Overactive Performance Monitoring as an Endophenotype for Obsessive-Compulsive Disorder: Evidence From a Treatment Study

Obsessive-compulsive disorder (OCD) is a complex and heterogeneous disorder characterized by intrusive obsessions and repetitive compulsions. Its lifetime prevalence is estimated to be 1%−3% worldwide (1). OCD leads to an enormous reduction in life quality and often follows a chronic course when not treated. There is increasing evidence from twin and family studies for small to moderate genetic effects (2). However, reliable evidence of specific genetic alterations has not yet emerged. Overall, data point to the involvement of gene variants in the serotonergic, dopaminergic, and glutamate systems (2). Combined, evidence suggests that OCD is genetically complex, with multiple genetic and environmental factors contributing to its development (2).

Hyperactive error signals that have been linked to OCD symptoms, such as feelings of incompleteness, doubt, and repetitive behavior, are assumed to play a central role in the pathophysiology of OCD (3). The anterior cingulate cortex is implicated in the processing of conflict and the generation of error signals (4, 5). Converging evidence from neuroimaging studies conducted at rest as well as during symptom provocation suggests that the anterior cingulate cortex as part of a frontal-striatal circuit is involved in the pathophysiology of OCD (2, 6). Furthermore, functional MRI (fMRI) studies point toward enhanced error- and conflict-related activity in the anterior cingulate cortex in OCD patients (7, 8). Consistent with this, the error-related negativity, a fronto-central event-related brain potential generated by the anterior cingulate cortex following an error (9), has been repeatedly found to be enhanced in OCD patients (10) across all symptom dimensions and unrelated to symptom severity (11). The magnitude of the error-related negativity has also been shown to be heritable (12), and larger amplitudes are evident in unaffected relatives of OCD patients (13, 14). Consequently, overactive error monitoring has been proposed as an endophenotype for OCD (14, 15). Endophenotypes are quantitative biological or cognitive markers that more closely relate to the genetic underpinnings than the clinical syndrome (16). To qualify as an endophenotype, a marker must 1) be associated with the illness, 2) be heritable, 3) be found in unaffected family members at a higher rate than in the general population, and 4) be state independent (16). Although enhanced performance monitoring in OCD fulfills the majority of these criteria, data evaluating its stability over time is still missing for adult patient populations. Evidence from pediatric OCD patients suggests that enhanced error-related brain activity persists after symptom reduction (17, 18). The purpose of the present study was to examine performance monitoring in adult OCD patients before and after symptom reduction. We used cognitive-behavioral therapy (CBT) with exposure and response prevention as an evidence-based treatment to achieve symptom reduction in OCD patients (19). To show that overactive performance monitoring in adult patients is state independent and not a secondary result of symptom expression is essential to validate the notion that this marker is an endophenotype for OCD.

Method

Participants

Sixty patients with OCD (women, N=31) and 60 healthy comparison subjects (women, N=32) were assessed at the first testing session. Forty-five patients (women, N=22) and 39 healthy comparison subjects (women, N=21) completed two testing sessions (T1 and T2). The presented results and sample characteristics focus on the sample that completed both testing sessions. Information about the subject flow, drop out reasons, as well as comparisons between study completers and noncompleters, is presented in the data supplement accompanying the online version of this article. Four patients and two healthy comparison subjects were excluded from the final analysis because of poor data quality or insufficient number of error trials (fewer than six [20]) on one of the two sessions. The final analysis sample consisted of 41 OCD patients and 37 healthy comparison subjects (Table 1). Patients were recruited from the OCD outpatient unit at Humboldt-Universität where they were treated. All patients fulfilled criteria for OCD and were diagnosed by trained clinicians using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) (21) and Axis II Disorders (22). CBT is recommended by the APA as a first-line treatment for OCD (19) and was administered in a naturalistic setting by experienced therapists specialized in the treatment of OCD. CBT included individually tailored exposure, psychoeducation, cognitive interventions, homework assignments, and relapse prevention. Weekly CBT sessions of 50 minutes, as well as blocks of exposure sessions, were held. T2 assessments for patients were conducted after 30 CBT sessions, which is the standard short-term therapy duration in Germany. Healthy comparison participants were recruited from the community through advertisement. For the healthy subjects, T2 was scheduled in accordance with the T1-T2 interval of the patient with whom they were matched. The mean interval between sessions was 49.1 weeks (SD=20.4) for OCD patients and 47.7 weeks (SD=18.1) for healthy comparison subjects and did not differ between groups (t=0.32, df=76, p=0.75). The groups were matched with regard to gender, age, and level of education. All participants had normal or corrected-to-normal vision and reported no history of head trauma, neurological disease, or psychotic or substance-related disorders. Healthy comparison subjects reported no family history of OCD and no past or present signs of psychiatric disease as assessed with SCID-I. Twenty-one OCD patients had one to three comorbid diagnoses as follows: affective disorders (major depression, N=12; dysthymia, N=2), anxiety disorders (social phobia, N=6; panic disorder, N=2; generalized anxiety disorder, N=2; specific phobia, N=2), eating disorders (bulimia, N=1), somatoform disorders (hypochondria, N=1), tic disorder (N=1), and personality disorders (obsessive-compulsive, N=5; avoidant, N=3). Twenty-one patients were receiving medication (selective serotonin reuptake inhibitors [SSRIs], N=15; tricyclic antidepressants, N=6). A detailed list of medications is presented in the online data supplement. All participants completed the Beck Depression Inventory-II (BDI-II) (23), the Obsessive Compulsive Inventory-Revised (24), and a test measuring verbal intelligence. Severity of obsessive-compulsive and depressive symptoms in patients was additionally assessed by trained clinicians using the Yale-Brown Obsessive Compulsive Scale (25, 26) and the Montgomery-Åsberg Depression Rating Scale (27). Participants provided written, informed consent after receiving written and verbal information about the study. Study procedures were in accordance with the ethical guidelines of the Declaration of Helsinki, as approved by the local ethics committee.

