Mapping gray and white matter volume abnormalities in early-onset psychosis: an ENIGMA multicenter voxel-based morphometry study.

INTRODUCTION: Regional gray matter (GM) alterations have been reported in early-onset psychosis (EOP, onset before age 18), but previous studies have yielded conflicting results, likely due to small sample sizes and the different brain regions examined. In this study, we conducted a whole brain voxel-based morphometry (VBM) analysis in a large sample of individuals with EOP, using the newly developed ENIGMA-VBM tool. METHODS: 15 independent cohorts from the ENIGMA-EOP working group participated in the study. The overall sample comprised T1-weighted MRI data from 482 individuals with EOP and 469 healthy controls. Each site performed the VBM analysis locally using the standardized ENIGMA-VBM tool. Statistical parametric T-maps were generated from each cohort and meta-analyzed to reveal voxel-wise differences between EOP and healthy controls as well as the individual-based association between GM volume and age of onset, chlorpromazine (CPZ) equivalent dose, and other clinical variables. RESULTS: Compared with healthy controls, individuals with EOP showed widespread lower GM volume encompassing most of the cortex, with the most marked effect in the left median cingulate (Hedges' g = 0.55, p = 0.001 corrected), as well as small clusters of lower white matter (WM), whereas no regional GM or WM volumes were higher in EOP. Lower GM volume in the cerebellum, thalamus and left inferior parietal gyrus was associated with older age of onset. Deficits in GM in the left inferior frontal gyrus, right insula, right precentral gyrus and right superior frontal gyrus were also associated with higher CPZ equivalent doses. CONCLUSION: EOP is associated with widespread reductions in cortical GM volume, while WM is affected to a smaller extent. GM volume alterations are associated with age of onset and CPZ equivalent dose but these effects are small compared to case-control differences. Mapping anatomical abnormalities in EOP may lead to a better understanding of the role of psychosis in brain development during childhood and adolescence.

The functional connectome in obsessive-compulsive disorder: resting-state mega-analysis and machine learning classification for the ENIGMA-OCD consortium.

Current knowledge about functional connectivity in obsessive-compulsive disorder (OCD) is based on small-scale studies, limiting the generalizability of results. Moreover, the majority of studies have focused only on predefined regions or functional networks rather than connectivity throughout the entire brain. Here, we investigated differences in resting-state functional connectivity between OCD patients and healthy controls (HC) using mega-analysis of data from 1024 OCD patients and 1028 HC from 28 independent samples of the ENIGMA-OCD consortium. We assessed group differences in whole-brain functional connectivity at both the regional and network level, and investigated whether functional connectivity could serve as biomarker to identify patient status at the individual level using machine learning analysis. The mega-analyses revealed widespread abnormalities in functional connectivity in OCD, with global hypo-connectivity (Cohen's d: -0.27 to -0.13) and few hyper-connections, mainly with the thalamus (Cohen's d: 0.19 to 0.22). Most hypo-connections were located within the sensorimotor network and no fronto-striatal abnormalities were found. Overall, classification performances were poor, with area-under-the-receiver-operating-characteristic curve (AUC) scores ranging between 0.567 and 0.673, with better classification for medicated (AUC = 0.702) than unmedicated (AUC = 0.608) patients versus healthy controls. These findings provide partial support for existing pathophysiological models of OCD and highlight the important role of the sensorimotor network in OCD. However, resting-state connectivity does not so far provide an accurate biomarker for identifying patients at the individual level.

Perceived stress modulates the activity between the amygdala and the cortex.

