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Obsessive-compulsive disorder (OCD) is a prevalent mental disorder affecting ~2-3% of the population. This disorder involves genetic and, possibly, epigenetic risk factors. The dynamic nature of epigenetics also presents a promising avenue for identifying biomarkers associated with symptom severity, clinical progression, and treatment response in OCD. We, therefore, conducted a comprehensive case-control investigation using Illumina MethylationEPIC BeadChip, encompassing 185 OCD patients and 199 controls recruited from two distinct sites in Germany. Rigorous clinical assessments were performed by trained raters employing the Structured Clinical Interview for DSM-IV (SCID-I). We performed a robust two-step epigenome-wide association study that led to the identification of 305 differentially methylated CpG positions. Next, we validated these findings by pinpointing the optimal set of CpGs that could effectively classify individuals into their respective groups. This approach identified a subset comprising 12 CpGs that overlapped with the 305 CpGs identified in our EWAS. These 12 CpGs are close to or in genes associated with the sweet-compulsive brain hypothesis which proposes that aberrant dopaminergic transmission in the striatum may impair insulin signaling sensitivity among OCD patients. We replicated three of the 12 CpGs signals from a recent independent study conducted on the Han Chinese population, underscoring also the cross-cultural relevance of our findings. In conclusion, our study further supports the involvement of epigenetic mechanisms in the pathogenesis of OCD. By elucidating the underlying molecular alterations associated with OCD, our study contributes to advancing our understanding of this complex disorder and may ultimately improve clinical outcomes for affected individuals.
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Epigenoma , Trastorno Obsesivo Compulsivo , Humanos , Trastorno Obsesivo Compulsivo/genética , Gravedad del Paciente , Índice de Severidad de la Enfermedad , AlemaniaRESUMEN
Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.
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Aprendizaje , Memoria a Corto Plazo , Memoria a Corto Plazo/fisiología , Aprendizaje Verbal , Herencia Multifactorial , EncéfaloRESUMEN
BACKGROUND: Obsessive-compulsive disorder (OCD) is a psychiatric disorder with multiple symptom dimensions (e.g. contamination, symmetry). OCD clusters in families and decades of twin studies clearly demonstrate an important role for genetics in the etiology of the disorder. METHODS: In this review, we summarize the genetic epidemiology and molecular genetic studies of OCD and obsessive-compulsive symptoms. RESULTS: OCD is a heritable, polygenic disorder with contributions from both common and rare variants, including de novo deleterious variations. Multiple studies have provided reliable support for a large additive genetic contribution to liability to OCD, with discrete OCD symptom dimensions having both shared and unique genetic risks. Genome-wide association studies have not produced significant results yet, likely because of small sample sizes, but larger meta-analyses are forthcoming. Both twin and genome-wide studies show that OCD shares genetic risk with its comorbid conditions (e.g. Tourette syndrome and anorexia nervosa). CONCLUSIONS: Despite significant efforts to uncover the genetic basis of OCD, the mechanistic understanding of how genetic and environmental risk factors interact and converge at the molecular level to result in OCD's heterogeneous phenotype is still mostly unknown. Future investigations should increase ancestral genetic diversity, explore age and/or sex differences in genetic risk for OCD and expand the study of pharmacogenetics, gene expression, gene × environment interactions and epigenetic mechanisms for OCD.
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Herencia Multifactorial/genética , Trastorno Obsesivo Compulsivo/genética , Anorexia Nerviosa/genética , Humanos , Fenotipo , Síndrome de Tourette/genética , Estudios en Gemelos como AsuntoRESUMEN
BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.
