A Systematic Review of Behavioral, Physiological, and Neurobiological Cognitive Regulation Alterations in Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) is characterized by cognitive regulation deficits. However, the current literature has focused on executive functioning and emotional response impairments in this disorder. Herein, we conducted a systematic review of studies assessing the behavioral, physiological, and neurobiological alterations in cognitive regulation in obsessive-compulsive patients using the PubMed database. Most of the studies included explored behavioral (distress, arousal, and frequency of intrusive thoughts) and neurobiological measures (brain activity and functional connectivity) using affective cognitive regulation paradigms. Our results pointed to the advantageous use of reappraisal and acceptance strategies in contrast to suppression to reduce distress and frequency of intrusive thoughts. Moreover, we observed alterations in frontoparietal network activity during cognitive regulation. Our conclusions are limited by the inclusion of underpowered studies with treated patients. Nonetheless, our findings support the OCD impairments in cognitive regulation of emotion and might help to improve current guidelines for cognitive therapy.


Introduction
Obsessive-compulsive disorder (OCD) is characterized by recurrent intrusive thoughts (obsessions) and repetitive or ritualistic actions or mental acts intended to diminish the anxiety and distress elicited by obsessions (compulsions). OCD patients often have comorbid conditions including anxiety disorders, major depressive disorder, bipolar disorder, obsessive-compulsive personality disorder, and tic disorders [1]. In addition to its distinctive symptoms, OCD is defined by cognitive deficits involving memory and attentional biases towards relevant/threatening stimuli, memory distrust, and difficulty in accessing internal states. Thus, these patients depend on external stimuli and reassurance [2,3]. The past literature has focused on the study of executive function in OCD patients, mainly by using memory, inhibition, attentional shifting, reversal learning, and interference tasks [3][4][5]. Given that OCD patients might be frequently focused on controlling or responding to their obsessions, they might have an overall impaired performance on executive tasks. They might have reduced cognitive flexibility during task performance because their cognitive resources are engaged by obsessive thoughts [4][5][6][7]. Indeed, prior research showed evidence that cognitive flexibility deficits emerge in emotionally relevant contexts for OCD patients (activation of disorder-specific fears), supporting the association between cognitive inflexibility and obsessive symptoms [8].

Materials and Methods
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) norms [22,23] for the systematic review. We searched PubMed (Medline) database on the 14 April 2020 using the combination of the following terms: (OCD OR "obsessive-compulsive disorder" OR "obsessive compulsive disorder") AND (regulation OR reappraisal OR control) AND cognitive. We restricted the findings to articles in English, with human participants, with the availability of a full-text document, and reporting original results (reviews and book chapters were excluded). The author SF conducted the search and the eligibility assessment. The results were discussed among all authors in case of doubt. First, we selected the articles by the title and then by the abstract content. Later, the full text of the articles was analyzed according to the inclusion criteria. The inclusion criteria were: (1) the existence of a control group with non-psychiatric participants (controls); (2) the existence of a patients' group with a primary diagnosis of OCD based on validated instruments (e.g., Diagnostic and Statistical Manual of Mental Disorders (DSM) [1]); (3) the inclusion of a direct statistical comparison between the control and the OCD group; (4) the assessment of cognitive regulation with behavioral, physiological, or neurobiological measurements. The exclusion criterion was the sole use of self-reported measures of cognitive regulation (e.g., psychometric scales or questionnaires). Both cross-sectional case-control and interventional controlled studies were included. We extracted the following information from each article: (1) group characterization; (2) group size; (3) group mean age; (4) group gender ratio; (5) diagnosis instrument; (6) mean Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total score; (7) treatment approaches; (8) psychometric characterization related to cognitive regulation; (9) task description; (10) behavioral results; (11) physiological outcomes; (12) neurobiological findings; (13) techniques employed. Studies with common authors were carefully analyzed to avoid data duplication. Figure 1 represents the selection process. The search yielded a total of 1198 studies and 19 articles were additionally identified through reference lists. No unpublished studies were found in the reference lists of the included studies. After abstract reading, we selected 43 articles and we included 11 studies after full-text reading. Two studies used the same sample [24,25] and one study had two experiments with distinct samples [26] (one with an overlapping sample from another study [27]). Thirty-two reports did not meet the study criteria: 12 articles only assessed self-reported measures of cognitive regulation; 10 articles did not explore cognitive regulation processes; 7 reports did not incorporate a healthy control group; 3 studies did not statistically compare OCD and control participants. The final selected articles were published between 1999 and 2019 by authors from the USA [26][27][28][29], Germany [30][31][32], The Netherlands/Sweden [24], The Netherlands/Norway [25], Turkey [33], and Spain/South Africa/USA [34].

