Uncovering the correlation between neurotransmitter-specific functional connectivity and multidimensional anxiety in a non-clinical cohort.

Research on anxiety faces challenges due to the wide range of symptoms, making it difficult to determine if different aspects of anxiety are linked to distinct neurobiological processes. Both alterations in functional brain connectivity (FC) and monoaminergic neurotransmitter systems are implicated as potential neural bases of anxiety. We aimed to investigate whole-brain FC involving monoaminergic nuclei and its association with anxiety dimensions in 178 non-clinical participants. Nine anxiety-related scales were used, encompassing trait and state anxiety scores, along with measures of cost-probability, hypervigilance, reward-punishment sensitivity, uncertainty, and trait worry. Resting-state functional magnetic resonance imaging data were acquired, focusing on seven brainstem regions representing serotonergic, dopaminergic, and noradrenergic nuclei, with their FC patterns voxel-wise correlated with the scales. All models underwent family-wise-error correction for multiple comparisons. We observed intriguing relationships: trait and state anxiety scores exhibited opposing correlations in FC between the dorsal raphe nucleus and the paracingulate gyrus. Additionally, we identified shared neural correlates, such as a negative correlation between the locus coeruleus and the frontal pole. This connection was significantly associated with scores on measures of probability, hypervigilance, reward sensitivity, and trait worry. These findings underscore the intricate interplay between anxiety dimensions and subcortico-cortical FC patterns, shedding light on the underlying neural mechanisms governing anxiety.

Cognitive and clinical predictors of a long-term course in obsessive compulsive disorder: A machine learning approach in a prospective cohort study.

BACKGROUND: Obsessive compulsive disorder (OCD) is a disabling illness with a chronic course, yet data on long-term outcomes are scarce. This study aimed to examine the long-term course of OCD in patients treated with different approaches (drugs, psychotherapy, and psychosurgery) and to identify predictors of clinical outcome by machine learning. METHOD: We included outpatients with OCD treated at our referral unit. Demographic and neuropsychological data were collected at baseline using standardized instruments. Clinical data were collected at baseline, 12 weeks after starting pharmacological treatment prescribed at study inclusion, and after follow-up. RESULTS: Of the 60 outpatients included, with follow-up data available for 5-17 years (mean = 10.6 years), 40 (67.7 %) were considered non-responders to adequate treatment at the end of the study. The best machine learning model achieved a correlation of 0.63 for predicting the long-term Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score by adding clinical response (to the first pharmacological treatment) to the baseline clinical and neuropsychological characteristics. LIMITATIONS: Our main limitations were the sample size, modest in the context of traditional ML studies, and the sample composition, more representative of rather severe OCD cases than of patients from the general community. CONCLUSIONS: Many patients with OCD showed persistent and disabling symptoms at the end of follow-up despite comprehensive treatment that could include medication, psychotherapy, and psychosurgery. Machine learning algorithms can predict the long-term course of OCD using clinical and cognitive information to optimize treatment options.

The genomics of visuospatial neurocognition in obsessive-compulsive disorder: A preliminary GWAS.

BACKGROUND: The study of Obsessive-Compulsive Disorder (OCD) genomics has primarily been tackled by Genome-wide association studies (GWAS), which have encountered troubles in identifying replicable single nucleotide polymorphisms (SNPs). Endophenotypes have emerged as a promising avenue of study in trying to elucidate the genomic bases of complex traits such as OCD. METHODS: We analyzed the association of SNPs across the whole genome with the construction of visuospatial information and executive performance through four neurocognitive variables assessed by the Rey-Osterrieth Complex Figure Test (ROCFT) in a sample of 133 OCD probands. Analyses were performed at SNP- and gene-level. RESULTS: No SNP reached genome-wide significance, although there was one SNP almost reaching significant association with copy organization (rs60360940; P = 9.98E-08). Suggestive signals were found for the four variables at both SNP- (P < 1E-05) and gene-levels (P < 1E-04). Most of the suggestive signals pointed to genes and genomic regions previously associated with neurological function and neuropsychological traits. LIMITATIONS: Our main limitations were the sample size, which was limited to identify associated signals at a genome-wide level, and the composition of the sample, more representative of rather severe OCD cases than a population-based OCD sample with a broad severity spectrum. CONCLUSIONS: Our results suggest that studying neurocognitive variables in GWAS would be more informative on the genetic basis of OCD than the classical case/control GWAS, facilitating the genetic characterization of OCD and its different clinical profiles, the development of individualized treatment approaches, and the improvement of prognosis and treatment response.

