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Pino Alonso,
Clara López-Solà,
Mónica Gratacós,
Miquel Angel Fullana,
Cinto Segalàs, Eva Real,
Narcís Cardoner,
Carles Soriano-Mas,
Ben J Harrison,
Xavier Estivill,
José M Menchón
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ABSTRACT: Cognitive models emphasize the importance of dysfunctional beliefs as overimportance/need to control thoughts, perfectionism, intolerance of uncertainty, responsibility, and overestimation of threat in obsessive-compulsive disorder (OCD). Twin studies suggest that these beliefs are significantly heritable, but candidate genes associated with them have not been analyzed. We genotyped the Val158Met in the COMT gene and Val66Met variant in the BDNF gene in 141 OCD patients and analyzed their single and interactive effects on the obsessive beliefs questionnaire (OBQ-44). Variability in dysfunctional beliefs was not affected by the COMT or BDNF genotype in isolation, but we detected a significant COMT×BDNF interaction effect on responsibility/overestimation of threat and overimportance/need to control thoughts scores. Subjects with the BDNF Met-present and the COMT Met-present genotype showed higher scores on responsibility/overestimation of threat. An interaction between dopaminergic and neurotrophic functional gene variants may influence dysfunctional beliefs hypothesized to contribute to the development of OCD.
Journal of anxiety disorders 03/2013; 27(3):321-327. · 2.68 Impact Factor
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Ben J Harrison,
Jesus Pujol,
Narcis Cardoner,
Joan Deus,
Pino Alonso,
Marina López-Solà,
Oren Contreras-Rodríguez, Eva Real,
Cinto Segalàs,
Laura Blanco-Hinojo,
José M Menchon,
Carles Soriano-Mas
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ABSTRACT: BACKGROUND: Functional neuroimaging studies have provided consistent support for the idea that obsessive-compulsive disorder (OCD) is associated with disturbances of brain corticostriatal systems. However, in general, these studies have not sought to account for the disorder's prominent clinical heterogeneity. METHODS: To address these concerns, we investigated the influence of major OCD symptom dimensions on brain corticostriatal functional systems in a large sample of OCD patients (n = 74) and control participants (n = 74) examined with resting-state functional magnetic resonance imaging. We employed a valid method for mapping ventral and dorsal striatal functional connectivity, which supported both standard group comparisons and linear regression analyses with patients' scores on the Dimensional Yale-Brown Obsessive-Compulsive Scale. RESULTS: Consistent with past findings, patients demonstrated a common connectivity alteration involving the ventral striatum and orbitofrontal cortex that predicted overall illness severity levels. This common alteration was independent of the effect of particular symptom dimensions. Instead, we observed distinct anatomical relationships between the severity of symptom dimensions and striatal functional connectivity. Aggression symptoms modulated connectivity between the ventral striatum, amygdala, and ventromedial frontal cortex, while sexual/religious symptoms had a specific influence on ventral striatal-insular connectivity. Hoarding modulated the strength of ventral and dorsal striatal connectivity with distributed frontal regions. CONCLUSIONS: Taken together, these results suggest that pathophysiological changes among orbitofrontal-striatal regions may be common to all forms of OCD. They suggest that a further examination of certain dimensional relationships will also be relevant for advancing current neurobiological models of the disorder.
Biological psychiatry 11/2012; · 8.93 Impact Factor
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Ben J Harrison,
Jesus Pujol,
Carles Soriano-Mas,
Rosa Hernández-Ribas,
Marina López-Solà,
Hector Ortiz,
Pino Alonso,
Joan Deus,
José M Menchon, Eva Real,
Cinto Segalàs,
Oren Contreras-Rodríguez,
Laura Blanco-Hinojo,
Narcís Cardoner
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ABSTRACT: Heightened moral sensitivity seems to characterize patients with obsessive-compulsive disorder (OCD). Recent advances in social cognitive neuroscience suggest that a compelling relationship may exist between this disorder-relevant processing bias and the functional activity of brain regions implicated in OCD.
