First-degree Relatives Of Obsessive-compulsive Disorder Patients Research Articles

Alterations of default mode and cingulo-opercular salience network and frontostriatal circuit: A candidate endophenotype of obsessive-compulsive disorder

BackgroundIt is gradually becoming clear that obsessive-compulsive disorder (OCD) patients have aberrant resting-state large-scale intrinsic networks of cingulo-opercular salience (SN), default mode (DMN), and front-parietal network (FPN). However, it remains unknown whether unaffected first-degree relatives of OCD patients have these alterations as a vulnerability marker to the disorder.MethodsWe performed resting-state functional magnetic resonance imaging (rsfMRI) scans of 47 medication-free OCD patients, 21 unaffected healthy first-degree relatives of OCD patients, and 62 healthy control (HC) participants. We explored differences between the three groups in the functional connectivity from SN (seeds: anterior-insula (AI) and dorsal anterior cingulate cortex (dACC)), DMN (seeds: medial prefrontal cortex (MPFC) and posterior parietal cortex (PCC)), and FPN (seeds: dorsolateral prefrontal cortex (DLPFC)).ResultsCompared to HC, both OCD patients and first-degree relatives showed significantly greater functional connectivity between AI and PCC and between DLPFC and the thalamus. Compared to first-degree relatives and HC, OCD patients showed reduced functional connectivity between PCC and DLPFC, and this altered functional connectivity was negatively correlated with anxiety and depressive symptom within OCD group.ConclusionsOCD patients and unaffected first-degree relatives of OCD patients showed overlapping alterations in resting state functional connectivity between the regions of SN and DMN and between DLPFC and the thalamus. Our results suggested that alterations between large-scale intrinsic networks and within the dorsal cognitive cortico-striato-thalamo-cortical (CSTC) circuit could represent endophenotype markers of OCD.

Polygenic risk for obsessive-compulsive disorder (OCD) predicts brain response during working memory task in OCD, unaffected relatives, and healthy controls

Alterations in frontal and parietal neural activations during working memory task performance have been suggested as a candidate endophenotype of obsessive-compulsive disorder (OCD) in studies involving first-degree relatives. However, the direct link between genetic risk for OCD and neuro-functional alterations during working memory performance has not been investigated to date. Thus, the aim of the current functional magnetic resonance imaging (fMRI) study was to test the direct association between polygenic risk for OCD and neural activity during the performance of a numeric n-back task with four working memory load conditions in 128 participants, including patients with OCD, unaffected first-degree relatives of OCD patients, and healthy controls. Behavioral results show a significant performance deficit at high working memory load in both patients with OCD and first-degree relatives (p < 0.05). A whole-brain analysis of the fMRI data indicated decreased neural activity in bilateral inferior parietal lobule and dorsolateral prefrontal cortex in both patients and relatives. Most importantly, OCD polygenic risk scores predicted neural activity in orbitofrontal cortex. Results indicate that genetic risk for OCD can partly explain alterations in brain response during working memory performance, supporting the notion of a neuro-functional endophenotype for OCD.

Error-related brain activity as a transdiagnostic endophenotype for obsessive-compulsive disorder, anxiety and substance use disorder.

