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Moderation of the Relationship between Toxoplasma gondii Seropositivity and Trait Impulsivity in Younger Men by the Phenylalanine-Tyrosine Ratio
Abstract
Previously, we reported that Toxoplasma gondii (T. gondii)-seropositivity is associated with higher impulsive sensation seeking in younger men. As dopaminergic and serotonergic signaling regulate impulsivity, and as T. gondii directly and indirectly affects dopaminergic signaling and induces activation of the kynurenine pathway leading to the diversion of tryptophan from serotonin production, we investigated if dopamine and serotonin precursors or the tryptophan metabolite kynurenine interact with the T. gondii–impulsivity association. In 950 psychiatrically healthy participants, trait impulsivity scores were related to T. gondii IgG seropositivity. Interactions were also identified between categorized levels of phenylalanine (Phe), tyrosine (Tyr), Phe:Tyr ratio, kynurenine (Kyn), tryptophan (Trp) and Kyn:Trp ratio, and age and gender. Only younger T. gondii-positive men with a high Phe:Tyr ratio, were found to have significantly higher impulsivity scores. There were no significant associations in other demographic groups, including women and older men. No significant effects or interactions were identified for Phe, Tyr, Kyn, Trp, or Kyn:Trp ratio. Phe:Tyr ratio, therefore, may play a moderating role in the association between T. gondii seropositivity and impulsivity in younger men. These results could potentially lead to individualized approaches to reduce impulsivity, based on combined demographic, biochemical and serological factors.
... We found that coexistence of a high plasma kynurenine (top quartile) and positive T. gondii IgG serology were necessary for a significant link between T. gondii and history of suicidal behavior in persons with a diagnosis of schizophrenia (95). In the endophenotypic direction (impulsivity, aggression), elevated levels of plasma phenylalanine/tyrosine (Phe:Tyr) ratios (specifically in the top quartile)-precursors of catecholamines including dopamine-interacted significantly with T. gondii seropositivity in younger males only in predicting impulsivity (115). Additionally, T. gondii seropositivity moderated the association between Phe:Tyr ratio and aggression (i.e., only in the T. gondii seropositive group-an association between a higher ratio between Phe:Tyr and aggression was significant) (116). ...
... This project (115) representing a follow-up on a previous study (114) that uncovered that T. gondii seropositivity is positively associated with impulsive sensation seeking in younger men. The study was based on the concepts that impulsivity is regulated by dopaminergic and serotonergic signaling, and, because T. gondii is known to directly affect dopaminergic signaling and tryptophan degradation pathways via immune activation, blood levels of precursors of serotonin and dopamine may change the association between T. gondii and impulsivity, and thus risk of suicide. ...
... In 950 psychiatrically healthy participants as described above and in Cook et al. (114), T. gondii IgG seropositivity was related to trait impulsivity scores (calculated as explained in detail in different reports) (114,115) in interaction with categorized levels (top 25% vs. bottom 75%) of Phe, Tyr, Kyn, and Trp measured by high performance liquid chromatography (HPLC), as described elsewhere (343,347). Phe:Tyr ratio and the Kyn:Trp ratio were calculated, and age and gender were used for adjustment in analysis of covariance (ANCOVA) with impulsivity scores as a dependent variable. ...
Within the general literature on infections and suicidal behavior, studies on Toxoplasma gondii ( T. gondii ) occupy a central position. This is related to the parasite's neurotropism, high prevalence of chronic infection, as well as specific and non-specific behavioral alterations in rodents that lead to increased risk taking, which are recapitulated in humans by T. gondii's associations with suicidal behavior, as well as trait impulsivity and aggression, mental illness and traffic accidents. This paper is a detailed review of the associations between T. gondii serology and suicidal behavior, a field of study that started 15 years ago with our publication of associations between T. gondii IgG serology and suicidal behavior in persons with mood disorders. This “legacy” article presents, chronologically, our primary studies in individuals with mood disorders and schizophrenia in Germany, recent attempters in Sweden, and in a large cohort of mothers in Denmark. Then, it reviews findings from all three meta-analyses published to date, confirming our reported associations and overall consistent in effect size [ranging between 39 and 57% elevation of odds of suicide attempt in T. gondii immunoglobulin (IgG) positives]. Finally, the article introduces certain links between T. gondii and biomarkers previously associated with suicidal behavior (kynurenines, phenylalanine/tyrosine), intermediate phenotypes of suicidal behavior (impulsivity, aggression) and state-dependent suicide risk factors (hopelessness/dysphoria, sleep impairment). In sum, an abundance of evidence supports a positive link between suicide attempts (but not suicidal ideation) and T. gondii IgG (but not IgM) seropositivity and serointensity. Trait impulsivity and aggression, endophenotypes of suicidal behavior have also been positively associated with T. gondii seropositivity in both the psychiatrically healthy as well as in patients with Intermittent Explosive Disorder. Yet, causality has not been demonstrated. Thus, randomized interventional studies are necessary to advance causal inferences and, if causality is confirmed, to provide hope that an etiological treatment for a distinct subgroup of individuals at an increased risk for suicide could emerge.
... Des études ont suggéré une association possible entre la séro-intensité et l'anxiété généralisée, les troubles paniques [291], la dépression [278], ou les troubles dysphoriques et l'anhédonie [292]. Une étude danoise suggère un impact de l'infection chronique sur la sévérité des symptômes dépressifs [204]. ...
... Une association positive entre séropositivité à T. gondii et agressivité ou impulsivité a été rapportée dans plusieurs populations [329], dont des adultes présentant ou non des troubles psychiatriques violents [292], [330], [331]. Au contraire, une étude de 2003 réalisée sur une sous-population de 857 militaires objectivait une impulsivité diminuée chez les patients T. gondii+ [322]. ...
Toxoplasma gondii est un parasite intra-cellulaire infectant près d’un tiers de la population mondiale. Généralement asymptomatique, la toxoplasmose est associée à une symptomatologie grave chez les patients immunodéprimés et dans le cas d’infection congénitale. Négligée par les pouvoirs publics, la phase chronique de l’infection a longtemps été sous-estimée. Cette méconnaissance entraîne donc des questions telles que quel est le meilleur protocole thérapeutique ? quelle est la meilleure stratégie diagnostique ? Récemment une stratégie de dissémination très avancée a été suspectée, sur la base de la théorie de la manipulation comportementale de l’hôte. Chez l’Homme, une telle manipulation peut avoir des effets majeurs cérébraux, neurologiques ou psychologiques. Quoi qu’il en soit, son impact sur le sommeil, qui constitue un index particulièrement sensible des fonctions cérébrales, est pour le moment inconnu. C’est pourquoi nous avons établi un modèle murin expérimental afin d’étudier les effets de Toxoplasma gondii sur le cycle éveil-sommeil. Nous avons montré que l’infection chronique par T. gondii était associée de manière persistante avec une augmentation de l’éveil et une diminution du sommeil, ce qui cadre avec la stratégie du parasite pour faciliter sa dissémination grâce à la prédation de son hôte. Nos résultats montrent pour la première fois les conséquences directes de l’infection toxoplasmique sur le comportement, pouvant avoir un impact majeur sur l’apparition de pathologies neuropsychiatriques et neurodégénératives.
... Yet, in essence, TG infections lead to similar changes in humans as it does in rodents. In particular, TG has been associated with changes in the production, file.v12.2 6 metabolism, and synthesis of hormones (e.g., testosterone) and neurotransmitters (e.g., dopamine, serotonin, and norepinephrine) in humans (Peng et al., 2018) which can create changes in personality. It has also been well established that the aforementioned effects are causally linked to TG infection, rather than the other way around (e.g. ...
There is growing evidence that human biology and behavior are influenced by infectious microorganisms. One such microorganism is the protozoan Toxoplasma gondii ( TG). Using longitudinal data covering the female population of Denmark, we extend research on the relationship between TG infection and entrepreneurial activity and outcomes. Results indicate that TG infection is associated with a subsequent increase in the probability of becoming an entrepreneur, and is linked to other outcomes including venture performance. With parasite behavioral manipulation antithetical to rational judgment, we join a growing conversation on biology and alternative drivers of business venturing.
... To this end, T. gondii infection is thought to trigger an immune response in the brain that could lead to decreased tryptophan availability, decreased serotonin biosynthesis and increased levels of kynurenic acid 196,197 . Of note, T. gondii infection may also amplify specific behavioural traits that are linked with suicidal behaviour such as aggression in women and impulsivity in men 198,199 . ...