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Trastornos de Ansiedad/diagnóstico , Atención/fisiología , Electroencefalografía , Endofenotipos , Trastorno Obsesivo Compulsivo/diagnóstico , Trastornos Relacionados con Sustancias/diagnóstico , Adulto , Trastornos de Ansiedad/genética , Trastornos de Ansiedad/fisiopatología , Trastornos de Ansiedad/psicología , Variación Contingente Negativa/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastorno Obsesivo Compulsivo/genética , Trastorno Obsesivo Compulsivo/fisiopatología , Trastorno Obsesivo Compulsivo/psicología , Trastornos Relacionados con Sustancias/genética , Trastornos Relacionados con Sustancias/fisiopatología , Trastornos Relacionados con Sustancias/psicologíaRESUMEN
Patients with obsessive-compulsive disorder (OCD) show dysfunctions of the fronto-striatal circuitry, which imply corresponding oculomotor deficits including smooth pursuit eye movements (SPEM). However, evidence for a deficit in SPEM is inconclusive, with some studies reporting reduced velocity gain while others did not find any SPEM dysfunctions in OCD patients. Interestingly, psychosis-like traits have repeatedly been linked to both OCD and impaired SPEM. Here, we examined a large sample of n = 168 patients with OCD, n = 93 unaffected first-degree relatives and n = 171 healthy control subjects to investigate whether elevated levels of schizotypy and SPEM deficits represent potential endophenotypes of OCD. We applied a SPEM task with high demands on predictive pursuit that is more sensitive to assess executive dysfunctions than a standard task with continuous visual feedback, as episodes of target blanking put increased demands on basal ganglia and prefrontal involvement. Additionally, we examined the relation between schizotypy and SPEM performance in OCD patients and their relatives. Results indicate that OCD patients and unaffected relatives do not show deficient performance in either standard or predictive SPEM. Yet, both patients and relatives exhibited elevated levels of schizotypy, and schizotypy was significantly correlated with velocity gain during standard trials in unmedicated and depression-free OCD patients. These findings highlight the role of schizotypy as a candidate endophenotype of OCD and add to the growing evidence for predisposing personality traits in OCD. Furthermore, intact gain may represent a key characteristic that distinguishes the OCD and schizophrenia patient populations.
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Endofenotipos , Trastorno Obsesivo Compulsivo/fisiopatología , Seguimiento Ocular Uniforme/fisiología , Trastorno de la Personalidad Esquizotípica/fisiopatología , Adulto , Familia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The proneness to minor errors and slips in everyday life as assessed by the Cognitive Failures Questionnaire (CFQ) constitutes a trait characteristic and is reflected in stable features of brain structure and function. It is unclear, however, how dynamic interactions of large-scale brain networks contribute to this disposition. To address this question, we performed a high model order independent component analysis (ICA) with subsequent dual regression on resting-state fMRI data from 71 subjects to extract temporal time courses describing the dynamics of 17 resting-state networks (RSN). Dynamic network interactions between all 17 RSN were assessed by linear correlations between networks' time courses. On this basis, we investigated the relationship between subject-level RSN interactions and the susceptibility to everyday cognitive failure. We found that CFQ scores were significantly correlated with the interplay of the cingulo-opercular network (CON) and a posterior parietal network which unifies clusters in the posterior cingulate, precuneus, intraparietal lobules and middle temporal regions. Specifically, a higher positive functional connectivity between these two RSN was indicative of higher proneness to cognitive failure. Both the CON and posterior parietal network are implicated in cognitive functions, such as tonic alertness and executive control. Results indicate that proper checks and balances between the two networks are needed to protect against cognitive failure. Furthermore, we demonstrate that the study of temporal network dynamics in the resting state is a feasible tool to investigate individual differences in cognitive ability and performance.