Increased neural error-signals have been observed in obsessive-compulsive disorder (OCD), anxiety disorders, and inconsistently in depression. Reduced neural error-signals have been observed in substance use disorders (SUD). Thus, alterations in error-monitoring are proposed as a transdiagnostic endophenotype. To strengthen this notion, data from unaffected individuals with a family history for the respective disorders are needed. The error-related negativity (ERN) as a neural indicator of error-monitoring was measured during a flanker task from 117 OCD patients, 50 unaffected first-degree relatives of OCD patients, and 130 healthy comparison participants. Family history information indicated, that 76 healthy controls were free of a family history for psychopathology, whereas the remaining had first-degree relatives with depression (n = 28), anxiety (n = 27), and/or SUD (n = 27). Increased ERN amplitudes were found in OCD patients and unaffected first-degree relatives of OCD patients. In addition, unaffected first-degree relatives of individuals with anxiety disorders were also characterized by increased ERN amplitudes, whereas relatives of individuals with SUD showed reduced amplitudes. Alterations in neural error-signals in unaffected first-degree relatives with a family history of OCD, anxiety, or SUD support the utility of the ERN as a transdiagnostic endophenotype. Reduced neural error-signals may indicate vulnerability for under-controlled behavior and risk for substance use, whereas a harm- or error-avoidant response style and vulnerability for OCD and anxiety appears to be associated with increased ERN. This adds to findings suggesting a common neurobiological substrate across psychiatric disorders involving the anterior cingulate cortex and deficits in cognitive control.

Impaired Antisaccades in Obsessive-Compulsive Disorder: Evidence From Meta-Analysis and a Large Empirical Study.

Increasing evidence indicates that patients with obsessive-compulsive disorder (OCD) exhibit alterations in fronto-striatal circuitry. Performance deficits in the antisaccade task would support this model, but results from previous small-scale studies have been inconclusive as either increased error rates, prolonged antisaccade latencies, both or neither have been reported in OCD patients. In order to address this issue, we investigated antisaccade performance in a large sample of OCD patients (n = 169) and matched control subjects (n = 183). As impaired antisaccade performance constitutes a potential endophenotype of OCD, unaffected first-degree relatives of OCD patients (n = 100) were assessed, as well. Furthermore, we conducted a quantitative meta-analysis to integrate our data with previous findings. In the empirical study, OCD patients exhibited significantly increased antisaccade latencies, intra-subject variability (ISV) of antisaccade latencies, and antisaccade error rates. The latter effect was driven by errors with express latency (80–130 ms), as patients did not differ significantly from controls with regards to regular errors (>130 ms). Notably, unaffected relatives of OCD patients showed elevated antisaccade express error rates and increased ISV of antisaccade latencies, as well. Antisaccade performance was not associated with state anxiety within groups. Among relatives, however, we observed a significant correlation between antisaccade error rate and harm avoidance. Medication status of OCD patients, symptom severity, depressive comorbidity, comorbid anxiety disorders and OCD symptom dimensions did not significantly affect antisaccade performance. Meta-analysis of 10 previous and the present empirical study yielded a medium-sized effect (SMD = 0.48, p < 0.001) for higher error rates in OCD patients, while the effect for latencies did not reach significance owing to strong heterogeneity (SMD = 0.51, p = 0.069). Our results support the assumption of impaired antisaccade performance in OCD, although effects sizes were only moderately large. Furthermore, we provide the first evidence that increased antisaccade express error rates and ISV of antisaccade latencies may constitute endophenotypes of OCD. Findings regarding these more detailed antisaccade parameters point to potentially underlying mechanisms, such as early pre-stimulus inhibition of the superior colliculus.

Volitional saccade performance in a large sample of patients with obsessive-compulsive disorder and unaffected first-degree relatives.

Recent evidence indicates that patients with obsessive-compulsive disorder (OCD) as well as their unaffected first-degree relatives show deficits in the volitional control of saccades, suggesting that volitional saccade performance may constitute an endophenotype of OCD. Here, we aimed to replicate and extend these findings in a large, independent sample. One hundred and fifteen patients with OCD, 103 healthy comparison subjects without a family history of OCD, and 31 unaffected first-degree relatives of OCD patients were examined using structured clinical interviews and performed a volitional saccade task as well as a prosaccade task. In contrast to previous reports, neither patients nor relatives showed impairments in the performance of volitional saccades compared to healthy controls. Notably, medicated patients did not differ from nonmedicated patients, and there was no effect of depressive comorbidity. Additional analyses investigating correlations between saccade performance and OCD symptom dimensions yielded no significant associations. In conclusion, the present results do not support the notion that volitional saccade execution constitutes an endophenotype of OCD. Possible explanations for inconsistencies with previous studies are discussed.