Although recent years have seen large decreases in the overall global rate of suicide fatalities, this trend is not reflected everywhere. Suicide and suicidal behaviour continue to present key challenges for public policy and health services, with increasing suicide deaths in some countries such as the USA. The development of suicide risk is complex, involving contributions from biological (including genetics), psychological (such as certain personality traits), clinical (such as comorbid psychiatric illness), social and environmental factors. The involvement of multiple risk factors in conveying risk of suicide means that determining an individual’s risk of suicide is challenging. Improving risk assessment, for example, by using computer testing and genetic screening, is an area of ongoing research. Prevention is key to reduce the number of suicide deaths and prevention efforts include universal, selective and indicated interventions, although these interventions are often delivered in combination. These interventions, combined with psychological (such as cognitive behavioural therapy, caring contacts and safety planning) and pharmacological treatments (for example, clozapine and ketamine) along with coordinated social and public health initiatives, should continue to improve the management of individuals who are suicidal and decrease suicide-associated morbidity. Suicide and suicidal behaviour continue to present key challenges for public policy and health services. This Primer discusses the global burden of suicide and suicidal behaviours, and provides an overview of our current understanding of the mechanisms of suicide, including risk factors for suicidal ideation and the transition from ideation to suicide attempt.
... Yet, in essence, TG infections lead to similar changes in humans as it does in rodents. In particular, TG has been associated with changes in the production, metabolism, and synthesis of hormones (e.g., testosterone) and neurotransmitters (e.g., dopamine, serotonin, and norepinephrine) in humans (Peng et al., 2018) which can create changes in personality. It has also been well established that the aforementioned effects are causally linked to TG infection, rather than the other way around (e.g. ...
There is growing evidence that human biology and behavior is influenced by infectious microorganisms. One such microorganism is the protozoan Toxoplasma gondii (TG). Using longitudinal data covering the female population of Denmark, we extend research on the relationship between TG infection and entrepreneurial activity and outcomes. Results indicate that TG infection is associated with a subsequent increase in the probability of becoming an entrepreneur, and is linked to other outcomes including venture performance. With parasite behavioral manipulation antithetical to rational judgement, we join a growing conversation on biology and alternative drivers of business venturing.
[ Note: the Article can be found at
https://www.researchgate.net/publication/338857788_Nothing_Ventured_Nothing_Gained_Parasite_Infection_is_Associated_with_Entrepreneurial_Initiation_Engagement_and_Performance ]
... It is possible that genetic effects resulting in a significant heritability may also lead to increased novelty seeking (exploration) [45,46] and impulsivity [47,48], which, in turn, may increase the risk of T. gondii infection through increased exposure and incomplete hand hygiene or non-hygienic food preparation, known risk factors for acquiring T. gondii. Thus, increased heritability may be manifested not so much by vulnerability to infection when exposed to oocyst or tissue cyst, but through behavioral traits [21,49,50], such as genetic effects on impulsivity and decision making that may lead to variation in individual exposure levels to T. gondii infection risk factors. To our knowledge, this is the first study of combined evaluation of, and reciprocal adjustment for, T. gondii heritability and household effects, in contrast to several such studies for malaria parasites. ...
Toxoplasma gondii (T. gondii) is an intracellular parasite infecting one third of the world’s population. Latent T. gondii infection has been associated with mental illness, including schizophrenia and suicidal behavior. T. gondii IgG antibody titers were measured via ELISA. The heritability of T. gondii IgG was estimated using a mixed model that included fixed effects for age and sex and random kinship effect. Of 2017 Old Order Amish participants, 1098 had positive titers (54.4%). The heritability for T. gondii serointensity was estimated to be 0.22 (p = 1.7 × 10−8 and for seropositivity, it was estimated to be 0.28 (p = 1.9 × 10−5). Shared household environmental effects (i.e., household effects) were also determined. Household effects, modeled as a random variable, were assessed as the phenotypic covariance between any two individuals who had the same current address (i.e., contemporaneous household), and nuclear household (i.e., the phenotypic covariance between parents and children only, not other siblings or spouses). Household effects did not account for a significant proportion of variance in either T. gondii serointensity or T. gondii seropositivity. Our results suggest a significant familial aggregation of T. gondii serointensity and seropositivity with significant heritability. The shared household does not contribute significantly to family aggregation with T. gondii, suggesting that there are possible unmeasured non-household shared and non-shared environmental factors that may play a significant role. Furthermore, the small but significant heritability effects justify the exploration of genetic vulnerability to T. gondii exposure, infection, virulence, and neurotropism.
... Since these findings emerged, research focussed increasingly on possible cognitive and behavioural changes by a latent T. gondii infection in humans. Indeed, neurocognitive changes have been reported in people with a latent T. gondii infection, whereby increased impulsiveness has been reported in people with T. gondii infection, although results so far are heterogeneous (Dickerson et al., 2014;Gale et al., 2015;Sugden et al., 2016;Peng et al., 2018). Nonetheless, meta-analyses did show overall a significant association of exposure to T. gondii with several psychiatric disorders, especially schizophrenia, suggesting that the infection could impact human behaviour as well (Sutterland et al., 2015). ...
Unnatural causes of death due to traffic accidents (TA) and suicide attempts (SA) constitute a major burden on global health, which remained stable in the last decade despite widespread efforts of prevention. Recently, latent infection with Toxoplasma gondii ( T. gondii ) has been suggested to be a biological risk factor for both TA and SA. Therefore, a systematic search concerning the relationship of T. gondii infection with TA and/or SA according to PRISMA guidelines in Medline, Pubmed and PsychInfo was conducted collecting papers up to 11 February 2019 (PROSPERO #CRD42018090206). The random-effect model was applied and sensitivity analyses were subsequently performed. Lastly, the population attributable fraction (PAF) was calculated. We found a significant association for antibodies against T. gondii with TA [odds ratio (OR) = 1.69; 95% confidence interval (CI) 1.20–2.38, p = 0.003] and SA (OR = 1.39; 95% CI 1.10–1.76, p = 0006). Indication of publication bias was found for TA, but statistical adjustment for this bias did not change the OR. Heterogeneity between studies on SA was partly explained by type of control population used (OR healthy controls = 1.9, p < 0.001 v. OR psychiatric controls = 1.06, p = 0.87) and whether subjects with schizophrenia only were analysed (OR schizophrenia = 0.87, p = 0.62 v. OR various = 1.8, p < 0.001). The association was significantly stronger with higher antibody titres in TA and in studies that did not focus on schizophrenia subjects concerning SA. PAF of a T. gondii infection was 17% for TA and 10% for SA. This indicates that preventing T. gondii infection may play a role in the prevention of TA or SA, although uncertainty remains whether infection and outcome are truly causally related.
... A high phenylalanine:tyrosine ratio, resulting from inhibition of phenylalanine hydroxylase [67,68], can be the consequence of Th1 activation, one of the central immune mechanisms responsible for containing T. gondii infection in immunocompetent hosts [69]. We recently reported how associations between T. gondii and aggression [70] or impulsivity [71], known to be in part modulated by dopaminergic pathways, interact with plasma peripheral levels of phenylalanine:tyrosine ratios. Independent of dopaminergic mechanisms, as any microbial organism, T. gondii can promote sleep through the induction of the immune system. ...
Background
Evidence links Toxoplasmagondii (T. gondii), a neurotropic parasite, with schizophrenia, mood disorders and suicidal behavior, all of which are associated and exacerbated by disrupted sleep. Moreover, low-grade immune activation and dopaminergic overstimulation, which are consequences of T. gondii infection, could alter sleep patterns and duration.
Methods
Sleep data on 833 Amish participants [mean age (SD) = 44.28 (16.99) years; 59.06% women] were obtained via self-reported questionnaires that assessed sleep problems, duration and timing. T. gondii IgG was measured with ELISA. Data were analyzed using multivariable logistic regressions and linear mixed models, with adjustment for age, sex and family structure.
Results
T. gondii seropositives reported less sleep problems (p < 0.005) and less daytime problems due to poor sleep (p < 0.005). Higher T. gondii titers were associated with longer sleep duration (p < 0.05), earlier bedtime (p< 0.005) earlier mid-sleep time (p < 0.05).
Conclusions
It seems unlikely that sleep mediates the previously reported associations between T. gondii and mental illness. Future longitudinal studies with objective measures are necessary to replicate our findings.
... einen Neuromodulator, der mit Impulsivität in Zusammenhang steht. Da jedoch der Mangel an Dopamin (wie auch der Mangel an Serotonin) mit Impulsivität in Verbindung gebracht wird, sind die Zusammenhänge komplex, betreffen möglicherweise nur bestimmte Untergruppen (jüngere Männer mit einem bestimmten Verhältnis der Vorstufen Phenylalanin und Thyrosin im Blut; nicht ältere Männer, nicht Frauen) und werden derzeit weiter aufgeklärt (24,26). Neuere Untersuchungen an Ratten zei-gen allerdings einen verminderten Dopamingehalt in Core-Bereich des Nukleus akkumbens und eine vermehrte Impulsivität, die auch mit Delay-aversion (aversives Erleben von Verzögerungen) einherging (32). ...