Neuropsychological performance and predictors of pharmacological treatment response in obsessive compulsive disorder.

BACKGROUND: Obsessive Compulsive Disorder (OCD) is characterized by the presence of executive dysfunctions. As organizational strategies may play an important role as a possible endophenotype of the disorder, we decided to investigate non-verbal memory and organizational abilities in OCD. We also investigated how organization and non-verbal memory differ between responder and non-responder patients to pharmacological treatment, to test whether cognitive functions can predict the response to pharmacological treatment. METHODS: In Study 1, executive and clinical functioning measures were applied to 162 OCD and 95 controls. In Study 2, clinical, intelligence and executive functioning measures were applied to 72 OCD responders and 63 OCD non-responder patients. RESULTS: OCD patients and controls from Study 1 differed in copy organization (p < 0.01) and delayed recall (p = 0.048). In Study 2, the OCD responders displayed better copy organization (p = 0.013) and lower depressive, anxious and OCD symptoms (p < 0.01 in the three cases). Scores in the following instruments were found to predict the response to pharmacological treatment: HDRS, Y-BOCS, Raven progressive matrices, and Direct digit subtest from the Wechsler's scale (p < 0.01 in all four cases). LIMITATIONS: In Study 1, the imbalance of the sample can be considered a limitation, whilst in Study 2, some of the levels of pharmacological resistance were not represented. CONCLUSIONS: In this study, non-verbal memory and organization was affected in OCD. Responder patients also displayed better executive functioning and fluid intelligence. Organizational ability is a predictor of pharmacological response to SSRI monotherapy in a predictive model controlling for anxious symptoms.

How is COVID-19 affecting patients with obsessive-compulsive disorder? A longitudinal study on the initial phase of the pandemic in a Spanish cohort.

BACKGROUND: Although the consequences of the COVID-19 pandemic on emotional health are evident, little is known about its impact on patients with obsessive-compulsive disorder (OCD). METHODS: One hundred and twenty-seven patients with OCD who attended a specialist OCD Clinic in Barcelona, Spain, were assessed by phone from April 27 to May 25, 2020, during the early phase of the pandemic, using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and a structured interview that collected clinical and sociodemographic information. Results were compared with those for 237 healthy controls from the same geographic area who completed an online survey. RESULTS: Although 65.3% of the patients with OCD described a worsening of their symptoms, only 31.4% had Y-BOCS scores that increased >25%. The risk of getting infected by SARS-CoV2 was reported as a new obsession by 44.8%, but this only became the main obsessive concern in approximately 10% of the patients. Suicide-related thoughts were more frequent among the OCD cohort than among healthy controls. The presence of prepandemic depression, higher Y-BOCS scores, contamination/washing symptoms, and lower perceived social support all predicted a significantly increased risk of OCD worsening. CONCLUSIONS: Most patients with OCD appear to be capable of coping with the emotional stress of the COVID-19 outbreak and its consequences during the initial phase of the pandemic. Nevertheless, the current crisis constitutes a risk factor for a significant worsening of symptoms and suicidal ideation. Action is needed to ensure effective and individualized follow-up care for patients with OCD in the COVID-19 era.

Is glutamate associated with fear extinction and cognitive behavior therapy outcome in OCD? A pilot study.

Cognitive behavioral therapy (CBT) including exposure and response prevention is a well-established treatment for obsessive-compulsive disorder (OCD) and is based on the principles of fear extinction. Fear extinction is linked to structural and functional variability in the ventromedial prefrontal cortex (vmPFC) and has been consistently associated with glutamate neurotransmission. The relationship between vmPFC glutamate and fear extinction and its effects on CBT outcome have not yet been explored in adults with OCD. We assessed glutamate levels in the vmPFC using 3T magnetic resonance spectroscopy, and fear extinction (learning and recall) using skin conductance responses during a 2-day experimental paradigm in OCD patients (n = 17) and in healthy controls (HC; n = 13). Obsessive-compulsive patients (n = 12) then received manualized CBT. Glutamate in the vmPFC was negatively associated with fear extinction recall and positively associated with CBT outcome (with higher glutamate levels predicting a better outcome) in OCD patients. Glutamate levels in the vmPFC in OCD patients were not significantly different from those in HC, and were not associated with OCD severity. Our results suggest that glutamate in the vmPFC is associated with fear extinction recall and CBT outcome in adult OCD patients.