T21 - Harm Avoidance And Childhood Adversities In Patients With Obsessive-Compulsive Disorder And Unaffected First-Degree Relatives: Evidence For A Diathesis-Stress Model

Background Obsessive-compulsive disorder (OCD) is a severe psychiatric disorder, which aggregates in families. Its etiology is assumed to involve interactions between genetically determined vulnerability factors and critical environmental influences. In the present study, we aim to investigate how the personality trait harm avoidance and the experience of different childhood adversities contribute to the development of OCD. Methods One hundred and sixty-nine patients with OCD, 157 healthy comparison subjects and 57 unaffected first-degree relatives of OCD patients were examined by trained clinical psychologists using the Structured Clinical Interview for DSM-IV (SKID). Harm avoidance was assessed using the Temperament and Character Inventory (TCI) and the severity of childhood adversities was measured with the Childhood Adversity Questionnaire (CTQ). Associations with depressive and obsessive-compulsive symptoms were investigated using the Beck Depression Inventory-II (BDI-II) and the Obsessive-Compulsive Inventory-Revised (OCI-R). Results Both OCD patients and unaffected relatives showed elevated levels of harm avoidance compared to healthy volunteers. Furthermore, patients exhibited significantly higher scores than relatives. This linear pattern was observed throughout all subscales of harm avoidance, and remained stable after controlling for the severity of depressive and obsessive-compulsive symptoms. With regards to childhood adversities, OCD patients reported higher levels than unaffected relatives and healthy volunteers, specifically on the subscales emotional abuse, emotional neglect, and experience of inconsistencies. Discussion The present findings support the role of harm avoidance as a potential endophenotype of OCD, and provide further evidence for a diathesis-stress model. While patients with OCD and unaffected first-degree relatives share elevated levels of harm avoidance, a heightened severity of childhood adversity was only observed in patients. A predisposition to exaggerated anxiety responses may thus take different trajectories depending on adverse environmental influences during childhood. In future research, we aim to investigate the genetic and epigenetic mechanisms underlying these findings.

ERROR-RELATED BRAIN ACTIVITY AS AN ENDOPHENOTYPE OF OBSESSIVE-COMPULSIVE DISORDER

abstract Endophenotypes are conceived as measurable but not directly observable features of mental disorders that link clinical symptoms with their genetic underpinnings. They promise to guide the search for specific causal gene variants but also to understand mechanisms of symptom generation more precisely. Several criteria have been listed that must been fulfilled by a trait to qualify for an endophenotype, like association with the disorder, presence in biological relatives of patients with the disorder, independence of symptom state, and heritability. Obsessive-compulsive disorder (OCD) is etiologically poorly understood but appears to be partially under genetic control. Identification of endophenotype candidates is therefore a viable strategy to make progress in understanding OCD. We conducted a series of studies evaluating the applicability of the error-related negativity (ERN) as an endophenotype of OCD. The ERN is an event-related brain potential elicited by the commission of errors but also by actions that are potentially false. We found larger ERN amplitudes in OCD patients compared to healthy controls in several independent studies case-control studies, with effects sizes (Cohen’s d) between 0.5 and 1.0 [2] . A twin study showed that shared genetic factors account for 47% of ERN variance [1] . Associations of enhanced ERN amplitudes with specific gene variants are preliminary as yet pointing to effects of genes coding serotonergic and dopaminergic neurotransmission. In a family study, first-degree relatives of OCD patients also showed enhanced ERN [2] , [3] , what was independently confirmed by another research group. To examine time stability and independence from symptom state, we measured ERN before and after completion of CBT in a group of 45 OCD patients. While symptoms improved, ERN remained unchanged supporting the notion that ERN enhancement is not a consequence of acute symptom state. In a cross-sectional study, associations between specific subtypes or symptom dimensions of OCD and ERN amplitudes could not be detected. These findings let us conclude that ERN is a stable trait that may be on the pathway between OCD-relevant genes and clinical symptoms. Further studies were conducted to examine mechanisms that influence ERN amplitudes. Intermittent punishment of errors elicited larger ERN amplitudes, which remained stable throughout an extinction phase. Furthermore, the ERN enhancement in OCD disappeared when patients were given a second task concurrently, possibly due to diminished resources available for performance monitoring. The ERN appears the best-confirmed endophenotype candidate of OCD to date. Now, larger studies must follow to identify the genetic variants contributing to enhanced ERN, to locate the brain areas driving the ERN effect, and to elucidate the connections between characteristics of error monitoring and the generation of specific symptoms. Direct modification of the ERN is a new challenge that might result in improved treatment of OCD. Finally, as ERN enhancements are also seen in other disorders like generalized anxiety disorder, social anxiety disorder and depression, a transdiagnostic concept is needed to obtain better accounts of psychopathology in OCD and other disorders.