... testosterone) and neurotransmitters (e.g. serotonin, dopamine and norepinephrine) have been explored [23]. Increases in testosterone, for instance, which have been linked to T. gondii infection [24], can enhance risk-taking behaviour, aggression and impulsivity in humans [17,25]. ...
Disciplines such as business and economics often rely on the assumption of rationality when explaining complex human behaviours. However, growing evidence suggests that behaviour may concurrently be influenced by infectious microorganisms. The protozoan Toxoplasma gondii infects an estimated 2 billion people worldwide and has been linked to behavioural alterations in humans and other vertebrates. Here we integrate primary data from college students and business professionals with national-level information on cultural attitudes towards business to test the hypothesis that T. gondii infection influences individual- as well as societal-scale entrepreneurship activities. Using a saliva-based assay, we found that students (n = 1495) who tested IgG positive for T. gondii exposure were 1.4× more likely to major in business and 1.7× more likely to have an emphasis in 'management and entrepreneurship' over other business-related emphases. Among professionals attending entrepreneurship events, T. gondii-positive individuals were 1.8× more likely to have started their own business compared with other attendees (n = 197). Finally, after synthesizing and combining country-level databases on T. gondii infection from the past 25 years with the Global Entrepreneurship Monitor of entrepreneurial activity, we found that infection prevalence was a consistent, positive predictor of entrepreneurial activity and intentions at the national scale, regardless of whether previously identified economic covariates were included. Nations with higher infection also had a lower fraction of respondents citing 'fear of failure' in inhibiting new business ventures. While correlational, these results highlight the linkage between parasitic infection and complex human behaviours, including those relevant to business, entrepreneurship and economic productivity.
Importance
The parasite Toxoplasma gondii has been associated with behavioral alterations and psychiatric disorders. Studies investigating neurocognition in people with T gondii infection have reported varying results. To systematically analyze these findings, a meta-analysis evaluating cognitive function in healthy people with and without T gondii seropositivity is needed.
Objective
To assess whether and to what extent T gondii seropositivity is associated with cognitive function in otherwise healthy people.
Data Sources
A systematic search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. A systematic search of PubMed, MEDLINE, Web of Science, PsycInfo, and Embase was performed to identify studies from database inception to June 7, 2019, that analyzed cognitive function among healthy participants with available data on T gondii seropositivity. Search terms included toxoplasmosis, neurotoxoplasmosis, Toxoplasma gondii, cognition disorder, neuropsychological, and psychomotor performance.
Study Selection
Studies that performed cognitive assessment and analyzed T gondii seroprevalence among otherwise healthy participants were included.
Data Extraction and Synthesis
Two researchers independently extracted data from published articles; if needed, authors were contacted to provide additional data. Quantitative syntheses were performed in predefined cognitive domains when 4 independent data sets per domain were available. Study quality, heterogeneity, and publication bias were assessed.
Main Outcomes and Measures
Performance on neuropsychological tests measuring cognitive function.
Results
The systematic search yielded 1954 records. After removal of 533 duplicates, an additional 1363 records were excluded based on a review of titles and abstracts. A total of 58 full-text articles were assessed for eligibility (including reference list screening); 45 articles were excluded because they lacked important data or did not meet study inclusion or reference list criteria. The remaining 13 studies comprising 13 289 healthy participants (mean [SD] age, 46.7 [16.0] years; 6586 men [49.6%]) with and without T gondii seropositivity were included in the meta-analysis. Participants without T gondii seropositivity had favorable functioning in 4 cognitive domains: processing speed (standardized mean difference [SMD], 0.12; 95% CI, 0.05-0.19; P = .001), working memory (SMD, 0.16; 95% CI, 0.06-0.26; P = .002), short-term verbal memory (SMD, 0.18; 95% CI, 0.09-0.27; P < .001), and executive functioning (SMD, 0.15; 95% CI, 0.01-0.28; P = .03). A meta-regression analysis found a significant association between older age and executive functioning (Q = 6.17; P = .01). Little suggestion of publication bias was detected.
Conclusions and Relevance
The study’s findings suggested that T gondii seropositivity was associated with mild cognitive impairment in several cognitive domains. Although effect sizes were small, given the ubiquitous prevalence of this infection globally, the association with cognitive impairment could imply a considerable adverse effect at the population level. Further research is warranted to investigate the underlying mechanisms of this association.
A growing body of evidence suggests a correlation between schizophrenia and exposure to infectious agents. The majority of studied cases concerns the infection caused by T. gondii, an obligatory intracellular parasite that infects about 1/3 of the entire human population, according to the available data. The acute stage of the disease, predominantly short-lived and transient, transforms into the latent and chronic phase in which the parasite localizes within tissue cysts, mainly in the central nervous system. The chronic toxo-plasmosis, primarily regarded as benign and asymptomatic, might be responsible, in light of current scientific evidence, for a vast array of neuropsychiatric symptoms. Numerous epidemiological case-control studies show a higher prevalence of T. gondii infestation in individuals with various psychiatric and behavior disorders, including schizophrenia. This paper tends to review the relevant studies that demonstrate links between schizophrenia and T. gondii infestation, of which the latter may be acquired in different developmental phases. Apart from epidemiological correlation studies, some papers on other associations were also presented, describing putative patophysiological mechanisms that might be at least partly responsible for chronic infection-induced neuromediator disturbances, together with morphological and functional alterations, e.g., low-grade neuroinflammation, which are likely to induce psychopathological symptoms. Toxoplasmosis is only one of the putative infectious agents that derange correct brain growth and differentiation , alongside genetic and environmental factors. All of them may lead eventually to schizophrenia. A better knowledge of infection mechanisms and its influence on neurobiochemical and neuropathological pathways may enable more efficient therapy and the prevention of this devastating disease.
Maladaptive decision making is associated with several neuropsychiatric disorders, including problem gambling and suicidal behavior. The prevalence of these disorders is higher in men versus women, suggesting gender-dependent regulation of their pathophysiology underpinnings. We assessed sex differences in decision making using the rat version of the Iowa gambling task. Female rats identified the most optimal choice from session 1, while male rats from session 5. Male, but not female rats, progressively improved their advantageous option responding and surpassed females. Estrus cycle phase did not affect decision making. To test whether pharmacological manipulations targeting the dopaminergic and stress systems affect decision making in a sex-dependent manner, male and female rats received injections of a dopamine D2 receptor (D2R) antagonist (eticlopride), D2R agonist (quinpirole), corticotropin-releasing factor 1 (CRF1) antagonist (antalarmin) and α2-adrenergic receptor antagonist (yohimbine; used as a pharmacological stressor). Alterations in mRNA levels of D2R and CRF1 were also assessed. Eticlopride decreased advantageous responding in male, but not female rats, while quinpirole decreased advantageous responding specifically in females. Yohimbine dose-dependently decreased advantageous responding in female rats, whereas decreased advantageous responding was only observed at higher doses in males. Antalarmin increased optimal choice responding only in female rats. Higher Drd2 and Crhr1 expression in the amygdala were observed in female vs male rats. Importantly, higher amygdalar Crhr1 expression was negatively correlated with advantageous responding specifically in females. This study is the first to demonstrate the relevance of dopaminergic- and stress-dependent sex differences in maladaptive decision making.
Objectives:
To investigate the association of schizophrenia and T. gondii, and to assess the association of infection with suicide attempts and age of onset of schizophrenia in these patients.
Methods:
Case-control study Fars Province, southern Iran. Cases were individuals with psychiatric diagnosis of schizophrenia as per Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Controls were healthy blood donors, frequency matched with patients according to age and sex. For detection of IgG antibodies, enzyme-linked immunosorbent assay (ELISA) was used. Data about demographic information in all subjects and duration of illness and history of suicide attempts in schizophrenia patients were collected using a brief questionnaire and hospital records. Chi-square test and multivariable logistic regression were used for statistical analyses.
Results:
Among 99 cases, 42 individuals (42%) were positive for T. gondii antibody, versus 41 (27%) among 152 controls (OR=2, 95%CI: 1.2-3.4, P=0.012). We compared the suicide attempts in schizophrenia patients based on their T. gondii serologic status. There was lower rate of suicide attempts in seropositive male patients than seronegative ones (OR=0.3, 95%CI: 0.1-0.97, P=0.04). Age of onset of schizophrenia did not differ between T. gondii infected and non-infected patients.
Conclusions:
These findings may have implications for schizophrenia and suicide prevention programs. However, clearly further studies are required to confirm them. This article is protected by copyright. All rights reserved.
