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Obsessive-Compulsive Disorder (OCD) poses a multifaceted challenge in psychiatry, with various subtypes and severities greatly impacting well-being. Recent scientific attention has turned towards lipid metabolism, particularly the neurolipidome, in response to clinical demands for cost-effective diagnostics and therapies. This scoping review integrates recent animal, translational, and clinical studies to explore impaired neurolipid metabolism mechanisms in OCD's pathogenesis, aiming to enhance future diagnostics and therapeutics. Five key neurolipids - endocannabinoids, lipid peroxidation, phospholipids, cholesterol, and fatty acids - were identified as relevant. While the endocannabinoid system shows promise in animal models, its clinical application remains limited. Conversely, lipid peroxidation and disruptions in phospholipid metabolism exhibit significant impacts on OCD's pathophysiology based on robust clinical data. However, the role of cholesterol and fatty acids remains inconclusive. The review emphasises the importance of translational research in linking preclinical findings to real-world applications, highlighting the potential of the neurolipidome as a potential biomarker for OCD detection and monitoring. Further research is essential for advancing OCD understanding and treatment modalities., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterized by the abrupt onset of significant obsessive-compulsive symptoms (OCS) and/or severe food restriction, together with other neuropsychiatric manifestations. An autoimmune pathogenesis triggered by infection has been proposed for at least a subset of PANS. The older diagnosis of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS) describes rapid onset of OCD and/or tics associated with infection with Group A Streptococcus. The pathophysiology of PANS and PANDAS remains incompletely understood. We recently found serum antibodies from children with rigorously defined PANDAS to selectively bind to cholinergic interneurons (CINs) in the striatum. Here we examine this binding in children with relapsing and remitting PANS, a more heterogeneous condition, collected in a distinct clinical context from those examined in our previous work, from children with a clinical history of Streptococcus infection. IgG from PANS cases showed elevated binding to striatal CINs in both mouse and human brain. Patient plasma collected during symptom flare decreased a molecular marker of CIN activity, phospho-riboprotein S6, in ex vivo brain slices; control plasma did not. Neither elevated antibody binding to CINs nor diminished CIN activity was seen with plasma collected from the same children during remission. These findings replicate what we have seen previously in PANDAS and support the hypothesis that at least a subset of PANS cases have a neuroimmune pathogenesis. Given the critical role of CINs in modulating basal ganglia function, these findings confirm striatal CINs as a locus of interest in the pathophysiology of both PANS and PANDAS., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Pittenger has served as a consultant and received research funding in the past year for Biohaven Pharmaceuticals, Transcend Therapeutics, Ceruvia Lifesciecnes, Freedom Biosciences, and Nobilis Therapeutics, and royalties from Oxford University Press, all for work unrelated to the current results. He is an inventor on a patent applications related to the use of neurofeedback and of psychedelic drugs for the treatment of OCD, also unrelated to this work. Dr. Che has received research funding from Duraviva Pharma for work unrealted to the current results. All other authors report no competing interests. The authors have declared that no conflict of interest exists., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Astrocytes are morphologically complex cells that serve essential roles. They are widely implicated in central nervous system (CNS) disorders, with changes in astrocyte morphology and gene expression accompanying disease. In the Sapap3 knockout (KO) mouse model of compulsive and anxiety-related behaviors related to obsessive-compulsive disorder (OCD), striatal astrocytes display reduced morphology and altered actin cytoskeleton and Gi-G-protein-coupled receptor (Gi-GPCR) signaling proteins. Here, we show that normalizing striatal astrocyte morphology, actin cytoskeleton, and essential homeostatic support functions by targeting the astrocyte Gi-GPCR pathway using chemogenetics corrected phenotypes in Sapap3 KO mice, including anxiety-related and compulsive behaviors. Our data portend an astrocytic pharmacological strategy for rescuing phenotypes in brain disorders that include compromised astrocyte morphology and tissue support., Competing Interests: Declaration of interests UCLA filed a US provisional patent (no. 63/658,760) based on this work. B.S.K. is on the editorial advisory board of Neuron., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Obsessive-compulsive disorder (OCD) is linked with dysfunction in frontal-striatal, fronto-limbic, and visual brain regions. Research using proton magnetic resonance spectroscopy ( 1 H-MRS) suggests that altered neurometabolite levels, like glutamate, may contribute to this dysfunction. However, static neurometabolite levels in OCD patients have shown inconsistent results, likely due to previous studies' limited focus on neurometabolite dynamics. We employ functional MRS (fMRS) and functional magnetic resonance imaging (fMRI) to explore these dynamics and brain activation during OCD symptom provocation. We utilized a combined 7-tesla fMRI-fMRS setup to examine task-related BOLD response and glutamate changes in the lateral occipital cortex (LOC) of 30 OCD participants and 34 matched controls during an OCD-specific symptom provocation task. The study examined main effects and between-group differences in brain activation and glutamate levels during the task. A whole sample task-effects analysis on data meeting predefined quality criteria showed significant glutamate increases (n = 41 (22 OCD, 19 controls), mean change: 3.2 %, z = 3.75, p < .001) and task activation (n = 54 (26 OCD, 28 controls), p < .001) in the LOC during OCD blocks compared to neutral blocks. However, no differences in task-induced glutamate dynamics or activation between groups were found, nor a correlation between glutamate levels and task activation. We were able to measure task-induced increases in glutamate and BOLD levels, emphasizing its feasibility for OCD research. The absence of group differences highlights the need for further exploration to discern to what extent neurometabolite dynamics differ between OCD patients and controls. Once established, future studies can use pre-post intervention fMRS-fMRI to probe the effects of therapies modulating glutamate pathways in OCD., Competing Interests: Declaration of competing interest The other authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Obsessive-compulsive disorder (OCD) is a debilitating mental disorder with obvious difficulties in treatment. Its pathogenesis has not been fully elucidated. Further understanding of etiology and mechanism needs to be explored further. We employed the isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic analysis to compare serum proteome profile between OCD patients and healthy controls, in order to find out the possible mechanism of OCD in the downstream biological process. Eighty-one drug-free OCD patients and 78 healthy controls were enrolled. A total of 475 proteins were identified. Totally, 80 proteins with p < 0.05 were selected for gene set enrichment analysis (GSEA), and only those with a fold change ≥1.2 and q value <0.2 between groups were accepted as differentially expressed proteins (DEPs). We observed a significant enrichment of immuno-inflammation-related pathways, along with intriguing expression trends that immuno-inflammation-related proteins were upregulated in GSEA. After that, 2 up-regulated proteins and 13 down-regulated ones were accepted as DEP. According to the available literature, most of the DEPs have not been reported in OCD. These DEPs were enriched in 121 gene ontology (GO) terms, including hepatocyte growth factor receptor activity, angiogenin-PRI complex, and so on. DEPs were enriched in pathways including adherens junction in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Alterations in DEPs including STXBP5L, GRN, and ANG were validated in OCD animal models. Our study suggested that OCD patients manifested multifactorial impairment in neuronal or non-neuronal cellular function under the inflammatory background. Further research employing larger sample sizes, longitudinal design, stratified analysis, and multiomics methodology will be needed. Experiments in laboratories were essential in illuminating the mechanism.