To test the hypothesis that patients with OCD demonstrate an increased response of relevant ventromedial prefrontal and orbitofrontal cortex regions in a functional magnetic resonance imaging study of difficult moral decision making.
Case-control cross-sectional study.
Hospital referral OCD unit and magnetic resonance imaging facility.
Seventy-three patients with OCD (42 men and 31 women) and 73 control participants matched for age, sex, and education level.
Functional magnetic resonance imaging activation maps representing significant changes in blood oxygenation level-dependent signal in response to 24 hypothetical moral dilemma vs nondilemma task vignettes and additional activation maps representing significant linear associations between patients' brain responses and symptom severity ratings.
In both groups, moral dilemma led to robust activation of frontal and temporoparietal brain regions. Supporting predictions, patients with OCD demonstrated significantly increased activation of the ventral frontal cortex, particularly of the medial orbitofrontal cortex. In addition, the left dorsolateral prefrontal cortex and left middle temporal gyrus were more robustly activated in patients with OCD. These results were unexplained by group differences in comorbid affective symptoms. Patients' global illness severity predicted the relative magnitude of orbitofrontal-striatal activation. The severity of "harm/checking" symptoms and "sexual/religious" obsessions predicted the magnitude of posterior temporal and amygdala-paralimbic activation, respectively.
The neural correlates of moral sensitivity in patients with OCD partly coincide with brain regions that are of general interest to pathophysiologic models of this disorder. In particular, these findings suggest that the orbitofrontal cortex together with the left dorsolateral prefrontal cortex may be relevant for understanding the link between neurobiological processes and certain maladaptive cognitions in OCD.
Archives of general psychiatry 07/2012; 69(7):741-9. · 12.26 Impact Factor
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ABSTRACT: Recent data from neuroimaging, genetic and clinical trials and animal models suggest a role for altered glutamatergic neuro transmission in the pathogenesis of obsessive-compulsive disorder (OCD). The aim of this study was to investigate whether variants in the GRIN2B gene, the gene encoding the NR2 subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor, may contribute to genetic susceptibility to OCD or to different OCD subphenotypes.
Between 2003 and 2008, we performed a case-control association study in which we genotyped 10 tag single-nucleotide polymorphisms (SNPs) in the 3' untranslated region (3' UTR) of GRIN2B. We performed SNP association and haplotype analysis considering the OCD diagnosis and different OCD subphenotypes: early-onset OCD, comorbid tic disorders and OCD clinical symptom dimensions.
We enrolled 225 patients with OCD and 279 controls recruited from the OCD Clinic at Bellvitge Hospital (Barcelona, Spain). No significant difference in the distribution of alleles or genotypes was detected between patients with OCD and controls. Nonetheless, on analyzing OCD subphenotypes, the rs1805476 SNP in male patients (95% confidence interval [CI] 1.37-4.22, p = 0.002) and a 4-SNP haplotype in the whole sample (rs1805476, rs1805501, rs1805502 and rs1805477; odds ratio 1.92, 95% CI 1.22-3.01; permutation p = 0.023) were significantly associated with the presence of contamination obsessions and cleaning compulsions.
Study limitations included the risk of population stratification associated with the case-control design, use of psychiatrically unscreened blood donors as the control group, reduced sample size of participants with certain OCD subphenotypes and tested polymorphisms limited to 3' UTR and exon 13 of GRIN2B.
Our results converge with recent data suggesting a possible contribution of glutamatergic variants to the genetic vulnerability to OCD or at least to certain OCD manifestations. The dissection of OCD into more homogeneous subphenotypes may constitute a useful tool to disentangle the complex genetic basis of the disorder.
