Facilitating the Sharing of Electrophysiology Data Analysis Results Through In-Depth Provenance Capture.

Scientific research demands reproducibility and transparency, particularly in data-intensive fields like electrophysiology. Electrophysiology data are typically analyzed using scripts that generate output files, including figures. Handling these results poses several challenges due to the complexity and iterative nature of the analysis process. These stem from the difficulty to discern the analysis steps, parameters, and data flow from the results, making knowledge transfer and findability challenging in collaborative settings. Provenance information tracks data lineage and processes applied to it, and provenance capture during the execution of an analysis script can address those challenges. We present Alpaca (Automated Lightweight Provenance Capture), a tool that captures fine-grained provenance information with minimal user intervention when running data analysis pipelines implemented in Python scripts. Alpaca records inputs, outputs, and function parameters and structures information according to the W3C PROV standard. We demonstrate the tool using a realistic use case involving multichannel local field potential recordings of a neurophysiological experiment, highlighting how the tool makes result details known in a standardized manner in order to address the challenges of the analysis process. Ultimately, using Alpaca will help to represent results according to the FAIR principles, which will improve research reproducibility and facilitate sharing the results of data analyses.

Cross-Frequency Phase-Amplitude Coupling between Hippocampal Theta and Gamma Oscillations during Recall Destabilizes Memory and Renders It Susceptible to Reconsolidation Disruption.

Avoidance memory reactivation at recall triggers theta-gamma hippocampal phase amplitude coupling (hPAC) only when it elicits hippocampus-dependent reconsolidation. However, it is not known whether there is a causal relationship between these phenomena. We found that in adult male Wistar rats, silencing the medial septum during recall did not affect avoidance memory expression or maintenance but abolished hPAC and the amnesia caused by the intrahippocampal administration of reconsolidation blockers, both of which were restored by concomitant theta burst stimulation of the fimbria-fornix pathway. Remarkably, artificial hPAC generated by fimbria-fornix stimulation during recall of a learned avoidance response naturally resistant to hippocampus-dependent reconsolidation made it susceptible to reactivation-dependent amnesia. Our results indicate that hPAC mediates the destabilization required for avoidance memory reconsolidation and suggest that the generation of artificial hPAC at recall overcomes the boundary conditions of this process.SIGNIFICANCE STATEMENT Theta-gamma hippocampal phase-amplitude coupling (hPAC) increases during the induction of hippocampus-dependent avoidance memory reconsolidation. However, whether hPAC plays a causal role in this process remains unknown. Using behavioral, electrophysiological, optogenetic, and biochemical tools in adult male Wistar rats, we demonstrate that reactivation-induced hPAC is necessary for avoidance memory destabilization, and that artificial induction of this patterned activity during recall of reconsolidation-resistant aversive memories renders them liable to the amnesic effect of reconsolidation inhibitors.

Systematic review and exploratory meta-analysis of the efficacy, safety, and biological effects of psychostimulants and atomoxetine in patients with schizophrenia or schizoaffective disorder.