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Corteza Cerebral/fisiología , Cognición/fisiología , Función Ejecutiva/fisiología , Neuroimagen Funcional/métodos , Red Nerviosa/fisiología , Adulto , Cerebelo/fisiología , Femenino , Humanos , Individualidad , Imagen por Resonancia Magnética , Masculino , Adulto JovenRESUMEN
Altered heart rate (HR) and heart rate variability (HRV) are common observations in psychiatric disorders. Yet, few studies have examined these cardiac measures in obsessive-compulsive disorder (OCD). The current study aimed to investigate HR and HRV, indexed by the root mean square of successive differences (RMSSD) and further time domain indices, as putative biological characteristics of OCD. Electrocardiogram was recorded during a five-minute resting state. Group differences between patients with OCD (n = 96), healthy participants (n = 112), and unaffected first-degree relatives of patients with OCD (n = 47) were analyzed. As potential moderators of group differences, we examined the influence of age and medication, respectively. As results indicated, patients with OCD showed higher HR and lower HRV compared to healthy participants. These group differences were not moderated by age. Importantly, subgroup analyses showed that only medicated patients displayed lower HRV compared to healthy individuals, while HR alterations were evident in unmedicated patients. Regarding unaffected first-degree relatives, group differences in HRV remained at trend level. Further, an age-moderated group differentiation showed that higher HRV distinguished relatives from healthy individuals in young adulthood, whereas at higher age lower HRV was indicative of relatives. Both the role of familial risk and medication in HRV alterations need further elucidation. Pending future studies, alterations in HR and potentially HRV might serve as useful indices to characterize the pathophysiology of OCD.
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Electrocardiografía , Familia , Frecuencia Cardíaca , Trastorno Obsesivo Compulsivo , Humanos , Trastorno Obsesivo Compulsivo/fisiopatología , Trastorno Obsesivo Compulsivo/genética , Frecuencia Cardíaca/fisiología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Adulto Joven , Adolescente , Factores de EdadRESUMEN
Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent genome-wide significant SNPs and a SNP-based heritability of 6.7%. Separate GWAS for clinical, biobank, comorbid, and self-report sub-groups found no evidence of sample ascertainment impacting our results. Functional and positional QTL gene-based approaches identified 249 significant candidate risk genes for OCD, of which 25 were identified as putatively causal, highlighting WDR6, DALRD3, CTNND1 and genes in the MHC region. Tissue and single-cell enrichment analyses highlighted hippocampal and cortical excitatory neurons, along with D1- and D2-type dopamine receptor-containing medium spiny neurons, as playing a role in OCD risk. OCD displayed significant genetic correlations with 65 out of 112 examined phenotypes. Notably, it showed positive genetic correlations with all included psychiatric phenotypes, in particular anxiety, depression, anorexia nervosa, and Tourette syndrome, and negative correlations with a subset of the included autoimmune disorders, educational attainment, and body mass index.. This study marks a significant step toward unraveling its genetic landscape and advances understanding of OCD genetics, providing a foundation for future interventions to address this debilitating disorder.
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Obsessive-compulsive disorder (OCD) has recently been linked to increased methylation levels in the oxytocin receptor (OXTR) gene, and OXTR hypermethylation has predicted a worse treatment response to cognitive-behavioural therapy (CBT). Furthermore, OCD is associated with childhood trauma and stressful life events, which have both been shown to affect OXTR methylation. Here, we aimed to replicate findings of increased OXTR methylation as a predictor of disease and worse treatment response in an independent sample that received treatment within the public health care system. In addition, we aimed to extend previous findings by examining associations between OXTR hypermethylation, environmental stressors, OCD diagnosis, and treatment response. Methylation levels at two CpGs within OXTR exon III were compared between n = 181 OCD patients and n = 199 healthy controls using linear regression analysis. In a subsample of OCD patients (n = 98) with documented treatment data, we examined associations between methylation and treatment response to CBT. Childhood adversity and stressful life events were assessed using Childhood Trauma Questionnaire and Life Experience Survey, respectively. OCD patients exhibited significant hypermethylation at CpG site cg04523291 compared to controls, and increased methylation was associated with impaired treatment response. Moreover, hypermethylation at cg04523291 was associated with stressful life events in OCD patients, and with childhood adversity in controls. Yet, there were no significant mediation effects. In conclusion, we replicated the association between OXTR hypermethylation and OCD in the largest sample, so far. Furthermore, our findings support the role of OXTR methylation as a promising biomarker for treatment response in OCD.