The significant link between stress and psychiatric disorders has prompted research on stress's impact on the brain. Interestingly, previous studies on healthy subjects have demonstrated an association between perceived stress and amygdala volume, although the mechanisms by which perceived stress can affect brain function remain unknown. To better understand what this association entails at a functional level, herein, we explore the association of perceived stress, measured by the PSS10 questionnaire, with disseminated functional connectivity between brain areas. Using resting-state fMRI from 252 healthy subjects spanning a broad age range, we performed both a seed-based amygdala connectivity analysis (static connectivity, with spatial resolution but no temporal definition) and a whole-brain data-driven approach to detect altered patterns of phase interactions between brain areas (dynamic connectivity with spatiotemporal information). Results show that increased perceived stress is directly associated with increased amygdala connectivity with frontal cortical regions, which is driven by a reduced occurrence of an activity pattern where the signals in the amygdala and the hippocampus evolve in opposite directions with respect to the rest of the brain. Overall, these results not only reinforce the pathological effect of in-phase synchronicity between subcortical and cortical brain areas but also demonstrate the protective effect of counterbalanced (i.e., phase-shifted) activity between brain subsystems, which are otherwise missed with correlation-based functional connectivity analysis.

The path towards type V deep eutectic solvents: inductive effects and steric hindrance in the system tert-butanol + perfluoro tert-butanol.

The solid-liquid phase behaviour of two tertiary alcohols, perfluoro-tert-butanol and tert-butanol, was studied here using experimental (ITC, DSC and density measurements) and theoretical (MD simulations) approaches. The phase diagram of the binary mixture reveals highly negative deviations from ideality at low concentrations, as well as the formation of co-crystals and is characterized by two eutectic points, a congruent melting point and a peritectic reaction corresponding to TBH : TBF stoichiometries of 2 : 1 and 1 : 1 respectively. Excess molar enthalpies and volumes were calculated, showing negative and positive deviations from ideality, respectively. The effect of acidity, stereochemical hindrance and phobic effects and how they affect intermolecular interactions in these binary mixtures is discussed, with the aim of designing and fine-tuning type V deep eutectic solvents. The results showed that the fluorination of tertiary alcohols can be used for the tuning of the mixing properties and solid-liquid phase diagrams.

Role of trazodone in treatment of major depressive disorder: an update.

Major depressive disorder (MDD) is the most common mood disorder and a leading cause of disability worldwide. Trazodone, a triazolopyridine serotonin receptor antagonist and reuptake inhibitor (SARI) antidepressant approved for major depressive disorder (MDD) in adults, has established efficacy that is comparable to other available antidepressants, and is effective for a range of depression symptoms, including insomnia, which is one of the most common and bothersome symptoms of depression. Also, trazodone's pharmacodynamic properties allow it to avoid the side effects of insomnia, anxiety and sexual dysfunction often associated with selective serotonin reuptake inhibitor antidepressants. In this narrative review, we have summarized recent clinical trials and real-world data on trazodone, including the recently introduced once-daily formulation, which has single dose pharmacokinetic properties that maintain effective blood trazodone levels for 24 h, while avoiding concentration peaks associated with side effects. This, combined with a low incidence of weight gain, and sexual dysfunction, may improve adherence to treatment. The most common adverse effects of trazodone are somnolence, headache, dizziness and xerostomia. It has minimal anticholinergic activity but may be associated infrequently with orthostatic hypotension (especially in patients with cardiovascular disease or older adults), QT interval prolongation, cardiac arrhythmias, and rare episodes of priapism. The low liability for activating side effects, the efficacy on symptoms such as insomnia and psychomotor agitation and the rapid onset of action make it useful for many depressed patients, both in monotherapy at nominal dosages of 150-300 mg/day, and in combination with other antidepressants at lower dosages.

Association of amygdala size with stress perception: Findings of a transversal study across the lifespan.

Daily routines are getting increasingly stressful. Interestingly, associations between stress perception and amygdala volume, a brain region implicated in emotional behaviour, have been observed in both younger and older adults. Life stress, on the other hand, has become pervasive and is no longer restricted to a specific age group or life stage. As a result, it is vital to consider stress as a continuum across the lifespan. In this study, we investigated the relationship between perceived stress and amygdala size in 272 healthy participants with a broad age range. Participants were submitted to a structural magnetic resonance imaging (MRI) to extract amygdala volume, and the Perceived Stress Scale (PSS) scores were used as the independent variable in volumetric regressions. We found that perceived stress is positively associated with the right amygdala volume throughout life.