OBJECTIVE: Our aim was to summarize the efficacy and safety of atomoxetine, amphetamines, and methylphenidate in schizophrenia. METHODS: We undertook a systematic review, searching PubMed/Scopus/Clinicaltrials.gov for double-blind, randomized, placebo-controlled studies of psychostimulants or atomoxetine in schizophrenia published up to 1 January 2017. A meta-analysis of outcomes reported in two or more studies is presented. RESULTS: We included 22 studies investigating therapeutic effects of stimulants (k=14) or measuring symptomatic worsening/relapse prediction after stimulant challenge (k=6). Six studies of these two groups plus one additional study investigated biological effects of psychostimulants or atomoxetine. No effect resulted from interventional studies on weight loss (k=1), smoking cessation (k=1), and positive symptoms (k=12), and no improvement was reported with atomoxetine (k=3) for negative symptoms, with equivocal findings for negative (k=6) and mood symptoms (k=2) with amphetamines. Attention, processing speed, working memory, problem solving, and executive functions, among others, showed from no to some improvement with atomoxetine (k=3) or amphetamines (k=6). Meta-analysis did not confirm any effect of stimulants in any symptom domain, including negative symptoms, apart from atomoxetine improving problem solving (k=2, standardized mean difference (SMD)=0.73, 95% CI=0.10-1.36, p=0.02, I2=0%), and trending toward significant improvement in executive functions with amphetamines (k=2, SMD=0.80, 95% CI=-1.68 to +0.08, p=0.08, I2=66%). In challenge studies, amphetamines (k=1) did not worsen symptoms, and methylphenidate (k=5) consistently worsened or predicted relapse. Biological effects of atomoxetine (k=1) and amphetamines (k=1) were cortical activation, without change in ß-endorphin (k=1), improved response to antipsychotics after amphetamine challenge (k=2), and an increase of growth hormone-mediated psychosis with methylphenidate (k=2). No major side effects were reported (k=6). CONCLUSIONS: No efficacy for stimulants or atomoxetine on negative symptoms is proven. Atomoxetine or amphetamines may improve cognitive symptoms, while methylphenidate should be avoided in patients with schizophrenia. Insufficient evidence is available to draw firm conclusions.

Psychometric properties of the modified Yale Food Addiction Scale 2 0 in a large Brazilian sample

Objective: The field of food addiction has attracted growing research attention. The modified Yale Food Addiction Scale 2.0 (mYFAS 2.0) is a screening tool based on DSM-5 criteria for substance use disorders. However, there is no validated instrument to assess food addiction. Methods: The mYFAS 2.0 has been transculturally adapted to Brazilian Portuguese. The data for this study was obtained through an anonymous web-based research platform: participants provided sociodemographic data and answered Brazilian versions of the the mYFAS 2.0 and the Barratt Impulsivity Scale (BIS-11). Analysis included an assessment of the Brazilian mYFAS 2.0's internal consistency reliability, factor structure, and convergent validity in relation to BIS-11 scores. Results: Overall, 7,639 participants were included (71.3% females; age: 27.2±7.9 years). The Brazilian mYFAS 2.0 had adequate internal consistency reliability (Cronbach's alpha = 0.89). A single factor solution yielded the best goodness-of-fit parameters for both the continuous and categorical version of the mYFAS 2.0 in confirmatory factor analysis. In addition, mYFAS 2.0 correlated with BIS-11 total scores (Spearman's rho = 0.26, p < 0.001) and subscores. Conclusion: The Brazilian mYFAS 2.0 demonstrated adequate psychometric properties in our sample; however, future studies should further evaluate its discriminant validity.

Violent criminal behavior in the context of bipolar disorder: Systematic review and meta-analysis.

BACKGROUND: Despite the potential importance of understanding violent criminal behavior (VCB) in individuals suffering from bipolar disorder (BD), previous findings are conflicting. The aims of the present study are to clarify the association of VCB and BD in comparison to general population and other psychiatric conditions. METHODS: A systematic review of literature from January 1st, 1980 through January 16th, 2017 from 3 electronic databases (MEDLINE/PubMed, EMBASE and PsycInfo), following the PRISMA and the MOOSE statements. Original peer-reviewed studies reporting data on VCB in BD were included. A random-effects meta-analysis was performed. Potential sources of heterogeneity were examined through subgroup and meta-regression analyses. The protocol was registered in PROSPERO, CRD42017054070. RESULTS: Twelve studies providing data from 58,475 BD participants. The prevalence of VCB in BD was 7.1% (95%CI = 3.0‒16.5%; k = 4). The association of BD and VCB compared to general population was not significant (OR = 2.784; 95% CI, 0.687‒11.287, P = .152). The association was significant only in cross-sectional studies, in studies in which VCB was assessed through self-reported measures, and in studies conducted in the USA. BD was more likely to be associated with VCB when BD patients were compared to controls with depressive disorders, whilst it was found to be less associated with VCB when BD was compared to psychotic disorders. LIMITATIONS: 1. the methodological heterogeneity across the included studies. 2. causal inferences were precluded by the inclusion of cross-sectional studies. CONCLUSIONS: These findings might provide a more balance portrait of the association between BD and VCB to clinicians, law enforcement and general public.