Background: Rapid-eye movement (REM) sleep deprivation (SD) can induce manic-like behaviors in rodents. On the other hand, lithium, as one of the oldest drugs used in neuropsychiatric disorders, is still one of the best drugs for the treatment and control of bipolar disorder. In this study, we aimed to investigate the role of chronic short-term REM SD in the induction of manic-like behaviors in female rats., Methods: The rats were exposed to REM SD for 14 days (6 hours/day). Lithium was intraperitoneally injected at the doses of 10, 50, and 100 mg/kg., Results: REM SD induced hyperactivity and OCD-like behavior, and decreased anxiety, depressive-like behavior, and pain subthreshold. REM SD also impaired passive avoidance memory and decreased hippocampal brain-derived neurotrophic factor (BDNF) expression level. Lithium at the doses of 50 and 100 mg/kg partly and completely abolished these effects, respectively. However, lithium (100 mg/kg) increased BDNF expression level in control and sham REM SD rats with no significant changes in behavior., Conclusions: Chronic short-term REM SD may induce a mania-like model and lead to OCD-like behavior and irritability. In the present study, we demonstrated a putative rodent model of mania induced by chronic REM SD in female rats. We suggest that future studies should examine behavioral and mood changes following chronic REM SD in both sexes. Furthermore, the relationship between manic-like behaviors and chronic REM SD should be investigated., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The purpose of this study was to examine N-acetyl aspartate (NAA)/creatine (Cr) and glutamate, glutamine, and gamma-aminobutyric acid complex (Glx)/Cr levels in patients with obsessive compulsive disorder (OCD) and healthy controls' orbitofrontal cortex (OFC) and caudate nucleus (CN) by proton magnetic resonance spectroscopy (1H-MRS) method and to investigate their relationship with oxidative stress markers glutathione peroxidase (GPx) and superoxide dismutase (SOD)., Methods: This study included patients with OCD (n = 25) and healthy controls (n = 25) ranging in age from 18 to 65. We used the ELISA method to evaluate serum SOD and GPx levels. Levels of NAA/Cr and Glx/Cr in the orbitofrontal cortex and caudate nucleus were measured using the 1H-MRS method., Results: Our study did not detect statistically significant differences in the orbitofrontal cortex Glx/Cr and NAA/Cr levels between the OCD patients and the control group. OCD patients exhibited a decrease in NAA/Cr levels, consistent with impaired neuronal integration, and an increase in Glx/Cr levels, consistent with hyperactivation, in the caudate nucleus compared to the control group. We observed a negative correlation between NAA/Cr levels in the caudate nucleus and the levels of SOD and GPx., Conclusions: Our study is the first to assess CN and OFC together in OCD patients using 3 T MR, investigating the relationship between neurometabolite concentrations and oxidative stress parameters. The negative correlation we observed between NAA/Cr levels and SOD and GPx in the caudate nucleus suggests that increased oxidative stress in this brain region in OCD patients may contribute to impaired neuronal integration and functionality., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Serotonin (5-HT) regulates working memory within the prefrontal cortex network, which is crucial for understanding obsessive-compulsive disorder. However, the mechanisms how network dynamics and serotonin interact in obsessive-compulsive disorder remain elusive. Here, we incorporate 5-HT receptors (5-HT1A, 5-HT2A) and dopamine receptors into a multistable prefrontal cortex network model, replicating the experimentally observed inverted U-curve phenomenon. We show how the two 5-HT receptors antagonize neuronal activity and modulate network multistability. Reduced binding of 5-HT1A receptors increases global firing, while reduced binding of 5-HT2A receptors deepens attractors. The obtained results suggest reward-dependent synaptic plasticity mechanisms may attenuate 5-HT related network impairments. Integrating serotonin-mediated dopamine release into circuit, we observe that decreased serotonin concentration triggers the network into a deep attractor state, expanding the domain of attraction of stable nodes with high firing rate, potentially causing aberrant reverse learning. This suggests a hypothesis wherein elevated dopamine concentrations in obsessive-compulsive disorder might result from primary deficits in serotonin levels. Findings of this work underscore the pivotal role of serotonergic dysregulation in modulating synaptic plasticity through dopamine pathways, potentially contributing to learned obsessions. Interestingly, serotonin reuptake inhibitors and antidopaminergic potentiators can counteract the over-stable state of high-firing stable points, providing new insights into obsessive-compulsive disorder treatment., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Emerging evidence suggests that the gut microbiota is closely related to psychiatric disorders. However, little is known about the role of the gut microbiota in the development of obsessive-compulsive disorder (OCD). Here, to investigate the contribution of gut microbiota to the pathogenesis of OCD, we transplanted fecal microbiota from first-episode, drug-naive OCD patients or demographically matched healthy individuals into antibiotic-treated specific pathogen-free (SPF) mice and showed that colonization with OCD microbiota is sufficient to induce core behavioral deficits, including abnormal anxiety-like and compulsive-like behaviors. The fecal microbiota was analyzed using 16 S rRNA full-length sequencing, and the results demonstrated a clear separation of the fecal microbiota of mice colonized with OCD and control microbiota. Notably, microbiota from OCD-colonized mice resulted in injured neuronal morphology and function in the mPFC, with inflammation in the mPFC and colon. Unbiased metabolomic analyses of the serum and mPFC region revealed the accumulation of succinic acid (SA) in OCD-colonized mice. SA impeded neuronal activity and induced an inflammatory response in both the colon and mPFC, impacting intestinal permeability and brain function, which act as vital signal mediators in gut microbiota-brain-immune crosstalk. Manipulations of dimethyl malonate (DM) have been reported to exert neuroprotective effects by suppressing the oxidation of accumulated succinic acid, attenuating the downstream inflammatory response and neuronal damage, and can help to partly improve abnormal behavior and reduce neuroinflammation and intestinal inflammation in OCD-colonized mice. We propose that the gut microbiota likely regulates brain function and behaviors in mice via succinic acid signaling, which contributes to the pathophysiology of OCD through gut-brain crosstalk and may provide new insights into the treatment of this disorder., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder characterized by intrusive obsessive thoughts and compulsive behaviors. Multiple studies have shown the association of polymorphisms in the SLC1A1 gene with OCD. The most common of these OCD-associated polymorphisms increases the expression of the encoded protein, excitatory amino acid transporter 3 (EAAT3), a neuronal glutamate transporter. Previous work has shown that increased EAAT3 expression results in OCD-relevant behavioral phenotypes in rodent models. In this study, we created a novel mouse model with targeted, reversible overexpression of Slc1a1 in forebrain neurons. The mice do not have a baseline difference in repetitive behavior but show increased hyperlocomotion following a low dose of amphetamine (3 mg/kg) and increased stereotypy following a high dose of amphetamine (8 mg/kg). We next characterized the effect of amphetamine on striatal cFos response and found that amphetamine increased cFos throughout the striatum in both control and Slc1a1 -overexpressing (OE) mice, but Slc1a1 -OE mice had increased cFos expression in the ventral striatum relative to controls. We used an unbiased machine classifier to robustly characterize the behavioral response to different doses of amphetamine and found a unique response to amphetamine in Slc1a1 -OE mice, relative to controls. Lastly, we found that the differences in striatal cFos expression in Slc1a1 -OE mice were driven by cFos expression specifically in D1 neurons, as Slc1a1 -OE mice had increased cFos in D1 ventral medial striatal neurons, implicating this region in the exaggerated behavioral response to amphetamine in Slc1a1 -OE mice., (Copyright © 2024 Kopelman et al.)