Task

An arrow-version of the flanker task was administered using Presentation software (Neurobehavioral Systems, Albany, Calif.). On each trial, five vertically aligned arrows were presented, and participants were instructed to indicate the direction of the central target arrow by button press. The flanker stimuli were presented for 100 ms before the target appeared. Then, flanker and target stimuli were presented simultaneously for 50 ms, followed by an intertrial interval that varied between 900 ms and 1,500 ms. One-half of the trials were compatible (i.e., flanker and target arrows pointed in the same direction), and one-half were incompatible (i.e., flanker and target arrows pointed in opposite directions). Stimulus compatibility and direction varied pseudo-randomly across trials. A total of 480 trials and 20 practice trials were presented, with short breaks every 60 trials. To encourage both fast and accurate behavior, performance-based feedback was given every 60 trials. The instruction reminded participants to respond more quickly when error rates were below 10%, to respond more accurately when error rates were above 20%, or to respond both quickly and accurately when error rates ranged between 10% and 20%. The duration of the experiment was about 25 minutes.

EEG Recording, Data Reduction, and Analysis

The EEG was recorded from 64 electrodes, with Cz as the recording reference. Electrodes were mounted on an electrode cap with equidistant electrode positions. External electrodes were placed at the following locations: below both eyes, nasion, and neck and below the T2 electrode (ground electrode). All impedances were kept below 5 kΩ. The EEG was sampled at 500 Hz and amplified with a band-pass filter of 0.01 Hz–250 Hz. Eye movement and blink artifacts were corrected using the multiple-source eye-correction method implemented in BESA, Version 5.2 ([Brain Electrical Source Analysis] MEGIS Software GmbH, Grafelfing, Germany). A low-pass filter at 40 Hz and a notch filter at 50 Hz were applied to the data. Response-locked epochs of 1,200 ms in length including a 200-ms preresponse epoch were extracted. The 200-ms preresponse epoch served as baseline for the response-related potentials. Only trials with response times between 100 ms and 700 ms were analyzed. Epochs containing a voltage step of more than 50 μV between consecutive data points or a voltage difference of 200 μV were rejected from averaging. Event-related potentials were quantified for correct (i.e., correct-related negativity) and erroneous (i.e., error-related negativity) reactions as the difference between the most negative peak occurring in a 150-ms epoch following the response and the immediately preceding positive peak at electrode FCz (28).

Statistical analyses were conducted using SPSS (version 20.0, SPSS, Armonk, N.Y.). We used t tests to assess group differences in clinical and demographic measures and error rates. Electrophysiological indicators of performance monitoring, as well as reaction times, were analyzed with repeated-measures analysis of variance using group (OCD patients, healthy comparison subjects) as a between-subject factor and response type (correct, error), and session (T1, T2) as within-subject factors. For the OCD group, additional control analyses with medication, treatment outcome, and comorbidity as between-subject factors were conducted. Not all patients showed symptom reduction after CBT. Accordingly, we divided the patient group into treatment responders (i.e., those with more than 30% symptom reduction) and nonresponders (i.e., those with less than 30% symptom reduction) to analyze symptom state independence. Treatment response groups are based on the criterion of 30% symptom reduction based on scores on the Yale-Brown Obsessive Compulsive Scale suggested as optimal for predicting improvement (26). Correlational analyses were used to examine associations between indices of performance monitoring and severity and changes in OCD symptoms. All statistical tests were two-tailed, using a significance level of α=0.05.