Mapping risk factors for depression across the lifespan: An umbrella review of evidence from meta-analyses and Mendelian randomization studies.

The development of depression may involve a complex interplay of environmental and genetic risk factors. PubMed and PsycInfo databases were searched from inception through August 3, 2017, to identify meta-analyses and Mendelian randomization (MR) studies of environmental risk factors associated with depression. For each eligible meta-analysis, we estimated the summary effect size and its 95% confidence interval (CI) by random-effects modeling, the 95% prediction interval, heterogeneity with I2, and evidence of small-study effects and excess significance bias. Seventy meta-analytic reviews met the eligibility criteria and provided 134 meta-analyses for associations from 1283 primary studies. While 109 associations were nominally significant (P < 0.05), only 8 met the criteria for convincing evidence and, when limited to prospective studies, convincing evidence was found in 6 (widowhood, physical abuse during childhood, obesity, having 4-5 metabolic risk factors, sexual dysfunction, job strain). In studies in which depression was assessed through a structured diagnostic interview, only associations with widowhood, job strain, and being a Gulf War veteran were supported by convincing evidence. Additionally, 8 MR studies were included and provided no consistent evidence for the causal effects of obesity, smoking, and alcohol consumption. The proportion of variance explained by genetic risk factors was extremely small (0.1-0.4%), which limited the evidence provided by the MR studies. Our findings suggest that despite the large number of putative risk factors investigated in the literature, few associations were supported by robust evidence. The current findings may have clinical and research implications for the early identification of individuals at risk for depression.

Environmental risk factors and nonpharmacological and nonsurgical interventions for obesity: An umbrella review of meta-analyses of cohort studies and randomized controlled trials.

BACKGROUND: Multiple environmental factors have been implicated in obesity, and multiple interventions, besides drugs and surgery, have been assessed in obese patients. Results are scattered across many studies and meta-analyses, and they often mix obese and overweight individuals. MATERIALS AND METHODS: PubMed and Cochrane Database of Systematic Reviews were searched through 21 January 2017 for meta-analyses of cohort studies assessing environmental risk factors for obesity, and randomized controlled trials investigating nonpharmacological and nonsurgical therapeutic interventions for obesity. We excluded data on overweight participants. Evidence from observational studies was graded according to criteria that included the statistical significance of the random-effects summary estimate and of the largest study in a meta-analysis, the number of obesity cases, heterogeneity between studies, 95% prediction intervals, small-study effects and excess significance. The evidence of intervention studies for obesity was assessed with the GRADE framework. RESULTS: Fifty-four articles met eligibility criteria, including 26 meta-analyses of environmental risk factors (166 studies) and 46 meta-analyses of nondrug, nonsurgical interventions (206 trials). In adults, the only risk factor with convincing evidence was depression, and childhood obesity, adolescent obesity, childhood abuse and short sleep duration had highly suggestive evidence. Infancy weight gain during the first year of life, depression and low maternal education had convincing evidence for association with paediatric obesity. All interventions had low or very-low-quality evidence with one exception of moderate-quality evidence for one comparison (no differences in efficacy between brief lifestyle primary care interventions and other interventions for paediatric obesity). Summary effect sizes were mostly small across compared interventions (maximum 5.1 kg in adults and 1.78 kg in children) and even these estimates may be inflated. CONCLUSIONS: Depression, obesity in earlier age groups, short sleep duration, childhood abuse and low maternal education have the strongest support among proposed risk factors for obesity. Furthermore, there is no high-quality evidence to recommend treating obesity with a specific nonpharmacological and nonsurgical intervention among many available, and whatever benefits in terms of magnitude of weight loss appear small.

