为节点，利用R语言构建无向加权网络探讨以上节点与THI得分的相关性。

结果：复杂网络分析结果提示THI得分与焦虑、睡眠障碍密切相关，焦虑较睡眠障碍与THI的关系更紧密；患者自觉耳鸣相关性焦虑与耳鸣相关性睡眠障碍之间有较强的关联。人口学特征、听力学及耳鸣相关检查与THI得分无明显相关性。

结论：焦虑和睡眠障碍彼此之间存在密切关系，且二者是影响耳鸣严重程度的关键因素。耳鸣的严重程度与人口学特征、听力学及耳鸣相关检查结果的相关性较弱。未来对于慢性主观性耳鸣的治疗，应更加关注对焦虑及睡眠状况的改善上。

第二部分：多个混合纯音、高斯白噪声与安慰剂对慢性主观性耳鸣的疗效分析：一项多中心、单盲、随机对照研究

目的：比较多个混合纯音（mixed pure tones with broadband noise, MPT+BBN）、高斯白噪声（broadband noise, BBN）与安慰剂对慢性主观耳鸣的疗效差异。

方法：本研究为一项多中心、单盲、随机、对照研究，在国内5家临床研究中心进行。符合入组标准的患者随机进入多个混合纯音、高斯白噪声与安慰剂三组，治疗3个月后进行随访。治疗前后患者分别进行听力学及耳鸣相关检查，填写心理声学量表。以THI量表得分作为主要评价标准。本研究对患者设盲。

结果：共105名患者入组，4名患者退出实验。经过治疗后，MPT+BBN组患者的耳鸣响度较BBN组和安慰剂组明显下降（p＜0.05）。MPT+BBN组患者的平均THI总分及子量表得分均较治疗前明显下降（p＜0.01），而BBN组和安慰剂组在治疗前后THI量表得分变化不明显。经过治疗后MPT+BBN组患者的THI得分下降程度明显高于BBN组和安慰剂组（p＜0.05），后两组间无明显差异（p＞0.05）。MPT+BBN组患者睡眠潜伏期、睡眠障碍及日间功能得分较治疗前下降（p＜0.05）。

结论：MPT+BBN可以降低耳鸣响度，同时改善耳鸣对患者产生的不良影响，而BBN与安慰剂的治疗效果不明显。声治疗的效果优于安慰剂，且基于耳鸣频率的定制音频效果优于非定制音频。

第三部分：影响多个混合纯音对慢性主观性耳鸣疗效的相关因素的初步分析

目的：初步探讨多个混合纯音（mixed pure tones with broadband noise, MPT+BBN）对慢性主观性耳鸣疗效的可能影响因素。

方法：回顾性研究了于2019年12月至2021年1月就诊于北京协和医院耳鼻喉科并接受“MPT+BBN声治疗”3个月的患者的临床资料，采集其人口学信息、听力学及耳鸣检查结果，通过THI量表、HADS量表、VAS_耳鸣响度和VAS_耳鸣烦恼评估耳鸣心理声学特征。以THI得分下降≥20分作为治疗有效的标准；设THI得分≥58分为失代偿性耳鸣。

结果：共65名患者符合入组条件，其中治疗有效者18（27.7%）名，无效者47（72.3%）名。两组患者在性别、焦虑、抑郁、耳鸣频率分布及THI得分上存在差异（p＜0.05），而在年龄、病程、伴随疾病、言语频率平均听阈、耳鸣侧别、VAS_耳鸣响度和VAS_耳鸣烦恼上，没有明显差异（p＞0.05）。二元logistic回归分析结果示相比较于高频耳鸣，低中频耳鸣患者经过MPT+BBN治疗后有效率是高频耳鸣的6.45倍（OR=6.45, 95% CI: 1.34～31.18, p=0.020）。失代偿性耳鸣的有效率是代偿性耳鸣的25.65倍（OR=25.65, 95% CI:5.25～125.34, p＜0.001）。

结论：耳鸣频率分布、耳鸣严重程度是影响多个混合纯音声治疗对慢性主观性耳鸣疗效的主要影响因素，低中频耳鸣、失代偿性耳鸣的治疗效果更好。

Part 1: Clinical characteristics of patients with chronic subjective tinnitus

Section 1: Analysis of the risk factors of decompensated tinnitus

Objective: This study was designed to investigate the risk factors of decompensated tinnitus and explore the interaction effect of these risk factors.

Methods: We retrospectively analyzed patients with chronic subjective tinnitus who presented to 5 different hospitals in China from September 2019 to November 2020. Demographic characteristics were recorded, and pure tone audiometry and tinnitus-related tests were conducted. Tinnitus severity, sleep, and mental health were assessed by administering the tinnitus handicap inventory (THI), Pittsburgh sleep quality index (PSQI), hospital anxiety and depression scale (HADS), and visual analogue scale (VAS) of tinnitus loudness and annoyance.