Results

Behavioral, Demographic, and Clinical Data

The characteristics of the final sample, which did not differ from the original sample (see the online data supplement), are summarized in Table 1. Patients with OCD and healthy comparison subjects did not differ in age (t=0.50, df=76, p=0.62), verbal IQ (t=0.90, df=76, p=0.39), and gender (χ²=0.00, p=0.99). As expected, OCD patients reported higher symptom severity (Obsessive-Compulsive Inventory-Revised: t=9.69, df=76, p<0.001; BDI II: t=6.83, df=76, p<0.001). Reaction times did not differ between groups. Patients with OCD committed fewer errors (F=5.33, df=1, 76, p<0.05; for further details on behavioral data, see the online data supplement).

Event-Related Potential Data

Event-related potentials for healthy comparison subjects and OCD patients for both sessions are presented in Figure 1. Both groups showed more pronounced negative amplitudes for errors compared with correct responses (F=233.24, df=1, 76, p<0.001). A significant main effect of group was observed (F=10.96, df=1, 76, p<0.001) but no interaction between response type and group (F=2.13, df=1, 76, p=0.15). Accordingly, patients with OCD had enhanced negativities after errors (effect size across both sessions: Cohen’s d=0.67) and correct reactions (Cohen’s d=0.64) compared with healthy comparison subjects. A main effect of session (F=4.02, df=1, 76, p<0.05) that was specified by an interaction between response type and session (F=8.72, df=1, 76, p<0.01) reflects that across both groups, the error-related negativity increased from T1 to T2 (t=2.73, df=76, p<0.01), whereas no change was observed for the correct-related negativity (t=0.22, df=76, p=0.83). Importantly, no interactions between session and group (F=0.02, df=1, 76, p=0.88) or session, response type, and group (F=0.001, df=1, 76, p=0.98) were observed. Thus, the factor session (i.e., the effect of CBT in OCD patients) did not differentially modulate performance monitoring between groups. This indicates that the enhancement of response-related negativities in OCD patients compared with healthy comparison subjects persisted after CBT, suggesting state independence. Post hoc tests for both testing sessions confirm that OCD patients showed larger amplitudes for erroneous (T1: t=2.44, df=76, p<0.01; T2: t=2.47, df=76, p<0.05) and correct (T1: t=2.77, df=76, p<0.01; T2: t=2.37, df=76, p<0.05) reactions. The pattern of results was replicated when analyzing mean amplitudes for response-related negativities (0 ms–100 ms) and when controlling for differences in error rates between groups using analysis of covariance.

Additional analyses were conducted to assess whether EEG measures in patients were influenced by medication status or presence of comorbid disorders. Neither a main effect for medication (F=1.89, df=1, 39, p=0.17), or comorbidity (F=0.04, df=1, 39, p=0.84), nor significant interactions for medication and comorbidity were found (all p values >0.20). This was replicated when comparing patients taking only SSRIs with those not receiving any medication (F=2.34, df=1, 32, p=0.14).

State Independence: Effects of Individual Symptom Variation on Performance Monitoring

Correlations between symptom reduction in obsessive-compulsive symptoms between T1 and T2 and changes in performance monitoring between sessions were not significant (all p values >0.4), suggesting independence of performance-monitoring activity from OCD symptom variation. Similarly, no significant association between OCD severity and performance-monitoring activity was observed for both groups (all p values >0.30; for details on correlations and to view scatter plots, see the online data supplement).