Journal of psychiatry & neuroscience: JPN 03/2012; 37(4):273-81. · 5.34 Impact Factor
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Jesus Pujol,
Iolanda Batalla,
Oren Contreras-Rodríguez,
Ben J Harrison,
Vanessa Pera,
Rosa Hernández-Ribas, Eva Real,
Laura Bosa,
Carles Soriano-Mas,
Joan Deus,
Marina López-Solà,
Josep Pifarré,
José M Menchón,
Narcís Cardoner
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ABSTRACT: Neuroimaging research has demonstrated the involvement of a well-defined brain network in the mediation of moral judgment in normal population, and has suggested the inappropriate network use in criminal psychopathy. We used functional magnetic resonance imaging (fMRI) to prove that alterations in the brain network subserving moral judgment in criminal psychopaths are not limited to the inadequate network use during moral judgment, but that a primary network breakdown would exist with dysfunctional alterations outside moral dilemma situations. A total of 22 criminal psychopathic men and 22 control subjects were assessed and fMRI maps were generated to identify (i) brain response to moral dilemmas, (ii) task-induced deactivation of the network during a conventional cognitive task and (iii) the strength of functional connectivity within the network during resting-state. The obtained functional brain maps indeed confirmed that the network subserving moral judgment is underactive in psychopathic individuals during moral dilemma situations, but the data also provided evidence of a baseline network alteration outside moral contexts with a functional disconnection between emotional and cognitive elements that jointly construct moral judgment. The finding may have significant social implications if considering psychopathic behavior to be a result of a primary breakdown in basic brain systems.
Social Cognitive and Affective Neuroscience 10/2011; · 6.13 Impact Factor
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Narcís Cardoner,
Ben J Harrison,
Jesús Pujol,
Carles Soriano-Mas,
Rosa Hernández-Ribas,
Marina López-Solá, Eva Real,
Joan Deus,
Hector Ortiz,
Pino Alonso,
José M Menchón
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ABSTRACT: OBJECTIVES. The abnormal processing of emotional stimuli is common to a variety of psychiatric disorders. Specifically, patients with prominent anxiety symptoms generally overreact to emotional cues, which has been linked to increased amygdala activation. However, in OCD, enhanced responses are predominantly obtained using disease-specific stimuli and preferentially involve frontostriatal systems. METHODS. We assessed 21 OCD patients and 21 healthy controls with fMRI during an emotional face-processing paradigm involving active response generation to test for alterations in both brain activation and task-induced functional connectivity of the frontal cortex, the amygdala and the fusiform face area. RESULTS. OCD patients showed significantly greater activation of "face-processing" regions including the amygdala, fusiform gyrus and dorsolateral prefrontal cortex. The reciprocal connectivity between face-processing regions was enhanced in OCD. Importantly, we detected significant correlations between patients' clinical symptom severity and both task-related region activation and network functional connectivity. CONCLUSIONS. The results suggest that OCD patients may show enhanced brain responsiveness during emotional face-processing when tasks involve active response generation. Our findings diverge from previously described alterations in anxiety disorders, as patients showed enhanced amygdala-prefrontal connectivity as opposed to negative reciprocal interaction. This pattern would appear to be disorder-specific and was significantly related to obsessive-compulsive symptom severity.
The World Journal of Biological Psychiatry 08/2011; 12(5):349-63. · 2.38 Impact Factor
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ABSTRACT: Neuroimaging and neuropsychological data from patients with an obsessive-compulsive disorder (OCD) indicate the dysfunction of the orbitofrontal cortex (OFC). Olfactory processing has been associated with OFC function, although results from OCD studies regarding this sensory modality have been inconclusive. No previous study has analyzed both odor discrimination and identification capacity in OCD patients using "Sniffin' Sticks" tests. The aim of our study was to assess odor threshold, identification, discrimination, and nonverbal memory in OCD patients, in order to determine whether these functions were affected.
