Early and late contingent negative variation (CNV) reflect different aspects of deficits in schizophrenia.

Abnormal reward processing and psychomotor slowing are well-known in schizophrenia (SZ). As a slow frontocentral potential, contingent negative variation (CNV) is associated with anticipatory attention, motivation and motor planning. The present study aims to evaluate the early and late amplitude and latencies of CNV in patients with SZ compared to healthy controls during a reward processing task and to show its association with clinical symptoms. We recruited 21 patients with SZ and 22 healthy controls to compare early and late CNV amplitude and latency values during a Monetary Incentive Delay (MID) Task between groups. Patients' symptom severity, levels of negative symptoms and depressive symptoms were assessed. Clinical features of the patients were further examined for their relation with CNV components. In conclusion, we found decreased early CNV amplitudes in SZ during the reward condition. They also displayed diminished and shortened late CNV responses for incentive cues, specifically at the central location. Furthermore, early CNV amplitudes exhibited a significant correlation with positive symptoms. Both CNV latencies were linked with medication dosage and the behavioural outcomes of the MID task. We revealed that early and late CNV exhibit different functions in neurophysiology and correspond to various facets of the deficits observed in patients. Our findings also emphasized that slow cortical potentials are indicative of deficient motivational processes as well as impaired reaction preparation in SZ. To gain a deeper understanding of the cognitive and motor impairments associated with psychosis, future studies must compare the effects of CNV in the early and late phases.

DNA methylation at DLGAP2 and risk for relapse in alcohol dependence during acamprosate treatment.

BACKGROUND: Alcohol use disorders are prevalent mental disorders with significant health implications. Epigenetic alterations may play a role in their pathogenesis, as DNA methylation at several genes has been associated with these disorders. We have previously shown that methylation in the DLGAP2 gene, coding for a synaptic density protein, is associated with alcohol dependence. In this study, we aimed to examine the association between DLGAP2 methylation and treatment response among patients undergoing acamprosate treatment. METHODS: 102 patients under acamprosate treatment were included. DNA methylation analysis at DLGAP2 was performed by bisulfite pyrosequencing at the start and after 3-month treatment. Treatment outcomes were having a relapse during the treatment and severity of craving at the end of three months. Cox proportional hazard and linear regression models were performed. RESULTS: Patients whose methylation levels were decreased during the treatment showed an increased risk for relapse within three months in comparison to the ones without methylation change (hazard ratio [HR]=2.44; 95% confidence interval [CI]=1.04, 5.73; p=0.04). For the same group, a positive association for the severity of craving was observed, yet statistical significance was not reached (ß=2.97; 95% CI=-0.41, 6.34; p=0.08). CONCLUSION: We demonstrate that patients whose DLGAP2 methylation levels decrease during acamprosate treatment are more likely to relapse compared to the ones without changes. This is in line with our previous findings showing that DLGAP2 methylation is lower in alcohol dependent subjects compared to controls, and might suggest a role for changes in DLGAP2 methylation in treatment response.

Reduced Reward Processing in Schizophrenia: A Comprehensive EEG Event-Related Oscillation Study.

It is well known that abnormal reward processing is a characteristic feature of various psychopathologies including schizophrenia (SZ). Reduced reward anticipation has been suggested as a core symptom of SZ. The present study aims to evaluate the event-related oscillations (EROs) delta, theta, alpha, beta, and gamma in patients with SZ during the Monetary Incentive Delay (MID) task, which elicits the neural activity of reward processing. Twenty-one patients with SZ and twenty-two demographically matched healthy controls were included in the study. EROs were compared between groups and correlation analyses were conducted to determine a possible relationship between clinical scores and ERO values. Compared with healthy controls, the SZ group had reduced (1) delta and theta amplitudes in the reward condition (2) total beta and non-incentive cue-related beta amplitudes, and (3) incentive cue-related frontal gamma amplitudes. These reductions can be interpreted as impaired dopaminergic neurotransmission and disrupted cognitive functioning in the reward processing of SZ. In contrast, SZ patients showed higher incentive cue-related theta and occipital gamma amplitudes compared to controls. These increments may reflect negative symptoms in SZ. Moreover, theta amplitudes showed a negative correlation with Calgary Depression Scale for Schizophrenia scores and a positive correlation with attentional impulsivity. This is the first study showing the impairments of SZ patients in EROs from delta to gamma frequency bands compared with healthy controls during reward anticipation. Being the first comprehensive study, our results can be interpreted as providing evidence for disrupted brain dynamics in the reward processing of SZ studied by EROs. It may become possible to help patients' wellness by improving our understanding of reward processing in schizophrenia and developing innovative rehabilitation treatments based on these findings.

