OBJECTIVE:To evaluate the feasibility and acceptability (eg, user experience) of 2 methods for home-based estimation of circadian timing among veterans with insomnia and a history of traumatic brain injury (TBI). SETTING:An outpatient setting at a Department of Veterans Affairs medical center. PARTICIPANTS:Veterans between the ages of 18 and 64 years with current insomnia and a history of mild-to-severe TBI. DESIGN:A prospective observational study evaluating the feasibility of 2 home-based methods for estimating circadian timing, that is, dim light melatonin onset (DLMO): (1) indirect prediction of DLMO using activity and light-exposure data collected through actigraphy (ie, pDLMO); and (2) estimation of DLMO via direct measurement of melatonin in self-collected salivary samples (ie, salivary DLMO). Participants wore an actigraphy device and completed sleep diaries for one week. They then spent one evening self-collecting 7 saliva samples under dim light conditions. Finally, participants completed a brief qualitative interview on their experiences. MAIN MEASURES:Primary outcomes were the success rates for estimation of each home-based DLMO method. Feasibility was set as 70% successful estimation for a given measure, for those who completed the respective procedures. RESULTS:pDLMO could be estimated for 27 of 29 participants (93.1%) who completed actigraphy data collection, meeting the feasibility goal. Salivary DLMO could only be estimated for 7 of 28 participants (25%) who completed saliva collection. Participants broadly expressed acceptance of both home-based DLMO methods and a willingness to use them again. Several barriers related to each method were identified that can inform future implementation efforts with this patient population. CONCLUSION:pDLMO is feasible and acceptable for estimating circadian timing in veterans with insomnia and past TBI. Using pDLMO could help identify circadian-sleep misalignment after TBI, helping personalize insomnia treatments based on patient-specific needs and interrupting the bidirectional cycle of insomnia and circadian dysregulation.

BACKGROUND:Periodontal disease (PD) is a common oral infection that is often exacerbated during pregnancy. Porphyromonas gingivalis (P. gingivalis), a keystone PD pathogen, promotes systemic inflammation, depressive-like behavior in animals, and can translocate to the brain and genital tract. Its capsular antigens (K1-K7) are key virulence factors. We hypothesized that seropositivity to specific P. gingivalis capsular K serotypes is associated with depressive symptoms and systemic inflammation during pregnancy. METHODS:In a prospective cohort of pregnant women (N = 114), depressive symptoms were assessed in each trimester of pregnancy using the Edinburgh Postnatal Depression Rating Scale (EPDS, ≥13 denoting moderate-to-severe depression symptoms). Plasma IgG antibodies against P. gingivalis K1-K7 serotypes and proinflammatory cytokines were measured. Statistical analyses included Firth's bias-reduced logistic regression and mixed-effects linear models. RESULTS:Approximately 25 % of participants were seropositive for at least one K serotype. IgG seropositivity to P. gingivalis K1 serotype was significantly associated with moderate-to-severe depressive symptoms during the first trimester (EPDS≥13; P = 0.035). Additionally, aggregated K seropositivity was significantly associated with elevated plasma IL-10 levels during the first trimester (P < 0.05, adjusted for multiple comparisons). Other cytokines were unrelated to P. gingivalis K seropositivity. LIMITATIONS:We did not assess clinical or radiological manifestations of PD, antibodies to non-capsular P. gingivalis antigens, or the presence of other PD pathogens. CONCLUSION:These results suggest the importance of integrating IgG K seropositivity (which, in addition to local oral pathogens, may also reflect their distal translocation) with clinical, bacteriological and radiological measures when studying associations between PD and affective dysregulation in pregnancy.

Markers of chronic infection Toxoplasma gondii (Nicolle et Manceaux, 1908) have been associated with suicidal self-directed violence (SSDV). We present the results of the first study relating T. gondii IgG serology with suicide attempts and suicidal ideation in United States Veterans, known to have higher suicide rates than members of the general population. We also related T. gondii serology to SSDV risk factors, including valid and reliable measures of trait impulsivity, aggression, self-reported depression, and sleep disturbance. We recruited 407 Veterans enrolled at three Veterans Affairs Medical Centers with mean ( S.D. ) age = 45.6 (11.6) years; 304 men (74.7%); 203 with a history of SSDV and 204 with no history of any self-directed violence (SDV). Seropositivity and serointensity, categorised as high (top quartile) or low (lower three quartiles), were analysed in relationship to SSDV, suicidal ideation and clinical risk factors using age and gender-adjusted linear and logistic methods, after transformations and nonparametric tests when appropriate. Associations between seropositivity and SSDV and its risk factors were not significant in all groups. High serointensity, while not associated with SSDV or repeat suicide attempts, was positively associated with suicidal ideation, depression, impulsivity, and daytime dysfunction due to sleepiness (p < 0.05), but only in Veterans with a history of SSDV. In Veterans without a history of SDV, no associations were significant. These associations remained significant after adjustment for certain socioeconomic factors (i.e., income, homelessness, military rank). Including education in the model downgraded the statistical significance of suicidal ideation and depression to statistical trends, but the significance of associations with impulsivity and daytime dysfunction due to sleepiness remained. Major limitations include the cross-sectional design, overall low seropositivity within the sample, and potentially spurious results due to multiple comparisons. Thus, the results of this report need to be replicated in larger samples, ideally longitudinally.