Results: A total of 338 patients were included (53.3% male, 46.7% females). Ninety-nine (29.3%) patients were in the decompensated group. Compared with the compensated tinnitus group, participants with decompensated tinnitus were older and more likely to have comorbidities and disturbed sleep due to tinnitus (p＜0.05). They had higher hearing thresholds, tinnitus loudness and minimum masking levels, and scored higher in THI, PSQI, HADS, VAS _loudness and VAS _annoyance (p＜0.05). Poor sleep and anxiety were possible risk factors of decompensated tinnitus by a binary logistic analysis. Sleep disturbances and anxiety had an additive interaction that accounted for 87% of the decompensated tinnitus cases in our study (RERI=10.96, S=18.22, AP=0.87).

Conclusion: Anxiety and sleep disturbances were possible risk factors of decompensated tinnitus. The combination of poor sleep and anxiety exerted a greater impact on tinnitus severity than either of them individually.

Section 2: Key factors of tinnitus severity: a complex network analysis

Objective: To explore the key factors related to the severity of chronic subjective tinnitus and investigate the relationship between these factors.

Methods: The same group of patients in the Section 1 were enrolled in this study. Demographic information, audiometric and tinnitus-related tests, scores of THI, HADS, PSQI, VAS _loudness and VAS _annoyance were set as nodes to construct a complex network by R statistical language.

Results: The results showed that anxiety and sleep disorder were closely related to THI score, and anxiety was more important. There was a strong correlation between self-reported anxiety and self-reported sleep problem. Demographic characteristics, audiologic and tinnitus-associated tests were not significantly related to THI score.

Conclusion: Anxiety and sleep disturbances were possible key factors related to tinnitus severity, and anxiety played a more important role, in line with the results of the first section. There was a certain correlation between sleep disorders and anxiety, and they might have a superimposed effect on tinnitus severity. Future therapies of tinnitus should pay more attention to releasing anxiety and insomnia.

Part 2: Comparison of the efficacy of mixed pure tones with broadband noise, broadband noise and placebo on chronic subjective tinnitus: a multicenter, single-blind, randomized controlled trial

Objective: To analyze the efficacy of mixed pure tones with broadband noise (MPT+BBN), broadband noise (BBN) and placebo on chronic subjective tinnitus.

Methods: This study was a multicenter, three-arm, single-blind, randomized controlled trial, which was conducted in 5 clinical research centers. Eligible study participants were randomized to MPT+BBN, BBN and placebo group for a 3-month treatment. Participants were instructed to undertake audiologic examinations, tinnitus-related tests and fill the psychological questionnaires (THI、HADS、VAS _loudness and VAS _annoyance) before and after treatment. The THI score was used as the primary evaluation criterion. Patients were blinded in this study.

Results: A total of 105 patients were enrolled and 4 withdrew from the trial. The tinnitus loudness in MPT+BBN group decreased more significantly after treatments than those in BBN group and placebo group (p＜0.05). The average scores of THI total and subscales in MPT+BBN group decreased after treatment (p<0.001), but there were no obvious changes in the other two groups. After treatments, the changes of THI scores decline much greater than the other groups (p＜0.05). The scores of sleep latency, sleep disturbance and daytime function in MPT+BBN group declined after treatment (p＜0.05).

Conclusion: Sound therapy played more positive roll than placebo in tinnitus. The efficacy of customized acoustic therapy was superior to non-customized sound therapy in the treatment of chronic subjective tinnitus.

Part 3. Affecting factors of mixed pure tones with broadband noise on chronic subjective tinnitus: a preliminary study

Objective: To analyze the affecting factors of mixed pure tones with broadband noise (MPT+BBN) on chronic subjective tinnitus.

Methods: We retrospectively analyzed patients with subjective chronic tinnitus who undertook MPT+BBN treatment for 3 months in Peking Union Medical College Hospital. Demographic information, audiologic and tinnitus-related tests were collected. All the patients filled the psychological questionnaires before and after treatment. The THI total score decreased more than 20 points was considered effective.

Results: A total of 65 patients were enrolled. 18 (27.7%) patients were in the effective group and 47 (72.3%) were in the non-effective group. More female patients (44.7%) and low-medium frequency tinnitus (50%) were in the effective group. Patients in effective group scored much higher in THI of pre-treatment than patients in non-effective group. The results of the binary logistic analysis showed that tinnitus pitch (OR=6.45, 95% CI: 1.34～31.18, p=0.020) and THI score of pre-treatment (OR=25.65, 95% CI:5.25～125.34, p＜0.001) were significantly related to therapeutic effectiveness.

Conclusion: The tinnitus pitch and the severity of tinnitus before treatment were the main factors affecting the curative effects of MPT+BBN on chronic subjective tinnitus. Patients with low-medium frequency and decompensated tinnitus may have better curative effects after 3-month MPT+BBN than others.