Visual stimuli and limbic activation varyingly influence obsessive-compulsive symptom expression and so impact treatment outcomes. Some symptom phenotypes, for example, covert repugnant thoughts, are likely less sensitive to sensory stimuli compared to symptoms with an extrinsic focus, that is, symptoms related to contamination, safety, and "just-right-perceptions." Toward an improved understanding of the neurocognitive underpinnings of obsessive-compulsive psychobiology, work in naturalistic animal model systems is useful. Here, we explored the impact of visual feedback and limbic processes on 24 normal (NNB) and large (LNB) nesting deer mice, respectively (as far as possible, equally distributed between sexes). Briefly, after behavioral classification into either the NNB or LNB cohorts, mice of each cohort were separated into two groups each and assessed for nesting expression under either standard light conditions or conditions of complete visual deprivation (VD). Nesting outcomes were assessed in terms of size and neatness. After nesting assessment completion, mice were euthanized, and samples of frontal-cortical and hippocampal tissues were collected to determine serotonin and noradrenaline concentrations. Our results show that LNB, as opposed to NNB, represents an inflexible and excessive behavioral phenotype that is not dependent on visually guided action-outcome processing, and that it associates with increased frontal-cortical and hippocampal noradrenaline concentrations, irrespective of lighting condition. Collectively, the current results are informing of the neurocognitive underpinnings of nesting behavior. It also provides a valuable foundation for continued investigations into the noradrenergic mechanisms that may influence the development and promulgation of excessive, rigid, and inflexible behaviors., (© 2024 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Neuroimaging studies have consistently established altered brain structure in obsessive-compulsive disorder (OCD). However, the molecular and genetic mechanisms underlying structural brain abnormalities remain unclear. In this study, we aimed to investigate altered gray matter volume and its underlying molecular and genetic mechanisms in patients with OCD. Gray matter morphological abnormalities measured with voxel based morphometry analysis were identified in patients with OCD in comparison to sex- and age-matched healthy controls (HCs). Spatial correlations between gray matter morphological abnormalities and neurotransmitter maps were calculated to identify neurotransmitters relating to structural abnormalities. Structural abnormalities related genes were identified by conducting transcriptome-neuroimaging spatial correlations. Compared with HCs, patients with OCD demonstrated significant morphological abnormalities in distributed brain areas, including gray matter atrophy in the anterior cingulate and increased gray matter volume in the thalamus, caudate and precentral and postcentral gyrus. The morphological abnormalities were significantly associated with dopamine synthesis capacity and expression profiles of 1110 genes enriched for trans-synaptic signaling, regulation of membrane potential, modulation of chemical synaptic transmission, brain development, synapse organization and regulation of neurotransmitter levels. These results elucidate the molecular and transcriptional basis of altered gray matter morphology and build linking between molecular, transcriptional and neuroimaging information facilitating an integrative understanding of OCD., Competing Interests: Declaration of competing interest All authors declared no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: Although hypothalamic-pituitary-adrenal (HPA) axis dysregulation in obsessive-compulsive disorder (OCD) has been reported, epigenetic changes in HPA axis-related genes have not been well studied in OCD. The present study investigated whether the epigenetic regulation of FK506-binding protein 51 gene (FKBP5) intron 7 is associated with OCD status in each sex. In addition, relationships among the DNA methylation levels of FKBP5 intron 7, OCD status and early-life trauma were explored., Methods: A total of 267 patients with OCD and 201 controls aged between 18 and 40 years were recruited. Demographic and clinical assessment, FKBP5 rs1360780 genotyping, and pyrosequencing of FKBP5 intron 7 were conducted. DNA was extracted from peripheral blood leucocytes. First, multivariate analysis of covariance for differential DNA methylation levels between OCD patients and controls was conducted with adjustment for FKBP5 rs1360780 genotype, early-life trauma, depressive symptoms, and age as covariates in each sex. Next, path analysis was conducted to determine the mediation effects of DNA methylation levels of FKBP5 between early-life trauma and OCD status. In addition, sensitivity analyses for medication and lifetime major depression were also performed., Results: DNA methylation at the FKBP5 intron 7 CpG site was significantly lower in men with OCD, compared to controls (mean difference -1.33%, 95% CI -2.11 to -0.55, p < 0.001). The results remained significant for drug naïve or free subjects (mean difference -1.27%, 95% CI -2.18 to -0.37, p = 0.006, in men) and for subjects without lifetime major depressive disorder (mean difference -1.60%, 95% CI -2.54 to -0.66, p < 0.001, in men). The mediation effect of DNA methylation levels was not significant between early-life trauma and OCD status., Conclusion: These findings suggest that epigenetic factors of HPA axis-related gene FKBP5 may play a role in the pathogenesis of OCD. Further studies are needed to determine how altered DNA methylation of FKBP5 intron 7 and HPA axis function are involved in OCD., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Obsessive-compulsive disorder (OCD) is a disabling mental condition that poses recurring bothersome intrusive thoughts, obsessions, and compulsions. Considering the positive impact of probiotics on neuropsychiatric disorders, herein, we investigated the effect of multistrain probiotic (Bifidobacterium lactis UBBLa-70, Bacillus coagulans Unique IS-2, Lactobacillus rhamnosus UBLR-58, Lactobacillus plantarum UBLP-40, Bifidobacterium infantis UBBI-01, Bifidobacterium breve UBBr-01, and glutamine) in the management of OCD-like phenotype in rats. Rats injected with quinpirole for 5 weeks showed an increased number of marble burying and self-grooming episodes. Quinpirole-injected animals also did less head dipping in the hole board test and avoided exploration of open spaces in the elevated-plus maze. These repetitive, compulsive, self-directed, and anxiety-like phenotypes were abolished after 8-week of multistrain probiotic treatment. The probiotic formulation also prevented the elevated mRNA expression of interleukin-6, tumor-necrosis factor-α, and C-reactive protein in the amygdala and dysregulated levels of 5-hydroxytryptamine, dopamine, and noradrenaline in the frontal cortex of quinpirole-injected rats. The level of brain-derived neurotrophic factor in the frontal cortex remained unaffected across the groups. The altered levels of goblet cells and crypt-to-villi ratio in quinpirole rats were prevented by multistrain probiotic treatment. The results of 16S-rRNA gene-sequencing of gut microbiota from feces contents revealed an elevation in the abundance of Allobaculum and Bifidobacterium species (specifically Bifidobacterium animalis), while the presence of Lactobacillus species (including Lactobacillus reuteri and Lactobacillus vaginalis) exhibited a decline in quinpirole-induced rats. These results imply that modifying the gut-brain axis may be a possible mechanism by which selective multistrain probiotic therapy prevents OCD-like behaviors., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