Our team's discovery of the link between chronic "latent" infection with Toxoplasma gondii (Nicolle et Manceaux, 1908) and suicidal behaviour, and our subsequent cross-diagnostic confirmatory work and mechanistic extensions, evolved from our neuroimmunology studies on affective and behavioural dysregulation exacerbated by allergic sensitisation and allergen exposure. Another root was studying behavioural changes and cytokine gene expression in the brain of rodents sensitised and exposed to aeroallergens. We "piggy-backed" our project funded to study coupling between aeroallergen sensitisation and exposure in patients with recurrent mood disorders, by measuring Toxoplasma gondii (T. gondii) antibodies in existing samples, and found associations between IgG serointensity and past suicide attempts. Successively, we then reported significant associations between T. gondii seropositivity and/or serointensity and suicidal behaviour in patients with schizophrenia in Germany, recent attempters in Sweden, and longitudinally in a cohort of Danish mothers. In the Danish mothers the exposure to T. gondii preceded self-directed harm and violent suicide attempts; the association was stronger with higher serointensity strata demonstrating a dose-effect. Furthermore, we identified links between T. gondii IgG and suicide endophenotypes of aggression and impulsivity in both individuals with no history of mental illness, and in patients with Intermittent Explosive Disorder (IED). We also found associations between T. gondii and risk factors of suicidal behaviour such as hopelessness and anhedonia in the Amish, depressive symptoms in pregnant women and women Veterans, frailty in older adults, and cognitive deficits in patients with bipolar disorder. Recently, we reported positive associations between T. gondii IgG serointensity with suicidal ideation, impulsivity, depression scores, and daytime dysfunction due to sleep problems in US Veterans who previously attempted suicide. Toxoplasma gondii emerged rather unexpectedly and then took over a considerable proportion of our neuroimmune research portfolio. It satisfied both intellectual appetites, and brought celebrations of discovery, with three systematic reviews and meta-analyses published to date, and a substantial majority of primary articles confirming our initial observations. Toxoplasma gondii also brought considerable frustrations, such as initial grant application setbacks, inability to completely demonstrate causality and, so far, prophylactic and therapeutic impotence for mental health applications in general. While we do not have, as of today, effective and safe treatments for chronic toxoplasmosis with demonstrated mental health benefits in immunocompetent hosts, there are reasons to be optimistic regarding future discoveries. These may include vaccines, novel medications using in silico exploration with biological confirmation, trials of reactivation prevention, as well as identification and targeting of mediating mechanisms. Yet the most justified reasons for optimism are the potential to apply machine learning (ML) and artificial intelligence (AI) methodologies to big data with a focus on interaction and causal inference. These novel approaches, utilising ML-weighted models that emulate randomised trials in electronic medical records, have the potential to reveal not only if T. gondii elevates risk and to what extent, but also for whom specifically, under which demographic, clinical and physiological circumstances, and what factors, or combinations thereof, might mitigate this risk.