Psychometric properties of the modified Yale Food Addiction Scale 2.0 in a large Brazilian sample.

OBJECTIVE: The field of food addiction has attracted growing research attention. The modified Yale Food Addiction Scale 2.0 (mYFAS 2.0) is a screening tool based on DSM-5 criteria for substance use disorders. However, there is no validated instrument to assess food addiction. METHODS: The mYFAS 2.0 has been transculturally adapted to Brazilian Portuguese. The data for this study was obtained through an anonymous web-based research platform: participants provided sociodemographic data and answered Brazilian versions of the the mYFAS 2.0 and the Barratt Impulsivity Scale (BIS-11). Analysis included an assessment of the Brazilian mYFAS 2.0's internal consistency reliability, factor structure, and convergent validity in relation to BIS-11 scores. RESULTS: Overall, 7,639 participants were included (71.3% females; age: 27.2±7.9 years). The Brazilian mYFAS 2.0 had adequate internal consistency reliability (Cronbach's alpha = 0.89). A single factor solution yielded the best goodness-of-fit parameters for both the continuous and categorical version of the mYFAS 2.0 in confirmatory factor analysis. In addition, mYFAS 2.0 correlated with BIS-11 total scores (Spearman's rho = 0.26, p < 0.001) and subscores. CONCLUSION: The Brazilian mYFAS 2.0 demonstrated adequate psychometric properties in our sample; however, future studies should further evaluate its discriminant validity.

Imaging genetics paradigms in depression research: Systematic review and meta-analysis.

Imaging genetics studies involving participants with major depressive disorder (MDD) have expanded. Nevertheless, findings have been inconsistent. Thus, we conducted a systematic review and meta-analysis of imaging genetics studies that enrolled MDD participants across major databases through June 30th, 2017. Sixty-five studies met eligibility criteria (N = 4034 MDD participants and 3293 controls), and there was substantial between-study variability in the methodological quality of included studies. However, few replicated findings emerged from this literature with only 22 studies providing data for meta-analyses (882 participants with MDD and 616 controls). Total hippocampal volumes did not significantly vary in MDD participants or controls carrying either the BDNF Val66Met 'Met' (386 participants with MDD and 376 controls) or the 5-HTTLPR short 'S' (310 participants with MDD and 230 controls) risk alleles compared to non-carriers. Heterogeneity across studies was explored through meta-regression and subgroup analyses. Gender distribution, the use of medications, segmentation methods used to measure the hippocampus, and age emerged as potential sources of heterogeneity across studies that assessed the association of 5-HTTLPR short 'S' alleles and hippocampal volumes. Our data also suggest that the methodological quality of included studies, publication year, and the inclusion of brain volume as a covariate contributed to the heterogeneity of studies that assessed the association of the BDNF Val66Met 'Met' risk allele and hippocampal volumes. In exploratory voxel-wise meta-analyses, MDD participants carrying the 5-HTTLPR short 'S' allele had white matter microstructural abnormalities predominantly in the corpus callosum, while carriers of the BDNF Val66Met 'Met' allele had larger gray matter volumes and hyperactivation of the right middle frontal gyrus compared to non-carriers. In conclusion, few replicated findings emerged from imaging genetics studies that included participants with MDD. Nevertheless, we explored and identified specific sources of heterogeneity across studies, which could provide insights to enhance the reproducibility of this emerging field.

Skin picking disorder: prevalence, correlates, and associations with quality of life in a large sample.