In line with the correlational results, event-related potentials at both testing sessions did not differ between OCD patients with and without symptom reduction (Figure 2). Using a response criterion of a 30% symptom reduction based on the Yale-Brown Obsessive Compulsive Scale, 21 OCD patients (51.2% of the sample) were classified as treatment responders. Treatment responders and nonresponders did not differ in clinical measures at T1 (BDI-II: t=0.51, df=39, p=0.62; Obsessive-Compulsive Inventory-Revised: t=1.15, df=39, p=0.26; Montgomery-Åsberg Depression Rating Scale: t=0.36, df=39, p=0.72; Yale-Brown Obsessive Compulsive Scale: t=0.84, df=39, p=0.41). Importantly, no main effect of symptom reduction on neural correlates of performance monitoring (F=0.29, df=1, 39, p=0.59), no interaction between symptom reduction and session (F=0.08, df=1, 39, p=0.78), and no interaction between symptom reduction, session, and response type (F=0.16, df=1, 39, p=0.69) were observed. Accordingly, even after CBT and significant symptom reduction in one group (i.e., responders), performance-monitoring activity did not differ between responders and nonresponders (errors: t=0.17, df=39, p=0.87; correct: t=0.54, df=39, p=0.59). Furthermore, both responders and nonresponders showed enhanced negativities after errors compared with healthy comparison subjects at both testing sessions (responders: T1: t=2.36, df=55, p<0.05, T2: t=2.07, df=55, p<0.05; nonresponders: T1: t=2.52, df=56, p<0.05, T2: t=2.15, df=1, 56, p<0.05). A similar enhancement was also observed after correct reactions (responders: T1: t=2.79, df=1, 55, p<0.01, T2: t=2.16, df=1, 56, p<0.05). However, for nonresponders, this effect fell short of statistical significance (nonresponders: T1: t=1.92, df=1, 56, p=0.06, T2: t=1.73, df=1, 56, p=0.09). Altogether, these results suggest that overactive performance monitoring in OCD can be observed independent of symptom state.

Test of Null Results

Central results of this study (i.e., between-session changes and the comparisons between responder and nonresponder) are null results. According to the endophenotype concept, this was expected when hypothesizing that overactive performance monitoring in OCD is robust against symptom state changes. However, it is difficult to confirm a null hypothesis in conventional significance testing. Therefore, we additionally examined and quantified the preference for either the null hypothesis or the alternative using a Bayes factor two-sample t test (29), in which r was set a priori at 1.0. For the comparison of responders and nonresponders on error-related negativity, the odds were greater than 4.3:1 favoring the null hypothesis (JZS Bayes factor). Accordingly, the null hypothesis was four times more probable than the alternative. A similar result was observed for correct reactions; again the null hypothesis was 3.8 times more probable compared with the alternative hypothesis (JZS Bayes factor=3.8). Because the odds favor the null hypothesis, we conclude that there are strong reasons to accept the conclusion that there is no difference between the patient groups. Similarly, no significant between-session changes were observed for responders, and the odds for the null relative to alternative hypothesis were greater than 3.2:1 for error-related brain activity and 4.8:1 for correct-related brain activity favoring the null hypothesis (JZS Bayes factor). Notably, the error-related negativity amplitude numerically slightly increased between the sessions, in both OCD patients and healthy comparison subjects. This clearly contradicts the idea that symptom reduction may be associated with a normalization of error-related brain potentials.

Discussion

OCD patients suffer from repetitive and stereotyped behaviors that are thought to be prompted by hyperactive error signals in the brain. Overactive performance monitoring in OCD is a well-replicated finding (10) and has been suggested as a promising endophenotype for the disorder (13–15). The present study aimed to further clarify the suitability of overactive performance monitoring as an endophenotype by investigating its state independency (16). Electrophysiological indicators of performance monitoring were measured before patients received CBT and after completing it. Symptoms commonly remit to variable degrees following therapy, but an endophenotype marker should be unaffected by these symptom changes over time. Consistent with findings from previous studies, OCD patients showed enhanced neural correlates of performance monitoring prior to CBT (10). Importantly, this alteration persisted after symptom reduction. Accordingly, both treatment responders and nonresponders continued to show enhanced neural responses to errors and correct reactions compared with healthy comparison subjects. Moreover, no correlations between symptom changes and variations in response-related brain potentials were observed. For both OCD patients and healthy comparison subjects, the error-related negativity amplitude increased between sessions, which may suggest that the significance of errors increased (30). Alternatively, the signal-to-noise ratio may have been superior at the second session. Overall, the retest-reliability for the error-related negativity (r=0.65, p<0.001) was similar in size to previously reported values (31), indicating that the error-related negativity is a stable, trait-like component that can be reliably measured.