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Metilación de ADN , Trastorno Obsesivo Compulsivo , Receptores de Oxitocina , Biomarcadores , Humanos , Trastorno Obsesivo Compulsivo/genética , Trastorno Obsesivo Compulsivo/terapia , Oxitocina , Receptores de Oxitocina/genéticaRESUMEN
Background: Indicators of increased error monitoring are associated with obsessive-compulsive disorder (OCD), as shown in electroencephalography and functional magnetic resonance imaging studies. As most studies used strictly controlled samples (excluding comorbidity and medication), it remains open whether these findings extend to naturalistic settings. Thus, we assessed error-related brain activity in a large, naturalistic OCD sample. We also explored which activity patterns might qualify as vulnerability endophenotypes or protective factors for the disorder. To this aim, a sample of unaffected first-degree relatives of patients with OCD was also included. Methods: Participants (84 patients with OCD, 99 healthy control participants, and 37 unaffected first-degree relatives of patients with OCD) completed a flanker task while blood oxygen level-dependent responses were measured with functional magnetic resonance imaging. Aberrant error-related brain activity in patients and relatives was identified. Results: Patients with OCD showed increased error-related activity in the supplementary motor area and within the default mode network, specifically in the precuneus and postcentral gyrus. Unaffected first-degree relatives showed increased error-related activity in the bilateral inferior frontal gyrus. Conclusions: Increased supplementary motor area and default mode network activity in patients with OCD replicates previous studies and might indicate excessive error signals and increased self-referential error processing. Increased activity of the inferior frontal gyrus in relatives may reflect increased inhibition. Impaired response inhibition in OCD has been demonstrated in several studies and might contribute to impairments in suppressing compulsive actions. Thus, increased inferior frontal gyrus activity in the unaffected relatives of patients with OCD may have contributed to protection from symptom development.
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BACKGROUND: Although cognitive behavioral therapy is a highly effective treatment for obsessive-compulsive disorder (OCD), yielding large symptom reductions on the group level, individual treatment response varies considerably. Identification of treatment response predictors may provide important information for maximizing individual treatment response and thus achieving efficient treatment resource allocation. Here, we investigated the predictive value of previously identified biomarkers of OCD, namely the error-related activity of the supplementary motor area (SMA) and the sensorimotor network (SMN, postcentral gyrus/precuneus). METHODS: Seventy-two participants with a primary diagnosis of OCD underwent functional magnetic resonance imaging (fMRI) scanning while performing a flanker task prior to receiving routine-care CBT. RESULTS: Error-related BOLD response of the SMN significantly contributed to the prediction of treatment response beyond the variance accounted for by clinical and sociodemographic variables. Stronger error-related SMN activity at baseline was associated with a higher likelihood of treatment response. CONCLUSIONS: The present results illustrate that the inclusion of error-related SMN activity can significantly increase treatment response prediction quality in OCD. Stronger error-related activity of the SMN may reflect the ability to activate symptom-relevant processing networks and may thus facilitate response to exposure-based CBT interventions.
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Terapia Cognitivo-Conductual , Corteza Motora , Trastorno Obsesivo Compulsivo , Humanos , Trastorno Obsesivo Compulsivo/diagnóstico por imagen , Trastorno Obsesivo Compulsivo/terapia , Terapia Cognitivo-Conductual/métodos , Imagen por Resonancia Magnética , Corteza Motora/diagnóstico por imagen , Resultado del TratamientoRESUMEN
Schizotypy refers to a set of personality traits that bear resemblance, at subclinical level, to psychosis. Despite evidence of similarity at multiple levels of analysis, direct comparisons of schizotypy and clinical psychotic disorders are rare. Therefore, we used functional magnetic resonance imaging (fMRI) to examine the neural correlates and task-based functional connectivity (psychophysiological interactions; PPI) of smooth pursuit eye movements (SPEM) in patients with recent onset psychosis (ROP; n = 34), participants with high levels of negative (HNS; n = 46) or positive (HPS; n = 41) schizotypal traits, and low-schizotypy control participants (LS; n = 61) using machine-learning. Despite strong previous evidence that SPEM is a highly reliable marker of psychosis, patients and controls could not be significantly distinguished based on SPEM performance or blood oxygen level dependent (BOLD) signal during SPEM. Classification was, however, significant for the right frontal eye field (FEF) seed region in the PPI analyses but not for seed regions in other key areas of the SPEM network. Applying the right FEF classifier to the schizotypal samples yielded decision scores between the LS and ROP groups, suggesting similarities and dissimilarities of the HNS and HPS samples with the LS and ROP groups. The very small difference between groups is inconsistent with previous studies that showed significant differences between patients with ROP and controls in both SPEM performance and underlying neural mechanisms with large effect sizes. As the current study had sufficient power to detect such differences, other reasons are discussed.