OBJECTIVE: Evidence suggests that skin picking disorder (SPD) could be a prevalent condition associated with comorbidity and psychosocial dysfunction. However, just a few studies have assessed the prevalence and correlates of SPD in samples from low- and middle-income countries. In addition, the impact of SPD on quality of life (QoL) dimension after multivariable adjustment to potential confounders remains unclear. METHODS: Data were obtained from a Brazilian anonymous Web-based research platform. Participants provided sociodemographic data and completed the modified Skin Picking-Stanford questionnaire, the Hypomania Checklist (HCL-32), the Patient Health Questionnaire-9 (PHQ-9), the Fagerström Test for Nicotine Dependence, Alcohol Use Disorder Identification Test (AUDIT), Symptom Checklist-90-Revised inventory (SCL-90R), early trauma inventory self report-short form, and the World Health Organization quality of life abbreviated scale (WHOQOL-Bref). Associations were adjusted to potential confounders through multivariable models. RESULTS: For our survey, 7639 participants took part (71.3% females; age: 27.2±7.9 years). The prevalence of SPD was 3.4% (95% CI: 3.0-3.8%), with a female preponderance (P<0.001). In addition, SPD was associated with a positive screen for a major depressive episode, nicotine dependence, and alcohol dependence, as well as suicidal ideation. Physical and psychological QoL was significantly more impaired in participants with SPD compared to those without SPD, even after adjustment for comorbidity. CONCLUSIONS: In this large sample, SPD was a prevalent condition associated with co-occurring depression, nicotine, and alcohol dependence. In addition, SPD was independently associated with impaired physical and psychological QoL. Public health efforts toward the early recognition and treatment of SPD are warranted.

The putative role of oxidative stress and inflammation in the pathophysiology of sleep dysfunction across neuropsychiatric disorders: Focus on chronic fatigue syndrome, bipolar disorder and multiple sclerosis.

Sleep and circadian abnormalities are prevalent and burdensome manifestations of diverse neuro-immune diseases, and may aggravate the course of several neuropsychiatric disorders. The underlying pathophysiology of sleep abnormalities across neuropsychiatric disorders remains unclear, and may involve the inter-play of several clinical variables and mechanistic pathways. In this review, we propose a heuristic framework in which reciprocal interactions of immune, oxidative and nitrosative stress, and mitochondrial pathways may drive sleep abnormalities across potentially neuroprogressive disorders. Specifically, it is proposed that systemic inflammation may activate microglial cells and astrocytes in brain regions involved in sleep and circadian regulation. Activated glial cells may secrete pro-inflammatory cytokines (for example, interleukin-1 beta and tumour necrosis factor alpha), nitric oxide and gliotransmitters, which may influence the expression of key circadian regulators (e.g., the Circadian Locomotor Output Cycles Kaput (CLOCK) gene). Furthermore, sleep disruption may further aggravate oxidative and nitrosative, peripheral immune activation, and (neuro) inflammation across these disorders in a vicious pathophysiological loop. This review will focus on chronic fatigue syndrome, bipolar disorder, and multiple sclerosis as exemplars of neuro-immune disorders. We conclude that novel therapeutic targets exploring immune and oxidative & nitrosative pathways (p.e. melatonin and molecular hydrogen) hold promise in alleviating sleep and circadian dysfunction in these disorders.

Food addiction: Prevalence, psychopathological correlates and associations with quality of life in a large sample.

OBJECTIVE: To determine the prevalence of food addiction in a large Brazilian non-clinical sample. Sociodemographic and psychopathological correlates of food addiction as well as associations with quality (QoL) domains were also investigated. METHODS: This cross-sectional study obtained data from a Brazilian anonymous web-based research platform (N = 7639; 71.3% females). Participants provided sociodemographic data and completed the modified Yale Food Addiction Scale 2.0, PHQ-9, hypomania checklist (HCL-32), Fagerström Test for Nicotine Dependence, AUDIT, modified Skin picking-Stanford questionnaire, Minnesota impulsive disorders interview, Symptom Checklist-90-Revised inventory (SCL-90R), early trauma inventory self report-short form, and the WHO Quality of Life instrument-Abbreviated version (WHOQOL-Bref). Associations were adjusted to potential confounders through multivariable models. RESULTS: The prevalence of food addiction was 4.32% (95%CI: 3.89-4.80%), and was more common among females. Food addiction was associated with a positive screen for a major depressive episode (OR = 4.41; 95%CI: 3.46-5.62), bipolar spectrum disorder (OR = 1.98; 95%CI: 1.43-2.75), and skin picking disorder (OR = 2.02; 95%CI: 1.31-3.09). Food addiction was also independently associated with exposure to early life psychological and sexual abuse (P = 0.008) as well as with reduced physical, psychological, social, and environment QoL (all P < 0.001). CONCLUSIONS: Food addiction may be common in low and middle-income countries, though possibly less prevalent than in the US. Food addiction was associated with co-occurring mood disorders and skin picking disorder as well as with early life psychological and sexual abuse. Finally, food addiction was independently associated with broad reductions in QoL. Public health efforts towards the early recognition and management of food addiction are warranted.