In this study, we utilized proton magnetic resonance spectroscopy (MRS) to understand the role of glutamate (Glu), glutamine (Gln), and gamma-aminobutyric acid (GABA) of OCD patients in the pregenual anterior cingulate cortex (pgACC). In total, 54 patients with OCD and 54 healthy controls (HC) matched for age and sex were included in the study. They underwent MRS in the pgACC region to calculate the concentrations of Glu, Gln, GABA, and Glu + Gln (Glx). After quality control of the MRS data, 21 OCD and 21 HC were statistically analyzed. The severity of symptoms were evaluated using the Yale-Brown Obsessive-Compulsive Scale (YBOCS). In the statistical analysis, we compared differences between groups for the metabolites; in the OCD we analyzed the correlations with symptom severity, medication status, age, and duration of illness. A significant decrease in Glx, in Glu, and in Gln in the pgACC were observed in the OCD compared to HC. The correlation statistics showed a significant positive correlation between Glu levels and the YBOCS compulsions subscale. The results indicate that patients with OCD present a disturbance in glutamatergic metabolism in the pgACC. The results also demonstrate that these changes correlate with the severity of compulsions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Currently, it is possible to study the pathogenesis of Tourette's syndrome (TS) in more detail, due to more advanced methods of neuroimaging. However, medical and surgical treatment options are limited by a lack of understanding of the nature of the disorder and its relationship to some psychiatric disorders, the most common of which is obsessive-compulsive disorder (OCD). It is believed that the origin of chronic tic disorders is based on an imbalance of excitatory and inhibitory influences in the Cortico-Striato-Thalamo-Cortical circuits (CSTC). The main CSTCs involved in the pathological process have been identified by studying structural and neurotransmitter disturbances in the interaction between the cortex and the basal ganglia. A neurotransmitter deficiency in CSTC has been demonstrated by immunohistochemical and genetic methods, but it is still not known whether it arises as a consequence of genetically determined disturbances of neuronal migration during ontogenesis or as a consequence of altered production of proteins involved in neurotransmitter production. The aim of this review is to describe current ideas about the comorbidity of TS with OCD, the involvement of CSTC in the pathogenesis of both disorders and the background of structural and neurotransmitter changes in CSTC that may serve as targets for drug and neuromodulatory treatments., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Obsessive-Compulsive disorder (OCD) is a long-term and persistent mental illness characterised by obsessive thoughts and compulsive behaviours. Numerous factors can contribute to the development or progression of OCD. These factors may result from the dysregulation of multiple intrinsic cellular pathways, including SIRT-1, Nrf2, and HO-1. Inhibitors of selective serotonin reuptake (SSRIs) are effective first-line treatments for OCD. In our ongoing research, we have investigated the role of SIRT-1, Nrf2, and HO-1, as well as the neuroprotective potential of Acetyl-11-keto-beta boswellic acid (AKBA) against behavioural and neurochemical changes in rodents treated with 8-OH-DPAT. In addition, the effects of AKBA were compared to those of fluvoxamine (FLX), a standard OCD medication. Injections of 8-OH-DPAT into the intra-dorso raphe nuclei (IDRN) of rats for seven days induced repetitive and compulsive behaviour accompanied by elevated oxidative stress, inflammatory processes, apoptosis, and neurotransmitter imbalances in CSF, blood plasma, and brain samples. Chronic administration of AKBA at 50 mg/kg and 100 mg/kg p.o. restored histopathological alterations in the cortico-striatal-thalamo-cortical (CSTC) pathway, including the cerebral cortex, striatum, and hippocampal regions. Our investigation revealed that when AKBA and fluvoxamine were administered together, the alterations were restored to a greater degree than when administered separately. These findings demonstrate that the neuroprotective effect of AKBA can serve as an effective basis for developing a novel OCD treatment., Competing Interests: Disclosure of potential conflicts of interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Aim: Although Repetitive Transcranial Magnetic Stimulation (rTMS) is a promising new noninvasive brain stimulation therapy, its underlying mechanisms of action remain unknown. OCD patients exhibit impaired response control and attention shifting, which is linked to some brain areas such as anterior cingulate cortex and basal ganglia. OCD patients also display altered neurometabolic concentrations in cortical cortical-striatal-thalamic-cortical (CSTC). In this study, we aimed to elucidate efficacy of rTMS treatment in alleviating related symptoms and pregenual anterior cingulate cortex (pACC) neurometabolites., Methods: OCD patients were randomly divided into either drug (n = 23) or drug + rTMS (n = 29) groups, and those in the latter group subjected to 4-week rTMS treatment. All participants were visited twice, at baseline and follow-up after four weeks. During both visits, all patients were subjected to 1H-MRS, then Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Global Assessment Function (GAF) used to assess severity of obsessive-compulsive symptoms. We also evaluated synchronous anxiety and depression by Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), Hamilton Anxiety Scale (HAM-A) and Hamilton Depression Scale (HAM-D)., Results: After 4 weeks of treatment, patients in the Drug + rTMS group displayed significantly lower Y-BOCS (p = 0.038), BDI (p = 0.009), HAM-D (p = 0.013), HAM-A (p = 0.012) scores than their counterparts in the Drug group. Conversely, patients in the Drug + rTMS group had significantly higher tNAA concentrations (p = 0.030) than those in the Drug group. Notably, the Drug + rTMS group exhibited higher, but insignificant Glu (p = 0.055) and Glx (p = 0.068) concentrations compared to the Drug group. Partial correlation analysis revealed a significant negative correlation between post HAM-A scores and 4-week change of pACC glutamate levels in the Drug + rTMS group (r = -0.434, p = 0.02)., Conclusion: rTMS treatment is an efficacious treatment therapy for OCD, mainly by inducing changes in neurometabolites., Competing Interests: Conflict of interest No conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Obsessive-compulsive disorder (OCD) is characterized by recurring obsessive thoughts and repetitive behaviors that are often associated with anxiety and perturbations in cortico-striatal signaling. Given the suboptimal response of OCD to current serotonergic interventions, there is a need to better understand the psychobiological mechanisms that may underlie the disorder. In this regard, investigations into adenosinergic processes might be fruitful. Indeed, adenosine modulates both anxiety- and motor behavioral output. Thus, we aimed to explore the potential associations between compulsive-like large nest building (LNB) behavior in deer mice, anxiety and adenosinergic processes. From an initial pool of 120 adult deer mice, 34 normal nest building (NNB)- and 32 LNB-expressing mice of both sexes were selected and exposed to either a normal water (wCTRL) or vehicle control (vCTRL), lorazepam (LOR) or istradefylline (ISTRA) for 7- (LOR) or 28 days after which nesting assessment was repeated and animals screened for anxiety-like behavior in an anxiogenic open field. Mice were then euthanized, the striatal tissue removed on ice and the adenosine A 2A receptor expression quantified. Our findings indicate that NNB and LNB behavior are not distinctly associated with measures of generalized anxiety and that ISTRA-induced changes in nesting expression are dissociated from changes in anxiety scores. Further, data from this investigation show that nesting in deer mice is directly related to striatal adenosine signaling, and that LNB is founded upon a lower degree of adenosinergic A 2A stimulation., Competing Interests: Competing interests The authors have no competing interests to declare that are relevant to the content of this article., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Obsessive-compulsive disorder (OCD) is as serious devastating anxiety disorder. Selective serotonin reuptake inhibitors (SSRIs) are largely used for the treatment of this mental disease. This pharmacological approach presents consistent limitations including modest efficacy and important side effects. There is pressing need, therefore, to develop new molecules with higher efficacy and safety. Nitric oxide (NO) is an intra-and inter-cellular messenger in the brain. Its involvement in the pathogenesis of OCD has been proposed. In a series of preclinical studies, the anxiolytic profile of NO modulators has been emerged. In the present review I intended to critically evaluate advances in research of these molecules as potential novel agents for the treatment of OCD, comment their advantages over currently used pharmacological therapy as well remaining challenges. Up to now, few preclinical studies have been carried out to this end. Nonetheless, experimental evidence proposes a role for NO and its modulators in OCD. Additional research is mandatory aiming to definitively determine a role for NO modulators for the treatment of OCD. A note of caution, however, is needed on account of potential neurotoxicity and narrow therapeutic window of NO compounds., Competing Interests: Declaration of competing interest The author reports no financial conflict of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Astrocytes and neurons extensively interact in the brain. Identifying astrocyte and neuron proteomes is essential for elucidating the protein networks that dictate their respective contributions to physiology and disease. Here we used cell-specific and subcompartment-specific proximity-dependent biotinylation 1 to study the proteomes of striatal astrocytes and neurons in vivo. We evaluated cytosolic and plasma membrane compartments for astrocytes and neurons to discover how these cells differ at the protein level in their signalling machinery. We also assessed subcellular compartments of astrocytes, including end feet and fine processes, to reveal their subproteomes and the molecular basis of essential astrocyte signalling and homeostatic functions. Notably, SAPAP3 (encoded by Dlgap3), which is associated with obsessive-compulsive disorder (OCD) and repetitive behaviours 2-8 , was detected at high levels in striatal astrocytes and was enriched within specific astrocyte subcompartments where it regulated actin cytoskeleton organization. Furthermore, genetic rescue experiments combined with behavioural analyses and molecular assessments in a mouse model of OCD 4 lacking SAPAP3 revealed distinct contributions of astrocytic and neuronal SAPAP3 to repetitive and anxiety-related OCD-like phenotypes. Our data define how astrocytes and neurons differ at the protein level and in their major signalling pathways. Moreover, they reveal how astrocyte subproteomes vary between physiological subcompartments and how both astrocyte and neuronal SAPAP3 mechanisms contribute to OCD phenotypes in mice. Our data indicate that therapeutic strategies that target both astrocytes and neurons may be useful to explore in OCD and potentially other brain disorders., (© 2023. The Author(s).)

Schizophrenia (SCZ) and obsessive-compulsive disorder (OCD) are complex polygenic disorders with brain morphology abnormalities. The etiologies and relationship of both disorders remain elusive, and should be further investigated. Thus, induced pluripotent stem cells (iPSCs) were generated from peripheral blood mononuclear cells (PBMCs) from an OCD patient, his mother with SCZ and his healthy father with reprograming method. All iPSCs were characterized to have normal karyotype and expression of pluripotency makers. These iPSCs will be a valuable model to elucidate the pathophysiological mechanisms and association of both diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The brain melanocortin system regulates numerous physiological functions and kinds of behavior. The agouti protein inhibits melanocortin receptors in melanocytes. The lethal yellow (A Y ) mutation puts the Agouti gene under the control of the Raly gene promotor and causes the agouti protein expression in the brain. In the present article, we investigated the effects of the A Y mutation on brain mRNA levels of Agouti , Raly , and melanocortin-related genes such as Agrp, Pomc, Mc3r, Mc4r , and their relationship to behavior., Methods: The experiment was performed on 6-month-old males and females of A Y /a and a/a (control) mice. Anxiety and obsessive-compulsive behavior were studied in elevated plus-maze and marble- burying tests. The mRNA levels were quantified by qPCR., Results: A Y mutation caused anxiety in males and obsessive-compulsive behavior in females. Positive correlation between Agouti and Raly genes mRNA levels were shown in the hypothalamus, hippocampus, and frontal cortex in A Y /a mice. Reduced RNA concentrations of Mc3r and Mc4r genes were found respectively in the hypothalamus and frontal cortex in A Y /a males. The Raly gene expression positively correlates with mRNA concentrations of the Mc3r gene in the hypothalamus and the Mc4r gene in the hypothalamus and frontal cortex., Conclusion: Possible association of obsessive-compulsive behavior with reduced Raly , Mc3r, or Mc4r gene expression is suggested., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The smoothened sonic hedgehog (Smo-Shh) pathway is one mechanism that influences neurogenesis, including brain cell differentiation and development during childhood. Shh signaling dysregulation leads to decreased target gene transcription, which contributes to increased neuronal excitation, apoptosis, and neurodegeneration, eventually leading to neurological deficits. Neuropsychiatric disorders such as OCD and related neurological dysfunctions are characterized by neurotransmitter imbalance, neuroinflammation, oxidative stress, and impaired neurogenesis, disturbing the cortico-striato-thalamo-cortical (CSTC) link neuronal network. Despite the availability of several treatments, such as selective serotonin reuptake inhibitors, some individuals may not benefit much from them. Several trials on the use of antipsychotics in the treatment of OCD have also produced inadequate findings. This evidence-based review focuses on a potential pharmacological approach to alleviating OCD and associated neuronal deficits by preventing neurochemical alterations, in which sonic hedgehog activators are neuroprotective, lowering neuronal damage while increasing neuronal maintenance and survival. As a result, stimulating SMO-Shh via its potential activators may have neuroprotective effects on neurological impairment associated with OCD. This review investigates the link between SMO-Shh signaling and the neurochemical abnormalities associated with the progression of OCD and associated neurological dysfunctions. Role of Smo-Shh signaling in serotonergic neurogenesis and in maintaining their neuronal identity. The Shh ligand activates two main transcriptional factors known as Foxa2 and Nkx2.2, which again activates another transcriptional factor, GATA (GATA2 and GATA3), in post mitotic precursor cells of serotonergic neurons-following increased expression of Pet-1 and Lmx1b after GATA regulates the expression of many serotonergic enzymes such as TPH2, SERT, VMAT, slc6a4, Htr1a, Htr1b (Serotonin receptor enzymes), and MAO that regulate and control the release of serotonin and maintain their neuronal identity after their maturation. Abbreviation: Foxa2: Forkhead box; GATA: Globin transcription factor; Lmx1b: LIM homeobox transcription factor 1 beta; TPH2: Tryptophan hydroxylase 2; Htr1a: Serotonin receptor 1a; Htr1b: Serotonin receptor 1b; SERT: Serotonin transporter; VMAT: Vesicular monoamine transporter; MAO: Monoamine oxidase., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