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BACKGROUND: Virtual reality (VR) technologies are playing an increasingly important role in the diagnostics and treatment of mental disorders. OBJECTIVE: To systematically review the current evidence regarding the use of VR in the diagnostics and treatment of mental disorders. DATA SOURCE: Systematic literature searches via PubMed (last literature update: 9th of May 2022) were conducted for the following areas of psychopathology: Specific phobias, panic disorder and agoraphobia, social anxiety disorder, generalized anxiety disorder, posttraumatic stress disorder (PTSD), obsessive-compulsive disorder, eating disorders, dementia disorders, attention-deficit/hyperactivity disorder, depression, autism spectrum disorder, schizophrenia spectrum disorders, and addiction disorders. ELIGIBILITY CRITERIA: To be eligible, studies had to be published in English, to be peer-reviewed, to report original research data, to be VR-related, and to deal with one of the above-mentioned areas of psychopathology. STUDY EVALUATION: For each study included, various study characteristics (including interventions and conditions, comparators, major outcomes and study designs) were retrieved and a risk of bias score was calculated based on predefined study quality criteria. RESULTS: Across all areas of psychopathology, k = 9315 studies were inspected, of which k = 721 studies met the eligibility criteria. From these studies, 43.97% were considered assessment-related, 55.48% therapy-related, and 0.55% were mixed. The highest research activity was found for VR exposure therapy in anxiety disorders, PTSD and addiction disorders, where the most convincing evidence was found, as well as for cognitive trainings in dementia and social skill trainings in autism spectrum disorder. CONCLUSION: While VR exposure therapy will likely find its way successively into regular patient care, there are also many other promising approaches, but most are not yet mature enough for clinical application. REVIEW REGISTRATION: PROSPERO register CRD42020188436. FUNDING: The review was funded by budgets from the University of Bonn. No third party funding was involved.
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Trastorno del Espectro Autista , Demencia , Trastornos Fóbicos , Terapia de Exposición Mediante Realidad Virtual , Realidad Virtual , Humanos , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/terapia , Trastornos Fóbicos/terapia , Trastornos de Ansiedad/diagnóstico , Trastornos de Ansiedad/terapiaRESUMEN
BACKGROUND: Benzodiazepines have reliable adverse effects on saccadic eye movements, but the impact of sex as a potential modulator of these effects is less clear. A recent study reported stronger adverse effects on the spatial consistency of saccades in females, which may reflect sex differences in cerebellar mechanisms. AIMS: We aimed to further examine the role of sex as a potential modulator of benzodiazepine effects by employing the saccadic adaptation paradigm, which is known to be sensitive to cerebellar functioning. METHODS: A total of n=50 healthy adults performed a horizontal step prosaccade task and a saccadic adaptation task under 0.5 mg lorazepam, 1 mg lorazepam and placebo in a double-blind, within-subjects design. RESULTS: In the prosaccade task, lorazepam had adverse effects on measures of peak velocity, latency and spatial consistency. The administration of 0.5 mg lorazepam led to significant reductions in gain-decrease adaptation, while a dose of 1 mg did not impair adaptation learning. Gain-increase adaptation was generally less pronounced, and unaffected by the drug. There were no significant drug×sex interactions in either task. CONCLUSIONS: We conclude that a low dose of lorazepam impairs gain-decrease adaptation independent of sex. At higher doses, however, increasing fatigue may facilitate adaptation and thus counteract the adverse effects observed at lower doses. With regards to prosaccades, our findings confirm peak velocity as well as latency and spatial measures as sensitive biomarkers of GABAergic effects.