Results
Brain Sci. 2020, 10, x FOR PEER REVIEW 3 of 18 or questionnaires). Both cross-sectional case-control and interventional controlled studies were included. We extracted the following information from each article: (1) group characterization; (2) group size; (3) group mean age; (4) group gender ratio; (5) diagnosis instrument; (6) mean Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total score; (7) treatment approaches; (8) psychometric characterization related to cognitive regulation; (9) task description; (10) behavioral results; (11) physiological outcomes; (12) neurobiological findings; (13) techniques employed. Studies with common authors were carefully analyzed to avoid data duplication. Figure 1 represents the selection process. The search yielded a total of 1198 studies and 19 articles were additionally identified through reference lists. No unpublished studies were found in the reference lists of the included studies. After abstract reading, we selected 43 articles and we included 11 studies after full-text reading. Two studies used the same sample [24,25] and one study had two experiments with distinct samples [26] (one with an overlapping sample from another study [27]). Thirty-two reports did not meet the study criteria: 12 articles only assessed self-reported measures of cognitive regulation; 10 articles did not explore cognitive regulation processes; 7 reports did not incorporate a healthy control group; 3 studies did not statistically compare OCD and control participants. The final selected articles were published between 1999 and 2019 by authors from the USA [26][27][28][29], Germany [30][31][32], The Netherlands/Sweden [24], The Netherlands/Norway [25], Turkey [33], and Spain/South Africa/USA [34].  [22,23].)

Results
The studies included 301 OCD patients and 254 healthy participants in total, with an average of 27.4 ± 17.6 patients (mean ± standard deviation) and 23.1 ± 11.2 control participants per study. The average age for OCD participants was 31.5 ± 3.8 years and 30.8 ± 5.1 years for controls. On average, 49.7 ± 8.1% of OCD patients and 54.4 ± 9.3% of controls were female. This agrees with past literature demonstrating that OCD has an equal prevalence for both genders in adulthood [35]. All OCD patients were diagnosed with the DSM-IV and had an average Y-BOCS total score of 22.4 ± 1.3 (one study with missing information). Five articles explored behavioral tasks (Table 1) and six studies evaluated neurobiological and/or behavioral processes with functional magnetic resonance imaging (fMRI) and electroencephalography ( Table 2). The studies included 301 OCD patients and 254 healthy participants in total, with an average of 27.4 ± 17.6 patients (mean ± standard deviation) and 23.1 ± 11.2 control participants per study. The average age for OCD participants was 31.5 ± 3.8 years and 30.8 ± 5.1 years for controls. On average, 49.7 ± 8.1% of OCD patients and 54.4 ± 9.3% of controls were female. This agrees with past literature demonstrating that OCD has an equal prevalence for both genders in adulthood [35]. All OCD patients were diagnosed with the DSM-IV and had an average Y-BOCS total score of 22.4 ± 1.3 (one study with missing information). Five articles explored behavioral tasks (Table 1) and six studies evaluated neurobiological and/or behavioral processes with functional magnetic resonance imaging (fMRI) and electroencephalography ( Table 2).   The selected studies comprised mostly the cognitive regulation of thoughts, mental images, or pictures. The authors evaluated the distress, disgust, arousal, and frequency of thoughts as the main behavioral outcomes, and brain activity/functional connectivity as neurobiological parameters. The tasks required the use of the following cognitive regulation strategies: suppression, distraction, acceptance, rescripting, and reappraisal.
The studies found that the suppression of negative/intrusive thoughts leads to an increase in the frequency of these thoughts during and after suppression [28,29], and an augmentation of the distress elicited by the thoughts after suppression [29] in OCD participants. Other authors found that the suppression of neutral thoughts (e.g., thinking about a "white bear") results in increased frequency of the target thought for OCD individuals solely during suppression [26,27]. Moreover, Koçak and colleagues reported better performance for the OCD group during the suppression of an abstract mental image [33]. Najmi et al. (2009) demonstrated that the distress associated with intrusive thoughts was higher after using suppression when compared to distraction and acceptance strategies. Additionally, they demonstrated that intrusive thoughts were more frequent after the suppression in comparison to the acceptance condition in OCD patients. Lastly, they reported that the distress caused by intrusive thoughts diminished after applying acceptance strategies in OCD individuals [29]. Other authors reported a reduction of arousal for aversive pictures after using reappraisal compared to distraction techniques in OCD individuals [31], and a decrease in distress for OCD-related pictures during the reappraisal condition [24,25]. Fink and colleagues [30] also found decreased disgust ratings for OCD-related pictures after cognitive reappraisal in OCD and control participants, but no statistically significant differences between groups.