Olfactory function was measured in 29 OCD patients and 29 healthy volunteers (HV) using the "Sniffin' Sticks" test and their nonverbal memory was scored with the Rey-Osterrieth Complex Figure Test.
OCD patients showed significant impairment in their odor performance and in their execution of the nonverbal memory task compared to HV. No statistical associations were found between the deficits in the two areas. The severity of depressive and obsessive-compulsive symptoms did correlate with olfactory identification.
Our findings support the hypothesis that olfactory and memory dysfunctions in OCD reflect different neurobiological alterations of the disorder, and point to the modulation effect of depressive and obsessive-compulsive symptoms on odor performance.
Depression and Anxiety 05/2011; 28(10):932-40. · 4.18 Impact Factor
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The Journal of Clinical Psychiatry 03/2011; 72(3):417-8. · 5.80 Impact Factor
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ABSTRACT: Environmental stressors are considered to play an important role in the triggering of mental disorders such as obsessive-compulsive disorder (OCD). Although there is extensive literature on traumatic life events, little is known about the role of nontraumatic but nonetheless stressful life events (SLEs) in OCD. The aim of this study was to establish whether OCD preceded by an SLE presents a different clinical pattern compared to non-SLE-preceded OCD.
We interviewed 412 OCD patients to assess both SLEs at onset of OCD and other clinical variables, including OCD symptom dimensions. Logistic regression was then applied to explore the relationship between clinical variables and OCD preceded by an SLE.
The SLE-preceded OCD group showed a later onset of the disorder (OR = 1.04, P = .015), a history of complicated birth (OR = 5.54, P<.001), less family history of OCD (OR = 0.42, P = .014), and the presence of contamination/cleaning symptoms (OR = 1.99, P = .01).
Patients with OCD onset close to an SLE and those without an SLE close to OCD onset show a distinct clinical pattern.
Depression and Anxiety 02/2011; 28(5):367-76. · 4.18 Impact Factor
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ABSTRACT: Ninety female outpatients with obsessive-compulsive disorder (OCD) completed a semistructured interview to assess the relationship between different OCD symptom dimensions and the onset of OCD at menarche or during the perinatal period. Patients with hoarding symptoms had an earlier age at menarche than non-hoarders (12.1 +/- 1.3 vs 13.0 +/- 1.5 years, p = 0.019) and were more likely to report OCD onset at menarche (OR = 4.1, p = 0.034). Patients with symptoms of the contamination/cleaning dimension were more likely to report the onset of their disorder during pregnancy or postpartum (OR = 9.3, p = 0.048).
Archives of Women s Mental Health 09/2009; 13(1):75-81. · 2.06 Impact Factor
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ABSTRACT: Several clinical and genetic studies have focused on the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of various mental disorders. Recent lines of evidence regarding the network hypothesis of treatment outcome point towards the involvement of BDNF variants in the pharmacologic response in mood disorders (MD). Furthermore, there is strong evidence of a role for the serotonergic system in the pathophysiology and treatment of OCD, and upregulation of BDNF has been observed with various classes of antidepressants, including selective serotonin reuptake inhibitors (SSRI). Thus, we hypothesized that the BDNF gene might also be associated with treatment outcome in OCD.
We performed a single-marker and haplotype association study of eight tag single nucleotide polymorphisms in the BDNF genomic region and related this to pharmacologic response in a sample of 131 OCD patients.
We found an association for a haplotype containing two single nucleotide polymorphisms that have previously been reported to be associated with treatment outcome in MD (rs908867 and rs1491850).
Our results support the hypothesis that the BDNF gene is involved in the response to psychopharmacologic treatment even though these preliminary findings await replication in a follow-up sample.
