The purpose of the research project is to analyze the long-term evolution of obsessive-compulsive disorder (OCD) from of a study of a cohort of patients prospectively followed over a period ranging from 5 to 20 years, treated for according to therapeutic guidelines mediating serotonin reuptake inhibitors (IRS) and drug enhancers (antipsychotics) and cognitive behavioral therapy and evaluated in a standardized manner.

To assess the long-term course of Obsessive-Compulsive Disorder (OCD) in a cohort of patients treated according to current clinical guidelines; to analyse possible prognostic factors associated with the long-term course of the disorder including clinical and sociodemographic variables, as well as genetic and neuroimaging biomarkers, and their interaction, and finally to study neuroanatomical and functional cerebral connectivity changes after 15 years of treatment in a subsample of patients.

Prospective, descriptive, and observational study of a cohort of OCD patients, receiving treatment at the Department of Psychiatry of Hospital de Bellvitge since 1998, according to a standardized protocol. Follow-up period ranges from 5 (n=423), to 10 (n= 247) and 15 years (123). Baseline clinical and sociodemographic assessment, long-term evolution and information on treatments provided are available for the whole sample. Data on whole exome sequencing is available for 300 of the patients included in the cohort and baseline structural neuroimaging and cerebral functional connectivity has been analysed in 168 subjects. To expand the analysis of genetic biomarkers, we propose the study of de novo variants through exome analysis of 50 trios (patient and both parents) selected among those subjects that have reached 15 years of follow-up (25 trios with patients within the “long-term remission” group and 25 trios with patients with chronic OCD). De novo variants detected in the trio analysis will be replicated in the rest of the sample. A structural and resting state MRI will be obtained in a subsample of 100 patients recruited among those who have completed a minimum follow-up period of 15 years, to assess cerebral changes associated with the long-term course of the disorder.

in the current moment the recruitment period of the study has ended and all the data is being statistically analysed in order to provide solid results in a short period of time.

The identification of those factors associated with an increased risk of chronic disease is an element essential to offer personalized treatment to our patients and improve their prognosis, emphasizing the intensive use of those therapeutic strategies for which we can predict a better response and modifying to the extent of, if possible, environmental factors or factors of access to treatment that contribute to perpetuate obsessive symptoms.

None Declared

Neuroimaging findings have reported aberrant functional connectivity in brain regions involved reward system in individuals with anorexia nervosa (AN) altering hedonic processing over food. Likewise, endocannabinoids such as Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG) have been involved in rewarding aspects of food intake.

To identify nucleus accumbens (NAcc) functional connectivity with whole-brain comparing between individuals with AN and controls. Furthermore, in a sub-study, to explore the interaction between NAcc functional connectivity and peripheral AEA and 2-AG levels.

A total of 60 adult women (18 to 56 years of age) took part in the present study. Twenty-six individuals belonged to the AN group (BMI<18) and 34 to the HC group (BMI=18-24.99). All participants underwent functional magnetic resonance in resting-state, and blood samples were obtained in fasting.

Negative functional connectivity was observed in the AN group compared with the control group between the NAcc and the cerebellum (pFWE<.001), between the NAcc and the insula (pFWE<.001), between the NAcc and the supramarginal gyrus (pFWE=.019), and between the NAcc and the postcentral gyrus (pFWE=.010). Analyses exploring the association between NAcc functional connectivity and peripheral endocannabinoids levels displayed altered NAcc-cerebellum functional connectivity was negatively associated with peripheral 2-AG levels in the AN group (r= -.553; p=.011).

Understanding the interaction between the reward system and peripheral endocannabinoids in patients with AN could contribute to better elucidate the pathophysiology of this disorder. Future studies will need to further investigate the clinical and therapeutic implications of these findings in patients with AN.

No significant relationships.

Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG) play a pivotal role in food intake and reward aspects of feeding. Aberrant functioning in the endocannabinoid system has been observed in patients with eating disorders (EDs). This dysfunction may influence the incentive processes stimulating behaviors towards food acquisition or the hedonic evaluation of ingested food.

The aims of this study are to compare fasting peripheral levels of AEA and 2-AG in ED patients, obese subjects (OB) and healthy controls (HCs), and to explore their association with clinical and anthropometric variables.

The sample included a total of 63 adult women. Peripheral blood samples were collected to investigate fasting levels of AEA and 2-AG in 31 ED patients: 22 Anorexia Nervosa (AN) and 9 Binge Eating Disorder (BED), compared to 21 OB and 11 HCs. Several clinical and anthropometric variables were also assessed.