Patient characteristics driving clinical utility in psychiatric pharmacogenetics: a reanalysis from the AB-GEN multicentric trial.

Clinical utility of commercial multi-gene pharmacogenetic tests in depression is starting to be studied with some promising results on efficacy and tolerability. Among the next steps is the definition of the patient profile that is most likely to benefit from testing. Here we present a reanalysis of data from the AB-GEN randomized clinical trial showing that clinical utility of pharmacogenetic testing can be markedly influenced by patient characteristics such as age, baseline severity and duration of current depressive episode.Trial registration ClinicalTrials.gov NCT02529462.

Manifesto for a European research network into Problematic Usage of the Internet.

The Internet is now all-pervasive across much of the globe. While it has positive uses (e.g. prompt access to information, rapid news dissemination), many individuals develop Problematic Use of the Internet (PUI), an umbrella term incorporating a range of repetitive impairing behaviours. The Internet can act as a conduit for, and may contribute to, functionally impairing behaviours including excessive and compulsive video gaming, compulsive sexual behaviour, buying, gambling, streaming or social networks use. There is growing public and National health authority concern about the health and societal costs of PUI across the lifespan. Gaming Disorder is being considered for inclusion as a mental disorder in diagnostic classification systems, and was listed in the ICD-11 version released for consideration by Member States (http://www.who.int/classifications/icd/revision/timeline/en/). More research is needed into disorder definitions, validation of clinical tools, prevalence, clinical parameters, brain-based biology, socio-health-economic impact, and empirically validated intervention and policy approaches. Potential cultural differences in the magnitudes and natures of types and patterns of PUI need to be better understood, to inform optimal health policy and service development. To this end, the EU under Horizon 2020 has launched a new four-year European Cooperation in Science and Technology (COST) Action Programme (CA 16207), bringing together scientists and clinicians from across the fields of impulsive, compulsive, and addictive disorders, to advance networked interdisciplinary research into PUI across Europe and beyond, ultimately seeking to inform regulatory policies and clinical practice. This paper describes nine critical and achievable research priorities identified by the Network, needed in order to advance understanding of PUI, with a view towards identifying vulnerable individuals for early intervention. The network shall enable collaborative research networks, shared multinational databases, multicentre studies and joint publications.

Ventromedial prefrontal cortex activity and pathological worry in generalised anxiety disorder.

BACKGROUND: 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.AimsTo study the association between worry and vmPFC activity evoked by the processing of learned safety and threat signals. METHOD: In total, 27 unmedicated patients with GAD and 56 healthy controls (HC) underwent a differential fear conditioning paradigm during functional magnetic resonance imaging. RESULTS: 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. CONCLUSIONS: 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.Declaration of interestNone.

Rate and characteristics of urgent hospitalisation in persons with profound intellectual disabilities compared with general population.

BACKGROUND: Little is known about the hospitalisation rate of adults with severe/profound intellectual disability (PID) presenting at emergency services or about the appropriateness of hospital admissions in this population. Examining the possible differences in the patterns of hospitalisation between people with PID and those without intellectual disability (ID) may shed light on aspects of health and illness in these patients and may in turn make it possible to differentiate more clearly between mild-moderate ID and PID. METHODS: After an evaluation of the emergency visits made by adults with PID and by people without ID, patients in both groups requiring one or more hospitalisations were subsequently followed up for 18 months. The appropriateness of the decision to hospitalise was assessed using the ambulatory care-sensitive conditions index. RESULTS: There were no differences in the proportion of people with PID and controls admitted to hospital after their emergency visit. The median hospital stay was higher for PIDs: 7.5 vs. 4 days for controls. People with PID were admitted more than controls for respiratory reasons and somewhat less for other somatic causes unrelated to the nervous system. There were no admissions for psychiatric causes in the group with PID other than unspecified conduct disorders. There were no differences in other diagnostic groups. The rate of inappropriate admissions was similar in the two study groups. CONCLUSIONS: In contrast to previous results reported for the group with ID as a whole, patients with PID consulting the emergency service were not admitted to hospital more frequently than the general population nor did they present a higher rate of inappropriate admissions. These results support the utility of maintaining two distinct groups of people with ID: mild-moderate and severe-profound.