Altered cognitive response to serotonin challenge as a candidate endophenotype for obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) implicates dysfunction of orbitofrontal and insula-related circuitry and of the serotonin system. There is an on-going search in psychiatry for intermediate biological markers, termed 'endophenotypes', that exist not only in patients with a given disorder but also in their clinically unaffected first-degree relatives. Pharmacological challenge is recognized as a means of eliciting an endophenotype, but this strategy has yet to be used in OCD. Twenty-three OCD patients without comorbidities (12 [52.2%] female), 13 clinically asymptomatic first-degree relatives of OCD patients (11 [84.6%] female) and 27 healthy controls (16 [59.3%] female) received single-dose escitalopram (20mg) and placebo in a randomized double-blind crossover design. Effects of treatment on decision-making were quantified using the Cambridge Gamble Task (CGT) in conjunction with a mixed model analysis of covariance (ANCOVA). There was a significant interaction between serotonergic challenge and group for risk adjustment on the CGT (F = 4.1406; p = 0.02). Only controls showed a significant placebo-drug change in risk adjustment (p = 0.02; versus p > 0.10). Numerically, escitalopram was associated with increase in risk adjustment in controls and reductions in the other groups. Change in risk adjustment was similar in OCD patients and relatives (p = 0.806) and differed significantly from controls (p = 0.007; p = 0.041, respectively). Individuals with OCD, and first-degree relatives, showed an altered cognitive response to serotonin challenge. This is the first demonstration of a candidate pharmacological challenge endophenotype for the disorder. Future work should confirm these findings in a larger sample size and ideally extend them to other cognitive paradigms, utilizing functional neuroimaging.

Cigarette smoking in obsessive-compulsive disorder and unaffected parents of OCD patients

BackgroundCigarette smoking is more prevalent among individuals with psychiatric disorders than the general population. Obsessive-compulsive disorder (OCD) may be an intriguing exception, although no recent study has investigated this hypothesis in OCD patients. Moreover, it is unknown whether reduced smoking rates are present in unaffected first-degree relatives of OCD patients. MethodsWe assessed smoking prevalence in adults with OCD and unaffected parents of youth with OCD (PYOCD). To this end, 113 adults with OCD completed online questionnaires assessing symptom severity and smoking status. Smoking status was obtained from an independent sample of 210 PYOCD assessed for psychiatric diagnoses. ResultsSmoking prevalence rates in adults with OCD (13.3%; n=15) and PYOCD (9.5%; n=20) samples were significantly lower than those found in representative samples of the general population (19–24%, all P<.001) and Axis I disorders (36–64%; all P<.001). There were no smokers in the adult OCD subset without clinically significant depressive symptoms (n=54). ConclusionLow prevalence of smoking in OCD may be familial and unique among psychiatric disorders, and might represent a possible state-independent OCD marker. Hypotheses concerning the uncharacteristically low prevalence rates are discussed with relation to OCD phenomenology and pathophysiology.