Veterans with a history of traumatic brain injury (TBI) are significantly more likely to develop insomnia than their non-injured peers, which contributes to functional impairment and diminished quality of life. Emerging evidence suggests that circadian abnormalities may underlie a sizeable subset of sleep disturbances following TBI, yet such abnormalities remain under-detected in this patient population. Pragmatic methods that estimate circadian timing (e.g., dim light melatonin onset [DLMO]) in the homes of veterans may help address this clinical gap. Preliminary findings are presented for a study examining the feasibility of two home-based methods of estimating DLMO among veterans with insomnia and a history of TBI. Veterans with insomnia and a history of TBI are being recruited to provide feedback on two different methods for estimating DLMO at home (target N = 30). The first method involves estimation of DLMO using salivary samples self-collected by veterans. The second method involves prediction of DLMO (pDLMO) using actigraphy-derived light data and the Kronauer limit-cycle model. Feasibility for each method is defined as the ability to measure DLMO for ≥70% of participants. To date, 20 veterans have been enrolled and 18 have completed the study. Saliva-based DLMO could only be estimated for 9 of 17 veterans (53%) who submitted collection kits. Potential explanations for undetermined DLMO estimates include difficulties using the collection kit and excessive light exposure. Additionally, all 9 veterans for whom DLMO could be estimated were exposed to light greater than 50 lux within 30 minutes of collecting the saliva samples ultimately used to determine DLMO. pDLMO was successfully estimated for 17 of the 18 veterans (94%) who returned actigraphy data. Estimation of pDLMO using actigraphy-derived light data appears to be a feasible method for estimating circadian timing in veterans with insomnia and past TBI. Data collection and analyses are ongoing. This research is supported by the Department of Veteran Affairs Rehabilitation Research and Development Service (Award #: D4414-P), as well as the Rocky Mountain Mental Illness Research, Education, and Clinical Center

Suicidal self-directed violence (SSDV) has been previously associated with Toxoplasma gondii (T. gondii) IgG positivity and intensity, blood levels of quinolinic acid (QUIN, positively), picolinic acid (PIC, negatively) and kynurenic acid (KYNA, negatively), and sleep disturbance (insomnia, daytime sleepiness, positively). We examined associations between T. gondii IgG serointensity, excitotoxic and neuroprotective kynurenines and their ratios, and sleep disturbance in U.S. Veterans enrolled in mental health treatment. Veterans from three Veterans Affairs Medical Centers participated in the study (N=407, mean age = 45.6 ± 11.6 years; 74.7% men). Of these, 203 had a history of SSDV, while 204 had no history of self-directed violence (SDV). T. gondii IgG was measured with ELISAs. QUIN and PIC were analyzed with GC-MS, KYNA with UPLC-MS/MS. Sleep disturbance was estimated using Pittsburgh Sleep Quality index (PSQI). Statistics included ANCOVAs and logistic regressions. High T. gondii serointensity (classified as high-top quartile) was significantly associated with daytime dysfunction due to sleepiness (p < 0.05) in SSDV positive Veterans. This relationship remained significant after adjusting for socioeconomic factors status. T. gondii seropositivity was significantly associated with QUIN positively and PIC/QUIN, and KYNA/QUIN negatively (p< 0.05). In turn, QUIN was positively associated with daytime dysfunction due to sleepiness (p=0.007) and KYNA/QUIN and PIC/QUIN ratios were negatively associated with sleep disturbance, sleep latency, daytime dysfunction, and PSQI total score (p< 0.05). Limitations include the cross-sectional design, low seropositivity, lack of data on sleep apnea and actual recording of sleep, and multiple comparisons. Sleep- wake dysregulation was positively associated with T. gondii serointensity and QUIN, and negatively with neuroprotective kynurenine ratios. These findings warrant replication in larger, longitudinal studies with direct measuring of sleep parameters. Veteran Administration CSR&D Merit Award (grant number 1 I01CX001310–01), PI Postolache, with local PIs Duncan (Atlanta, GA), Brenner (Aurora, CO) and Postolache (Baltimore, MD).

Objective: Seasonal patterns are often undetectable in population-based depression studies, calling into question the existence of winter seasonal affective disorder (SAD). If SAD has construct validity, individuals with SAD should show spontaneous depression remission in the summer. Data are sparse on prospectively assessed summer mood status in confirmed SAD patients. Method: We conducted prospective summer followup of community adults who, the winter before, were diagnosed with Major Depression, Recurrent with Seasonal Pattern on the Structured Clinical Interview for DSM-IV Axis I Disorders, developed a current SAD episode on the Structured Interview Guide for the Hamilton Rating Scale for Depression-Seasonal Affective Disorder Version (SIGH-SAD), and enrolled in a clinical trial comparing group cognitive-behavioral therapy for SAD and light therapy. In July/August after treatment, 143/153 (93.5 %) participants provided data on the SIGH-SAD, the Beck Depression Inventory-Second Edition, and the Longitudinal Interval Followup Evaluation (LIFE). Results: Summer mean depression scores were in the normal range, with the substantial majority in remission across different measures. On the LIFE, 113/143 (79.0 %) experienced complete summer remission, 19/143 (13.3 %) experienced partial summer remission, and 11/143 (7.7 %) had major depression in the summer. Depression scores were significantly lower at summer than post-treatment in both treatments, indicating incomplete treatment response. Limitations: This was a single-site study with a relatively homogeneous sample. Conclusions: Supporting construct validity for SAD, the substantial majority experienced complete summer remission, with a minority in partial remission and a very small minority in episode. Both treatments left residual symptoms at treatment endpoint compared to summer.