SLIT and NTRK-like protein-5 (SliTrk5) is one of the six members of SliTrk protein family, which is widely expressed in the central nervous system (CNS), regulating and participating in many essential steps of central nervous system development, including axon and dendritic growth, neuron differentiation, and synaptogenesis. SliTrk5, as a neuron transmembrane protein, contains two important conservative domains consisting of leucine repeats (LRRs) located at the amino terminal in the extracellular region and tyrosine residues (Tyr) located at the carboxyl terminal in the intracellular domains. These special structures make SliTrk5 play an important role in the pathological process of the CNS. A large number of studies have shown that SliTrk5 may be involved in the pathogenesis of CNS diseases, such as obsessive-compulsive-disorder (OCD), attention deficit/hyperactivity disorder (ADHD), glioma, autism spectrum disorders (ASDs), and Parkinson's disease (PD). Targeting SliTrk5 is expected to become a new target for the treatment of CNS diseases, promoting the functional recovery of CNS. The purpose of this article is to review the current research progression of the role of SliTrk5 in CNS and its potential mechanisms in CNS diseases., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Yan Liu et al.)

Obsessive-compulsive disorder is varyingly associated with cognitive impairment, that is, deficits in spatial working memory, although it seems unlikely that this is generalised across all domains of functioning. Further, it is unclear whether symptoms will respond to potentially novel, non-serotonergic drugs that have shown promise as so-called cognitive enhancers. Here, we studied low (Norm-N; n = 31) and compulsive-like high (Comp-H; n = 34) stereotypical deer mice (Peromyscus maniculatus bairdii) to establish (1) whether there is a relationship between stereotypical intensity and working memory ability as measured by spontaneous T-maze arm alternation and (2) if and how stereotypy and its association with changes in working memory, would respond to the known anti-compulsive agent, escitalopram, and the proposed cognitive enhancer, levetiracetam. After assessing the stereotypical and alternation behaviour of all animals at baseline, they were divided into three socially housed drug exposure groups, that is, water control (n = 11 per phenotype), escitalopram 50 mg/kg/d (n = 11 per phenotype) and levetiracetam 75 mg/kg/d (Norm-N: n = 9; Comp-H: n = 12). Drugs were administered for 28 days before stereotypy and alternation assessment were repeated. The present data indicate a weak negative relationship between stereotypical intensity and spontaneous alternation. While levetiracetam increased the time spent engaging in normal rodent activity by Comp-H, but not Norm-N animals, neither of the interventions affected the expression of Comp-H behaviour or the alternation behaviour of deer mice. In conclusion, this work points to some degree of cognitive involvement in Comp-H expression, which should be explored to further our understanding of compulsive-like stereotypy., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Childhood-onset obsessive-compulsive disorder (OCD) has been associated with immune dysregulation, including aberrant plasma inflammatory markers and increased rates of infectious and immune-mediated disorders. Saliva may provide a minimally-invasive tool for assessing oral mucosal immunity and inflammatory biomarkers in this population. The primary aim of this study was to compare salivary defense proteins and inflammatory mediators in saliva from children and youth with OCD and healthy controls, and evaluate their associations with measures of oral health and OCD phenotype., Methods: In this cross-sectional observational study, saliva was collected from 41 children and youth with childhood-onset OCD and 46 healthy controls. Levels of lysozyme, α-amylase, secretory immunoglobulin A (sIgA), C-reactive protein (CRP), interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) were quantified by enzyme-linked immunosorbent assays or electrochemiluminescent-based immunoassays., Results: All analytes were detectable in saliva. When adjusting for salivary flow rate and total protein, multiple linear regression models including demographic variables, oral health measures, and OCD status explained a significant proportion of the variance in IL-6, IL-1β, and sIgA but not TNF-α, CRP, α-amylase, or lysozyme levels. Diagnosis of OCD was associated with significantly higher IL-6 (β = 0.403, p = 0.026), while severity of OCD was a significant predictor of increased cytokines (IL-6, β = 0.325, p = 0.009; IL-1β, β = 0.284, p = 0.020; TNF-α, β = 0.269, p = 0.036), but not other analytes., Conclusion: These data point to the feasibility of analyzing soluble immune mediators in the saliva in childhood-onset OCD, suggesting that pro-inflammatory cytokines are associated with OCD diagnosis and symptom severity. Further work is required to elucidate the factors contributing to this association and implications for clinical practice., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Obsessive-compulsive disorder (OCD) has a complex etiology that seems to include immune dysfunction and alterations in circulating monocytes. To investigate the immune basis and the functional dysregulation of monocytes in this disease, we analyzed gene expression in the peripheral monocytes of pediatric patients with OCD (N = 102) compared to controls (N = 47). We examined gene expression in primary cultures of peripheral monocytes from participants, under basal conditions and under exposure to lipopolysaccharide (LPS) to stimulate immune response. Whole-genome expression was assessed in 8 patients and 8 controls. Differentially expressed genes were identified followed by protein-protein interaction network construction and functional annotation analysis to identify the genes and biological processes that are altered in the monocytes of OCD patients. We also explored the expression levels of selected genes in monocytes from the other participants using qPCR. Several changes in gene expression were observed in the monocytes of OCD patients, with several immune processes involved under basal conditions (antigen processing and presentation, regulation of immune system and leukocyte cell adhesion) and after LPS stimulation (immune and inflammatory response, cytokine production and leukocyte activation). Despite the qPCR analysis provided no significant differences between patients and controls, high correlations were observed between the expression levels of some of the genes and inflammatory markers (i.e., T helper 17 and regulatory T cell levels, total monocyte and proinflammatory monocyte subset levels, and the cytokine production by resting and stimulated monocytes) of the study participants. Our findings provide more evidence of the involvement of monocyte dysregulation in early-onset OCD, indicating a proinflammatory predisposition and an enhanced immune response to environmental triggers., (© 2022. The Author(s).)

Obsessive-compulsive disorder (OCD) is a disabling condition that often begins in childhood. Genetic studies in OCD have pointed to SLC1A1, which encodes the neuronal glutamate transporter EAAT3, with evidence suggesting that increased expression contributes to risk. In mice, midbrain Slc1a1 expression supports repetitive behavior in response to dopaminergic agonists, aligning with neuroimaging and pharmacologic challenge studies that have implicated the dopaminergic system in OCD. These findings suggest that Slc1a1 may contribute to compulsive behavior through altered dopaminergic transmission; however, this theory has not been mechanistically tested. To examine the developmental impact of Slc1a1 overexpression on compulsive-like behaviors, we, therefore, generated a novel mouse model to perform targeted, reversible overexpression of Slc1a1 in dopaminergic neurons. Mice with life-long overexpression of Slc1a1 showed a significant increase in amphetamine (AMPH)-induced stereotypy and hyperlocomotion. Single-unit recordings demonstrated that Slc1a1 overexpression was associated with increased firing of dopaminergic neurons. Furthermore, dLight1.1 fiber photometry showed that these behavioral abnormalities were associated with increased dorsal striatum dopamine release. In contrast, no impact of overexpression was observed on anxiety-like behaviors or SKF-38393-induced grooming. Importantly, overexpression solely in adulthood failed to recapitulate these behavioral phenotypes, suggesting that overexpression during development is necessary to generate AMPH-induced phenotypes. However, doxycycline-induced reversal of Slc1a1/EAAT3 overexpression in adulthood normalized both the increased dopaminergic firing and AMPH-induced responses. These data indicate that the pathologic effects of Slc1a1/EAAT3 overexpression on dopaminergic neurotransmission and AMPH-induced stereotyped behavior are developmentally mediated, and support normalization of EAAT3 activity as a potential treatment target for basal ganglia-mediated repetitive behaviors., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Repetitive behavioral phenotypes are a trait of several neuropsychiatric disorders, including obsessive-compulsive disorder (OCD). Such behaviors are typified by complex interactions between cognitive and neurobiological processes which most likely contribute to the suboptimal treatment responses often observed. To this end, exploration of the adenosinergic system may be useful, since adenosine-receptor modulation has previously shown promise to restore control over voluntary behavior and improve cognition in patients presenting with motor repetition. Here, we employed the deer mouse (Peromyscus maniculatus bairdii) model of compulsive-like behavioral persistence, seeking to investigate possible associations between stereotypic motor behavior and cognitive flexibility as measured in the T-maze continuous alternation task (T-CAT). The effect of istradefylline, a selective adenosine A 2A receptor antagonist at two doses (10 and 20 mg kg -1  day -1 ) on the expression of stereotypy and T-CAT performance in high (H) and non-(N) stereotypical animals, was investigated in comparison to a control intervention (six groups; n = 8 or 9 per group). No correlation between H behavior and T-CAT performance was found. However, H but not N animals presented with istradefylline-sensitive spontaneous alternation and stereotypy, in that istradefylline at both doses significantly improved the spontaneous alternation scores and attenuated the stereotypical expression of H animals. Thus, evidence is presented that anti-adenosinergic drug action improves repetitive behavior and spontaneous alternation in stereotypical deer mice, putatively pointing to a shared psychobiological construct underlying naturalistic stereotypy and alterations in cognitive flexibility in deer mice., (© 2021 Wiley Periodicals LLC.)