Background
Psychiatric patients have an increased risk of some infections like toxoplasmosis. Investigations on Toxoplasma gondii infection among psychiatric patients have been limited in Mashhad, Northeast of Iran. In this case-control study, prevalence of T. gondii was investigated by serological method.
Methods
This case-control study was performed among psychiatric patients admitted to Avicenna Hospital in Mashhad, Northeast of Iran. Three hundred and fifty inpatients and 350 controls were examined in 2012–2013 for detection of IgG and IgM antibodies against T. gondii in their blood sera by ELISA. Socio-demographic and clinical manifestations of the patients were obtained.
Results
Anti-T. gondii IgG antibodies was found in 164 (46.85%) of 350 psychiatric inpatients and 120 (34.28%) of 350 controls. Seventeen (4.85%) of psychiatric individuals and 3 (0.85%) of control group were IgM+/IgG− indicating acute form of toxoplasmosis. There were no statistically significant differences between the case and control groups. In patient group, schizophrenic patients had the highest positive rate (46.28%) and bipolar mood disorder had the second most prevalent rate (20%). Of 162 schizophrenia patients, 65 (40.1%) had latent infection which was higher than that observed in controls.
Conclusion
The prevalence of T. gondii infection among psychiatric patients suffering from schizophrenia was more in Mashhad, compared with control group.
Toxoplasma gondii, a ubiquitous intracellular parasite, has a strong tropism for the brain tissue, where it forms intracellular cysts within the neurons and glial cells, establishing a chronic infection. Although latent toxoplasmosis is generally assumed to be asymptomatic in immunocompetent individuals, it is now clear that it can induce behavioral manipulations in mice and infected humans. Moreover, a strong relation has emerged in recent years between toxoplasmosis and psychiatric disorders. The link between T. gondii and schizophrenia has been the most widely documented, however, a significant association with bipolar disorder (BD) and suicidal/aggressive behaviors has also been detected. T. gondii may play a role in the etiopathogenesis of psychiatric disorders affecting neurotransmitters, especially dopamine, that are implicated in the emergence of psychosis and behavioral Toxoplasma-induced abnormalities, and inducing brain inflammation by the direct stimulation of inflammatory cytokines in the central nervous system. Besides this, there is increasing evidence for a prominent role of immune dysregulation in psychosis and BD. The aim of this review is to describe recent evidence suggesting a link between Toxoplasma gondii and BD, focusing on the interaction between immune responses and this infectious agent in the etiopathogenesis of psychiatric symptoms.
We previously reported that trait aggression, proposed as an endophenotype for suicidal behavior, is positively associated with Toxoplasma gondii (T. gondii) seropositivity in females, but not in males. Additionally, older males seropositive for T. gondii had lower scores on measures of trait aggression, including self-aggression. Trait aggression may be influenced by dopaminergic signaling, which is known to be moderated by gender and age, and potentially enhanced in T. gondii positives through the intrinsic production of dopamine by the microorganism. Therefore, we investigated associations between trait aggression and interactions between T. gondii enzyme-linked immunoabsorbant assay (ELISA) IgG titer-determined seropositivity and high-performance liquid chromatography- (HPLC-) measured blood levels of dopamine precursors phenylalanine (Phe), tyrosine (Tyr), and their ratio in a sample of 1000 psychiatrically healthy participants. Aggressive traits were assessed using the questionnaire for measuring factors of aggression (FAF), the German version of the Buss-Durkee hostility questionnaire. We found that 1) the decrease in trait aggression scores in T. gondii-positive older males was only present in individuals with a low Phe:Tyr ratio, and 2) that there was a positive correlation between Phe:Tyr ratio and total aggression and selected subscales of aggression in T. gondii-positive males, but not in T. gondii-negative males. These findings point toward a gender-specific reciprocal moderation by Phe:Tyr ratio and T. gondii seropositivity of their associations with aggression scores, and lead to experimental interventions geared to manipulating levels of dopamine precursors in selected T. gondii positive individuals with increased propensity for aggression.
Background:
Toxoplasma gondii (T. gondii) is a protozoan parasite present in around a third of the human population. Infected individuals are commonly asymptomatic, though recent reports have suggested that infection might influence aspects of the host's behavior. In particular, Toxoplasma infection has been linked to schizophrenia, suicide attempt, differences in aspects of personality and poorer neurocognitive performance. However, these studies are often conducted in clinical samples or convenience samples.
Methods/results:
In a population-representative birth-cohort of individuals tested for presence of antibodies to T. gondii (N = 837) we investigated the association between infection and four facets of human behavior: neuropsychiatric disorder (schizophrenia and major depression), poor impulse control (suicidal behavior and criminality), personality, and neurocognitive performance. Suicide attempt was marginally more frequent among individuals with T. gondii seropositivity (p = .06). Seropositive individuals also performed worse on one out of 14 measures of neuropsychological function.
Conclusion:
On the whole, there was little evidence that T. gondii was related to increased risk of psychiatric disorder, poor impulse control, personality aberrations or neurocognitive impairment.
Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.
Individuals with genotypes that code for reduced dopaminergic brain activity often exhibit a predisposition towards aggression. However, it remains largely unknown how dopaminergic genotypes may increase aggression. Lower-functioning dopamine systems motivate individuals to seek reward from external sources such as illicit drugs and other risky experiences. Based on emerging evidence that aggression is a rewarding experience, we predicted that the effect of lower-functioning dopaminergic functioning on aggression would be mediated by tendencies to seek the environment for rewards. Caucasian female and male undergraduates (N = 277) were genotyped for five polymorphisms of the Dopamine D2 Receptor (DRD2) gene, reported their previous history of aggression, and their dispositional reward-seeking. Lower-functioning DRD2 profiles were associated with greater sensation-seeking, which then predicted greater aggression. Our findings suggest that lower-functioning dopaminergic activity puts individuals at risk for violence because it motivates them to experience aggression's hedonically rewarding qualities.
Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan, is elevated in the brain of patients with psychotic disorders. Therefore, lowering brain KYNA levels might be a novel approach in the treatment of psychotic disorders. The present in vivo electrophysiological study aimed to investigate the effect of an inhibitor of kynurenine aminotransferase (KAT) II, the primary enzyme for KYNA synthesis, on dopamine (DA) neurons in the ventral tegmental area (VTA). Acute administration of the KAT II inhibitor PF-04859989 (5 or 10 mg/kg) was associated with a short-onset, time-dependent decrease in firing rate and burst activity of DA neurons, both parameters reaching a 50% reduction within 45 min. Furthermore, PF-04859989 reduced the number of spontaneously active DA cells as measured 4- 6 after administration. Pretreatment with D-cycloserine (30 mg/kg) or CGP-52432 (10mg/kg) prevented the inhibitory action of PF-04859989 (5 mg/kg) on firing rate and burst firing activity. In contrast, pretreatment with methyllycaconitine (MLA, 4 mg/kg) did not change the response, whereas picrotoxin (4.5 mg/kg) partially prevented the inhibitory effects of PF-04859989 (5 mg/kg, i.v.). Our results show that a specific inhibition of KAT II is associated with a marked reduction in VTA DA firing activity. This effect appears to be specifically executed by NMDA-receptors and mediated indirectly via a GABA(B)-receptor-induced disinhibition of DA neurons. Our findings are in line with the view that endogenous KYNA, by modulation of the NMDA-receptor, exerts important physiological roles in the brain.
Infection by the neurotropic agent Toxoplasma gondii alters rodent behavior and can result in neuropsychiatric symptoms in humans. Little is understood regarding the effects of infection on host neural processes but alterations to dopaminergic neurotransmission are implicated. We have previously reported elevated levels of dopamine in infected dopaminergic cells however the involvement of the host enzymes and fate of the produced dopamine were not defined. In order to clarify the effects of infection on host dopamine biosynthetic enzymes and dopamine packaging we examined enzyme levels and activity and dopamine accumulation and release in T. gondii infected neurosecretory cells. Although the levels of the host tyrosine hydroxylase and DOPA decarboxylase did not change significantly in infected cultures, DOPA decarboxylase was found within the parasitophorous vacuole, the vacuolar compartment where the parasites reside, as well as in the host cytosol in infected dopaminergic cells. Strikingly, DOPA decarboxylase was found within the intracellular parasite cysts in infected brain tissue. This finding could provide some explanation for observations of dopamine within tissue cysts in infected brain as a parasite-encoded enzyme with tyrosine hydroxylase activity was also localized within tissue cysts. In contrast, cellular dopamine packaging appeared unchanged in single-cell microamperometry experiments and only a fraction of the increased dopamine was accessible to high potassium-induced release. This study provides some understanding of how this parasite produces elevated dopamine within dopaminergic cells without the toxic ramifications of free cytosolic dopamine. The mechanism for synthesis and packaging of dopamine by T. gondii infected dopaminergic cells may have important implications for the effects of chronic T. gondii infection on humans and animals.
Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
Over the past decade, clinical data have accumulated showing that inflammation might contribute to the pathophysiology of suicide. To evaluate the associations and to identify the support for pathways linking inflammatory processes with suicidal behaviour, a comprehensive review of the literature was undertaken.
The search terms 'cytokine', 'risk factors', 'kynurenine', 'asthma', 'allergy', 'autoimmunity', 'traumatic brain injury', 'infection' along with the terms 'inflammation' and 'suicide' were entered into PubMed, and a thorough analysis of the publications and their reference lists was performed.
The effects of inflammation on mood and behaviour could partially be mediated by kynurenine pathway metabolites, modulating neuroinflammation and glutamate neurotransmission. At the same time, the triggers of the inflammatory changes documented in suicidal patients may be attributed to diverse mechanisms such as autoimmunity, neurotropic pathogens, stress or traumatic brain injury.
Targeting the inflammatory system might provide novel therapeutic approaches as well as potential biomarkers to identify patients at increased risk. For the goal of improved detection and treatment of suicidal individuals to be achieved, we need to develop a detailed understanding of the origin, mechanisms and outcomes of inflammation in suicidal behaviour.
© 2015 The Authors. Acta Psychiatrica Scandinavica Published by John Wiley & Sons Ltd.
Impulsivity critically relates to many psychiatric disorders. Given the multifaceted construct that impulsivity represents, defining core aspects of impulsivity is vital for the assessment and understanding of clinical conditions. Choice impulsivity (CI), involving the preferential selection of smaller sooner rewards over larger later rewards, represents one important type of impulsivity. The International Society for Research on Impulsivity (InSRI) convened to discuss the definition and assessment of CI and provide recommendations regarding measurement across species. Commonly used preclinical and clinical CI behavioral tasks are described, and considerations for each task are provided to guide CI task selection. Differences in assessment of CI (self-report, behavioral) and calculating CI indices (e.g., area-under-the-curve, indifference point, and steepness of discounting curve) are discussed along with properties of specific behavioral tasks used in preclinical and clinical settings. The InSRI group recommends inclusion of measures of CI in human studies examining impulsivity. Animal studies examining impulsivity should also include assessments of CI and these measures should be harmonized in accordance with human studies of the disorders being modeled in the preclinical investigations. The choice of specific CI measures to be included should be based on the goals of the study and existing preclinical and clinical literature using established CI measures. (PsycINFO Database Record
(c) 2015 APA, all rights reserved).
Human personality traits which can be reliably measured by any of a number of rating scales, show a considerable heritable component. The tridimensional personality questionnaire (TPQ) is one such instrument and was designed by Cloninger to measure four distinct domains of temperament - Novelty Seeking, Harm Avoidance, Reward Dependence and Persistence-that are hypothesized to be based on distinct neurochemical and genetic substrates. Cloninger proposed that individual variations in the Novelty Seeking trait are mediated by genetic variability in dopamine transmission. Individuals who score higher than average on the TPQ Novelty Seeking scale are characterized as impulsive, exploratory, fickle, excitable, quick-tempered and extravagant, whereas those who score lower than average tend to be reflective, rigid, loyal, stoic, slow-tempered and frugal. We now show that higher than average Novelty Seeking test scores in a group of 124 unrelated Israeli subjects are significantly associated with a particular exonic polymorphism, the 7 repeat allele in the locus for the D4 dopamine receptor gene (D4DR). The association of high Novelty Seeking and the 7-repeat allele was independent of ethnicity, sex or age of the subjects. This work, together with the accompanying confirmations in this issue, provides the first replicated association between a specific genetic locus involved in neurotransmission and a normal personality trait.
Impulsivity is associated with various psychopathologies, and elevated impulsivity is typically disadvantageous. This manuscript reviews recent investigations into the neurobiology of impulsivity using human imaging techniques and animal models. Both human imaging and preclinical pharmacological manipulations have yielded important insights into the neurobiological underpinnings of impulsivity. A more thorough understanding of the complex neurobiology underlying aspects of impulsivity may provide insight into new treatment options that target elevated impulsivity and psychopathologies such as addictions.
Phenylalanine and tyrosine are precursor amino acids required for the synthesis of dopamine, the main neurotransmitter implicated in the neurobiology of schizophrenia. Inflammation, increasingly implicated in schizophrenia, can impair the function of the enzyme Phenylalanine hydroxylase (PAH; which catalyzes the conversion of phenylalanine to tyrosine) and thus lead to elevated phenylalanine levels and reduced tyrosine levels. This study aimed to compare phenylalanine, tyrosine, and their ratio (a proxy for PAH function) in a relatively large sample of schizophrenia patients and healthy controls.
We measured non-fasting plasma phenylalanine and tyrosine in 950 schizophrenia patients and 1000 healthy controls. We carried out multivariate analyses to compare log transformed phenylalanine, tyrosine, and phenylalanine:tyrosine ratio between patients and controls.
Compared to controls, schizophrenia patients had higher phenylalanine (p<0.0001) and phenylalanine: tyrosine ratio (p<0.0001) but tyrosine did not differ between the two groups (p = 0.596).
Elevated phenylalanine and phenylalanine:tyrosine ratio in the blood of schizophrenia patients have to be replicated in longitudinal studies. The results may relate to an abnormal PAH function in schizophrenia that could become a target for novel preventative and interventional approaches.
Impulsivity is a multidimensional construct which has been associated with dopaminergic neurotransmission. Nonetheless, until this moment, few studies addressed the relationship between different types of impulsivity and the single nucleotide polymorphism caused by a substitution of valine (val) with methionine (met) in the 158 codon of the Catechol-o-Methyltransferase gene (COMT-val158met). The present study aimed to investigate the association between val158met COMT polymorphism and impulsive behavior measured by two neuropsychological tests.
We administered two neuropsychological tests, a Continuous Performance Task and the Iowa Gambling Task were applied to 195 healthy participants to characterize their levels of motor, attentional and non-planning impulsivity. Then, subjects were grouped by genotype, and their scores on impulsivity measures were compared. There were no significant differences between group scores on attentional and motor impulsivity. Those participants who were homozygous for the met allele performed worse in the Iowa Gambling Task than val/val and val/met subjects.
Our results suggest that met allele of val158met COMT polymorphism is associated with poor performance in decision-making/cognitive impulsivity task. The results reinforce the hypothesis that val and met alleles of the val158met polymorphism show functional dissociation and are related to different prefrontal processes.
Background:
Dopamine agonist therapy is the main risk factor for impulse control disorders in Parkinson's disease (PD). However, it is unclear whether bilateral deep brain stimulation of the subthalamic nucleus also causes impairment in decision making.
Objectives:
To assess the role of dopamine agonist therapy and deep brain stimulation on reflection impulsivity in non-demented patients with PD.
Methods:
We recruited 61 PD patients, 20 treated with L-dopa in combination with a dopamine agonist, 14 taking L-dopa monotherapy, a further 16 PD patients with bilateral subthalamic nucleus deep brain stimulation treated with L-dopa in combination with a dopamine agonist, and 11 PD patients with bilateral subthalamic nucleus deep brain stimulation taking L-dopa but not a dopamine agonist. Results were compared with 18 healthy controls. Patients who had evidence of impulsive compulsive behaviour were excluded. Reflection impulsivity was assessed with the beads task, which is a validated information sampling task.
Results:
All patients treated with a dopamine agonist gathered significantly less information and made more irrational decisions than all other groups regardless of whether they had surgical treatment.
Conclusions:
Our results imply that dopamine agonist therapy but not deep brain stimulation leads to "reflection impulsivity" in PD.
BACGROUND: It has recently been shown that the behavioural effects resulting from latent T. gondii infection in immunocompetent people could pose as a threat to their welfare. AIM. The aim of the study was to evaluate the prevalence of T. gondii infection in a group of people who died suddenly in Warsaw and its vicinity.
The studied group (n = 169 people) included 42 road traffic accident victims who were driving a vehicle (bicycle (n = 6), a motorbike (n = 3), a motorcycle (n = 13), a car (n = 20)) prior to sudden death and 41 people whose death resulted from suicide. Blood samples were collected post-mortem and examined for the presence of T. gondii, IgG antibodies and ethyl alcohol.