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Lorazepam/farmacología , Movimientos Sacádicos , Adulto , Benzodiazepinas/farmacología , Relación Dosis-Respuesta a Droga , Medidas del Movimiento Ocular , Femenino , Moduladores del GABA/farmacología , Voluntarios Sanos , Humanos , Masculino , Movimientos Sacádicos/efectos de los fármacos , Movimientos Sacádicos/fisiología , Factores Sexuales , Análisis y Desempeño de TareasRESUMEN
BACKGROUND: Inhibitory control is a crucial executive function with high relevance to mental and physical well-being. However, there are still unanswered questions regarding its neural mechanisms, including the role of the major inhibitory neurotransmitter, γ-aminobutyric acid (GABA). AIMS: This study examined the effects of lorazepam (0.5 mg and 1 mg), a positive allosteric modulator at the GABAA receptor, on response inhibition and interference control. We also explored the heterogeneity of inhibitory control and calculated delta plots to explore whether lorazepam affects the gradual build-up of inhibition and activation over time. METHODS: N = 50 healthy participants performed antisaccade, Eriksen flanker and Simon tasks in a within-subjects, placebo-controlled, double-blind randomized design. RESULTS: Lorazepam increased reaction time (RT) and error rates dose dependently in all tasks (p ⩽ 0.005). In the antisaccade and Simon tasks, lorazepam increased congruency effects for error rate (p ⩽ 0.029) but not RT (p ⩾ 0.587). In the Eriksen flanker task, both congruency effects were increased by the drug (p ⩽ 0.031). Delta plots did not reflect drug-induced changes in inhibition and activation over time. Delta plots for RT in the Simon task were negative-going, as expected, whereas those for the antisaccade and flanker tasks were positive-going. CONCLUSIONS: This study provides evidence for GABAergic involvement in performance on response inhibition and interference control tasks. Furthermore, our findings highlight the diversity of the broader construct of inhibitory control while also pointing out similarities between different inhibitory control tasks. In contrast to RT and error rates, the cognitive processes indexed by delta plots may not be sensitive to GABAergic modulation.
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Atención/efectos de los fármacos , Función Ejecutiva/efectos de los fármacos , GABAérgicos/farmacología , Inhibición Psicológica , Lorazepam/farmacología , Desempeño Psicomotor/efectos de los fármacos , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Receptores de GABA-A/efectos de los fármacos , Adulto JovenRESUMEN
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.
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Corteza Prefontal Dorsolateral/fisiopatología , Memoria a Corto Plazo/fisiología , Trastorno Obsesivo Compulsivo/fisiopatología , Lóbulo Parietal/fisiopatología , Adolescente , Adulto , Anciano , Mapeo Encefálico/métodos , Corteza Prefontal Dorsolateral/diagnóstico por imagen , Familia , Femenino , Predisposición Genética a la Enfermedad , Voluntarios Sanos , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Herencia Multifactorial , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/fisiopatología , Trastorno Obsesivo Compulsivo/diagnóstico , Trastorno Obsesivo Compulsivo/genética , Lóbulo Parietal/diagnóstico por imagen , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Adulto JovenRESUMEN
Patients with obsessive-compulsive disorder (OCD) show deficient planning capacity in the Tower of London (TOL) problem solving task. Preliminary evidence for similar deficits in unaffected first-degree relatives suggests that impaired planning may constitute an endophenotype of OCD. However, results on this issue are inconsistent, possibly owing to small sample sizes and variability in problem structure across TOL tasks. Here, we adopted a computerized version of the TOL task featuring a 2â¯×â¯2 factorial design (high/low search depthâ¯×â¯full/partial tower goal state) and examined a well-characterized sample of nâ¯=â¯72 OCD patients, nâ¯=â¯76 unaffected first-degree relatives and nâ¯=â¯102 healthy comparison subjects. Both OCD patients and relatives exhibited significantly less accurate problem solving than controls. Search depth, goal hierarchy, or the number of minimum moves did not moderate these group differences. Medication, OCD symptoms, and depressive comorbidity did not affect TOL performance in patients, suggesting a state-independent effect. In conclusion, we found that OCD patients as well as unaffected first-degree relatives show deficient TOL performance across a range of task conditions, strongly supporting the role of impaired planning as an endophenotype of OCD, and contributing to the growing evidence for fronto-striatal dysfunctions in OCD.