Gilles de la Tourette syndrome (GTS) is a complex neurodevelopmental disorder characterized by motor and vocal tics. Most of the GTS individuals have comorbid diagnoses, of which obsessive-compulsive disorder (OCD) and attention deficit-hyperactivity disorder (ADHD) are the most common. Several neurotransmitter systems have been implicated in disease pathogenesis, and amongst these, the dopaminergic and the serotonergic pathways are the most widely studied. In this study, we aimed to investigate whether the serotonin transporter (SERT) gene ( SLC6A4 ) was differentially expressed among GTS individuals compared to healthy controls, and whether DNA variants (the SERT-linked polymorphic region 5-HTTLPR, together with the associated rs25531 and rs25532 variants, and the rare Ile425Val variant) or promoter methylation of SLC6A4 were associated with gene expression levels or with the presence of OCD as comorbidity. We observed that SLC6A4 expression is upregulated in GTS individuals compared to controls. Although no specific genotype, allele or haplotype was overrepresented in GTS individuals compared to controls, we observed that the L AC /L AC genotype of the 5-HTTLPR/rs25531/rs25532 three-locus haplotype was associated with higher SLC6A4 mRNA expression levels in GTS individuals, but not in the control group.

Background: Cognitive behavioral therapy (CBT) is an effective, first-line treatment for pediatric obsessive-compulsive disorder (OCD). While neural predictors of treatment outcomes have been identified in adults with OCD, robust predictors are lacking for pediatric patients. Herein, we sought to identify brain structural markers of CBT response in youth with OCD., Methods: Twenty-eight children/adolescents with OCD and 27 matched healthy participants (7- to 18-year-olds, M = 11.71 years, SD = 3.29) completed high-resolution structural and diffusion MRI (all unmedicated at time of scanning). Patients with OCD then completed 12-16 sessions of CBT. Subcortical volume and cortical thickness were estimated using FreeSurfer. Structural connectivity (streamline counts) was estimated using MRtrix., Results: Thinner cortex in nine frontoparietal regions significantly predicted improvement in Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) scores (all ts > 3.4, FDR-corrected ps < .05). These included middle and superior frontal, angular, lingual, precentral, superior temporal, and supramarginal gyri (SMG). Vertex-wise analyses confirmed a significant left SMG cluster, showing large effect size (Cohen's d = 1.42) with 72.22% specificity and 90.00% sensitivity in predicting CBT response. Ten structural connections between cingulo-opercular regions exhibited fewer streamline counts in OCD (all ts > 3.12, Cohen's ds > 0.92) compared with healthy participants. These connections predicted post-treatment CY-BOCS scores, beyond pretreatment severity and demographics, though not above and beyond cortical thickness., Conclusions: The current study identified group differences in structural connectivity (reduced among cingulo-opercular regions) and cortical thickness predictors of CBT response (thinner frontoparietal cortices) in unmedicated children/adolescents with OCD. These data suggest, for the first time, that cortical and white matter features of task control circuits may be useful in identifying which pediatric patients respond best to individual CBT., (© 2019 Association for Child and Adolescent Mental Health.)

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.

Rationale: Checking is a functional behaviour that provides information to guide behaviour. However, in obsessive-compulsive disorder (OCD), checking may escalate to dysfunctional levels. The processes underpinning the transition from functional to dysfunctional checking are unclear but may be associated with individual differences that support the development of maladaptive behaviour. We examined one such predisposition, sign-tracking to a pavlovian conditioned stimulus, which we previously found associated with dysfunctional checking. How sign-tracking interacts with another treatment with emerging translational validity for OCD-like checking, chronic administration of the dopamine D 2 receptor agonist quinpirole, is unknown., Objectives: We tested how functional and dysfunctional checking in the rat observing response task (ORT) was affected by chronic quinpirole administration in non-autoshaped controls and autoshaped animals classified as sign-trackers or goal-trackers., Methods: Sign-trackers or goal-trackers were trained on the ORT before the effects of chronic quinpirole administration on checking were assessed. Subsequently, the effects on checking of different behavioural challenges, including reward omission and the use of unpredictable reinforcement schedules, were tested., Results: Prior autoshaping increased checking. Sign-trackers and goal-trackers responded differently to quinpirole sensitization, reward omission and reinforcement uncertainty. Sign-trackers showed greater elevations in dysfunctional checking, particularly during uncertainty. By contrast, goal-trackers predominantly increased functional checking responses, possibly in response to reduced discrimination accuracy in the absence of cues signalling which lever was currently active., Conclusions: The results are discussed in terms of how pavlovian associations influence behaviour that becomes compulsive in OCD and how this may be dependent on striatal dopamine D 2 receptors.

We aimed to evaluate [3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-0- 11 C-methyloxime] ([ 11 C]ABP688) small animal positron emission tomography (μPET) as a biomarker to visualize possible longitudinal changes in metabotropic glutamate receptor 5 (mGluR5) availability in the brain of SAP90/PSD-95 associated protein 3 (Sapap3) knockout (ko) mice, showing obsessive compulsive disorder (OCD)-like behavior., Methods: Alongside the assessment of grooming, we performed [ 11 C]ABP688 μPET/CT imaging in wildtype (wt; n=10) and ko (n=11) mice both at 3 and 9 months. Using the simplified reference tissue method (SRTM), the nondisplaceable binding potential (BP ND ) was calculated representing the in vivo availability of the metabotropic glutamate receptor 5 (mGluR5) in the brain with the cerebellum as a reference region. Longitudinal voxel-based statistical parametric mapping (SPM) was performed on BP ND images. Results were verified using [ 11 C]ABP688 ex vivo autoradiography, [ 3 H]ABP688 in vitro autoradiography, and mGluR5 immunohistochemistry., Results: Cross-sectional comparisons revealed significantly increased grooming parameters in ko animals, at both time points. A significant longitudinal increase in % grooming duration (+268.25%; p<0.05) reflected aggravation of this behavior in ko mice. [ 11 C]ABP688 μPET revealed significantly lower mGluR5 availability in the cortex, striatum, hippocampus, and amygdala of ko mice at both ages. A significant longitudinal BP ND decline was present for ko mice (p<0.01: cortex -17.14%, striatum -19.82%, amygdala -23.57%; p<0.05: hippocampus -15.53%), which was confirmed by SPM (p<0.01)., Conclusion: Sapap3 ko mice show a decline in mGluR5 availability in OCD relevant brain regions parallel to the worsening of OCD-like behavior. This demonstrates a potential role for [ 11 C]ABP688 PET as a biomarker to monitor disease progression in vivo., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The cortisol response in patients with obsessive-compulsive disorder (OCD) during exposure with response prevention (ERP), a stressful but very effective psychotherapeutic treatment, has shown contradictory findings in three prior studies with low sample sizes. In a larger cohort of 51 patients with OCD we repeatedly measured subjective units of distress (SUD) and the adrenocortical stress hormones cortisol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) in saliva during the very first session of ERP and on the day before. Expectedly, SUD were increased on the ERP day before the session and further rose during ERP, but salivary cortisol and DHEA were statistically indistinguishable from the comparison condition. Interestingly, DHEA-S was significantly elevated throughout the ERP versus the comparison day, but did not further increase in acute response to ERP. According to an explorative analysis in a subsample, hormone levels on the comparison or the ERP day did not predict anti-OCD treatment response one month later. These results corroborate our prior findings of cortisol non-response despite considerable subjective stress in ERP. The role of DHEA-S in anticipatory anxiety and the effects of augmentative cortisol therapy in ERP need further study., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Rationale: Obsessive-compulsive disorder (OCD) is characterized by repetitive behaviors exacerbated by stress. Many OCD patients do not respond to available pharmacotherapies, but neurosurgical ablation of the anterior cingulate cortex (ACC) can provide symptomatic relief. Although the ACC receives noradrenergic innervation and expresses adrenergic receptors (ARs), the involvement of norepinephrine (NE) in OCD has not been investigated., Objective: To determine the effects of genetic or pharmacological disruption of NE neurotransmission on marble burying (MB) and nestlet shredding (NS), two animal models of OCD., Methods: We assessed NE-deficient (Dbh -/-) mice and NE-competent (Dbh +/-) controls in MB and NS tasks. We also measured the effects of anti-adrenergic drugs on NS and MB in control mice and the effects of pharmacological restoration of central NE in Dbh -/- mice. Finally, we compared c-fos induction in the locus coeruleus (LC) and ACC of Dbh -/- and control mice following both tasks., Results: Dbh -/- mice virtually lacked MB and NS behaviors seen in control mice but did not differ in the elevated zero maze (EZM) model of general anxiety-like behavior. Pharmacological restoration of central NE synthesis in Dbh -/- mice completely rescued NS behavior, while NS and MB were suppressed in control mice by anti-adrenergic drugs. Expression of c-fos in the ACC was attenuated in Dbh -/- mice after MB and NS., Conclusion: These findings support a role for NE transmission to the ACC in the expression of stress-induced compulsive behaviors and suggest further evaluation of anti-adrenergic drugs for OCD is warranted.