Biological psychiatry 08/2009; 66(7):674-80. · 8.93 Impact Factor
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P Alonso,
M Gratacòs,
J M Menchón,
C Segalàs,
J R González,
J Labad,
M Bayés, E Real,
R de Cid,
A Pertusa,
G Escaramís,
J Vallejo,
X Estivill
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ABSTRACT: Recent work suggests that neurotrophic factors may contribute to the genetic susceptibility to obsessive-compulsive disorder (OCD). Among other clinical dimensions, the presence of hoarding obsessions and compulsions has been shown to be correlated with a number of clinical and neuroimaging findings, as well as with a different pattern of genetic inheritance. We used a linkage disequilibrium (LD)-mapping approach to investigate whether neurotrophic tyrosine kinase receptor type 3 (NTRK3), the high-affinity receptor of neurotrophin 3 (NT-3), plays a role in increasing susceptibility to hoarding in OCD. We performed an association study of 52 tag single nucleotide polymorphisms (tagSNPs) covering the whole NTRK3 gene in a sample comprising 120 OCD patients and 342 controls. Single nucleotide polymorphism association and haplotype analysis were performed. Thirty-six of our patients (30%) exhibited significant hoarding obsessions and compulsions. A significant association of two SNPs in the 3' downstream region of NTRK3 gene and obsessive-compulsive hoarding was identified: rs1017412 [odds ratio (OR) = 2.16; P = 0.001] and rs7176429 (OR = 2.78; P = 0.0001), although only the latter remained significant after Bonferroni correction. Although the haplotype analysis did not show significant results, a more extended block of LD in the OCD hoarders with respect to the control group was observed, suggesting a lower haplotype diversity in these individuals. Our findings suggest that NTRK3 may contribute to the genetic susceptibility to hoarding in OCD and may constitute an interesting gene to focus on in studies of the genetic basis of obsessive-compulsive hoarding.
Genes Brain and Behavior 07/2008; 7(7):778-85. · 3.48 Impact Factor
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Pino Alonso,
Mónica Gratacòs,
José M Menchón,
Jerónimo Saiz-Ruiz,
Cinto Segalàs,
Enrique Baca-García,
Javier Labad,
José Fernández-Piqueras, Eva Real,
Concepción Vaquero,
Mercedes Pérez,
Helen Dolengevich,
Juan R González,
Mónica Bayés,
Rafael de Cid,
Julio Vallejo,
Xavier Estivill
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ABSTRACT: Family, twin and molecular studies provide increasing evidence for the importance of genetic factors in obsessive-compulsive disorder (OCD). Recent work suggests that brain-derived neurotrophic factor (BDNF) may be involved in OCD pathophysiology. We used a linkage disequilibrium (LD)-mapping approach to investigate the role that BDNF and its specific receptor neurotrophic tyrosine kinase receptor type 2 (NTRK2) may play in increasing susceptibility to OCD.
Eight tag single nucleotide polymorphisms (tagSNPs) covering the BDNF gene region and 46 tagSNPs in the NTRK2 region were genotyped in 215 OCD patients and 342 control subjects. Single nucleotide polymorphism association and haplotype analysis were performed. The possible relationship between genetic factors and clinical characteristics including age of OCD onset, tic disorders, clinical dimensions, and family history of OCD were investigated.
Haplotype analysis revealed a significant association between OCD and a five-marker protective haplotype located toward the 5' of the BDNF gene (odds ratio [OR] = .80; 95% confidence interval [CI] = .69-.92; permutation p value = .006) containing the functional valine (Val)66-to-methionine (Met) variant. A significant association between a NTRK2 intronic SNP (rs2378672) and OCD was identified (p < .0001) in female patients under an additive model. A protective haplotype located in intron 19 of NTRK2 was also associated with OCD (OR = .76; 95% CI = .66-.87; permutation p value = .001).
These findings support a role for the BDNF/NTRK2 signaling pathway in genetic susceptibility to OCD.
