Investigating the neural basis for checking, selective attention and working memory in obsessive compulsive disorder, through MEG and TMS

我们似乎都认识一些人，他们倾向于反复检查门是否锁上了，烤箱是否关了，闹钟是否设置了等等。彻底的检查甚至可以被视为尽职尽责的一部分，我们接受这样一个事实，即有些人“稍微做得过头了”，然而，在极端情况下，这种检查可能会以强迫性检查的形式出现，在临床上被诊断为强迫症（OCD）的一部分。尽管文献中一致报道了检查的不适应性质和典型人群中亚临床强迫检查倾向的高比率（约15%），但迄今为止，所涉及的认知和大脑系统尚未得到彻底的调查。我们最近的研究让我们相信，有强迫性检查倾向的人抑制外部干扰的能力较差，这些干扰被认为是有威胁的，而控制内部干扰和引起进一步恐惧的想法的效率也较低，因此，促进了焦虑和缺乏控制的恶性循环。这种感知威胁和控制缺陷的循环会影响个人短期记忆的内容。我们进一步提出，控制和抑制分心的缺陷可能是其他临床综合征的类似神经病理形式的基础，而强迫症中记忆功能控制缺陷的强烈衰弱影响和观察到的连锁效应强调了这种综合征是研究的最佳起点。采用一种专注于强迫性检查的症状特异性方法，将进一步有助于澄清迄今为止与强迫症表型异质性相关的强迫症患者不一致的结果。因此，通过我们完善的实验范例，本项目的主要目标将是通过比较临床强迫症检查者、亚临床高检查者和非检查者，来表征注意力和短期记忆任务中缺乏抑制和控制的神经特征。其他人和我们团队的大量研究表明，脑电波(即：“节奏”或“振荡”)是理解大规模大脑网络内的交流是如何建立的关键。为此，我们将采用尖端的神经成像技术，以脑磁图（MEG）和经颅磁刺激（TMS）的形式与脑电图（EEG）共同记录。除了详细描述我们的特定范例和患者群体（OCD）之外的缺乏抑制和控制的振荡生物标志物外，我们将使用频率调谐TMS的新应用来模拟大脑振荡，目的有以下两个。首先，通过控制大脑振荡，频率调谐的TMS-EEG将允许我们测试哪些振荡特征在行为中起因果作用，提供控制缺陷和增加强迫症风险的生物标志物以及新的候选内表型。其次，如果经颅磁刺激诱发的振荡直接改善了高检查器的性能，那么将实现未来治疗应用的概念验证。

We all seem to know someone who tends to check repeatedly whether the door is locked, the oven is off, the alarm is set, etc. Thorough checking may even be regarded as part of being conscientious and we accept the fact that some people 'slightly overdo it', which, however, in the extreme can take on the form of compulsive checking, clinically diagnosed as part of Obsessive Compulsive Disorder (OCD). Despite consistent reporting in the literature of the maladaptive nature of checking and the high rate of subclinical compulsive checking tendencies in the typical population (~15%), the involved cognitive and brain systems have not been thoroughly investigated so far. Our recent research led us to believe that individuals with compulsive checking tendencies are less able to suppress external distractions that are perceived as threatening and are less efficient at controlling internal thoughts that are distracting and evoke further fear, thus, promoting a vicious circle of anxiety and deficient control. Such a circle of perceived threat and control deficits affects the contents of the individual's short-term memory. We further suggest that deficits in the control and suppression of distractions might underlie in a similar neuropathological form other clinical syndromes, while the strongly debilitating influences and the observed knock-on effects of deficient control on memory functions in OCD emphasise this syndrome as an optimal starting point for research. Adopting a symptom-specific approach focused on compulsive checking will further help clarifying the inconsistent results with OCD patients so far that have been related to the heterogeneity in OCD phenotypes. By means of our well-developed experimental paradigms the primary goal of this project will therefore be to characterise the neural signatures of deficient suppression and control in attention and short-term memory tasks by comparing clinical OCD checkers to subclinical high checkers and to non-checkers. A substantial body of research by others and by our team suggests that brain waves (i.e. "rhythms" or "oscillations") are key to understanding how communication within large-scale brain networks is established. To this end, we will employ cutting-edge neuroimaging in form of Magnetoencephalography (MEG) and transcranial magnetic stimulation (TMS) with Electroencephalography (EEG) co-recordings. Besides characterising in detail the oscillatory biomarkers of deficient suppression and control beyond our particular paradigms and patient group (OCD) we will use the emerging new application of frequency-tuned TMS to mimic brain oscillations with the following two aims. First, by controlled entrainment of brain oscillations, frequency-tuned TMS-EEG will allow us to test which oscillatory signatures play a causal role in behaviour, providing biomarkers of control deficits and increased risk of OCD as well as new candidate endophenotypes. Second, if TMS-induced oscillations directly improve performance in high checkers then a proof of concept will be achieved for future therapeutic applications.