Enhanced Punishment Responses in Patients With Schizophrenia: An Event-Related Potential Study.

It is well known that abnormal reward processing is a characteristic feature of various psychopathologies including schizophrenia. Reduced reward anticipation has been suggested as a core symptom of schizophrenia. The Monetary Incentive Delay Task (MID) is frequently used to detect reward anticipation. The present study aims to evaluate the amplitude and latency of event-related potential (ERP) P300 in patients with schizophrenia (SCH) compared to healthy controls during the MID task. Twenty patients with SCH and 21 demographically matched healthy controls (HC) were included in the study. ERP P300 amplitude and latency values were compared between groups using an MID task in which reward and loss cues were presented. Relations between P300 and clinical facets were investigated in the patient group. SCH group had enhanced mean P300 amplitudes and delayed peak latency in the punishment condition compared with HC. These higher responses were also associated with negative symptoms. SCH group showed altered reward processing as being more sensitive to loss of reward conditions as firstly evidenced by electrophysiological methods, possibly due to abnormality in various systems including social withdrawal, social defeat, and behavioral inhibition system.

Prenatal exposure to phthalates and gender-specific play behavior at seven years of age in the SELMA study.

BACKGROUND: A growing body of evidence shows that prenatal exposure to phthalates affects child development. Since many phthalates have been shown to alter endocrine signaling, they may influence reproductive development, neurodevelopment, and child behavior. Indeed, a few studies reported associations between prenatal phthalate exposure and gender-specific play behavior. However, evidence for this relationship is limited, and previous findings are based on single phthalates, while human exposure entails mixtures of chemicals. OBJECTIVE: We aimed to investigate the associations between prenatal exposure to single phthalates, as well as a phthalate mixture, and gender-specific play behavior. METHODS: A total of 715 mother-child pairs from the Swedish Environmental Longitudinal, Mother and Child, Asthma and Allergy (SELMA) study were included. In the median week 10 of pregnancy, phthalate metabolites were measured in urine. Gender-specific play behavior was measured with Preschool Activities Inventory at the age of seven years. Linear and weighted quantile sum regressions were used; data was stratified by sex. Models were adjusted for child and maternal age, maternal education, parental attitudes toward play behavior, and urinary creatinine concentration. RESULTS: For boys, single compound analyses revealed negative associations of prenatal exposure to di-isononyl phthalate (DINP) concentrations with masculine (ß = -1.44; 95% CI = -2.72, -0.16) and composite (ß = -1.43; 95% CI = -2.72, -0.13) scores. Suggestive associations were also observed with a mixture approach identifying DINP as the main contributor of the association of decreased masculine play. Among girls, higher urinary concentrations of 2,4-methyl-7-oxyooctyl-oxycarbonyl-cyclohexane carboxylic acid (MOiNCH) was associated with decreased feminine (ß = -1.59; 95% CI = -2.62, -0.57) and masculine scores (ß = -1.22; 95% CI = -2.14, -0.29), whereas the mixture analyses did not yield conclusive results for girls. CONCLUSION: Our findings suggest associations of prenatal exposure to DINP with decreased masculine play behavior in boys while the results for girls were not fully conclusive.

The Relationship Between Cardiovascular Disease Risk and Major Depression.