Comparing groups, significant differences in AEA levels were found (p=0.001). Specifically, individuals with AN exhibited lower AEA than OB (p<0.001) and BED (p=0.007), while OB showed higher AEA than HCs (p=0.015). 2-AG was positively correlated with hostility dimension in EDs and negatively associated with impulsive traits in OB. AEA showed a direct association with body dissatisfaction in AN, contrary to OB. Finally, in AN, AEA negatively correlated with the body mass index, while 2-AG was positively associated with the fat mass.

These results suggest an interaction between biological and clinical factors defining a vulnerability pathway that could help fitting personalized therapeutic approaches in each condition.

No significant relationships.

Altered fear learning processes could be mechanistically linked to the development and/or maintenance of obsessive-compulsive disorder (OCD). From a clinical perspective, the first-line psychological treatment for OCD is cognitive-behavioral therapy (CBT), which is based on the principles of fear learning. However, no previous functional magnetic resonance imaging (fMRI) studies have evaluated the predictive capacity of regional brain activations during fear learning on CBT response in patients with OCD.

We aimed at exploring whether brain activation during fear learning in patients with OCD are associated with CBT outcome.

We assessed 18 patients with OCD and 18 healthy participants during a 2-day experimental protocol where brain activation and skin conductance responses (SCR) where assessed during fear conditioning, extinction learning, and extinction recall within the fMRI scanner. Following the protocol, patients with OCD received CBT.

We found non-significant between-group differences in SCR during fear learning. Patients with OCD showed significantly diminished activation of the dorsal anterior cingulate cortex and the right insula during fear conditioning. Importantly, our analyses revealed a significant negative association between clinical improvement after CBT and activity at the right insula during fear conditioning (x = 39, y = 12, z = -11; t = 5.64; p<0.001; k = 928). This finding is displayed in Figure 1 below.

Patients with OCD may require less fear-conditioned brain responses to achieve the same level of psychophysiological fear conditioning as healthy participants. Interestingly, insula activations during fear-conditioned responses may represent a potential predictor biomarker of response to CBT for OCD.

No significant relationships.

Electroconvulsive therapy (ECT) is the most effective and fast acting therapy for treatment-resistant depression (TRD). Animal research has consistently pointed to neuroplasticity as a central mechanism of ECT action (1), however evidence in humans remains scarce (2; 3).

We assessed two independent samples of TRD patients referred for ECT. The Barcelona-sample included 13 subjects treated with bitemporal ECT and 10 healthy volunteers (HV). Four successive 3T structural MRIs were acquired: baseline, 24-48 hours after the 1st ECT session, 24-48 hours after the 9th ECT, and two weeks after ECT course completion. HV were scanned twice five weeks apart. Within the framework of the Barcelona-Sydney Clinical Imaging Collaboration, we also scanned 10 patients treated mainly with right unilateral ECT (Sydney-sample). Whole-brain longitudinal grey matter (GM) changes were measured using intra-subject diffeomorphic registration, within SPM12b.

In the Barcelona-sample, over the course of treatment bitemporal ECT produced a linear increase of GM volume in the limbic system (involving bilateral hippocampi and amygdalae). Additionally, volumetric increase within the right subgenual cortex was detected from baseline to the 9th ECT session. Such volume changes were not observed in HV. Furthermore, GM volume expansion correlated positively with depressive symptom improvement and neurocognitive performance (memory and executive function). Hippocampal and amygdalar volume increases were replicated in the Sydney-sample, although limited to the stimulated hemisphere.

ECT effects described here could be accounted for by the induction of regionally specific structural plasticity. Nevertheless, other mechanisms such as neurovascular changes should not be discarded.

Research integrating neuroimaging and molecular genetics has yielded important insights into how variability in brain chemistry predicts brain function and structure, behaviour and risk for psychopathology. Disrupted neurotransmission of glutamate within corticalstriatal-thalamocortical circuitry has been hypothesized to play a role in the pathogenesis of Obsessive-Compulsive Disorder (OCD). Candidate gene studies have identified associations between variants in glutamate system genes and OCD, particularly for SLC1A1, although these results remain controversial after GWAS and meta-analytical approaches.

To examine the effects of multiple polymorphisms of the glutamatergic pathway on frontostriatal connectivity, measured by resting state functional magnetic resonance imaging (fMRI), in OCD.