It is difficult to believe that in about 1960 practically nothing was known about the thymus and some of its products, T cells bearing αβ receptors for antigen. Thus I was lucky to join the field of T cell biology almost at its beginning, when knowledge about the cells was just getting off the ground and there was so much to discover. This article describes findings about these cells made by others and myself that led us all from ignorance, via complete confusion, to our current state of knowledge. I believe I was fortunate to practice science in very supportive institutions and with very collaborative colleagues in two countries that both encourage independent research by independent scientists, while simultaneously ignoring or somehow being able to avoid some of the difficulties of being a woman in what was, at the time, a male-dominated profession.

Obsessive-compulsive disorder (OCD) is a chronic psychiatric disorder, of unknown etiology, that affects 2.5% of the population. An appropriate therapeutic response to conventional treatment is seen. Some studies use augmentative treatment by antipsychotics, glutamatergic, lithium, buspirone, and others agents to improve the therapeutic response. In this study, we aimed to evaluate the efficacy and tolerability of aripiprazole and quetiapine as augmentative treatments in patients with selective serotonin reuptake inhibitor (SSRI) refractory OCD. The OCD patients were initially treated for 12 weeks with a SSRI. If after 12 weeks their Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score was more than 16, they were randomly assigned to either the aripiprazole or the quetiapine augmentation group for an additional 12 weeks. There were no significant differences in age, sex, education, marital status, or score of Y-BOCS and Clinical Global Impression-Severity Scale (CGI-S) between groups ( p > 0.05) at the outset of the study. Significant differences were noted after 1 month when compared with results at 2, 3, and 4 months in both groups ( p < 0.001). Both quetiapine and aripiprazole may be effective and well-tolerated augmentative agents in the treatment of SSRI-refractory OCD. Because of positive results, aripiprazole may be considered more effective and may have a more rapid onset in terms of therapeutic response.

Background: Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections syndrome (PANDAS) identifies patients with acute onset of obsessive-compulsive and tic disorders. The objective of this study was to evaluate serum NOX2 levels, as well as 8-iso-prostaglandin F2α (8-iso-PGF2α) and lipopolysaccharide (LPS) of PANDAS patients., Methods: In this study we wanted to compare serum levels of soluble NOX2-dp (sNOX-2-dp), iso-PGF2α and LPS in 60 consecutive subjects, including 30 children affected by PANDAS and 30 controls (CT) matched for age and gender. Serum zonulin was used as intestinal permeability assay., Results: Compared with CT, PANDAS children had increased serum levels of sNOX-2-dp, 8-iso-PGF2α and LPS. Bivariate analysis showed that serum sNOX2-dp was significantly correlated with LPS (Rs = 0.359; p = 0.005), zonulin (Rs = 0.444; p < 0.001) and 8-iso-PGF2α (Rs = 0.704; p < 0.001). Serum LPS significantly correlated with zonulin (Rs = 0.610; p < 0.001), and 8-iso-PGF2α (Rs = 0.591; p = 0.001). Finally, a multiple linear regression analysis showed that serum 8-iso-PGF2α and zonulin were the only independent variables associated with sNOX2-dp (R 2  = 68%)., Conclusion: This study shows that children affected by PANDAS have high circulating levels of sNOX2-dp, isoprostanes and of LPS that could be involved in the process of neuroinflammation.

We studied the influence of intraperitoneal injection of ATP-sensitive potassium channels inhibitor glibenclamide in doses of 0.01, 0.1, 1, and 10 mg/kg on the effects of a new pyrazolo[C]pyridine derivative GIZh-72 (4,6-dimethyl-2-(4-chlorphenyl)-2,3-dihydro-1Hpyrazolo[ 4,3-C]pyridine-3-on, chloral hydrate; 20 mg/kg, intraperitoneally) in the marble burying and open-field tests in mice. It was found that glibenclamide produced an anxiolytic effect in the open-field test (in a dose of 0.01 mg/kg) and anticompulsive effect in the marble burying test (in doses of 1 and 10 mg/kg). The observed behavioral effects of glibenclamide did not depend on blood glucose level. At the same time, glibenclamide in subeffective (0.01 and 0.1 mg/kg) and effective (1 and 10 mg/kg) doses potentiated the psychotropic effects of GIZh-72 in these tests. It can be assumed that the psychotropic effects of GIZh-72 depend on functional activity of ATP-sensitive potassium channels.

We studied the effects of GABA derivatives on anxious and compulsive behavior of progeny of rats with experimental preeclampsia provoked by replacement of drinking water for 1.8% NaCl solution from the first day of pregnancy to delivery. In comparison with progeny of health rats, the offspring of dams with complicated pregnancy demonstrated high level of anxiety and the development of obsessive-compulsive disorder both at the early (40 and 70 days) and late (6 and 12 months) stages of ontogeny. GABA derivatives succicard, salifen, and phenibut reduced symptoms of experimental preeclampsia in offspring of various age by decreasing the level of anxiety and reducing compulsive behavior. The efficacy of the examined derivatives was similar to that of the reference drug Pantogam.

Family, adoption and twin studies have highlighted the significant role of heritable influences on individual differences in opioid addiction. Meanwhile, obsessive-compulsive disorder (OCD) is a disorder wherein the individual experiences recurring thoughts that cause irrational fears and anxiety. In the present study, adult male and female rats received morphine solution for 21 days and were drug-free for 10 days. Offspring were used in 4 distinct groups; (1) paternal morphine-exposed, (2) maternal morphine-exposed, (3) maternal and paternal morphine-exposed, and (4) drug-naïve subjects. We assessed the grooming behavior and marble burying test as an indicator of obsessive-compulsive behavior. To clarify the mechanisms underlying these changes, the mRNA level of BDNF, the phosphorylation level of CREB and the protein level of D2 dopamine receptor (DR) were evaluated in the nucleus accumbens (NAc). The grooming behavior in male offspring with one or two morphine-abstinent parent(s) increased compared with the offspring of drug naïve rats. In addition, the offspring of morphine-exposed parents buried more marbles when compared with the offspring of drug-naïve parents. Also, the BDNF mRNA was down-regulated in the NAC. However, the levels of phospho-CREB and D2 DR were elevated. Previous studies indicated that exposure to morphine in adulthood enhances the risk of psychiatric disorders in offspring. OCD is one the comorbid disorders with addiction and increases the risk of substance abuse disorder in patients. In this survey, we found that morphine exposure in parents before gestation can encourage obsessive-compulsive behavior in offspring., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Previous studies have shown associations between obsessive-compulsive disorder (OCD) and hypothalamic-pituitary-adrenal axis activity (HPA). We aimed to investigate the association between obsessive-compulsive (OC) symptoms and HPA axis functionality in a non-clinical sample and to explore whether there are sex differences in this relationship., Methods: One hundred eighty-three healthy individuals without any psychiatric diagnosis (80 men, 103 women; mean age 41.3 ± 17.9 years) were recruited from the general population. The Obsessive-Compulsive Inventory Revised (OCI-R) was used to assess OC symptoms. State-trait anxiety, perceived stress, and stressful life events were also assessed. Saliva cortisol levels were determined at 6 time points (awakening, 30 and 60 min post-awakening, 10:00 a.m., 23:00 p.m. and 10:00 a.m. the following day of 0.25 mg dexamethasone intake [that occurred at 23:00 p.m.]). Three HPA axis measures were calculated: cortisol awakening response (CAR), cortisol diurnal slope, and cortisol suppression ratio after dexamethasone (DSTR). Multiple linear regression analyses were used to explore the association between OC symptoms and HPA axis measures while adjusting for covariates. Our main analyses were focused on OCI-R total score, but we also explored associations with specific OC symptom dimensions., Results: No significant differences were observed between males and females in OC symptoms, anxiety measures, stress, or cortisol measures. In the multiple linear regression analyses between overall OC symptoms and HPA axis measures, a female sex by OC symptoms significant interaction (standardized beta = - 0.322; p = 0.023) for the CAR (but not cortisol diurnal slope nor DSTR) was found. Regarding specific symptom dimensions, two other sex interactions were found: a blunted CAR was associated with obsessing symptoms in women, whereas a more flattened diurnal cortisol slope was associated with ordering symptoms in men., Conclusions: There are sex differences in the association between OC symptoms and HPA axis measures in healthy individuals.