Of the 169 people tested, T. gondii IgG antibodies were found in the serum of 93 (55%) of which 25 (59.5%) were drivers and 26 (63.4%) people who died as a result of suicide. With respect to the prevalence of T. gondii infection no statistically significant differences were found between the study (61.4%) and control group (49.4%); (p = 0.09). A statistically significant result was recorded in the 38-58 age group between suicide and control groups (71.4% vs. 44.4%; p < 0.05). Positive test results for the presence of ethyl alcohol in the blood were reported among 49.7% of the studied population: 25.7% among drivers, 67.6% among suicides and 51.8% in the control group. To a statisctically siginificant degree, IgG T. gondii antibodies were found to occur more frequently in people with positive blood alcohol test results among suicides (72% vs. 50%; p < 0.05) and among the control group (60% vs. 40%; p < 0.05) than in their equivalents with negative test results.
Our work confirmed the usefulness of serologically testing samples collected post-mortem for epidemiological purposes. The small size of the study group made it impossible to evaluate the potential associations between exposure to T. gondii infection and the probability of sudden death. The significance of Toxoplasma gondii infection as a risk factor for self-destructive behaviour merits further study.
Impulsivity shares high co-morbidity with substance abuse in humans and high impulsivity in rats has been identified as a predictive factor of cocaine addiction-like behaviors. Despite the evidence that high impulsivity is associated with altered function of corticostriatal networks, the specific neural substrates underlying the increased vulnerability of impulsive individuals to develop cocaine addiction remain unknown. We therefore investigated specific neural correlates of high impulsivity within the corticostriatal circuitry and determined how they interact with a protracted history of cocaine self-administration. We used in situ hybridization to map brain expression of two major genes implicated in impulsivity, encoding dopamine D2 (DA D2R) and 5-HT2c (5-HT2cR) receptors, and an immediate early gene associated with neuronal plasticity, zif268, in groups of rats selected for high and low impulsivity (HI and LI) on a 5-choice serial reaction time task (5-CSRTT) immediately after 5-CSRTT training, and following, ten or fifty days of cocaine self-administration. HI rats exhibited decreased DA D2R mRNA in the mesolimbic pathway, and increased 5-HT2cR mRNA in the orbitofrontal cortex compared with LI rats. HI rats also showed decreased zif268 mRNA in the ventral and dorsomedial striatum. Cocaine exposure decreased striatal D2R mRNA in both HI and LI rats. It decreased 5-HT2cR mRNA differentially in striatal and prefrontal areas between HI and LI rats, and selectively decreased zif268 mRNA in the orbitofrontal and infralimbic cortices of HI animals. These findings implicate novel markers underlying the vulnerability of impulsive rats to cocaine addiction that localise to the orbitofrontal cortex, infralimbic cortex, and striatum.Neuropsychopharmacology accepted article preview online, 1 May 2013; doi:10.1038/npp.2013.95.
Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. While systemic autoimmune diseases are well-documented causes of neuropsychiatric disorders, synaptic autoimmune encephalitides with psychotic symptoms often go under-recognized. Parallel to the link between psychiatric symptoms and autoimmunity in autoimmune diseases, neuroimmunological abnormalities occur in classical psychiatric disorders (for example, major depressive, bipolar, schizophrenia, and obsessive-compulsive disorders). The pathophysiology of these conditions traditionally stressed dysregulation of the glutamatergic and monoaminergic systems, but the mechanisms causing these neurotransmitter abnormalities remained elusive. We review autoimmunity and neuropsychiatric disorders, and the human and experimental evidence supporting the pathogenic role of neuroinflammation in selected classical psychiatric disorders. Understanding how psychosocial, genetic, immunological and neurotransmitter systems interact can reveal pathogenic clues and help target new preventive and symptomatic therapies.
Parasite location has been proposed as an important factor in the behavioural changes observed in rodents infected with the protozoan Toxoplasma gondii. During the chronic stages of infection, encysted parasites are found in the brain but it remains unclear whether the parasite has tropism for specific brain regions. Parasite tissue cysts are found in all brain areas with some, but not all, prior studies reporting higher numbers located in the amygdala and frontal cortex. A stochastic process of parasite location does not, however, seem to explain the distinct and often subtle changes observed in rodent behaviour. One factor that could contribute to the specific changes is increased dopamine production by T. gondii. Recently, it was found that cells encysted with parasites in the brains of experimentally infected rodents have high levels of dopamine and that the parasite encodes a tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of this neurotransmitter. A mechanism is proposed that could explain the behaviour changes due to parasite regulation of dopamine. This could have important implications for T. gondii infections in humans.
Appropriate choice about delayed reward is fundamental to the survival of animals. Although animals tend to prefer immediate reward, delaying gratification is often advantageous. The dorsal raphe (DR) serotonergic neurons have long been implicated in the processing of delayed reward, but it has been unclear whether or when their activity causally directs choice. Here, we transiently augmented or reduced the activity of DR serotonergic neurons, while mice decided between differently delayed rewards as they performed a novel odor-guided intertemporal choice task. We found that these manipulations, precisely targeted at the decision point, were sufficient to bidirectionally influence impulsive choice. The manipulation specifically affected choices with more difficult trade-off. Similar effects were observed when we manipulated the serotonergic projections to the nucleus accumbens (NAc). We propose that DR serotonergic neurons preempt reward delays at the decision point and play a critical role in suppressing impulsive choice by regulating decision trade-off.
Previous studies have identified elevations in antibodies to Toxoplasma gondii in individuals with a history of suicide attempts but studies have not measured the association between suicide attempts and a panel of antibody markers. We assessed 162 patients receiving treatment for schizophrenia, bipolar disorder, or major depression on the Columbia Suicide Severity Rating Scale for suicide attempt history and other clinical measures. All participants had a blood sample drawn from which were measured antibodies to Toxoplasma gondii and other neurotropic infectious agents. A total of 72 (44%) of participants had a lifetime suicide attempt; these individuals had elevated levels of IgM class antibodies to Toxoplasma gondii and Cytomegalovirus (CMV). We also found an association between the levels of these antibodies and the number of suicide attempts. There was a particularly strong odds of a suicide attempt history in individuals who had elevated levels of IgM antibodies to both Toxoplasma gondii and to CMV suggesting an additive risk associated with the antibodies. These findings remained significant when adjusting for current cigarette smoking and history of drug/alcohol use which were also associated with suicide attempts. We did not find an association between a suicide attempt history and IgG class antibodies to Toxoplasma gondii, CMV, or IgM or IgG antibodies to the Epstein Barr Virus or other antigens tested. The identification of blood-based antibody markers should provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts in individuals with serious mental illnesses.
Toxoplasma gondii (TOXO) is a neuroinvasive protozoan parasite that induces the formation of persistent cysts in mammalian brains. It infects approximately 1.1 million people in the United States annually. Latent TOXO infection is implicated in the etiology of psychiatric disorders, especially schizophrenia (Scz), and has been correlated with modestly impaired cognition. The acoustic startle response (ASR) is a reflex seen in all mammals. It is mediated by a simple subcortical circuit, and provides an indicator of neural function. We previously reported the association of TOXO with slowed acoustic startle latency, an index of neural processing speed, in a sample of schizophrenia and healthy control subjects. The alterations in neurobiology with TOXO latent infection may not be specific to schizophrenia. Therefore we examined TOXO in relation to acoustic startle in an urban, predominately African American, population with mixed psychiatric diagnoses, and healthy controls. Physiological and diagnostic data along with blood samples were collected from 364 outpatients treated at an inner-city hospital. TOXO status was determined with an ELISA assay for TOXO-specific IgG. A discrete titer was calculated based on standard cut-points as an indicator of seropositivity, and the TOXO-specific IgG concentration served as serointensity. A series of linear regression models were used to assess the association of TOXO seropositivity and serointensity with ASR magnitude and latency in models adjusting for demographics and psychiatric diagnoses (PTSD, major depression, schizophrenia, psychosis, substance abuse). ASR magnitude was 11.5% higher in TOXO seropositive subjects compared to seronegative individuals (p=0.01). This effect was more pronounced in models with TOXO serointensity that adjusted for sociodemographic covariates (F=7.41, p=.0068; F=10.05, p=0.0017), and remained significant when psychiatric diagnoses were stepped into the models. TOXO showed no association with startle latency (t=0.49, p=0.63) in an unadjusted model, nor was TOXO associated with latency in models that included demographic factors. After stepping in individual psychiatric disorders, we found a significant association of latency with a diagnosis of PTSD (F=5.15, p=0.024), but no other psychiatric diagnoses, such that subjects with PTSD had longer startle latency. The mechanism by which TOXO infection is associated with high startle magnitude is not known, but possible mechanisms include TOXO cyst burden in the brain, parasite recrudescence, or molecular mimicry of a host epitope by TOXO. Future studies will focus on the neurobiology underlying the effects of latent TOXO infection as a potential inroad to the development of novel treatment targets for psychiatric disease.
Importance
Findings suggest that infections might be linked to the development of psychiatric disorders and suicidal behavior. Large-scale studies are needed to investigate the effect of infection on the risk of suicide.