The present results are consistent with results in pediatric OCD patients revealing that increased error-related negativity (17) and increased error-related activity in the anterior cingulate cortex (18) are maintained over the course of successful therapy. Together, these results indicate that brain correlates of overactive performance monitoring in OCD are independent of symptom state and seem to represent an underlying risk marker or endophenotype. The persistence of enhanced performance monitoring after symptom reduction is remarkable given some findings suggesting that hyperactivity of fronto-striatal brain circuits in OCD patients during resting state and after symptom provocation normalizes, at least in part, with symptom reduction during psychological or pharmacological treatment (2, 32). Brain structures showing such functional normalization include the nucleus caudatus (33), the thalamus (28), and the anterior cingulate cortex (e.g., references 34, 35). Although state-dependent variations in anterior cingulate functions have been shown, overactive performance monitoring, which has been linked to activity in this region, appears to be independent of current symptom state (17, 18). It is not entirely clear how the trait-like error-related negativity and state-like anterior cingulate cortex activity at rest and during symptom provocation are related to each other in healthy individuals and in OCD patients. Future studies should evaluate this by concurrent measures of EEG and fMRI during rest, symptom provocation, and performance monitoring in a follow-up design.

It should be noted that enhanced error monitoring has not only been found in OCD but also in depression, social anxiety, and generalized anxiety disorder, as well as in nonclinical individuals showing associated traits (10, 36, 37). These conditions characterized by overactive error monitoring are frequently comorbid (1). These disorders overlap in symptoms, comorbidities, and neural correlates, which suggests partially overlapping etiological factors. Consequently, overactive performance monitoring may represent an endophenotype beyond the diagnostic borders of OCD and therefore represents an interesting marker for the Research Domain Criteria (38). This initiative tries to establish biologically meaningful dimensions of psychological dysfunction irrespective of disorder categories. Performance monitoring is a fundamental behavioral function, and its abnormalities at both ends of the distribution (i.e., enhancement and reduction) have been implicated in multiple forms of psychopathology (15, 36). More specifically, overactive performance monitoring may be a transdiagnostic dimensional trait that is shared by individuals who are highly sensitive to the commission of errors (10, 36).

However, enhanced performance monitoring after correct reactions may represent a more specific marker of OCD (e.g., references 11, 14, 39) that has not been reported for generalized anxiety disorder (e.g. reference 40) or depression (e.g., reference 41). The present study provides further evidence for hyperactive performance monitoring associated with both correct and erroneous responses in OCD (e.g., references 11, 14, 39). This nonspecific enhancement of performance monitoring (to both correct responses and errors) in OCD may relate to the feeling that something is wrong and needs to be repeated regardless of actual outcome and may therefore relate to repetitive behavior and compulsions. Performance-monitoring signals are assumed to trigger the adjustment of cognitive control (42). Therefore, a permanently overactive performance-monitoring system might account for the greater urge to control actions and thoughts, a characteristic commonly observed in OCD and assumed to enhance vulnerability according to cognitive models of OCD (43).

The present work adds important evidence for the role of performance monitoring as an endophenotype for OCD, but it has limitations that should be noted. Since a naturalistic OCD patient sample was examined, some patients were medicated and some had current comorbid disorders. However, post hoc tests showed that results were not significantly affected by medication or comorbidity in the patient group. We could not analyze the subgroup of remitted patients (Yale-Brown Obsessive Compulsive Scale score <7), since this subgroup was too small (N=7) to attain sufficient statistical power. Numerically, there was no decrease in performance monitoring in this subgroup. Future research should also explore the stability of overactive performance monitoring over longer periods of clinical stabilization.

Furthermore, it remains to be clarified whether endophenotypes mediate between genes and the clinical phenotype or are risk indicators that share genes with the clinical phenotype (44). In addition to genes, environmental risk factors, such as aversive learning experiences regarding errors (45), can influence both the endophenotype and the clinical phenotype. In general, evidence identifying specific genes or mechanisms by which endophenotypes drive psychopathology has been limited (46). However, one major gain from endophenotype research may be the development of transdiagnostic concepts that are not limited to categorical diagnoses (46) as proposed in the Research Domain Criteria (38). Furthermore, the identification of endophenotypes enhances our understanding of the complex psychiatric disorders and can enable the early detection of individuals at risk and inspire research on new treatment strategies and targets. To examine whether performance-monitoring processes can be altered by specific interventions or training models that directly target it, and whether such changes in performance monitoring may lead to changes in symptoms as expected by a mediator model of endophenotypes (44), is a highly interesting and important avenue for future research. The current finding that overactive performance monitoring is independent of symptom changes in adult patients with OCD further validates its role as an endophenotype indicating vulnerability for OCD.