Biological psychiatry 04/2008; 63(6):619-28. · 8.93 Impact Factor
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ABSTRACT: Memory deficits have been reported in several neuropsychological studies of obsessive-compulsive disorder (OCD). Dysfunction in nonverbal memory has been consistently reported, whereas findings on verbal memory are more heterogeneous. The authors studied 50 patients with OCD who were matched for sex, age, educational level, and hand dominance with 50 healthy controls (HC). Cognitive performance in both groups was assessed on verbal and nonverbal memory tasks, and several clinical variables were also assessed in the patient group. Patients with OCD showed a pattern of cognitive dysfunction with alterations in areas of nonverbal memory (recall and recognition), and verbal memory (learning and recall). Older age at onset of OCD was associated with poorer performance on verbal memory tasks. Low scores on some verbal memory tasks were associated with severity of OCD, and nonverbal memory was influenced by depressive symptoms. The study suggests the existence of dysfunction in the execution of verbal and nonverbal memory tasks in OCD; the influence of clinical variables depends on the specific neuropsychological function.
Neuropsychology 04/2008; 22(2):262-72. · 3.82 Impact Factor
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ABSTRACT: Poor insight has been reported in 15% to 36% of patients with obsessive-compulsive disorder (OCD), but little is known about its clinical correlations. This study examines insight among patients with OCD using a standardized instrument, the Brown Assessment of Beliefs Scale, and analyzes its relationship with clinical factors. Insight was assessed in 132 patients with OCD, before and after pharmacologic treatment, using the Brown Assessment of Beliefs Scale. Differences between patients with good and poor insight on sociodemographic variables, OCD severity, comorbidity, and treatment response were studied. Stability of insight after pharmacologic treatment was also examined. Thirty-nine patients (29.5%) exhibited poor insight. They showed more depressive symptoms (P = .001) and personality disorders (P = .001), especially the schizotypal form, than did good insight subjects, but there were no significant differences in treatment response. Insight significantly improves after treatment (P < .001). Our results suggest that insight in OCD varies widely and constitutes a dynamic phenomenon that can improve after treatment and is influenced by clinical conditions such as affective status or personality.
Comprehensive Psychiatry 03/2007; 49(3):305-12. · 2.26 Impact Factor
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ABSTRACT: The Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS) is a promising new instrument that allows patient and clinician ratings of dimension-specific symptom severity, as well as estimates of global symptom severity in patients with obsessive-compulsive disorder (OCD). The goal of this study was to further explore the psychometric properties of the DY-BOCS in a Spanish sample.
The internal consistency, reliability, and convergent and divergent validity of the Spanish adaptation of the DY-BOCS were assessed in a sample of 51 Spanish adult patients with OCD.
All the subscales of the Spanish DY-BOCS showed high internal consistency. The interrater reliability was excellent for all component scores, and the level of agreement between self-report and expert ratings was high for most symptom dimensions. The subscales of the DY-BOCS were largely independent from one another and from global OCD severity. The convergent and divergent validities of the DY-BOCS subscales were adequate.
The Spanish version of the DY-BOCS is a reliable and valid clinical tool for the assessment of obsessive-compulsive symptom dimensions.
Comprehensive psychiatry 51(6):641-8. · 2.08 Impact Factor
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ABSTRACT: Although clinical and genetic data for obsessive-compulsive disorder (OCD) support the hypothesis of sexual dimorphism, the neuropsychological findings remain inconclusive. The aim of our study was to determine whether there are differences in cognitive performance between men and women with OCD as compared with healthy controls (HCs). A neuropsychological battery was administered to 50 patients with OCD (31 men and 19 women) and 50 HCs matched by sex, age, and educational level with patients. We evaluated intelligence, attention, episodic memory, and use of organizational strategies during encoding of verbal and nonverbal information. Male patients scored worse than controls did in measures of nonverbal memory tasks, whereas the cognitive performance of women with OCD was consistent with that of their HC counterparts. These results suggest a distinct pattern of cognitive dysfunction specific to the patients' sex.
Comprehensive psychiatry 51(3):303-11. · 2.08 Impact Factor