An overview of the first 5 years of the ENIGMA obsessive-compulsive disorder working group: The power of worldwide collaboration.

Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive-compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA.

Multimodal meta-analysis of structural gray matter, neurocognitive and social cognitive fMRI findings in schizophrenia patients.

Neuroimaging research has shown that patients with schizophrenia (SCZ) present brain structural and functional alterations, but the results across imaging modalities and task paradigms are difficult to reconcile. Specifically, no meta-analyses have tested whether the same brain systems that are structurally different in SCZ patients are also involved in neurocognitive and social cognitive tasks. To answer this, we conducted separate meta-analyses of voxel-based morphometry, neurocognitive functional magnetic resonance imaging (fMRI), and social cognitive fMRI studies. Next, with a multimodal approach, we identified the common alterations across meta-analyses. Further exploratory meta-analyses were performed taking into account several clinical variables (illness duration, medication status, and symptom severity). A cluster covering the dorsomedial prefrontal cortex (dmPFC) and the supplementary motor area (SMA), and the right inferior frontal gyrus (IFG), presented shared structural and neurocognitive-related activation decreases, while the right angular gyrus presented shared decreases between structural and social cognitive-related activation. The exploratory meta-analyses replicated to some extent these findings, while new regions of alterations appeared in patient subgroups with specific clinical features. In conclusion, we found task-specific correlates of brain structure and function in SCZ, which help summarize and integrate a growing literature.

Spontaneous self-assembly and structure of perfluoroalkylalkane surfactant hemimicelles by molecular dynamics simulations.

Fully atomistic molecular-dynamics (MD) simulations of perfluoroalkylalkane molecules at the surface of water show the spontaneous formation of aggregates whose size and topography closely resemble the experimentally observed hemimicelles for this system. Furthermore, the grazing incidence X-ray diffraction (GIXD) pattern calculated from the simulation trajectories reproduces the experimental GIXD spectra previously obtained, fully validating the MD simulation results. The detailed analysis of the internal structure of the aggregates obtained by the MD simulations supports a definite rational explanation for the spontaneous formation, stability, size, and shape of perfluoroalkylalkane hemimicelles at the surface of water.

Brain structural covariance networks in obsessive-compulsive disorder: a graph analysis from the ENIGMA Consortium.

Brain structural covariance networks reflect covariation in morphology of different brain areas and are thought to reflect common trajectories in brain development and maturation. Large-scale investigation of structural covariance networks in obsessive-compulsive disorder (OCD) may provide clues to the pathophysiology of this neurodevelopmental disorder. Using T1-weighted MRI scans acquired from 1616 individuals with OCD and 1463 healthy controls across 37 datasets participating in the ENIGMA-OCD Working Group, we calculated intra-individual brain structural covariance networks (using the bilaterally-averaged values of 33 cortical surface areas, 33 cortical thickness values, and six subcortical volumes), in which edge weights were proportional to the similarity between two brain morphological features in terms of deviation from healthy controls (i.e. z-score transformed). Global networks were characterized using measures of network segregation (clustering and modularity), network integration (global efficiency), and their balance (small-worldness), and their community membership was assessed. Hub profiling of regional networks was undertaken using measures of betweenness, closeness, and eigenvector centrality. Individually calculated network measures were integrated across the 37 datasets using a meta-analytical approach. These network measures were summated across the network density range of K = 0.10-0.25 per participant, and were integrated across the 37 datasets using a meta-analytical approach. Compared with healthy controls, at a global level, the structural covariance networks of OCD showed lower clustering (P < 0.0001), lower modularity (P < 0.0001), and lower small-worldness (P = 0.017). Detection of community membership emphasized lower network segregation in OCD compared to healthy controls. At the regional level, there were lower (rank-transformed) centrality values in OCD for volume of caudate nucleus and thalamus, and surface area of paracentral cortex, indicative of altered distribution of brain hubs. Centrality of cingulate and orbito-frontal as well as other brain areas was associated with OCD illness duration, suggesting greater involvement of these brain areas with illness chronicity. In summary, the findings of this study, the largest brain structural covariance study of OCD to date, point to a less segregated organization of structural covariance networks in OCD, and reorganization of brain hubs. The segregation findings suggest a possible signature of altered brain morphometry in OCD, while the hub findings point to OCD-related alterations in trajectories of brain development and maturation, particularly in cingulate and orbitofrontal regions.