Altered functional connectivity of the subthalamus and the bed nucleus of the stria terminalis in obsessive-compulsive disorder.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Obsessive-compulsive disorder in the elderly: A report from the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS).

INTRODUCTION: Obsessive-compulsive disorder (OCD) is a highly disabling condition, with frequent early onset. Adult/adolescent OCD has been extensively investigated, but little is known about prevalence and clinical characterization of geriatric patients with OCD (G-OCD≥65years). The present study aimed to assess prevalence of G-OCD and associated socio-demographic and clinical correlates in a large international sample. METHODS: Data from 416 outpatients, participating in the ICOCS network, were assessed and categorized into 2 groups, age

Brain volumetric and metabolic correlates of electroconvulsive therapy for treatment-resistant depression: a longitudinal neuroimaging study.

Recent research suggests that neuroplastic and neuroinflammatory changes may account for the mode of action of electroconvulsive therapy (ECT), although extant data do not allow for a clear disambiguation between these two hypotheses. Multimodal neuroimaging approaches (for example, combining structural and metabolic information) may help in clarifying this issue. Here we aimed to assess longitudinal changes in (i) regional gray matter (GM) volumes and (ii) hippocampal metabolite concentrations throughout an acute course of bitemporal ECT, as well as (iii) to determine the association between imaging changes and clinical improvement. We assessed 12 patients with treatment-resistant depression (TRD) at four time points (pre-treatment, after the first ECT session, after the ninth ECT session and 15 days after ECT course completion) and 10 healthy participants at two time points, 5 weeks apart. Patients with TRD showed bilateral medial temporal lobe (MTL) and perigenual anterior cingulate cortex volume increases. Left MTL volume increase was associated with (i) a hippocampal N-acetylaspartate concentration decrease, (ii) a hippocampal Glutamate+Glutamine concentration increase and (iii) significant clinical improvement. The observed findings are, in part, compatible with both neuroplastic and neuroinflammatory changes induced by ECT. We postulate that such phenomena may be interrelated, therefore reconciling the neuroplasticity and neuroinflammatory hypotheses of ECT action.

Pain underreporting associated with profound intellectual disability in emergency departments.

BACKGROUND: Little information is available regarding the visits made by persons with profound intellectual disability (PID) to general hospital emergency departments (ED). This study aims to know whether persons with PID who attend ED are given the same type of diagnoses as people with no such disability. METHODS: Over a period of 18 months, we gathered data from all non-scheduled visits to an ED by persons with PID to identify the reason for consultation (according to the classification used by the Spanish Society for Emergency Nursing) and the final diagnosis upon discharge. The results were compared with data obtained from a control group of people with no ID who attended an ED for any reason during the same period. RESULTS: Somatic complaints were the main reason for ED attendance among persons with PID (90% of consultations). These complaints were more often related to the central nervous system than was the case among non-ID patients (16 vs. 4.7%), whereas other kinds of non-central nervous system somatic complaint were less common among persons with PID (74 vs. 91%). A diagnosis implying physical pain was given less often to people with PID than to controls (3 vs. 20%). CONCLUSIONS: The results suggest that persons with PID are less able to conceptualise and communicate information about their symptoms, especially as regards pain, and that this influences the diagnosis they are given when attending an ED. Professionals working in this environment need to be aware of this possibility so as not to underestimate or overlook such symptoms and the illnesses related to them.

Cognitive behavioral therapy for compulsive buying behavior: Predictors of treatment outcome.

BACKGROUND: Compulsive buying behavior (CBB) is receiving increasing consideration in both consumer and psychiatric-epidemiological research, yet empirical evidence on treatment interventions is scarce and mostly from small homogeneous clinical samples. OBJECTIVES: To estimate the short-term effectiveness of a standardized, individual cognitive behavioral therapy intervention (CBT) in a sample of n=97 treatment-seeking patients diagnosed with CBB, and to identify the most relevant predictors of therapy outcome. METHOD: The intervention consisted of 12 individual CBT weekly sessions, lasting approximately 45minutes each. Data on patients' personality traits, psychopathology, sociodemographic factors, and compulsive buying behavior were used in our analysis. RESULTS: The risk (cumulative incidence) of poor adherence to the CBT program was 27.8%. The presence of relapses during the CBT program was 47.4% and the dropout rate was 46.4%. Significant predictors of poor therapy adherence were being male, high levels of depression and obsessive-compulsive symptoms, low anxiety levels, high persistence, high harm avoidance and low self-transcendence. CONCLUSION: Cognitive behavioral models show promise in treating CBB, however future interventions for CBB should be designed via a multidimensional approach in which patients' sex, comorbid symptom levels and the personality-trait profiles play a central role.

