Identification of functional biomarkers for tinnitus and hyperacusis in animals and humans

慢性耳鸣(幻影噪音)和慢性听力亢进(基于响度的声音耐受性降低)影响了10%-20%的人口。根据公认的年龄、压力和噪音对这两个实体的负面影响，预计人群中的患病率将会上升。对于耳鸣和听觉过敏，目前还没有治愈的方法。耳鸣和听力亢进并不意味着对声音的敏感度高于正常阈值，这两种疾病的神经相关性都是未知或有争议的。这很难解释为什么这两个实体经常与恐惧相关的疾病或精神障碍等共病共存。到目前为止，几乎所有的耳鸣文献都认为，感觉剥夺通过增加中枢神经获得来传递耳鸣的感知，从而增加自发放电率。相反，基于动物研究，我们观察到耳鸣更多地与未能增加中枢神经增益有关，而与信噪比降低和噪声水平升高有关。此外，我们还可以首先建立一种基于中枢听觉反应的动物模型，该模型的神经中枢反应可以与患有行为耳鸣的动物区分开来。使用这些动物模型，我们可以在初步研究中使用r-FC-BOLD-MRI验证皮质区域功能连接性的成功使用。令我们惊讶的是，在我们团队中进行的第一项人类试点研究可以证实我们在动物研究中的观察结果，显示耳鸣患者的中枢听觉反应降低而不是增强。因此，结合ABR波的精细结构分析、诱发的BOLD fMRI和r-fcMRI，可以发现耳鸣患者的听觉特异流减少。在压力和注意力调节区域观察到的大胆fMRI反应的变化，其他人在之前的研究中也观察到了这些变化，似乎与观察到的听觉特异性反应减少有关。我们假设，到目前为止，耳鸣中听觉特异性信息流的减少在人类身上没有被发现，因为低水平的听觉脑区以前在神经成像研究中被省略了。基于这一信息，本研究旨在利用已建立的程序，在动物模型和人类患者中识别和区分耳鸣和听觉过敏的神经相关性。这些研究将在患有耳鸣和听力亢进的动物和人类中使用听力测量、ABR精细结构分析、BOLD功能磁共振和体液分析。这项研究将由神经科、耳鼻喉科临床和研究单位的专家团队进行。在主申请人的协调下，这个团队已经批准了一次成功的合作。这些结果是未来任何耳鸣和听觉过敏治疗干预策略的基础，也是建立客观诊断工具以验证治疗成功的关键。

Chronic tinnitus (phantom noise) and chronic hyperacusis (decreased tolerance of sound based on loudness) effects 10-20% of the population. Based on acknowledged negative influences of age, stress and noise on probably both entities, the prevalence within the population is expected to increase. For both, tinnitus and hyperacusis, currently no cure exists. Tinnitus and hyperacusis do not imply a higher than normal threshold sensitivity to sound and for both pathologies the neural correlate is unknown or controversial. It is elusive of why probably both entities often co-occur with comorbidities as fear-associated diseases or psychiatric disorders. Almost all tinnitus literature up to now argue for increased spontaneous firing rates following sensory deprivation that convey to the percept of tinnitus through increased central neural gain. In contrast, based on animal studies, we observed that tinnitus is rather associated with a failure to increase central neural gain linked to reduced signal to noise ratio and elevated noise levels. We moreover could establish first a hyperacusis animal model, that based on central auditory responses can be distinguished in its neural central responses from animals with behavioural tinnitus. Using these animal models we could verify in preliminary studies a successful use of functional connectivities in cortical regions using r-fc-BOLD-MRI. To our surprise, first human pilot studies performed in our group, could confirm our observations in animal studies, showing reduced, rather than enhanced, central auditory responsiveness in tinnitus patients. Accordingly, a combination of fine-structure analysis of ABR wave, evoked BOLD fMRI and r-fcMRI pointed to reduced auditory-specific flow in tinnitus patients. Observed changes in BOLD fMRI responses in stress- and attentional-regulating regions, that were also observed by others in previous studies, appeared to be linked to the observed reduced auditory-specific responses. We hypothesize that reduced auditory-specific information flow in tinnitus has until now escaped detection in humans, as low-level auditory brain regions were previously omitted from neuroimaging studies. Based on this previous information the current study aims to use the established procedures to identify and distinguish the neural correlate of tinnitus and hyperacusis in animal models and human patients. The studies will use audiometry, fine-structure analysis of ABR, BOLD fMRI and body fluid analysis in animals and humans with tinnitus and hyperacusis. The study will be performed by a team of specialist in the department of neurology, the ENT clinic and research unit. Coordinated by the primary applicant, this team has already approved a successful cooperation. The results are fundamental for any future tinnitus and hyperacusis therapeutic intervention strategy and are essential for the establishment of objective diagnostic tools to validate therapeutic success.