Individual multilocus genetic profile scores (MGPS) reflecting the additive effects of multiple alleles of the glutamatergic pathway, analysed by the Affymetrix GeneticChip® SNP array, were compiled for 134 OCD patients and 63 healthy controls. Association between these genetic scores and brain functional connectivity patterns between the dorsal and ventral striatal regions and limbic cortical areas including the orbitofrontal cortex and surrounding areas, such as the anterior prefrontal and perigenual anterior cingulate cortex, were investigated.

In the entire group, glutamatergic MGPS were significantly associated with connectivity patterns involving the ventral striatum and orbitofrontal cortex. Distinct relationships between MGPS and functional connectivity between the ventral striatum, amygdala, ventromedial frontal cortex and insula between OCD and healthy subjects emerged.

Glutamatergic genetic risk variants are related to normal frontostriatal connectivity; a fact that might explain the role of glutamatergic pathway disruptions in the susceptibility to develop OCD.

Neuropsychological and neuroimaging studies of response inhibition in cannabis users have reported inconsistent results. The age of onset of cannabis use and individual genetic differences may play a critical role in the regulation of inhibition in cannabis users.

We examine the influence of COMT Val158Met functional polymorphism on the response inhibition brain network in a group of early-onset chronic cannabis users compared with healthy controls.

fMRI data was acquired from 27 chronic cannabis users who began use cannabis before 16 years of age, and 29 non-using control subjects matched in terms of age, educational level and intelligence quotient while undergoing the Multi-Source Interference Task (MSIT). Participants were male, Caucasians aged between 18 and 30 years. All were assessed by a structured psychiatric interview (PRISM) to exclude any lifetime Axis-I disorder (DSM-IV). COMT genotyping was performed and resonance imaging data was analysed by voxel-based morphometry (VBM).

Both groups did not differ on their behavioural performance and brain responses during the MSIT task. A significant group-by-genotype interaction was observed on task-related brain activation (and on MSIT reaction times), in which met carrier load was associated with increased activation in cannabis users and val carrier load with increased activation in controls. The interaction pattern included the medial frontal cortex, ACC, inferior frontal gyrus, ventral striatum, anterior mesencephalon, inferior parietal and superior temporal cortices and the PCC.

Chronic cannabis exposure interacts with the genetically driven dopamine function in the modulation of the neural mechanisms related to response inhibition.

Grants:PNSD/2011/050, PNSD2006/101, SGR2009/1435.

Pathological worry is a hallmark feature of generalised anxiety disorder (GAD), associated with dysfunctional emotional processing. The ventromedial prefrontal cortex (vmPFC) is involved in the regulation of such processes, but the link between vmPFC emotional responses and pathological v. adaptive worry has not yet been examined.

To study the association between worry and vmPFC activity evoked by the processing of learned safety and threat signals.

In total, 27 unmedicated patients with GAD and 56 healthy controls (HC) underwent a differential fear conditioning paradigm during functional magnetic resonance imaging.

Compared to HC, the GAD group demonstrated reduced vmPFC activation to safety signals and no safety–threat processing differentiation. This response was positively correlated with worry severity in GAD, whereas the same variables showed a negative and weak correlation in HC.

Poor vmPFC safety–threat differentiation might characterise GAD, and its distinctive association with GAD worries suggests a neural-based qualitative difference between healthy and pathological worries.

None.

The assessment of inter-regional functional connectivity (FC) has allowed for the description of the putative mechanism of action of treatments such as deep brain stimulation (DBS) of the nucleus accumbens in patients with obsessive–compulsive disorder (OCD). Nevertheless, the possible FC alterations of other clinically-effective DBS targets have not been explored. Here we evaluated the FC patterns of the subthalamic nucleus (STN) and the bed nucleus of the stria terminalis (BNST) in patients with OCD, as well as their association with symptom severity.

Eighty-six patients with OCD and 104 healthy participants were recruited. A resting-state image was acquired for each participant and a seed-based analysis focused on our two regions of interest was performed using statistical parametric mapping software (SPM8). Between-group differences in FC patterns were assessed with two-sample t test models, while the association between symptom severity and FC patterns was assessed with multiple regression analyses.