Non-pharmacological treatment of gambling disorder: a systematic review of randomized controlled trials.

BACKGROUND: The main focus of the non-pharmacological treatment of Gambling Disorder (GD) is the behaviour, cognition and motivation of the patient, addressing the psychological determinants of gambling. Although there is not a gold standard non-pharmacological treatment yet, many studies already had promising results, and the outcomes were even better when pharmacotherapies were combined with psychotherapies. This review intended to synthesise the efficacy of various available non-pharmacological therapies for GD evaluated in randomized controlled trials. METHODS: A systematic search was conducted in PubMed and in Cochrane Library for randomized controlled trials. Studies were included if participants had GD as their primary diagnosis and excluded if patients had other comorbidities. RESULTS: From 320 records identified, 22 studies were included in the critical appraisal. They included a total of 1694 patients, with a mean age of 42.94 years, and a 62.31% of males. Seven trials revealed the efficacy of cognitive behaviour therapy in improving significantly the outcomes. Three studies assessing cognitive therapy showed significant improvements in gambling symptoms, while one study showed improvements in gambling behaviour using exposure therapy. Combined or separate motivational interviewing and imaginal desensitization had significant results in 4 trials. Four other studies also showed efficacy for: couples therapy, node-link mapping therapy, 12-step facilitated and personalized feedback intervention. Physical exercise had promising results but did not reach significance. CONCLUSION: The literature included in this review showed the heterogeneity of available psychotherapies. The majority of studies supported the efficacy of the tested therapies, while some of them, due to limitations such as small sample sizes or inadequate control groups, failed to reach significance.

Elevated levels of neutrophil gelatinase-associated lipocalin among OCD patients: an exploratory study.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disease that is characterized by its clinical heterogeneity and complex pathophysiology. This complexity comes from the diversity of pathophysiological factors that have been proposed to be involved in the natural history of the disorder. Many theories on OCD pathology support inflammation as a pathophysiological factor, although studies are not consistent on the presence of a pro-inflammatory state among OCD patients. However, some pre-clinical animal studies suggest lipocalin-2 (LCN2), an analogous form of the acute-phase pro-inflammatory protein neutrophil gelatinase-associated lipocalin (NGAL), may be involved in in the regulation of the stress response, which is thought to be disrupted in OCD. METHODS: Twenty-one OCD patients and 19 healthy subjects participated in this exploratory study. Levels of NGAL were assessed in the peripherous blood of all participants. Severity of disease was assessed using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). RESULTS: OCD patients exhibited significantly higher levels of NGAL when compared to healthy control subjects. No correlation was found between elevated levels of NGAL and severity of symptoms. CONCLUSIONS: This is the first study to report elevated levels of NGAL among OCD patients, adding evidence for a possible role of immune dysregulation in the pathophysiology of OCD.

Executive functions and insight in OCD: a comparative study.

BACKGROUND: Around 25 to 30% of patients with obsessive-compulsive disorder (OCD) do not respond to treatment. These patients have the longest duration of disease and the worst prognosis. Following years of research on this topic, insight has emerged as a potential explanation for this therapeutic resistance. Therefore, it has become important to characterize OCD patients with poor insight. Few studies have focused on the neuropsychological and cognitive characteristics of these patients. METHODS: To help fill this gap, we divided 57 patients into two groups, one with good insight and the other with poor insight, assessed their neuropsychological functions-through a Rey's figure test, a California verbal learning test, a Toulouse-Piéron test and a Wisconsin Card Sorting Test (WCST)-and compared the results with those of a paired control group. RESULTS: The statistical analysis, with a significance level of 95%, revealed differences in the executive function tests, and particularly in the WCST (p ≤ 0.001) and trail-making-test (TMT A/B) (p = 0.002). CONCLUSIONS: These differences suggest that the neuropsychological profile of poor-insight patients is different from their good-insight counterparts, emphasize the role played by the executive functions in insight and highlights the need for more accurate neurocognitive research and treatment.