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Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/psicología , Cognición , Endofenotipos , Función Ejecutiva , Salud de la Familia , Trastorno Obsesivo Compulsivo/complicaciones , Trastorno Obsesivo Compulsivo/psicología , Solución de Problemas , Adulto , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
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.
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Previous research in patients with obsessive-compulsive disorder (OCD) has indicated performance decrements in working memory (WM) and response inhibition. However, underlying neural mechanisms of WM deficits are not well understood to date, and empirical evidence for a proposed conceptual link to inhibition deficits is missing. We investigated WM performance in a numeric n-back task with four WM load conditions during functional Magnetic Resonance Imaging (fMRI) in 51 patients with OCD and 49 healthy control participants who were matched for age, sex, and education. Additionally, a stop signal task was performed outside the MRI scanner in a subsample. On the behavioral level, a significant WM load by group interaction was found for both accuracy (p < 0.02) and reaction time measures (p < 0.03), indicating increased reaction times as well as reduced accuracy specifically at high WM load (3-back) in patients with OCD. Whole-brain analyses of fMRI-data identified neural correlates of a load-dependent WM decrement in OCD in the supplementary motor area (SMA) and the inferior parietal lobule (IPL). Within the OCD sample, SMA-activity as well as n-back performance were correlated with stop signal task performance. Results from behavioral and fMRI-analyses indicate a reduced WM load-dependent modulation of neural activity in OCD and suggest a common neural mechanism for inhibitory dysfunction and WM decrements in OCD.
Asunto(s)
Encéfalo/fisiopatología , Inhibición Psicológica , Trastornos de la Memoria/fisiopatología , Memoria a Corto Plazo/fisiología , Trastorno Obsesivo Compulsivo/fisiopatología , Trastorno Obsesivo Compulsivo/psicología , Adulto , Mapeo Encefálico , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos de la Memoria/complicaciones , Trastorno Obsesivo Compulsivo/complicacionesRESUMEN
Repeated drug use modifies the emotional and cognitive processing of drug-associated cues. These changes are supposed to persist even after prolonged abstinence. Several studies demonstrated that smoking cues selectively attract the attention of smokers, but empirical evidence for such an attentional bias among successful quitters is inconclusive. Here, we investigated whether attentional biases persist after smoking cessation. Thirty-eight former smokers, 34 current smokers, and 29 non-smokers participated in a single experimental session. We used three measures of attentional bias for smoking stimuli: A visual probe task with short (500ms) and long (2000ms) picture stimulus durations, and a modified Stroop task with smoking-related and neutral words. Former smokers and current smokers, as compared to non-smokers, showed an attentional bias in visual orienting to smoking pictures in the 500ms condition of the visual probe task. The Stroop interference index of smoking words was negatively related to nicotine dependence in current smokers. Former smokers and mildly dependent smokers, as compared to non-smokers, showed increased interference by smoking words in the Stroop task. Neither current nor former smokers showed an attentional bias in maintained attention (2000ms visual probe task). In conclusion, even after prolonged abstinence smoking cues retain incentive salience in former smokers, who differed from non-smokers on two attentional bias indices. Attentional biases in former smokers operate mainly in early involuntary rather than in controlled processing, and may represent a vulnerability factor for relapse. Therefore, smoking cessation programs should strengthen self-control abilities to prevent relapses.