Paper II

2.2.1 Research question

The goal of this paper was to investigate if unaffected siblings of OCD patients show similar distress, brain activation and functional connectivity during emotion

provocation and regulation as patients, relative to healthy controls without a family history of OCD.

2.2.2 Participants and measures

The study included 43 unmedicated patients with OCD, 19 unaffected siblings of these patients, and 38 unrelated healthy controls. A diagnosis of OCD and comorbid disorders was done using the Structural Clinical Interview for DSM-IV (SCID, First, Spitzer, Gibbon, & Williams, 2002). Symptom severity of OCD was determined using the Y-BOCS, depressive symptoms were measured using the Montgomery–

Åsberg Depression Rating Scale (MADRS, Montgomery & Asberg, 1979), and use of reappraisal and suppression as emotion regulation strategies was measured using the Emotion Regulation Questionnaire (ERQ, Gross & John, 2003).

2.2.3 Experimental design of emotion regulation task

All participants performed an emotion regulation task, which has been extensively used to probe brain regions involved in various forms of emotion regulation in both healthy participants and participants with mental disorders (de Wit et al., 2015;

Goldin, Manber-Ball, Werner, Heimberg, & Gross, 2009; Ochsner et al., 2004; Rive et al., 2013). The task involves the appraisal of emotionally neutral pictures, OCD-related aversive pictures (such as dirty toilets, door handles, water taps, or

asymmetric objects), or general fear-related pictures (such as spiders, bears or guns).

The participants were either instructed to attend the picture naturally or intentionally try to reduce its emotional relevance using cognitive reappraisal techniques. During the task the participants were first given the instruction to either “attend” or

“regulate” and where then show a picture for 10 seconds. They were then asked to rate their distress using a visual analogue scale.

2.2.4 Preprocessing and statistical analyses

Group differences in demographic characteristics, symptoms of OCD and depression, ERQ, and distress during emotion provocation and regulation were analyzed using chi-square or t-tests. Changes in distress during emotion provocation and regulation were analyzed using repeated-measures ANOVA. Tukey or Games-Howell

corrections were used to adjust for multiple comparisons.

Group comparisons of activation during emotion provocation and regulation were performed in SPM12. Participant-specific maps of BOLD signal, and its two derivatives, during provocation (fear attend/regulate > neutral attend, OCD attend/regulate > neutral attend) were included in separate second-level, random effects ANOVAs. Three by three ANOVAs for fear and OCD-related provocation included group (OCD patients, siblings, HC) as a between-subject factor and HRF (canonical, temporal, dispersion) as a within-subject factor. The interaction between groups and picture type was modelled in a separate 3 X 2 X 3 ANOVA with group as a between-subject factor and HRF and picture type (fear, OCD-related) as within-subject factors. Separate one-way ANOVAS were used for emotion regulation and regulation-related function connectivity.

In Paper II we primarily focused our analyses to regions of the brain where OCD patients have previously been shown to differ from healthy controls during emotion processing or cognitive reappraisal. We therefore formed our hypotheses on emotion provocation on significant regions from our meta-analysis comparing OCD patients and healthy controls in Paper I (Thorsen, Hagland, et al., 2018). At that time no meta-analysis of the neural correlates of emotion regulation in OCD had been published, so we based our hypotheses on cognitive reappraisal on significant regions from the two largest meta-analysis of healthy controls (Buhle et al., 2014; Frank et al., 2014). We then investigated these specific regions using small volume correction (Worsley et al., 1996), and adjusted the p-values of comparisons between the groups using SISA-Bonferroni corrections

(http://www.quantitativeskills.com/sisa/calculations/bonhlp.htm; Perneger, 1998).

2.2.5 Ethics

The study was approved by the ethical approval board of the VU University Medical Center (Amsterdam, the Netherlands) and all participants provided written informed consent. The participants were not placed at risk by the procedure and had the right to withdraw at any time without giving a reason. In accordance with the ethical

approvals, all data were deidentified prior to being available to the Norwegian PhD student and there was no way of identifying the participants. The PhD student was also formally associated with VUMC when working with the data.

2.2.6 Results

We found that unaffected siblings of OCD patients reported similar levels of distress as unrelated healthy controls during emotion provocation and regulation, and significantly less distress than OCD patients. This suggests that they did not appraise the aversive stimuli as threatening.

During emotion provocation no significant differences was found between the three groups for fear-related stimuli. For OCD-related stimuli OCD patients showed significantly altered activation in the right amygdala/hippocampus compared to healthy controls, which was mainly driven by differences in timing and shape of the BOLD response. Siblings were intermediate and not significantly different from either group during OCD-related emotion provocation.

During emotion regulation no significant differences was found between the three groups for fear-related stimuli, similar to emotion provocation. During OCD-related regulation siblings showed significantly higher activation in the left temporo-occipital cortex compared to both OCD patients and healthy controls. OCD patients showed significantly higher dmPFC activation compared to healthy controls, where siblings were intermediate and not significantly different from either. Exploratory analyses of functional connectivity between the dmPFC and amygdala showed that siblings showed distinctly higher co-activation of these structures during regulation of OCD-related stimuli, which was significantly greater than OCD patients.