Endophenotypes are mediator traits between genetic influences and clinical phenotypes. Meta-analyses have consistently shown modest impairments of executive functioning in obsessive compulsive disorder (OCD) patients compared to healthy controls. Similar deficits have also been reported in unaffected relatives of OCD patients, but have not been quantified. We conducted the first meta-analysis combining all studies investigating executive functioning in unaffected relatives of individuals with OCD to quantify any deficits. A search of Pubmed, Medline and PsychInfo databases identified 21 suitable papers comprising 707 unaffected relatives of OCD patients and 842 healthy controls. Effect sizes were calculated using random effects models. Unaffected relatives displayed a significant impairment in global executive functioning. Analyses of specific executive functioning subdomains revealed impairments in: planning, visuospatial working memory and verbal fluency. Deficits in executive functioning are promising endophenotypes for OCD. To identify further biomarkers of disease risk/resilience in OCD, we suggest examining specific executive functioning domains.

Aberrant microglia activity is associated with many neurological and psychiatric disorders, yet our knowledge about the pathological mechanisms is incomplete. Here, we describe a genetically defined microglia sublineage in mice which has the ability to suppress obsessive compulsion and anxiety symptoms. These microglia derive from precursors expressing the transcription factor Hoxb8. Selective ablation of Hoxb8-lineage microglia or the Hoxb8 gene revealed that dysfunction in this cell type causes severe over-grooming and anxiety-like behavior and stress responses. Moreover, we show that the severity of the pathology is set by female sex hormones. Together, our findings reveal that different microglia lineages have distinct functions. In addition, our data suggest a mechanistic link between biological sex and genetics, two major risk factors for developing anxiety and related disorders in humans., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The goal of this article is to clarify the role of various growth factors in the establishment and progression of obsessive-compulsive disorder (OCD). OCD is a chronic mental disorder with recurrent intrusive thoughts and/or repetitive compulsive behaviors that increase during stressful periods. Growth and neurotrophic factors may be contributing factors in the pathophysiology of OCD. Many of them are synthesized and released within the central nervous system and act as trophic agents in neurons; some of them are involved in brain growth, development, neurogenesis, myelination and plasticity, while others take part in the protection of the nervous system following brain injuries. This paper attempts to identify all articles investigating the relationship between OCD and neurotrophic and growth factors, in both animal and human studies, with a focus on adult brain studies. Based on the PubMed and Scopus and Science Direct search tools, the available articles and studies are reviewed. Out of 230 records in total, the ones related to our review topic were taken into account to further understand the pathophysiological mechanism(s) of OCD, providing methods to improve its symptoms via the modification of neurotrophins and growth factor imbalances., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The thalamus plays an important role in pathological mechanisms underlying obsessive-compulsive disorder (OCD). As the thalamus is a heterogeneous brain region, functional connectivity (FC) between thalamic subregions and other brain regions is worth investigating in OCD. In addition, the relationship between abnormal FC and clinical symptoms is still unclear. In this study, we used resting-state functional magnetic resonance imaging to scan 45 OCD patients and 43 well-matched healthy controls (HCs). Thalamic subregions were defined according to the Human Brainnetome Atlas. The fractional amplitude of low-frequency fluctuations (fALFF) and FC seeding-based connectivity were compared using a two-sample t-test. Correlations between abnormal FC and clinical symptoms were analyzed in OCD patients. Compared with HCs, increased fALFF was found in the bilateral thalamus, and increased FC was observed between the right posterior parietal thalamus (PPtha) and left middle occipital gyrus (LMOG) and between the right occipital thalamus (Otha) and right middle occipital gyrus (RMOG) in OCD patients. In addition, OCD patients had reduced FC between the left sensory thalamus (Stha) and left orbital inferior frontal gyrus, right PPtha and left prefrontal cortex, and between the right Otha and left inferior parietal gyrus (LIPG), respectively. Within the OCD group, the FC between right PPtha-LMOG was correlated with severity of clinical symptoms. These results revealed that the FC between the thalamus and occipital lobe is related to obsessive-compulsive symptoms in OCD patients. This finding provides more accurate information about the involvement of the thalamus in the pathophysiology of OCD., (Copyright © 2019. Published by Elsevier B.V.)

Objective: Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder with an etiopathophysiology that seems to include immune alterations. Previous studies have suggested that variations in the levels of circulating T cell subpopulations may be involved in psychiatric diseases. However, the role of these cells in OCD remains unexplored. Hence, the present study aimed to examine the levels of T helper 1 (Th1), Th2, Th17 and regulatory T (Treg) cells in patients with early-onset OCD and healthy controls., Methods: The assessment was performed in 99 children and adolescents with OCD and 46 control subjects. The percentages of circulating Th1, Th2, Th17 and Treg cells were evaluated using flow cytometry., Results: OCD patients had significantly higher levels of Th17 cells and lower percentages of Treg cells than healthy controls (p = 0.001 and p = 0.005, respectively). Furthermore, levels of Th17 cells progressively increased with the duration (p = 0.005) and severity of OCD (p = 0.008), whereas the percentages of Treg cells significantly declined with the duration of the disorder (p = 1.8 × 10 -5 )., Conclusions: These results provide more evidence of the involvement of immune dysregulation, specifically an imbalance in the levels of circulating T helper and regulatory T cells, in the pathophysiology of early-onset OCD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

BTB/POZ domain-containing 3 (BTBD3) was identified as a potential risk gene in the first genome-wide association study of obsessive-compulsive disorder (OCD). BTBD3 is a putative transcription factor implicated in dendritic pruning in developing primary sensory cortices. We assessed whether BTBD3 also regulates neural circuit formation within limbic cortico-striato-thalamo-cortical circuits and behaviors related to OCD in mice. Behavioral phenotypes associated with OCD that are measurable in animals include compulsive-like behaviors and reduced exploration. We tested Btbd3 wild-type, heterozygous, and knockout mice for compulsive-like behaviors including cage-mate barbering, excessive wheel-running, repetitive locomotor patterns, and reduced goal-directed behavior in the probabilistic learning task (PLT), and for exploratory behavior in the open field, digging, and marble-burying tests. Btbd3 heterozygous and knockout mice showed excessive barbering, wheel-running, impaired goal-directed behavior in the PLT, and reduced exploration. Further, chronic treatment with fluoxetine, but not desipramine, reduced barbering in Btbd3 wild-type and heterozygous, but not knockout mice. In contrast, Btbd3 expression did not alter anxiety-like, depression-like, or sensorimotor behaviors. We also quantified dendritic morphology within anterior cingulate cortex, mediodorsal thalamus, and hippocampus, regions of high Btbd3 expression. Surprisingly, Btbd3 knockout mice only showed modest increases in spine density in the anterior cingulate, while dendritic morphology was unaltered elsewhere. Finally, we virally knocked down Btbd3 expression in whole, or just dorsal, hippocampus during neonatal development and assessed behavior during adulthood. Whole, but not dorsal, hippocampal Btbd3 knockdown recapitulated Btbd3 knockout phenotypes. Our findings reveal that hippocampal Btbd3 expression selectively modulates compulsive-like and exploratory behavior.