Purpose of Review Inhalation of airborne pollutants in the natural and built environment is ubiquitous; yet, exposures are different across a lifespan and unique to individuals. Here, we reviewed the connections between mental health outcomes from airborne pollutant exposures, the biological inflammatory mechanisms, and provide future directions for researchers and policy makers. The current state of knowledge is discussed on associations between mental health outcomes and Clean Air Act criteria pollutants, traffic-related air pollutants, pesticides, heavy metals, jet fuel, and burn pits. Recent Findings Although associations between airborne pollutants and negative physical health outcomes have been a topic of previous investigations, work highlighting associations between exposures and psychological health is only starting to emerge. Research on criteria pollutants and mental health outcomes has the most robust results to date, followed by traffic-related air pollutants, and then pesticides. In contrast, scarce mental health research has been conducted on exposure to heavy metals, jet fuel, and burn pits. Specific cohorts of individuals, such as United States military members and in-turn, Veterans, often have unique histories of exposures, including service-related exposures to aircraft (e.g. jet fuels) and burn pits. Research focused on Veterans and other individuals with an increased likelihood of exposure and higher vulnerability to negative mental health outcomes is needed. Summary Future research will facilitate knowledge aimed at both prevention and intervention to improve physical and mental health among military personnel, Veterans, and other at-risk individuals.

Major depressive disorder (MDD) increases the risk of type 2 diabetes (T2D) by 60% in untreated patients, and hypercortisolism is common in MDD as well as in some patients with T2D. Patients with MDD, despite hypercortisolism, show inappropriately normal levels of corticotropin-releasing hormone (CRH) and plasma adrenocorticotropin (ACTH) in the cerebrospinal fluid, which might implicate impaired negative feedback. Also, a positive feedback loop of the CRH–norepinephrine (NE)–CRH system may be involved in the hypercortisolism of MDD and T2D. Dysfunctional CRH receptor 1 (CRHR1) and CRH receptor 2 (CRHR2), both of which are involved in glucose regulation, may explain hypercortisolism in MDD and T2D, at least in a subgroup of patients. CRHR1 increases glucose-stimulated insulin secretion. Dysfunctional CRHR1 variants can cause hypercortisolism, leading to serotonin dysfunction and depression, which can contribute to hyperglycemia, insulin resistance, and increased visceral fat, all of which are characteristics of T2D. CRHR2 is implicated in glucose homeostasis through the regulation of insulin secretion and gastrointestinal functions, and it stimulates insulin sensitivity at the muscular level. A few studies show a correlation of the CRHR2 gene with depressive disorders. Based on our own research, we have found a linkage and association (i.e., linkage disequilibrium [LD]) of the genes CRHR1 and CRHR2 with MDD and T2D in families with T2D. The correlation of CRHR1 and CRHR2 with MDD appears stronger than that with T2D, and per our hypothesis, MDD may precede the onset of T2D. According to the findings of our analysis, CRHR1 and CRHR2 variants could modify the response to prolonged chronic stress and contribute to high levels of cortisol, increasing the risk of developing MDD, T2D, and the comorbidity MDD-T2D. We report here the potential links of the CRH system, NE, and their roles in MDD and T2D.

OBJECTIVE:Alterations in the activity of the transcription factor 7-like 2 (TCF7L2) generate defects previously associated with neuropsychiatric disorders. We investigated the role of the TCF7L2 gene in major depressive disorder (MDD), type 2 diabetes (T2D), and MDD-T2D comorbidity. We tested whether TCF7L2 is in linkage to and/or in linkage disequilibrium (LD, namely association) with MDD, T2D, and MDD-T2D.PATIENTS AND METHODS:In 212 families with T2D and MDD in the Italian population, we analyzed 80 microarray-based SNPs using Pseudomarker software for linkage to and LD with T2D and MDD under the recessive model with complete penetrance (R1). In a secondary analysis, we tested the variants under the dominant models with complete penetrance (D1), recessive with incomplete penetrance (R2), and recessive with incomplete penetrance (R2).RESULTS:We found several novel linkage signals and genetic associations. In addition, we found two new transcription-factor (TF) binding sites created by two risk variants found: the MDD-risk variant rs12255179 creates a new TF-binding site for the CCAAT/enhancer-binding protein α (C/EBPα), and the T2D-risk variant rs61872794 creates a new TF-binding site for the organic cation-uptake transporter (OCT1). Both new binding sites are related to insulin metabolism.CONCLUSIONS:These results highlight the cross-interactivity between T2D and MDD. Further replication is needed in diverse ethnic groups.