Introduction: Cardiovascular risk in depression has been investigated in small clinical samples and population-based studies revealing inconclusive results. However, cardiovascular risk in drug-naive depressed patients has not been tested extensively. Methods: Body mass index-based Framingham Cardiovascular Risk Scores and soluble intercellular adhesion molecule-1 (sICAM-1) levels were used to assess the risk of cardiovascular disease in drug-naive depressed patients and healthy volunteers. Conclusion: There were no significant differences in Framingham Cardiovascular Risk Scores and individually assessed risk variables between patients and healthy controls (HC). Both groups were comparable in terms of sICAM-1. Results: The widely recognized association between cardiovascular risk and major depression might be more prominent in older depressed patients and patients with recurring episodes.

Psychosocial health modifies associations between HPA-axis function and brain structure in older age.

BACKGROUND: Dysregulation of the negative feedback loop of the hypothalamic-pituitary-adrenal (HPA) axis may have damaging effects on the brain, potentially under influence of psychosocial health factors. We studied associations between functioning of the negative feedback loop of HPA-axis, measured with a very low-dose dexamethasone suppression test (DST), and brain structure in middle-aged and older adults, and whether these associations were modified by psychosocial health. METHODS: From 2006 to 2008, 1259 participants (mean age 57.6 ± 6.4, 59.6 % female) of the population-based Rotterdam Study completed a very low-dose DST (0.25 mg) and underwent magnetic resonance imaging (MRI) of the brain. Self-reported psychosocial health (depressive symptoms, loneliness, marital status, perceived social support) were assessed in the same time period. Multivariable linear and logistic regression were used to study cross-sectional associations between cortisol response and brain volumetrics, cerebral small vessel disease markers and white matter structural integrity. To assess the effect of psychosocial health on these associations, analyses were further stratified for psychosocial health markers. RESULTS: Cortisol response was not associated with markers of global brain structure in the overall study sample. However, in participants with clinically relevant depressive symptoms, a diminished cortisol response was associated with smaller white matter volume (mean difference: - 1.00 mL, 95 %CI = - 1.89;- 0.10) and smaller white matter hyperintensity volume (mean difference: - 0.03 mL (log), 95 %CI = - 0.05;0.00). In participants with low/moderate perceived social support compared to those with high social support, a diminished cortisol response was associated with larger gray matter volume (mean difference: 0.70 mL, 95 %CI = 0.01;1.39) and higher fractional anisotropy (standardized mean difference 0.03, 95 %CI = 0.00;0.06). CONCLUSION: Diminished function of the HPA-axis is differently associated with brain structure in community-dwelling middle-aged and older adults with clinically relevant depressive symptoms or suboptimal social support, but not in adults without depressive symptoms or with optimal social support.

Exploring gender dysphoria and related outcomes in a prospective cohort study: protocol for the Swedish Gender Dysphoria Study (SKDS).

INTRODUCTION: There has been a drastic increase in the reported number of people seeking help for gender dysphoria in many countries over the last two decades. Yet, our knowledge of gender dysphoria and related outcomes is restricted due to the lack of high-quality studies employing comprehensive approaches. This longitudinal study aims to enhance our knowledge of gender dysphoria; different aspects will be scrutinised, focusing primarily on the psychosocial and mental health outcomes, prognostic markers and, secondarily, on the underlying mechanisms for its origin. METHODS AND ANALYSIS: The Swedish Gender Dysphoria Study is an ongoing multicentre longitudinal cohort study with 501 registered participants with gender dysphoria who are 15 years old or older. Participants at different phases of their clinical evaluation process can enter the study, and the expected follow-up duration is three years. The study also includes a comparison group of 458 age- and county-matched individuals without gender dysphoria. Data on the core outcomes of the study, which are gender incongruence and experienced gender dysphoria, body satisfaction and satisfaction with gender-affirming treatments, as well as other relevant outcomes, including mental health, social functioning and life satisfaction, are collected via web surveys. Two different research visits, before and after starting on gender-affirming hormonal treatment (if applicable), are planned to collect respective biological and cognitive measures. Data analysis will be performed using appropriate biostatistical methods. A power analysis showed that the current sample size is big enough to analyse continuous and categorical outcomes, and participant recruitment will continue until December 2022. ETHICS AND DISSEMINATION: The ethical permission for this study was obtained from the Local Ethical Review Board in Uppsala, Sweden. Results of the study will be presented at national and international conferences and published in peer-reviewed journals. Dissemination will also be implemented through the Swedish Gender Dysphoria Study network in Sweden.

