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

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.

Compulsive checking, the most common symptom in OCD [6, 7] and present in about 15% of the typical population [7], will be targeted in a symptom-specific approach to candidate risk markers and endophenotypes of OCD that avoids inconsistencies due to phenotype heterogeneity [12]. By means of novel experimental paradigms, Magnetoencephalography (MEG) and frequency-tuned transcranial magnetic stimulation (TMS) we will provide unprecedented insights into the cortical networks involved in working memory and executive control and their dynamic interplay in compulsive checking as measured by means of phase- and amplitude relations within and across brain areas and frequencies. Substantial research by others and by our team suggests that neural oscillations are the key for understanding processing within- and between brain areas: A change in amplitude or phase of a single oscillation reflects a change in local neural processing, while amplitude and/or phase correlations (e.g. synchronisation) between two distant oscillations reflect the functional connectivity between two neural populations. Therefore, time-frequency components observed at the MEG sensors will be localized with Dynamic Imaging of Coherent Sources (DICS), developed by J Gross. DICS localises coherent sources in relation to a reference area, thus, identifying task-specific phase coupling between distant cortical areas. Significant oscillatory effects will then be correlated to behaviour and checking score, and will be targeted with frequency-tuned TMS, which is an emerging new technique developed by G Thut that mimics brain oscillations by means of short trains of magnetic pulses. This allows us to test the relevance of an oscillatory signature for overt behaviour in an unprecedented way. The main aim of the project will be to identify biomarkers for executive deficits in patients and people at risk and to provide a proof-of-concept for a therapeutic application of frequency-tuned TMS.

The phenotypic heterogeneity of OCD has complicated the genotype-phenotype relationship in OCD as it has in a variety of disorders with high heritability but little as yet in the way of clear genotypic identity. Thus the search for measurable disorder-associated markers has been actively pursued, yet, results have been mixed so far. Heterogeneous findings of behavioural and imaging research in OCD most probably reflect heterogeneous populations, and it has been suggested that focussing on symptom dimensions (as opposed to OCD itself) may be a better way of understanding the disorder [12]. Thus our research will focus on compulsive checking and the associated neurocognitive deficits in executive control and episodic memory from a functional brain network perspective.

Specifically, we will employ our novel selective attention (SA) and working memory (WM) tasks with ecologically valid stimuli (our refs [7]) to tap into compulsive checking symptomatology and observe deficient signatures at the functional network level. Using cutting-edge technology (MEG) we will investigate neural oscillations (i.e. brain rhythms) as the basis for functional connectivity to characterise deficient neural coupling in OCD as processing unfolds within the brain networks for executive control and working memory. Deficient oscillatory signatures will then be targeted by using the emerging new application of frequency-tuned TMS (our refs [15]; see TMS box). This method will allow us to "mimic" brain oscillations by applying short trains of pulses that entrain neural populations into firing according to the frequency of the TMS pulses. Oscillatory signatures that play a causal role in clinical and/or subclinical checking behaviour will thus be revealed.

In essence the impact of this research will be threefold. Firstly, we will gain an unprecedented amount of insight into OCD by understanding the detrimental effects of checking compulsions not only at the cognitive but at the neural systems level. This will give rise to new explanatory theories and specific models of core deficiencies in cortical processing that could be efficiently targeted with pharmacological and non-pharmacological interventions. Secondly, the detailed understanding of deficient oscillatory signatures and functional connectivity in OCD will provide new candidate biomarkers and endophenotypes with the potential to improve diagnosis, risk evaluation and drug development. Thirdly, a proof-of-concept that frequency-tuned TMS directly modulates deficient brain oscillations and impacts on behaviour, could result in a novel putative therapeutic intervention.

The academic community will be reached via its standard ways of dissemination at conferences and in high impact journals aiming not only at researchers of OCD, but at the wider academic audience interested clinically or generally in functional cortical networks of working memory and executive control. The wider public will be informed in an appropriate manner via internet, radio, television, and specific publications in outlets aimed at such an audience. Sufferers of OCD and their relatives will be reached via appropriate organisations and charities by providing information for use on their websites and the offer to give oral presentations to their members. Finally, we will specifically target potential users of our research maximising the chances of immediate impact. Via established networks within the Institutes of Health and Wellbeing (IHW) and of Neuroscience and Psychology (INP) we will widely disseminate our findings to users in clinics and the pharmaceutical industry using their feedback to identify potential attendees for a dedicated workshop to disseminate our findings in concentrated form and to identify potential synergies for the future.