Modulation of Irisin and Physical Activity on Executive Functions in Obesity and Morbid obesity.

Whether the executive profile is different between obesity (OB) and morbid obesity (MO) remains unclear. Recent evidence suggests that physical activity (PA) can act as a cognitive enhancer. Irisin is a recently discovered hormone associated with some of the positive effects of PA. The objective of the study was to investigate the executive profile in OB and MO, and to explore the role of PA and irisin. 114 participants were included (21 OB, 44 MO and 49 healthy controls-HC) in the study and assessed with the Wisconsin Card Sorting Test, Stroop Color and Word Test, and Iowa Gambling Task. All participants were female, aged between 18 and 60 years. Results showed a similar dysfunctional profile on decision making in OB and MO compared with HC. Thus, no specific neuropsychological profiles between OB and MO can be clearly observed in our sample. However, a negative correlation was found between irisin and executive functioning. These results demonstrate a specific executive profile in OB and a relevant and negative modulation of irisin on executive functioning. Although irisin might be a promising target for the treatment of obesity, its effects on cognition might be considered when thinking about its therapeutic use.

Exon-focused genome-wide association study of obsessive-compulsive disorder and shared polygenic risk with schizophrenia.

Common single-nucleotide polymorphisms (SNPs) account for a large proportion of the heritability of obsessive-compulsive disorder (OCD). Co-ocurrence of OCD and schizophrenia is commoner than expected based on their respective prevalences, complicating the clinical management of patients. This study addresses two main objectives: to identify particular genes associated with OCD by SNP-based and gene-based tests; and to test the existence of a polygenic risk shared with schizophrenia. The primary analysis was an exon-focused genome-wide association study of 370 OCD cases and 443 controls from Spain. A polygenic risk model based on the Psychiatric Genetics Consortium schizophrenia data set (PGC-SCZ2) was tested in our OCD data. A polygenic risk model based on our OCD data was tested on previous data of schizophrenia from our group. The most significant association at the gene-based test was found at DNM3 (P=7.9 × 10(-5)), a gene involved in synaptic vesicle endocytosis. The polygenic risk model from PGC-SCZ2 data was strongly associated with disease status in our OCD sample, reaching its most significant value after removal of the major histocompatibility complex region (lowest P=2.3 × 10(-6), explaining 3.7% of the variance). The shared polygenic risk was confirmed in our schizophrenia data. In conclusion, DNM3 may be involved in risk to OCD. The shared polygenic risk between schizophrenia and OCD may be partially responsible for the frequent comorbidity of both disorders, explaining epidemiological data on cross-disorder risk. This common etiology may have clinical implications.

Brain structural correlates of obsessive-compulsive disorder with and without preceding stressful life events.

Objectives There is growing evidence supporting a role for stressful life events (SLEs) at obsessive-compulsive disorder (OCD) onset, but neurobiological correlates of such effect are not known. We evaluated regional grey matter (GM) changes associated with the presence/absence of SLEs at OCD onset. Methods One hundred and twenty-four OCD patients and 112 healthy controls were recruited. Patients were split into two groups according to the presence (n = 56) or absence (n = 68) of SLEs at disorder's onset. A structural magnetic resonance image was acquired for each participant and pre-processed with Statistical Parametric Mapping software (SPM8) to obtain a volume-modulated GM map. Between-group differences in sociodemographic, clinical and whole-brain regional GM volumes were assessed. Results SLEs were associated with female sex, later age at disorder's onset, more contamination/cleaning and less hoarding symptoms. In comparison with controls, patients without SLEs showed GM volume increases in bilateral dorsal putamen and the central tegmental tract of the brainstem. By contrast, patients with SLEs showed specific GM volume increases in the right anterior cerebellum. Conclusions Our findings support the idea that neuroanatomical alterations of OCD patients partially depend on the presence of SLEs at disorder's onset.