Peripheral Alterations in Cytokine and Chemokine Levels After Antidepressant Drug Treatment for Major Depressive Disorder: Systematic Review and Meta-Analysis.

Mounting evidence suggests that aberrations in immune-inflammatory pathways contribute to the pathophysiology of major depressive disorder (MDD), and individuals with MDD may have elevated levels of predominantly pro-inflammatory cytokines and C-reactive protein. In addition, previous meta-analyses suggest that antidepressant drug treatment may decrease peripheral levels of interleukin-1 beta (IL-1ß) and IL-6. Recently, several new studies examining the effect of antidepressants on these cytokines have been published, and so we performed an updated meta-analysis of studies that measured peripheral levels of cytokines and chemokines during antidepressant treatment in patients with MDD. The PubMed/MEDLINE, EMBASE, and PsycInfo databases were searched from inception through March 9, 2017. Forty-five studies met inclusion criteria (N = 1517). Peripheral levels of IL-6, tumor necrosis factor-alpha (TNF-α), IL-1ß, IL-10, IL-2, IL-4, interferon-γ, IL-8, the C-C motif ligand 2 chemokine (CCL-2), CCL-3, IL-1 receptor antagonist, IL-13, IL-17, IL-5, IL-7, and the soluble IL-2 receptor were measured in at least three datasets and thus were meta-analyzed. Antidepressant treatment significantly decreased peripheral levels of IL-6 (Hedges g = -0.454, P <0.001), TNF-α (g = -0.202, P = 0.015), IL-10 (g = -0.566, P = 0.012), and CCL-2 (g = -1.502, P = 0.006). These findings indicate that antidepressants decrease several markers of peripheral inflammation. However, this meta-analysis did not provide evidence that reductions in peripheral inflammation are associated with antidepressant treatment response although few studies provided separate data for treatment responders and non-responders.

Zika Virus as an Emerging Neuropathogen: Mechanisms of Neurovirulence and Neuro-Immune Interactions.

Zika virus (ZIKV) is an emerging arbovirus of the genus Flaviviridae, which causes a febrile illness and has spread from across the Pacific to the Americas in a short timeframe. Convincing evidence has implicated the ZIKV to incident cases of neonatal microcephaly and a set of neurodevelopmental abnormalities referred to as the congenital Zika virus syndrome. In addition, emerging data points to an association with the ZIKV and the development of the so-called Guillain-Barre syndrome, an acute autoimmune polyneuropathy. Accumulating knowledge suggests that neurovirulent strains of the ZIKV have evolved from less pathogenic lineages of the virus. Nevertheless, mechanisms of neurovirulence and host-pathogen neuro-immune interactions remain incompletely elucidated. This review provides a critical discussion of genetic and structural alterations in the ZIKV which could have contributed to the emergence of neurovirulent strains. In addition, a mechanistic framework of neuro-immune mechanisms related to the emergence of neuropathology after ZIKV infection is discussed. Recent advances in knowledge point to avenues for the development of a putative vaccine as well as novel therapeutic strategies. Nevertheless, there are unique unmet challenges that need to be addressed in this regard. Finally, a research agenda is proposed.