Very Late Onset of Obsessive-Compulsive Disorder: Case Report and Review of Published Cases in Those More Than 60 Years Old.

ABSTRACT: It is widely agreed that obsessive-compulsive disorder (OCD) is less common among the elderly. However, several studies suggest that a third peak of OCD onset may occur after the age of 65. The onset of OCD in the elderly is unusual and mostly related to nonpsychiatric diagnoses. Nonetheless, some reports have documented late-onset OCD in older adults with no detection of cerebral abnormalities. Such differences in age of onset may be associated with phenotypical differences in disease severity, comorbidity, and treatment response across patients. In this report, we describe the case of late-onset OCD in an 80-year old man with no specific focal brain structural abnormality. The report could improve awareness of the disorder in the elderly and contribute to a better identification of clinical characteristics and additional risk factors of OCD.

Characterization of Extracellular Vesicles from Entamoeba histolytica Identifies Roles in Intercellular Communication That Regulates Parasite Growth and Development.

Extracellular vesicles (EVs) secreted by eukaryotic and prokaryotic cells to transport lipids, proteins, and nucleic acids to the external environment have important roles in cell-cell communication through cargo transfer. We identified and characterized EVs from Entamoeba histolytica, a protozoan parasite and a human pathogen. Conditioned medium from amebic parasites contained particles consistent with the expected size and morphology of EVs. Mass spectrometry was used to characterize the EV proteome and showed that it was enriched in common exosome marker proteins, including proteins associated with vesicle formation, cell signaling, and metabolism, as well as cytoskeletal proteins. Additionally, the EVs were found to selectively package small RNAs (sRNA), which were protected within the vesicles against RNase treatment. Sequencing analysis of the sRNA contained in EVs revealed that the majority were 27 nucleotides (nt) in size and represented a subset of the cellular antisense small RNA population that has previously been characterized in Entamoeba RNA interference (RNAi) pathway proteins, including Argonaute, were also present in amebic EVs. Interestingly, we found that the amebic EVs impacted intercellular communication between parasites and altered encystation efficiency. EVs isolated from encysting parasites promoted encystation in other parasites, whereas EVs from metabolically active trophozoites impeded encystation. Overall, the data reveal that Entamoeba secrete EVs that are similar in size and shape to previously characterized exosomes from other organisms and that these EVs contain a defined protein and small RNA cargo and have roles in intercellular communication among parasites and influence growth kinetics.

Altered response to risky decisions and reward in patients with obsessive­compulsive disorder

Background: Patients with obsessive­compulsive disorder (OCD) employ ritualistic behaviours to reduce or even neutralize the anxiety provoked by their obsessions. The presence of excessive rumination and indecision has motivated the view of OCD as a disorder of decision-making. Most studies have focused on the "cold," cognitive aspects of decision-making. This study expands current understanding of OCD by characterizing the abnormalities associated with affective, or "hot" decision-making. Methods: We performed a functional MRI study in a sample of 34 patients with OCD and 33 sex- and age-matched healthy controls, during which participants made 2-choice gambles taking varying levels of risk. Results: During risky decisions, patients showed significantly reduced task-related activation in the posterior cingulum, lingual gyrus and anterior cingulate cortex. We identified significant group × risk interactions in the calcarine cortex, precuneus, amygdala and anterior cingulate cortex. During the outcome phase, patients with OCD showed stronger activation of the orbitofrontal cortex, anterior cingulate cortex and putamen in response to unexpected losses. Limitations: The group of patients not receiving medication was very small (n = 5), which precluded us from assessing the effect of medication on risk-taking behaviour in these patients. Conclusion: Obsessive­compulsive disorder is associated with abnormal brain activity patterns during risky decision-making in a set of brain regions that have been consistently implicated in the processing of reward prediction errors. Alterations in affective "hot" processes implicated in decision-making may contribute to increased indecisiveness and intolerance to uncertainty in patients with OCD.