Associations Between Blood Levels of NLRP3 Inflammasome Components and Obsessive Compulsive Disorder.

Introduction: Even though the effect of inflammation on pathogenesis of obsessive compulsive disorder (OCD) is known, information regarding the underlying mechanisms are yet to be revealed. The NLRP3 inflammasome complex is an important component of the innate immune system that initiates and mediates inflammatory response to a variety of stimuli. This study aims to inquire into a possible association between NLRP3 inflammasome complex and OCD. Methods: This case-control study included 103 participants (51 cases with OCD and 52 healthy controls). All participants were evaluated with the Yale Brown Obsessive Compulsive Scale, Hamilton Depression Scale, and Hewitt Multidimensional Perfectionism Scale. RNA and proteins were extracted from peripheral blood mononuclear cells. Expression of NLRP3 inflammasome components were determined using quantitative real-time polymerase chain reaction (PCR) and Western blotting. Levels of Serum IL-1beta and IL-18 cytokine were determined by ELISA. Results: NEK7 and CASP1 mRNA levels were significantly higher in OCD patients, compared to controls. Pro-caspase-1 protein levels were elevated, as well. Regression analysis showed that NEK7 mRNA and pro-caspase-1 protein levels can differentiate OCD and healthy control groups. Conclusion: Our results provide insight into the molecular alterations that could explain the inflammation-OCD association.

Exposure to endocrine-disrupting chemicals and implications for neurodevelopment.

Human brain development is a complex multistep process that is partly coordinated by the endocrine system. Any interference with the endocrine system might affect this process and result in deleterious outcomes. Endocrine-disrupting chemicals (EDCs) represent a large group of exogenous chemicals with the capacity of interfering with endocrine functions. In different population-based settings, associations between exposure to EDCs, particularly in prenatal life, and adverse neurodevelopmental outcomes have been demonstrated. These findings are strengthened by numerous experimental studies. Although mechanisms underlying these associations are not entirely delineated, disruption of thyroid hormone and, to a lesser extent, sex hormone signalling have been shown to be involved. Humans are constantly exposed to mixtures of EDCs, and further research combining epidemiological and experimental settings is required to improve our understanding of the link between real-life exposures to these chemicals and their impact on neurodevelopment.

Associations of neuroimaging markers with depressive symptoms over time in middle-aged and elderly persons.

BACKGROUND: Cerebrovascular disease is regarded as a potential cause of late-life depression. Yet, evidence for associations of neuroimaging markers of vascular brain disease with depressive symptoms is inconclusive. We examined the associations of neuroimaging markers and depressive symptoms in a large population-based study of middle-aged and elderly persons over time. METHODS: A total of 4943 participants (mean age = 64.6 ± 11.1 years, 55.7% women) from the Rotterdam Study were included. At baseline, total brain volume, gray matter volume, white matter volume, white matter hyperintensities volume, cortical infarcts, lacunar infarcts, microbleeds, white matter fractional anisotropy, and mean diffusivity (MD) were measured with a brain MRI (1.5T). Depressive symptoms were assessed twice with the Center for Epidemiologic Studies Depression scale (median follow-up time: 5.5 years, IQR = 0.9). To assess temporal associations of neuroimaging markers and depressive symptoms, linear mixed models were used. RESULTS: A smaller total brain volume (ß = -0.107, 95% CI -0.192 to -0.022), larger white matter hyperintensities volume (ß = 0.047, 95% CI 0.010-0.084), presence of cortical infarcts (ß = 0.194, 95% CI 0.047-0.341), and higher MD levels (ß = 0.060, 95% CI 0.022-0.098) were cross-sectionally associated with more depressive symptoms. Longitudinal analyses showed that small total brain volume (ß = -0.091, 95% CI -0.167 to -0.015) and presence of cortical infarcts (ß = 0.168, 95% CI 0.022-0.314) were associated with increasing depressive symptoms over time. After stratification on age, effect sizes were more pronounced at older ages. CONCLUSIONS: Neuroimaging markers of white matter microstructural damage were associated with depressive symptoms longitudinally in this study of middle-aged and elderly persons. These associations were more pronounced at older ages, providing evidence for the role of white matter structure in late-life depressive symptomatology.