Prior Learning of Relevant Nonaversive Information Is a Boundary Condition for Avoidance Memory Reconsolidation in the Rat Hippocampus.

Reactivated memories can be modified during reconsolidation, making this process a potential therapeutic target for posttraumatic stress disorder (PTSD), a mental illness characterized by the recurring avoidance of situations that evoke trauma-related fears. However, avoidance memory reconsolidation depends on a set of still loosely defined boundary conditions, limiting the translational value of basic research. In particular, the involvement of the hippocampus in fear-motivated avoidance memory reconsolidation remains controversial. Combining behavioral and electrophysiological analyses in male Wistar rats, we found that previous learning of relevant nonaversive information is essential to elicit the participation of the hippocampus in avoidance memory reconsolidation, which is associated with an increase in theta- and gamma-oscillation power and cross-frequency coupling in dorsal CA1 during reactivation of the avoidance response. Our results indicate that the hippocampus is involved in memory reconsolidation only when reactivation results in contradictory representations regarding the consequences of avoidance and suggest that robust nesting of hippocampal theta-gamma rhythms at the time of retrieval is a specific reconsolidation marker.SIGNIFICANCE STATEMENT Posttraumatic stress disorder (PTSD) is characterized by maladaptive avoidance responses to stimuli or behaviors that represent or bear resemblance to some aspect of a traumatic experience. Disruption of reconsolidation, the process by which reactivated memories become susceptible to modifications, is a promising approach for treating PTSD patients. However, much of what is known about fear-motivated avoidance memory reconsolidation derives from studies based on fear conditioning instead of avoidance-learning paradigms. Using a step-down inhibitory avoidance task in rats, we found that the hippocampus is involved in memory reconsolidation only when the animals acquired the avoidance response in an environment that they had previously learned as safe and showed that increased theta- and gamma-oscillation coupling during reactivation is an electrophysiological signature of this process.

Peripheral inflammatory markers in Alzheimer's disease: a systematic review and meta-analysis of 175 studies.

OBJECTIVES: Increasing evidence suggests that inflammation is involved in Alzheimer's disease (AD) pathology. This study quantitatively summarised the data on peripheral inflammatory markers in patients with AD compared with healthy controls (HC). METHODS: Original reports containing measurements of peripheral inflammatory markers in AD patients and HC were included for meta-analysis. Standardised mean differences were calculated using a random effects model. Meta-regression and exploration of heterogeneity was performed using publication year, age, gender, Mini-Mental State Examination (MMSE) scores, plasma versus serum measurements and immunoassay type. RESULTS: A total of 175 studies were combined to review 51 analytes in 13 344 AD and 12 912 HC patients. Elevated peripheral interleukin (IL)-1ß, IL-2, IL-6, IL-18, interferon-γ, homocysteine, high-sensitivity C reactive protein, C-X-C motif chemokine-10, epidermal growth factor, vascular cell adhesion molecule-1, tumour necrosis factor (TNF)-α converting enzyme, soluble TNF receptors 1 and 2, α1-antichymotrypsin and decreased IL-1 receptor antagonist and leptin were found in patients with AD compared with HC. IL-6 levels were inversely correlated with mean MMSE scores. CONCLUSIONS: These findings suggest that AD is accompanied by a peripheral inflammatory response and that IL-6 may be a useful biological marker to correlate with the severity of cognitive impairment. Further studies are needed to determine the clinical utility of these markers.

Thyroid autoimmunity in bipolar disorder: A systematic review.