In comparison with controls, patients with OCD showed: (1) increased FC between the left STN and the right pre-motor cortex, (2) decreased FC between the right STN and the lenticular nuclei, and (3) increased FC between the left BNST and the right frontopolar cortex. Multiple regression analyses revealed a negative association between clinical severity and FC between the right STN and lenticular nucleus.

This study provides a neurobiological framework to understand the mechanism of action of DBS on the STN and the BNST, which seems to involve brain circuits related with motor response inhibition and anxiety control, respectively.

The size of particular sub-regions within the ventromedial prefrontal cortex (vmPFC) has been associated with fear extinction in humans. Exposure therapy is a form of extinction learning widely used in the treatment of obsessive-compulsive disorder (OCD). Here we investigated the relationship between morphometric measurements of different sub-regions of the vmPFC and exposure therapy outcome in OCD.

A total of 74 OCD patients and 86 healthy controls underwent magnetic resonance imaging (MRI). Cortical thickness and volumetric measurements were obtained for the rostral anterior cingulate cortex (rACC), the medial orbital frontal cortex and the subcallosal cortex. After MRI acquisition, patients were enrolled in an exposure therapy protocol, and we assessed the relationship between MRI-derived measurements and treatment outcome. Baseline between-group differences for such measurements were also assessed.

Compared with healthy controls, OCD patients showed a thinner left rACC (p = 0.008). Also, left rACC thickness was inversely associated with exposure therapy outcome (r – 0.32, p = 0.008), and this region was significantly thinner in OCD patients who responded to exposure therapy than in those who did not (p = 0.006). Analyses based on regional volumetry did not yield any significant results.

OCD patients showed cortical thickness reductions in the left rACC, and these alterations were related to exposure therapy outcome. The precise characterization of neuroimaging predictors of treatment response derived from the study of the brain areas involved in fear extinction may optimize exposure therapy planning in OCD and other anxiety disorders.

Distorted images of the observable self are considered crucial in the development and maintenance of social anxiety. We generated an experimental situation in which participants viewed themselves from an observer's perspective when exposed to scrutiny and evaluation by others.

Twenty patients with social anxiety disorder (SAD) and 20 control subjects were assessed using functional magnetic resonance imaging (fMRI) during the public exposure of pre-recorded videos in which they were each shown performing a verbal task. The examiners acted as the audience in the experiment and rated performance. Whole-brain functional maps were computed using Statistical Parametric Mapping.

Robust activation was observed in regions related to self-face recognition, emotional response and general arousal in both study groups. Patients showed significantly greater activation only in the primary visual cortex. By contrast, they showed significant deactivation or smaller activation in dorsal frontoparietal and anterior cingulate cortices relevant to the cognitive control of negative emotion. Task-related anxiety ratings revealed a pattern of negative correlation with activation in this frontoparietal/cingulate network. Importantly, the relationship between social anxiety scores and neural response showed an inverted-U function with positive correlations in the lower score range and negative correlations in the higher range.

Our findings suggest that exposure to scrutiny and evaluation in SAD may be associated with changes in cortical systems mediating the cognitive components of anxiety. Disorder severity seems to be relevant in shaping the neural response pattern, which is distinctively characterized by a reduced cortical response in the most severe cases.

Social anxiety often involves a combination of hypervigilance and avoidance to potentially warning signals including the facial expression of emotions. Functional imaging has demonstrated an increase in amygdala response to emotional faces in subjects with social anxiety. Nevertheless, it is unclear to what extent visual areas processing faces influence amygdala reactivity in different socially anxious individuals. We assessed the influence of the fusiform gyrus activation on amygdala response to emotional faces in the non-clinical range of social anxiety.

Twenty-two normal subjects showing a wide range in social anxiety scores were examined using functional magnetic resonance imaging (fMRI) during the processing of happy and fearful faces. A dimensional analysis approach was used involving voxel-wise mapping of the correlation between subjects' social anxiety scores and amygdala activation, before and after controlling for fusiform gyrus activation.

We observed that only after controlling for subjects' level of activation of the fusiform gyrus was there an association between social anxiety ratings and amygdala response to both happy and fearful faces. The fusiform gyrus influence was more robust during the fear condition. Of note, fusiform gyrus response to fearful faces showed a negative correlation with additional behavioral assessments related to avoidance, including social anxiety scores, harm avoidance and sensitivity to punishment.

Relevant interactions among the emotional face-processing stages exist in the non-clinical range of social anxiety that may ultimately attenuate amygdala responses. Future research will help to establish the role of this effect in a clinical context.