Objective
To estimate the association between hospitalization with infection and the risk of death by suicide.
Design, Setting, and Participants
Nationwide, population-based, prospective cohort study with more than 149 million person-years of follow-up. Data were analyzed with survival analysis techniques and were adjusted for sex, age, calendar period, cohabitation status, socioeconomic status, and the Charlson Comorbidity Index. Individual data were drawn from Danish longitudinal registers. A total of 7.22 million individuals 15 years or older living in Denmark between January 1, 1980, and December 31, 2011, were observed during a 32-year follow-up period.
Main Outcomes and Measures
The risk of death by suicide was identified in the Danish Cause of Death Register. Incidence rate ratios (IRRs) and accompanying 95% CIs were used as measures of relative risk.
Results
In 7 221 578 individuals (3 601 653 men and 3 619 925 women) observed for a total of 149 061 786 person-years, 32 683 suicides were observed during the follow-up period. Among the suicides, 7892 (24.1%) individuals had previously been diagnosed as having an infection during a hospitalization. Hospitalization with infection was linked to an elevated risk of suicide, with an IRR of 1.42 (95% CI, 1.38-1.46) compared with those without prior infection. Dose-response relationships were observed with respect to the number of hospital contacts for different infections. For example, having 7 or more infections was linked to an IRR of 2.90 (95% CI, 2.14-3.93). The number of days of treatment for infections was associated with an elevated risk of suicide in a dose-response relationship. More than 3 months of hospital treatment was linked to an IRR of 2.38 (95% CI, 2.05-2.76). The population-attributable risk associated with hospitalization with infection accounted for 10.1% of suicides.
Conclusions and Relevance
An increased risk of death by suicide was found among individuals hospitalized with infection in prospective and dose-response relationships. These findings indicate that infections may have a relevant role in the pathophysiological mechanisms of suicidal behavior.
Purpose of review: The apicomplexan protozoan Toxoplasma gondii has a striking predilection for infecting the central nervous system and has been suggested as a risk factor for schizophrenia. Here, we address some of the mechanisms by which T. gondii achieves this by manipulating signaling pathways of the host brain cells. Recent findings: Recent years have brought notable progress in the understanding of how the opportunistic parasite T. gondii establishes a successful infection in mammalian brain by secreting effector molecules that manipulate multiple cell functions. Many pathways involved in this inter-kingdom signaling, such as dopaminergic, GABAergic and kynurenine pathways, also have key roles in the development of schizophrenia. More understanding of T. gondii-brain cell interaction holds the key to unlocking the mystery of T. gondii-mediated schizophrenia pathogenesis. Summary: T. gondii usurps a variety of host signaling pathways to ensure physiological adaptation, evasion of host immune defense systems, and efficient replication. A detailed knowledge of T. gondii signaling molecules involved in this cross-kingdom communication with host brain cells will probably provide novel means of pharmacologically manipulating host cellular pathways to promote efficient elimination of the parasite and may permit the development of new schizophrenia-modifying therapeutics. Copyright
Decision making under risk involves balancing the potential of gaining rewards with the possibility of loss and/or punishment. Tolerance to risk varies between individuals. Understanding the biological basis of risk tolerance is pertinent because excessive tolerance contributes to adverse health and safety outcomes. Yet, not much is known about biological factors mediating inter-individual variability in this regard. We investigate if latent Toxoplasma gondii infection can cause risk tolerance. Using a rodent model of the balloon analogous risk task, we show that latent T. gondii infection leads to a greater tolerance of reward forfeiture. Furthermore, effects of the infection on risk can be recapitulated with testosterone supplementation alone, demonstrating that greater testosterone synthesis by the host post-infection is sufficient to change risk tolerance. T. gondii is a frequent parasite of humans and animals. Thus, the infection status can potentially explain some of the inter-individual variability in the risky decision making.
Toxoplasma gondii (T. gondii) chronic infection and elevated kynurenine (KYN) levels have been individually associated with non-fatal suicidal self-directed violence (NF-SSDV). We aimed to test the hypothesis that the association between T. gondii seropositivity and history of NF-SSDV would be stronger in schizophrenia patients with high plasma KYN levels than in those with lower KYN levels. We measured anti-T. gondii IgG antibodies and plasma KYN in 950 patients with schizophrenia, and used logistic regression to evaluate the relationship between NF-SSDV and KYN in patients who were either seropositive or seronegative for T. gondii. For those with KYN levels in the upper 25th percentile, the unadjusted odds ratio for the association between NF-SSDV history and KYN in T. gondii seropositive patients was 1.63 (95% CI 1.01 to 2.66), p = 0.048; the adjusted odds ratio was 1.95 (95% CI 1.15 to 3.30), p = 0.014. Plasma KYN was not associated with a history of NF-SSDV in T. gondii seronegative patients. The results suggest that T. gondii and KYN may have a nonlinear cumulative effect on the risk of NF-SSDV among those with schizophrenia. If confirmed by future longitudinal studies, this result is expected to have both theoretical and clinical implications for the prevention and treatment of suicidal behavior.
Rats infected with the protozoan parasite Toxoplasma gondii exhibit reduced avoidance of predator odours. This behavioural change is likely to increase transmission of the parasite from rats to cats. Here, we show that infection with T. gondii increases the propensity of the infected rats to make more impulsive choices, manifested as delay aversion in an intertemporal choice task. Concomitantly, T. gondii infection causes reduction in dopamine content and neuronal spine density of the nucleus accumbens core, but not of the nucleus accumbens shell. These results are consistent with a role of the nucleus accumbens dopaminergic system in mediation of choice impulsivity and goal-directed behaviours. Our observations suggest that T. gondii infection in rats causes a syndromic shift in related behavioural constructs of innate aversion and making foraging decisions.
© 2015 The Author(s) Published by the Royal Society. All rights reserved.
To perform a meta-analysis on studies reporting prevalence of Toxoplasma gondii (T. gondii) infection in any psychiatric disorder compared with healthy controls. Our secondary objective was to analyze factors possibly moderating heterogeneity.
A systematic search was performed to identify studies into T. gondii infection for all major psychiatric disorders versus healthy controls. Methodological quality, publication bias, and possible moderators were assessed.
A total of 2866 citations were retrieved and 50 studies finally included. Significant odds ratios (ORs) with IgG antibodies were found in schizophrenia (OR 1.81, P < 0.00001), bipolar disorder (OR 1.52, P = 0.02), obsessive-compulsive disorder (OR 3.4, P < 0.001), and addiction (OR 1.91, P < 0.00001), but not for major depression (OR 1.21, P = 0.28). Exploration of the association between T. gondii and schizophrenia yielded a significant effect of seropositivity before onset and serointensity, but not IgM antibodies or gender. The amplitude of the OR was influenced by region and general seroprevalence. Moderators together accounted for 56% of the observed variance in study effects. After controlling for publication bias, the adjusted OR (1.43) in schizophrenia remained significant.
These findings suggest that T. gondii infection is associated with several psychiatric disorders and that in schizophrenia reactivation of latent T. gondii infection may occur.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Recent models of the development of addiction propose a transition from a pleasure-driven to a heavily automatized behaviour, marked by a loss of cognitive control. This study investigated the deficits in different components of cognitive functions including behavioural inhibition in response to alcohol-related stimuli in alcohol-dependent patients (ADP) and healthy controls (HC). The aims of the study were to identify which particular cognitive functions are impaired in ADP. Furthermore, we analysed the association between cognitive deficits and relapse rates and the reversibility of cognitive deficits under abstinence in a 6-month follow-up period. Ninety-four recently detoxified ADP and 71 HC completed the cognitive tasks as well as questionnaire measures assessing drinking behaviour and personality traits. Compared with HC, ADP showed poorer performance in response initiation, response inhibition, complex-sustained attention and executive functions. Impairment in response inhibition was a significant predictor for relapse, yet the strongest predictor was the interaction between the number of previous detoxifications and response-inhibition deficits. The results of a moderation analysis showed that patients with many previous detoxifications and large deficits in response inhibition showed the highest relapse risk. These findings indicate that interventions should take into account inhibitory deficits especially in ADP with a high number of previous detoxifications.
© 2015 Society for the Study of Addiction.
• Cerebrospinal fluid levels of 5-hydroxyindoleacetic acid, a metabolite of serotonin, were measured in relation to aggression, impulsivity, and social functioning in 29 children and adolescents with disruptive behavior disorders. The cerebrospinal fluid 5-hydroxyindoleacetic acid level was low compared with that of age-, sex-, and race-matched patients with obsessive-compulsive disorder. Within the disruptive group, significant negative correlations with age-corrected 5-hydroxyindoleacetic acid level were seen for the child's report of aggression toward people and the expressed emotionality of the child toward his or her mother; other correlations of age-corrected 5-hydroxyindoleacetic acid level with measures of aggression were in the expected negative direction but did not reach statistical significance. Impulsivity per se and socioenvironmental factors were not significantly related to cerebrospinal fluid 5-hydroxyindoleacetic acid concentration.