From nano-seggregation to mesophases: probing the liquid structure of perfluoroalkylalkanes with 129Xe NMR spectroscopy.

In this work we demonstrate that pure perfluoroalkylalkane diblock molecules are not isotropic liquids and self organize forming domains at the nanometric scale. 129Xe NMR spectra were obtained as a function of temperature for seven liquid perfluoroalkylalkanes, covering a range of relative lengths of the hydrogenated and fluorinated segments. The results support the presence of domains richer in the hydrogenated groups, in which xenon is preferentially dissolved. The average local concentration within the xenon coordination sphere is estimated to be 0.05 mole fraction higher in hydrogenated groups than the stoichiometric proportion. Atomistic molecular dynamics simulations support this analysis and allow a detailed analysis of the liquid structure. Furthermore, 129Xe NMR spectra in perfluorohexylhexane (F6H6) and perfluorohexyloctane (F6H8) obtained as a function of temperature, clearly detect the existence of two distinct environments in the fluid, one richer in hydrogenated groups and another richer in fluorinated groups, consistent with the formation of mesophases. It is important to stress that nano-segregation is this case observed in liquids interacting exclusively through dispersion forces, unlike most common examples of segregation which are determined by hydrogen bonding and polarity. Given the simple molecular structure and interactions of the studied PFAA, we believe that the present results can have a general impact in understanding the early mechanisms of segregation, phase separation and self-assembly.

The rates of co-occurring behavioural addictions in treatment-seeking individuals with obsessive-compulsive disorder: a preliminary report.

Objectives: To assess the rates of co-occurring putative 'behavioural addictions' in patients with obsessive-compulsive disorder (OCD).Methods: Twenty-three international centres specialising in the treatment of OCD were invited to participate in a survey of the rates of behavioural addictions and other relevant comorbidity within their samples.Results: Sixteen of 23 (69.6%) invited centres from 13 countries had sufficient data to participate in the survey. The use of validated diagnostic tools was discrepant, with most centres relying on a 'clinical diagnosis' to diagnose behavioural addictions. The final sample comprised of 6916 patients with a primary diagnosis of OCD. The reported rates of behavioural addictions were as follows: 8.7% for problematic internet use, 6.8% for compulsive sexual behaviour disorder, 6.4% for compulsive buying, 4.1% for gambling disorder and 3.4% for internet gaming disorder.Conclusions: Behavioural addictions should be better assessed for patients with OCD. The absence of diagnostic scales developed specifically for behavioural addictions and overlapping obsessive-compulsive phenomena such as compulsive checking of information on the internet may explain the relatively high rate of problematic internet use in this sample. The study encourages better efforts to assess and to conceptualise the relatedness of behavioural addictions to obsessive-compulsive 'spectrum' disorders.

From nano-emulsions to phase separation: evidence of nano-segregation in (alkane + perfluoroalkane) mixtures using 129Xe NMR Spectroscopy.

In this work we demonstrate that mixtures of (hexane + perfluorohexane) above the upper critical solution temperature segregate by forming domains at the nanometric scale. 129Xe NMR spectra obtained for solutions of xenon in liquid mixtures of (hexane + perfluorohexane) as a function of temperature suggest the existence of domains richer in the hydrogenated component, in which xenon "prefers" to be solvated. The average local concentration within the xenon coordination sphere is at least 0.05 higher in hexane mole fraction than the nominal concentration of the mixture. Atomistic molecular dynamics simulations support this analysis in excellent agreement with the experimental data. Additionally, 129Xe NMR spectra in pure perfluoroalkanes allow a detailed analysis of the liquid structure, continuing that previously reported for the liquid alkanes. It should be emphasised that nano-segregation is here observed in fluids governed exclusively by dispersion interactions, in contrast to other examples in which hydrogen bonding and polarity play important roles. Given its simplicity, this case study is thus prone to have a general impact in understanding the early mechanisms of segregation, phase separation and self-assembly.