BACKGROUND: Accumulating evidence points to the pathophysiological relevance between immune dysfunction and mood disorders. High rates of thyroid dysfunction have been found in patients with bipolar disorder (BD), compared to the general population. A systematic review of the relationship between BD and thyroid autoimmunity was performed. METHODS: Pubmed, EMBASE and PsycINFO databases were searched up till January 28th, 2017. This review has been conducted according to the PRISMA statements. Observational studies clearly reporting data among BD patients and the frequency of autoimmune thyroid pathologies were included. RESULTS: 11 original studies met inclusion criteria out of 340 titles first returned from the global search. There is evidence of increased prevalence of circulating thyroid autoantibodies in depressed and mixed BD patients, while there is no evidence showing a positive relationship between BD and specific autoimmune thyroid diseases. There is a controversy about the influence of lithium exposure on circulating thyroid autoantibodies, even if most of studies seem not to support this association. A study conducted on bipolar twins suggests that autoimmune thyroiditis is related to the genetic vulnerability to develop BD rather than to the disease process itself. Females are more likely to develop thyroid autoimmunity. LIMITATIONS: The samples, study design and outcomes were heterogeneous. CONCLUSION: Thyroid autoimmunity has been suggested to be an independent risk factor for bipolar disorder with no clear association with lithium exposure and it might serve as an endophenotype for BD.

Validation of the Brazilian Portuguese version of the Premenstrual Symptoms Screening Tool (PSST) and association of PSST scores with health-related quality of life

Objective: To develop and validate a Brazilian Portuguese version of the Premenstrual Symptoms Screening Tool (PSST), a questionnaire used for the screening of premenstrual syndrome (PMS) and of the most severe form of PMS, premenstrual dysphoric disorder (PMDD). The PSST also rates the impact of premenstrual symptoms on daily activities. Methods: A consecutive sample of 801 women aged ≥ 18 years completed the study protocol. The internal consistency, test-retest reliability, and content validity of the Brazilian PSST were determined. The independent association of a positive screen for PMS or PMDD and quality of life determined by the World Health Organization Quality of Life instrument-Abbreviated version (WHOQOL-Bref) was also assessed. Results: Of 801 participants, 132 (16.5%) had a positive screening for PMDD. The Brazilian PSST had adequate internal consistency (Cronbach’s alpha = 0.91) and test-retest reliability. The PSST also had adequate convergent/discriminant validity, without redundancy. Content validity ratio and content validity index were 0.61 and 0.94 respectively. Finally, a positive screen for PMS/PMDD was associated with worse WHOQOL-Bref scores. Conclusions: These findings suggest that PSST is a reliable and valid instrument to screen for PMS/PMDD in Brazilian women.

Systematic assessment of environmental risk factors for bipolar disorder: an umbrella review of systematic reviews and meta-analyses.

OBJECTIVES: The pathophysiology of bipolar disorder is likely to involve both genetic and environmental risk factors. In our study, we aimed to perform a systematic search of environmental risk factors for BD. In addition, we assessed possible hints of bias in this literature, and identified risk factors supported by high epidemiological credibility. METHODS: We searched the Pubmed/MEDLINE, EMBASE and PsycInfo databases up to 7 October 2016 to identify systematic reviews and meta-analyses of observational studies that assessed associations between putative environmental risk factors and BD. For each meta-analysis, we estimated its summary effect size by means of both random- and fixed-effects models, 95% confidence intervals (CIs), the 95% prediction interval, and heterogeneity. Evidence of small-study effects and excess of significance bias was also assessed. RESULTS: Sixteen publications met the inclusion criteria (seven meta-analyses and nine qualitative systematic reviews). Fifty-one unique environmental risk factors for BD were evaluated. Six meta-analyses investigated associations with a risk factor for BD. Only irritable bowel syndrome (IBS) emerged as a risk factor for BD supported by convincing evidence (k=6; odds ratio [OR]=2.48; 95% CI=2.35-2.61; P<.001), and childhood adversity was supported by highly suggestive evidence. Asthma and obesity were risk factors for BD supported by suggestive evidence, and seropositivity to Toxoplasma gondii and a history of head injury were supported by weak evidence. CONCLUSIONS: Notwithstanding that several environmental risk factors for BD were identified, few meta-analyses of observational studies were available. Therefore, further well-designed and adequately powered studies are necessary to map the environmental risk factors for BD.