Disease And Medication Effects On Inhibitory Control In OCD: A Meta- And Mega-analysis Of Task-based FMRI Data Of The ENIGMA-OCD Consortium - Info and Reading Options

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Individuals with obsessive-compulsive disorder (OCD) have specific cognitive, emotional and behavioral dysfunctions that are both a consequence and a cause of altered brain structure and function. The ENIGMA consortium was founded to advance our understanding of the neurobiology of brain disorders (Thompson et al., 2020), including OCD, by using worldwide data. This is the largest OCD brain imaging consortium established to date, who’s combined sample includes thousands of individuals with OCD, both adult and pediatric, and healthy controls. Using structural MRI, diffusion MRI, and resting state functional MRI analyses, the ENIGMA-OCD consortium has already found that some OCD-related brain alterations may arise during neurodevelopment, while others are associated with duration of illness or medication use (van den Heuvel et al., 2022). Recently, the ENIGMA-OCD consortium conducted its first analyses of OCD-related alterations in brain function, focusing on emotional processing and executive control—two functional domains known to be disrupted in OCD. To investigate these effects, we pooled data from 16 independent negative valence-processing tasks (N=633 OCD, N=453 healthy controls) and 15 independent executive control tasks (N=475 OCD, N=345 controls). During negative valence processing, relative to healthy controls, individuals with OCD showed very strong evidence of weaker activation of the lateral occipital cortex (P+<0.001) that was additionally related to greater OCD severity, late-onset of disease, and an unmedicated status (Dzinalija et al., 2024). During executive control, individuals with OCD also showed moderate to strong evidence of weaker activation in the frontal eye fields, precuneus, and inferior parietal lobule (all P+<0.1) that was also related to greater OCD severity (Dzinalija et al., in preparation). Crucially, despite significant variation in paradigms, we observed common task activation patterns across individuals with OCD and controls that encompassed fronto-limbic areas during negative valence processing, and dorsal cognitive areas during executive control, validating this methodological approach to mega-analysis. This represented the first time in psychiatry that individual-subject fMRI data from different task paradigms within a domain were combined into a single large group-level analysis. This image-based approach to meta-analysis provides a richer and more accurate characterization of activation than traditional coordinate-based meta-analyses. Having successfully demonstrated case-control differences in negative valence processing and executive control, we next investigate inhibitory control, a sub-construct of the ‘cognitive systems’ domain of the the Research Domain Criteria (RDoC, Insel et al., 2010) in which individuals with OCD show deficits. Inhibitory control refers to the ability to inhibit an automatic or prepotent response that is unwanted or inappropriate in pursuit of an alternative goal. Tasks like the Stop-signal task and the Flanker task are frequently used in the MRI to investigate the neural correlates of inhibitory control, and have pointed to the involvement of the ventral cognitive circuit encompassing the dorso-lateral prefrontal cortex (dlPFC), the pre-supplementary motor area (pre-SMA), and the dorsal caudate (Shephard et al., 2021). When inhibitory control has been investigated in OCD through meta-analysis, it has frequently been conflated with executive control (Casale et al., 2011; Ragson et al., 2017; Eng et al., 2019; Pico-Perez et al., 2020), making it difficult to disentangle which cognitive state is most strongly related to OCD-related functional alterations. We aim to study the cognitive functions involved in inhibitory control in OCD independently of higher-order executive control (such as working memory, planning, and task-switching). We investigate multiple processes of inhibitory control, including inhibiting an initiated motor response (action cancellation as captured by the Stop-signal task), inhibiting a prepotent or instinctual response (action restraint as captured by the Go/No-go and eye-blink suppression tasks) and inhibiting intrusion of distracting or irrelevant stimuli (interference control as captured by Flanker and Stroop tasks). We also investigate error processing in these tasks - when a participant fails to appropriately inhibit a response - as individuals with OCD have demonstrated hyperactivation during error processing (Norman et al., 2019). We pool individual participant data from 16 different international samples that-acquired inhibitory control tasks into one image-based mega-analysis, and further investigate relevant clinical characteristics of OCD, such as severity, age of onset, and medication usage. Medication usage in the form of SSRIs has previously been demonstrated to decrease activation in a Stop-signal task (van der Straten, 2024), and lower activation is associated with greater symptom severity (de Wit et al., 2012). Early onset of OCD was found to be correlated with worse executive control performance (Zheng et al., 2015), though its relationship with neural activation during inhibition is unclear.

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