Background: Persistent inflammation related to aging ("inflammaging") is exacerbated by chronic infections and contributes to frailty in older adults. We hypothesized associations between Toxoplasma gondii (T. gondii), a common parasite causing an oligosymptomatic unremitting infection, and frailty, and secondarily between T. gondii and previously reported markers of immune activation in frailty.Methods: We analyzed available demographic, social, and clinical data in Spanish and Portuguese older adults [N = 601; age: mean (SD) 77.3 (8.0); 61% women]. Plasma T. gondii immunoglobulin G (IgG) serointensity was measured with an enzyme-linked immunosorbent assay. The Fried criteria were used to define frailty status. Validated translations of Mini-Mental State Examination, Geriatric Depression Scale, and the Charlson Comorbidity Index were used to evaluate confounders. Previously analyzed biomarkers that were significantly associated with frailty in both prior reports and the current study, and also related to T. gondii serointensity, were further accounted for in multivariable logistic models with frailty as outcome.Results: In T. gondii-seropositives, there was a significant positive association between T. gondii IgG serointensity and frailty, accounting for age (p = .0002), and resisting adjustment for multiple successive confounders. Among biomarkers linked with frailty, kynurenine/tryptophan and soluble tumor necrosis factor receptor II were positively associated with T. gondii serointensity in seropositives (p < .05). Associations with other biomarkers were not significant.Conclusions: This first reported association between T. gondii and frailty is limited by a cross-sectional design and warrants replication. While certain biomarkers of inflammaging were associated with both T. gondii IgG serointensity and frailty, they did not fully mediate the T. gondii-frailty association.

Major depressive disorder(MDD)and type 2 diabetes(T2D)are two common complex multifactorial disorders that share several genetic and environmental risk factors such as hypercortisolism and related genes'risk variants within the stress response and the neuroendocrine hypothalamic-pituitary axis.Under stress,the pituitary gland releases prolactin(PRL),whose effects are pleiotropic and include mood control and insulin secretion from the beta cells.1 Variations in the prolactin receptor(PRLR)gene are associated in rodent models with stress level,depression-like behavior,2 and hepatic insulin sensitivity3 and in humans with maternal glucose homeostasis and gesta-tional diabetes.4 Furthermore,prolonged breastfeeding has been associated with reduced incidence of T2D,potentially related to PRL action.To our knowledge,no studies are reporting PRLR as a risk gene for MDD or T2D.Therefore,we aimed to investigate if the PRLR gene encoding for the PRLR plays a role in the familial comor-bidity of MDD and T2D.

Associations between personality traits and biomarkers related to chronic infection and inflammation have been previously reported. This study examines these associations focusing on their interactive effects with a data driven approach.

Abstract Background Alongside affective episodes, cognitive dysfunction is a core symptom of bipolar disorder. The intracellular parasite T. gondii has been positively associated with both, the diagnosis of bipolar disorder and poorer cognitive performance, across diagnostic boundaries. This study aims to investigate the association between T. gondii seropositivity, serointensity, and cognitive function in an euthymic sample of bipolar disorder. Methods A total of 76 participants with bipolar disorder in remission were tested for T. gondii-specific IgG and IgM antibodies and for cognitive performance using neuropsychological test battery. Cognitive parameters were categorized into three cognitive domains (attention and processing speed, verbal memory, and executive function). Statistical analysis of associations between continuous indicators of cognitive function as dependent variables in relationship to T. gondii, included multivariate analyses of co-variance for seropositivity, and partial correlations with IgG serointensity in IgG seropositives. All analyses were controlled for age and premorbid IQ. Results In seropositives (n = 27), verbal memory showed significant inverse partial correlations with IgG antibody levels (short delay free recall (r=–0.539, p = 0.005), long delay free recall (r=–0.423, p = 0.035), and immediate recall sum trial 1–5 (r=–0.399, p = 0.048)). Cognitive function did not differ between IgG seropositive and seronegative individuals in any of the cognitive domains (F (3,70) = 0.327, p = 0.806, n = 76). IgM positives (n = 7) were too few to be analyzed. Conclusions This investigation is the first to show an association between T. gondii IgG serointensity and memory function in a well-diagnosed bipolar disorder sample. It adds to the existing literature on associations between latent T. gondii infection and cognition in bipolar disorder, while further research is needed to confirm and expand our findings, eliminate potential sources of bias, and establish cause-effect relationships.