Retinal ganglion cell function as objective biomarker for subgroups of depressive disorders

缺乏有效的生物标志物是精神病诊断的一个重大挑战。对于抑郁症，我们已经开发了一种新的，客观的方法：模式视网膜电图（PERG），一种在眼科建立的视网膜神经节细胞功能的非侵入性测量，在抑郁症患者中减少了约50%。假设的机制是神经递质稳态的破坏，涉及调节视觉处理的多巴胺能系统。该项目旨在建立必要的先决条件，成功地将神经节细胞评估纳入抑郁症的日常诊断。一些主要的障碍是方法上的：技术上要求严格的PERG需要适当的眼睛屈光，这在日常的精神病学常规中无法保证。使用闪光诱发的明视负反应（PhNR），另一种与神经节细胞功能相关的方法，类似于PERG，可以解决这个问题，因为它不依赖于良好的光学。另一个障碍与角膜电极的使用有关，这是一些患者不能容忍的。最近的技术创新允许使用具有前所未有的信噪比的皮肤电极记录响应于闪光刺激（包括PhNR）的ERG信号。这些电极被放置在眼睛下方的面部皮肤上。此外，合适的商业设备可以促进眼科以外的应用。该项目的一个临床重点是鉴别诊断。现在的共识是，相当不同的病理生理机制可能是一个单一的主要精神障碍的基础，如ICD-10中的集群。考虑到这一点，我们将评估我们的方法来区分抑郁谱系障碍，区分情感障碍的不同亚型，并将其与自闭症谱系障碍和注意缺陷多动障碍区分开来的能力。使用闪光视网膜电图，可以评估其他视网膜细胞类型的功能参数。通过更详细地跟踪视网膜信号传递级联中细胞反应的调制，我们将能够测试我们关于潜在病理生理学的假设。这些目标将通过检查患有不同亚型情感障碍的广泛患者来实现，其中（1）将比较PhNR和PERG的诊断潜力，（2）将测试不同类型的电极，和（3）将评估与神经节细胞功能无关的ERG参数，以（a）阐明病理生理机制和（B）确定其鉴别诊断潜力。有关团体的合作结合了全面的方法能力和内容方面的独特专长。

The lack of valid biomarkers is a substantial challenge in psychiatric diagnosis. For depressive disorders we have developed a novel, objective approach: The pattern electroretinogram (PERG), a non-invasive measure of the retinal ganglion cell function established in ophthalmology, is reduced by around 50% in patients with depression. The assumed mechanism is a disruption of neurotransmitter homeostasis, involving the dopaminergic system, which modulates visual processing. The project aims at establishing the necessary prerequisites for the successful integration of ganglion cell assessment in daily routine diagnostics of depressive disorders. Some of the main hurdles are of methodological nature: The technically demanding PERG requires proper refraction of the eye, which cannot be guaranteed in daily psychiatric routine. Using the flash-evoked photopic negative response (PhNR), another correlate of ganglion cell function, similar to the PERG, could resolve this problem as it does not rely on good optics. Another obstacle is associated with the use of cornea electrodes, which are not tolerated by some patients. Recent technical innovations allow for recording of ERG signals in response to flash stimuli, including the PhNR, using skin electrodes with an unprecedented signal-to-noise ratio. These electrodes are placed on the facial skin below the eye. Furthermore, suitable commercial devices can facilitate the application outside ophthalmology. One clinical focus of the project concerns differential diagnostics. It is now consensus that rather diverse pathophysiological mechanisms may underlie a single major mental disorder as clustered in ICD-10. Accounting for this, we will assess the capacity of our approach to differentiate among disorders of the depressive spectrum, to distinguish between the different subtypes of affective disorders, and to separate these from autism-spectrum and attention deficit hyperactivity disorders.The project furthermore aims at identifying and elucidating pathophysiological interrelations. Using the flash electroretinogram, functional parameters of other retinal cell types can be assessed. By tracking the modulations of cell responses within the retinal signal transmission cascade in more detail, we will be able to test our hypotheses as to the underlying pathophysiology. These objectives will be accomplished by examining a broad range of patients with different sub-types of affective disorders, in which (1) PhNR and PERG will be compared with respect to their diagnostic potential, (2) different types of electrodes will be tested, and (3) ERG parameters unrelated to ganglion cell function will be assessed to (a) shed light on pathophysiological mechanisms and (b) identify their differential diagnostic potential. The cooperation of the groups involved combines comprehensive methodological competence with distinct expertise in content.