Cognitive reappraisal of fear-related pictures corresponded to decreased activity in the left middle frontal gyrus and right superior temporal gyrus, while reappraisal of OCD-related pictures increased activity in the right superior frontal gyrus and right lingual gyrus for OCD patients [24,25]. Moreover, these authors reported decreased functional connectivity in the left posterior insula and right amygdala during the reappraisal of fear-related images [24,25]. These results were consistent with the altered correlation between functional connectivity of the left amygdala-left posterior insula and the reappraisal abilities in OCD individuals reported by other authors [34]. Distraction strategies during the presentation of OCD-related pictures led to decreased activity in a left cluster including the amygdala, dorsal ACC, insula, and postcentral gyrus, and the right anterior cerebellum in OCD participants [32]. Both reappraisal and distraction strategies during the visualization of pictures were associated with decreased responses in centro-parietal regions (late positive potential) in healthy participants but not in OCD patients [31]. Lastly, suppression and manipulation of a mental image were linked to decreased activity in the right hemisphere in the inferior parietal lobule, posterior cingulate cortex, and superior frontal gyrus in OCD [33]. Figure 2 contains a summary of these findings and the Supplementary Table S1 presents a detailed description of the studies' behavioral tasks. Brain Sci. 2020, 10, x FOR PEER REVIEW 9 of 18 All the studies included were cross-sectional case-control studies. We assessed the quality of the studies with the National Institute for Clinical Excellence (NICE) checklist for case-control studies [36]. Overall, the selected publications had good quality in terms of the definition of the research question, exclusion criteria for cases and controls, and differentiation between cases and controls. Some studies failed to recruit comparable groups for cases and controls, to clearly address confound variables, and to describe statistical results with error values. None of the studies reported information about the participation rate and differences between participants and non-participants (Table 3). All the studies included were cross-sectional case-control studies. We assessed the quality of the studies with the National Institute for Clinical Excellence (NICE) checklist for case-control studies [36]. Overall, the selected publications had good quality in terms of the definition of the research question, exclusion criteria for cases and controls, and differentiation between cases and controls. Some studies failed to recruit comparable groups for cases and controls, to clearly address confound variables, and to describe statistical results with error values. None of the studies reported information about the participation rate and differences between participants and non-participants (Table 3).

Discussion
Herein, we systematically reviewed studies assessing cognitive regulation alterations in OCD in terms of behavioral, physiological, and neurobiological findings. Concerning behavior, these studies showed that distress and intrusive thoughts can be attenuated by cognitive reappraisal and acceptance strategies. Neuroimaging studies found altered brain responses mainly in dorsal prefrontal, temporal, parietal, and limbic regions during cognitive regulation in OCD participants. Other authors showed that reappraisal capacity was associated with functional connectivity changes between the amygdala and posterior insula in OCD.
Psychiatric diseases are generally characterized by impaired emotion regulation abilities, with excessive suppression and reduced acceptance of emotions [37,38]. Previous literature using psychometric instruments demonstrated that OCD patients have difficulties in cognitive regulation. They reported increased deficits in emotion regulation, namely diminished reappraisal abilities and increased use of suppression strategies [39,40]. Some of the studies included in this review also indicated the same trend by using self-reported questionnaires [24,25,30,31,34]. The beneficial effect of reappraisal over suppression in OCD patients and other individuals has been supported by past findings [21,41,42]. These authors denoted that reappraisal occurs before the complete unfolding of the emotional response and is more effective to control the negative impact of emotions, while the suppression process starts during the emotional response itself [21,[41][42][43][44].
Suppression consists of the inhibition of emotions, physiological responses, or behaviors in the face of stimuli [41][42][43]. Thought suppression might become chronic if associated with unpleasant emotions and lead to increased frequency of suppressed thoughts [29,44]. Our findings support the notion that suppression is a maladaptive strategy in OCD because it is linked to a subsequent higher occurrence of intrusive thoughts and enhanced distress [28,29]. Our results also showed that suppression is linked to increased internal attributions of weakness and incapacity to control intrusive thoughts in OCD [27]. Thus, OCD patients might often adopt suppression strategies as an effort to control obsessions [29]. Indeed, one of the studies included in this review showed that OCD patients have a higher performance during suppression [33]. In contrast to previous findings demonstrating increased responses in the dlPFC and inferior parietal cortex during suppression in healthy individuals [42], Koçak et al. (2011) found blunted superior frontal gyrus and inferior parietal lobule activity in OCD during suppression. The inferior parietal cortex is involved in shifting attention away from the self [42]. The dlPFC involvement in cognitive regulation is discussed below. These altered responses in prefrontal and parietal cortices might underline the maladaptive use of suppression in OCD.