The role of the brain-derived neurotrophic factor SNP rs2883187 in the phenotypic expression of obsessive-compulsive disorder

We investigated the association between a brain-derived neurotrophic factor (BDNF) gene polymorphism and clinical features in a sample of patients with obsessive-compulsive disorder (OCD). A total of 100 patients diagnosed with OCD according to the Diagnostic and Statistical Manual IV criteria and 110 control subjects were included in this study. The distribution of a single nucleotide polymorphism rs2883187 was compared in OCD patients and normal controls. Clinical features were compared between the subgroups of OCD patients with different genotypes. There was no significant difference for the allele frequencies and genotype distributions between the OCD and control groups. The Hamilton Anxiety Rating Scale, Yale-Brown Obsessive Compulsive Scale obsession and total scores were found to be higher in patients with the CC genotype than in the patients who are homozygous for the T allele. The rates of OCD in first-degree relatives of OCD patients who were homozygous for the C allele were significantly higher, compared to those with CT and TT genotypes. Our results indicate that the CC genotype may be associated with the severity and increased familial loading of OCD. Further investigation based on larger populations is needed to reveal the full association of the BDNF polymorphism with OCD.

Impaired volitional saccade control: first evidence for a new candidate endophenotype in obsessive–compulsive disorder

Recent research suggests that patients with obsessive-compulsive disorder (OCD) have deficits in the volitional control of saccades. Specific evidence comes from increased latencies of saccadic eye movements when they were volitionally executed but not when they were visually guided. The present study sought to test whether this deviance represents a cognitive endophenotype. To this end, first-degree relatives of OCD patients as genetic risk carriers were compared with OCD patients and healthy controls without a family history of OCD. Furthermore, as volitional response generation comprises selection and initiation of the required response, the study also sought to specify the cognitive mechanisms underlying impaired volitional response generation. Twenty-two unaffected first-degree relatives of OCD patients, 22 unmedicated OCD patients, and 22 healthy comparison subjects performed two types of volitional saccade tasks measuring response selection or only response initiation, respectively. Visually guided saccades were used as a control condition. Our results showed that unaffected first-degree relatives and OCD patients were significantly slowed compared to healthy comparison subjects in volitional response selection. Patients and relatives did not differ from each other. There was no group difference in the visually guided control condition. Taken together, the study provides first evidence that dysfunctional volitional response selection is a candidate endophenotype for OCD.

P02-374 - Lack of mental flexibility as endophenotype in autism spectrum disorder and obsessive comulsive disorder families

IntroductionResults from clinical and molecular genetic studies suggest that autism spectrum disorder (ASD) and obsessive compulsive disorder (OCD) could have a shared pattern of heritability. Among a large number of clinical variables evaluated, obsessive compulsive/repetitive behaviors have been found to be highly correlated among autism probands and their relatives. Empirical evidence from neuropsychological studies suggest that an appropriate model for repetitive behaviours is a deficit of executive functions specifically flexibility. Given the lack of flexibility observed in ASD and OCD probands, we hypothesised that it could represent a shared endophenotype in both families.MethodsSeven cognitive tests belonging to executive functions, central coherence and theory of mind were proposed to 58 unaffected first-degree relatives of probands with ASD and 61 unaffected first-degree relatives of OCD patients and compared with 34 healthy controls. A principal component analysis (PCA) was performed.ResultsASD relatives - specifically mothers - performed significantly worse on all the tests than OCD relatives and controls. Moreover, inside the OCD group, female individuals performed significantly worse than males. Finally, the PCA indicate that the cognitive profiles of the ASD relatives and the OCD relatives were similar but distinct from controls.ConclusionLack of cognitive flexibility is observed in ASD and OCD families and might constitute a shared intermediate cognitive phenotype. Our study constitutes an effort to clarify the relationship between ASD and OCD having implications for our nosological understanding of both disorders.