Growth Characteristics of Long-Nosed Skate Dipturus oxyrinchus (Linnaeus, 1758) Inhabiting the Northeastern Mediterranean Sea.

This study aims to determine the age and growth characteristics of Dipturus oxyrinchus living in the Northeastern Mediterranean Sea and to present data that can provide a comparison with previous studies on the same subject. A total of 255 long-nose skates at a total length of 12.2-93.5 cm and weight of 8.34-3828 g were collected as non-target species from a commercial fishing boat. The male-female ratio was determined as 1:1.27. Using the von Bertalanffy equation and the Gompertz or logistic growth models, the growth parameters of Dipturus oxyrinchus were estimated as L∞ = 154.0, K = 0.064, t0 = -1.622; L∞ = 104.0, K = 0.35, I = 4.99; L∞ = 128.40, K = 0.19, I = 4.39 for all individuals, respectively. Maximum absolute growth was calculated as 9.33 cm at 5-6 years of age. Maximum relative growth at 1-2 years of age was estimated as 36.39%. Both absolute and relative growth were minimal in the 11-12 age group. The highest condition factor value was estimated as 0.416 in the 8-year-old group. As a result, the growth data of long-nose skates were obtained for the first time in the Northeastern Mediterranean Sea.

Impact of endocrine disrupting chemicals on neurodevelopment: the need for better testing strategies for endocrine disruption-induced developmental neurotoxicity.

INTRODUCTION: Brain development is highly dependent on hormonal regulation. Exposure to chemicals disrupting endocrine signaling has been associated with neurodevelopmental impairment. This raises concern about exposure to the suspected thousands of endocrine disruptors, and has resulted in efforts to improve regulation of these chemicals. Yet, the causal links between endocrine disruption and developmental neurotoxicity, which would be required for regulatory action, are still largely missing. AREAS COVERED: In this review, we illustrate the importance of two endocrine systems, thyroid hormone and retinoic acid pathways, for neurodevelopment. We place special emphasis on TH and RA synthesis, metabolism, and how endocrine disrupting chemicals known or suspected to affect these systems are associated with developmental neurotoxicity. EXPERT OPINION: While it is clear that neurodevelopment is dependent on proper hormonal functioning, and evidence is increasing for developmental neurotoxicity induced by endocrine disrupting chemicals, this is not grasped by current chemical testing. Thus, there is an urgent need to develop test methods detecting endocrine disruption in the context of neurodevelopment. Key to this development is further mechanistic insights on the involvement of endocrine signaling in neurodevelopment as well as increased support to develop and validate new test methods for the regulatory context.

Schizophrenia in microcephalic osteodysplastic primordial dwarfism type II syndrome: supporting evidence for an association between the PCNT gene and schizophrenia.

Schizophrenia is a genetically complex disease that is related to neurodevelopmental abnormalities. Several genetic polymorphisms and genetic syndromes associated with neurodevelopmental processes have been linked to schizophrenia. In this case report, we present a case with an association between microcephalic osteodysplastic primordial dwarfism type II and schizophrenia. Microcephalic osteodysplastic primordial dwarfism type II syndrome is a rare, autosomal recessive disease that occurs as a result of the mutations in the pericentrin (PCNT) gene that are responsible for cell cycle and division. In this report, we discuss the possible association between the PCNT gene and schizophrenia.