Distraction consists of shifting attention away from intrusive thoughts to focus on neutral/alternative stimulus [21,29,42,45]. In this review, we observed that distraction reduces the distress elicited by intrusive thoughts when compared to suppression [29]. Moreover, other authors indicated decreased responses in the amygdala, dorsal ACC, insula, postcentral gyrus, and cerebellum in OCD participants during distraction [32]. Previous studies demonstrated increased responses in the ACC and parietal cortex and diminished activity in the amygdala and insula using distraction paradigms in healthy individuals [42,45]. The dorsal ACC and the inferior/superior parietal cortex are responsible for the allocation of attentional resources [38,42] and present decreased activity during reappraisal in individuals with anxiety disorders [38]. The dorsal ACC is also associated with the update of working memory and performance monitoring [42] and provides the connection between areas involved in the appraisal of affective stimuli (e.g., amygdala) and vlPFC and dlPFC regions associated with the initiation and execution of regulation [46]. Thus, despite the indication of reduced distress and amygdala and insular activity with the use of distraction strategies, OCD patients might have functional impairment in ACC and parietal areas. Lastly, distraction seems to be effective in the short term to decrease stress and negative arousal but not as a recurrent emotional regulation strategy, mainly when compared to reappraisal strategies [21,42,44], as reported by Paul and colleagues [31].
Acceptance refers to the experience of distressing situations without trying to alter their meaning [29,47]. Mindfulness techniques involve acceptance, consisting of nonjudgmental awareness of an experience [21,48]. Individuals with higher distress tolerance have stronger acceptance and mindfulness skills [44]. Thus, acceptance-based strategies might be efficient to target the distress elicited by obsessions. Indeed, previous studies showed that the acceptance and commitment therapy has beneficial effects for OCD patients, namely in reducing the severity of obsessive, compulsive, anxiety, and depressive symptoms [49,50]. Moreover, the recurrent employment of acceptance is associated with reduced use of maladaptive strategies such as suppression and decreased level of depressive and anxiety symptoms [21,47]. Thus, acceptance-based strategies might be adopted to treat OCD patients when standard cognitive-behavioral therapy (CBT) is unavailable or as a complement to CBT.
Cognitive reappraisal involves the modification of the significance of initial appraisals [38,42,43,46,51,52]. The most common reappraisal strategies are the reinterpretation of the stimuli with a more positive meaning or distancing from it with the viewing perspective of an unrelated observer [21,37,38,41,42,45,48,51]. In line with our conclusions, the previous literature points to increased activity in the inferior frontal gyrus, posterior insula, and occipitotemporal regions, and decreased response in the dorsomedial prefrontal cortex (dmPFC)/dlPFC and temporal gyrus during cognitive reappraisal in patients with mood and anxiety disorders [37,38]. Moreover, studies with healthy individuals also reported the involvement of the dlPFC/dmPFC, parietal and temporal cortex, and the amygdala and insula in cognitive reappraisal processes [42,45,51,52]. The prefrontal alterations might indicate the deficient allocation of attention and impaired monitoring/manipulation of emotion-related information [37,38,42,51,52]. The increased activation of occipitotemporal regions might translate into enhanced attention to negative stimuli [37,52]. Additionally, the prefrontal and parietal cortex have a modulatory effect on lateral temporal regions associated with semantic and perceptual representations to alter the emotional significance of external stimuli [42,52]. In line with the findings of Paul et al. (2016) reviewed here, the downregulation of emotions during reappraisal is also linked to decreased late positive potential amplitude in centroparietal regions, representing a reduction in sustained attention towards the negative stimuli [38]. Moreover, patients with anxiety disorders have decreased inferior/superior parietal responses during reappraisal of negative stimuli [38] that might be associated with impaired inhibitory control [37] or blunted recruitment of attentional resources [38]. Thus, OCD patients seem to have impaired cognitive reappraisal processes because they did not present diminished late positive potential. Previous studies also found that healthy participants with higher reappraisal abilities have lower values of functional connectivity between the amygdala and anterior insula [43] and that the anterior insula activity is associated with the amygdala function during emotion regulation [46]. Additionally, the posterior insula and amygdala responses are downregulated by reappraisal strategies [42]. These authors suggest that the insula is involved in the selection of appropriate strategies to subsequently downregulate the amygdala activity in the face of negative emotions. The absence of this association in OCD individuals [34] might indicate that their cognitive reappraisal deficits are underlined by an impaired functional connection between amygdalar and insular regions. The results from other authors included in our review also support impairments in functional connectivity in the amygdala and insula during fear reappraisal [24,25].