Overactive Error-Related Brain Activity as a Candidate Endophenotype for Obsessive-Compulsive Disorder: Evidence From Unaffected First-Degree Relatives

Hyperactivity in frontal-striatal circuits is assumed to be involved in the pathophysiology of obsessive-compulsive disorder (OCD). In line with that, electrocortical correlates of overactive performance monitoring have been found to be associated with OCD independent from symptom state. The purpose of the present study was to elucidate whether overactive performance monitoring may represent a candidate endophenotype for OCD. In this case, unaffected first-degree relatives of OCD patients should also show this trait. Amplitudes of the error-related negativity and the correct-related negativity in the event-related brain potential during a flanker task were used to assess performance monitoring in three carefully matched groups: 30 patients with OCD, 30 unaffected first-degree relatives of OCD patients, and 30 healthy comparison subjects. Relative to the healthy comparison subjects, both unaffected first-degree relatives and OCD patients showed increased error-related brain potentials. No significant correlation was obtained between amplitudes and symptom severity measures, neither in patients nor in first-degree relatives. Increased error-related brain potentials were observed not only in OCD patients but also in unaffected first-degree relatives. Overactive error monitoring may reflect a trait marker for OCD that is independent of the presence of clinical symptoms. Thus, enhanced error-related brain activity represents a candidate neurocognitive endophenotype for OCD.

Seeking out candidate endophenotypes for OCD. Neurocognitive findings in unaffected relatives.

Background:Obsessive compulsive disorder (OCD) is a highly heritable neuropsychiatric disorder. Attempts to elucidate contributing genes have met with limited success. Intermediate markers of brain dysfunction (cognitive endophenotypes) may help focus the search for genetic contributions. Such markers should be present in people at risk of developing OCD in the absence of clinical symptoms. In prior work, OCD patients showed impairment on tests of response inhibition and cognitive flexibility (Chamberlain et al., 2005, 2006).Methods:First-degree relatives of OCD patients, patient probands, and matched healthy volunteers without a family history of OCD undertook neuropsychological assessment (n=20 per group).Results:Compared to matched controls without a family history of OCD, unaffected first-degree relatives of OCD patients showed impaired response inhibition (p<0.05) and cognitive flexibility (p<0.05). These deficits were comparable to those in the patients themselves.Conclusions:Brain-based cognitive markers of inhibitory functions may be of utility in the search for OCD endophenotypes. Examination of relationships between these abnormalities, genetics, and structural/functional brain changes, will help to elucidate aetiological contributions to OCD and putative spectrum disorders.

Shared executive dysfunctions in unaffected relatives of patients with autism and obsessive-compulsive disorder

Background Executive dysfunctions have been studied as a potential endophenotype associated with the genetic basis of autism. Given that recent findings from clinical and molecular genetic studies suggest that autism and obsessive-compulsive disorder (OCD) could share a common pattern of heritability, we assessed executive functions as a possible common cognitive endophenotype in unaffected family members of individuals with either autism or OCD. Methods Five tests assessing executive functions (Tower of London, verbal fluency, design fluency, trail making and association fluency) were proposed to 58 unaffected first-degree relatives (parents and siblings) of probands with autism and 64 unaffected first-degree relatives of OCD patients. Results were compared with those of 47 healthy controls matched for age, sex, and level of education. Results In the Tower of London test, both groups of unaffected relatives showed significantly lower scores and longer response times compared with controls. No differences were observed between autism and OCD relatives and healthy controls in the four other tasks (verbal fluency, design fluency, trail making test and association fluency). Conclusions Our findings show the existence of executive dysfunction in the unaffected first-degree relatives of probands with OCD, similar to those observed in the relatives of patients with autism. These results support and extend previous cognitive studies on probands indicating executive dysfunctions in autism and OCD. Planning and working memory processes could thus represent a common cognitive endophenotype in autism and OCD that could help in the identification of genes conferring vulnerability to these disorders.