CBT is one of the first-line treatments for OCD [53,54] and aims at improving negative appraisals and dysfunctional beliefs with reappraisal strategies [44,52,55,56]. After CBT, the activity in brain regions associated with affective processing (orbitofrontal cortex, ACC, thalamus, and caudate) usually decreases and there is an enhancement of brain response in regions linked to neurocognitive processes (dlPFC, parietal cortex, putamen, and cerebellum) [55,57]. However, some studies also report the reduction of dlPFC activity after CBT [55]. Thus, CBT seems to restore prefrontal control over subcortical regions [55] by increasing activity in frontal and parietal regions. Indeed, improved set-shifting, inhibitory, visuospatial, verbal memory, and working memory abilities have been reported after CBT and cognitive training [58]. Moreover, dysfunctional beliefs decrease after CBT and cognitive therapy [56,59,60], although other authors found controversial results [61,62].
Our conclusions are limited by the modest sample sizes (more than half of the studies with less than 30 participants per group), the concurrent medication and/or CBT (only three studies included patients without medication [24,25,32]), and the inclusion of patients with comorbidities (e.g., major depressive disorder, anxiety disorders, and phobias; only one study reported the exclusion of comorbidities [33]). Additionally, many of the studies did not provide information about the different OCD dimensions of the patients included, hindering the comparison between patients with different symptomatology. Moreover, the majority of the publications did not study correlations between the main outcome measures and the severity of OCD disorder. Most of the studies also lacked information about specific treatment approaches and treatment duration, as well as the age of onset of OCD, preventing the analysis of putative effects of these factors on the main outcomes. Moreover, the majority of the studies explored suppression and reappraisal strategies, preventing the extraction of robust information for other strategies (e.g., acceptance). Most of the studies employed emotion-related stimuli or paradigms analyzing intrusive thoughts (except [33]). OCD is also characterized by an imbalance between cognitive and reward pathways that explains the execution of rewarding compulsive actions in response to uncontrollable obsessional thoughts [63]. Thus, tasks of cognitive regulation of reward processing are critical for future studies [64]. Lastly, some studies might have not been included in this review because our search process was conducted only in the Medline database. However, we complemented our search with reference lists.
To better tackle the cognitive regulation alterations in OCD, future studies should use cognitive regulation tasks assessing behavioral parameters (e.g., distress, anxiety, and occurrence of intrusive thoughts) in combination with neuroimaging methods with the additional incorporation of physiological measures (e.g., heart and respiratory rate and skin conductance) to obtain objective parameters of anxiety/distress changes. Moreover, the inclusion of treatment naïve patients and the use of larger samples is crucial. Additionally, the use of more ecological/personalized approaches might be more appropriate to disentangle the mechanisms involved (e.g., asking OCD participants to regulate their obsessions without using other external stimuli) [21].

Conclusions
This review provides further insight into the cognitive regulation alterations in OCD that might guide the improvement of cognitive therapy and CBT. Overall, we observed altered brain responses in regions belonging to the frontoparietal network (dlPFC/dmPFC, inferior/superior parietal cortex, and superior temporal cortex) during cognitive regulation. This conclusion suggests an impairment in attention allocation and deficient control of emotion-related information [18,19]. Moreover, this review suggests a beneficial effect of reappraisal and acceptance strategies and a detrimental effect of suppression approaches regarding the reduction of distress and frequency of intrusive thoughts after cognitive regulation. Nonetheless, further research needs to be conducted to compare the efficacy of different cognitive regulation strategies. The studies included in this review described experiments involving suppression, distraction, acceptance, and cognitive reappraisal strategies. In this way, this review highlights the lack of studies exploring the effects of other cognitive regulation strategies for OCD patients (e.g., neutralizing and worry).

Supplementary Materials:
The following are available online at http://www.mdpi.com/2076-3425/10/11/797/s1, Table S1: Detailed description of the behavioral tasks of the studies included in the systematic review. Funding: This work has been funded by national funds, through the Foundation for Science and Technology (FCT)-project UIDB/50026/2020 and UIDP/50026/2020-and by the projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). S.F. was supported by a combined Ph.D. scholarship from the FCT and the company iCognitus4ALL-IT Solutions, Lda (grant number PD/BDE/127839/2016). The funding sources had not been involved in the study design, the collection, analysis, and interpretation of data, in the writing of the report, and in the decision to submit the article for publication.

Conflicts of Interest:
The authors declare no conflict of interest.