The zoonotic pathogen Toxoplasma gondii infects over 1/3 of the human population. The intracellular parasite can persist lifelong in the CNS within neurons modifying their function and structure, thus leading to specific behavioral changes of the host. In recent years, several in vitro studies and murine models have focused on the elucidation of these modifications. Furthermore, investigations of the human population have correlated Toxoplasma seropositivity with changes in neurological functions; however, the complex underlying mechanisms of the subtle behavioral alteration are still not fully understood. The parasites are able to induce direct modifications in the infected cells for example by altering dopamine metabolism, by functionally silencing neurons as well as by hindering apoptosis. Moreover, indirect effects of the peripheral immune system and alterations of the immune status of the CNS, observed during chronic infection, might also contribute to changes in neuronal connectivity and synaptic plasticity. In this review we will provide an overview and highlight recent advances, which describe changes in the neuronal function and morphology upon T. gondii infection.This article is protected by copyright. All rights reserved.
Background
Patients with depression and suicidality suffer from low-grade neuroinflammation. Pro-inflammatory cytokines activate indoleamine 2,3-dioxygenase, an initial enzyme of the kynurenine pathway. This pathway produces neuroactive metabolites, including quinolinic- and kynurenic acid, binding to the glutamate N-methyl-D-aspartate-receptor, which is hypothesized to be part of the neural mechanisms underlying symptoms of depression. We therefore hypothesized that symptoms of depression and suicidality would fluctuate over time in patients prone to suicidal behavior, depending on the degree of inflammation and kynurenine metabolite levels in the cerebrospinal fluid (CSF).
Methods
We measured cytokines and kynurenine metabolites in CSF, collected from suicide attempters at repeated occasions over two years (total patient samples n=143, individuals n=30) and healthy controls (n=36). The association between the markers and psychiatric symptoms were assessed using the Montgomery Åsberg Depression Rating Scale and the Suicide Assessment Scale.
Results
Quinolinic acid was increased and kynurenic acid decreased over time in suicidal patients versus healthy controls. Furthermore, we found a significant association between low kynurenic acid and severe depressive symptoms, as well as between high interleukin-6 levels and more severe suicidal symptoms.
Conclusions
We demonstrate a long-term dysregulation of the kynurenine pathway in the central nervous system of suicide attempters. An increased load of inflammatory cytokines was coupled to more severe symptoms. We therefore suggest that patients with a dysregulated kynurenine pathway are vulnerable to develop depressive symptoms upon inflammatory conditions, as a result the excess production of the NMDA-receptor agonist quinolinic acid. This study provides a neurobiological framework supporting the use of NMDA-receptor antagonists in the treatment of suicidality and depression.
Congenital toxoplasmosis and toxoplasmic encephalitis can be associated with severe neuropsychiatric symptoms. However, which host cell processes are regulated and how Toxoplasma gondii affects these changes remain unclear. MicroRNAs (miRNAs) are small noncoding RNA sequences critical to neurodevelopment and adult neuronal processes by coordinating the activity of multiple genes within biological networks. We examined the expression of over 1000 miRNAs in human neuroepithelioma cells in response to infection with Toxoplasma. MiR-132, a cyclic AMP-responsive element binding (CREB)-regulated miRNA, was the only miRNA that was substantially upregulated by all three prototype Toxoplasma strains. The increased expression of miR-132 was also documented in mice following infection with Toxoplasma. To identify cellular pathways regulated by miR-132, we performed target prediction followed by pathway enrichment analysis in the transcriptome of Toxoplasma-infected mice. This led us to identify 20 genes and dopamine receptor signaling was their strongest associated pathway. We then examined myriad aspects of the dopamine pathway in the striatum of Toxoplasma-infected mice 5 days after infection. Here we report decreased expression of D1-like dopamine receptors (DRD1, DRD5), metabolizing enzyme (MAOA) and intracellular proteins associated with the transduction of dopamine-mediated signaling (DARPP-32 phosphorylation at Thr34 and Ser97). Increased concentrations of dopamine and its metabolites, serotonin (5-HT) and 5-hydroxyindoleacetic acid were documented by HPLC analysis; however, the metabolism of dopamine was decreased and 5-HT metabolism was unchanged. Our data show that miR-132 is upregulated following infection with Toxoplasma and is associated with changes in dopamine receptor signaling. Our findings provide a possible mechanism for how the parasite contributes to the neuropathology of infection.
Background:
Animal and clinical studies suggest a link between inflammation and oxidative stress. Because oxidative stress is an inherent part of inflammation, and inflammation is associated with behavioral aggression in lower mammals and humans, we hypothesized that markers of oxidative stress would be related to aggression in human subjects. In this case-control study, markers of oxidative stress and aggression were assessed in human subjects with histories of recurrent, problematic, impulsive aggressive behavior and in nonaggressive comparator subjects.
Methods:
Plasma levels of 8-hydroxy-2'-deoxyguanosine and 8-isoprostane were examined in the context of measures of aggression and impulsivity in physically healthy subjects with intermittent explosive disorder (n = 69), nonaggressive subjects with Axis I or II disorders (n = 61), and nonaggressive subjects with no history of Axis I or II disorders (n = 67).
Results:
Levels of plasma 8-hydroxy-2'-deoxyguanosine and 8-isoprostane were significantly higher in subjects with intermittent explosive disorder compared with psychiatric or normal control subjects. In addition, both oxidative stress markers correlated with a composite measure of aggression; more specifically, 8-hydroxy-2'-deoxyguanosine correlated with measures reflecting a history of actual aggressive behavior in all subjects.
Conclusions:
These data suggest a positive relationship between plasma markers of oxidative stress and aggression in human subjects. This finding adds to the complex picture of the central neuromodulatory role of aggression in human subjects.
An HPLC method was developed to quantify serum concentrations of phenylalanine and tyrosine simultaneously using fluorescence detection without derivatization.
Serum protein is precipitated with trichloroacetic acid, 0.015mM dihydrogen-phosphate solution is used for separation on reversed-phase C18 material, acetonitrile is avoided. Both amino acids are monitored utilizing their natural fluorescence at 210nm excitation and 302nm emission wavelengths.
One analytical run is completed within 7min. Lower detection limit for Phe and Tyr is 0.3μM. Comparison of the new method with a classical HPLC method for total amino acids and using UV-absorption detection reveals a highly significant relationship for Phe and Tyr.
The new HPLC method allows rapid and very sensitive measurement of phenylalanine and tyrosine concentrations. (n=117).
The association of Toxoplasma gondii infection with suicide attempts has been scarcely evaluated. Two hundred eighty-three psychiatric outpatients (156 patients with history of suicide attempt and 127 control patients without history of suicide attempt) were examined with enzyme-linked immunoassays for Toxoplasma immunoglobulin G (IgG) and IgM antibodies. Seroprevalences of Toxoplasma IgG and IgM in the cases and the controls were similar: 7 (4.5%) and 3 (1.9%) vs. 10 (7.9%) and 3 (2.4%) (p = 0.23 and p = 0.55), respectively. In contrast, the Toxoplasma IgG levels higher than 150 IU/ml were more frequently observed in the cases than in the controls (100% vs. 50%, respectively; p = 0.04). The seroprevalence of Toxoplasma infection increased with age and with the number of suicide attempts. Toxoplasma seropositivity was associated with reflex impairment, national trips, and snake meat consumption. Our results suggest that although seroprevalence of Toxoplasma infection is not associated with suicide attempts, a high anti-Toxoplasma antibody level is, therefore warranting further research.
Impulsivity is considered a personality trait affecting behavior in many life domains, from recreational activities to important decision making. When extreme, it is associated with mental health problems, such as substance use disorders, as well as with interpersonal and social difficulties, including juvenile delinquency and criminality. Yet, trait impulsivity may not be a unitary construct. We review commonly used self-report measures of personality trait impulsivity and related constructs (e.g., sensation seeking), plus the opposite pole, control or constraint. A meta-analytic principal-components factor analysis demonstrated that these scales comprise 3 distinct factors, each of which aligns with a broad, higher order personality factor-Neuroticism/Negative Emotionality, Disinhibition versus Constraint/Conscientiousness, and Extraversion/Positive Emotionality/Sensation Seeking. Moreover, Disinhibition versus Constraint/Conscientiousness comprise 2 correlated but distinct subfactors: Disinhibition versus Constraint and Conscientiousness/Will versus Resourcelessness. We also review laboratory tasks that purport to measure a construct similar to trait impulsivity. A meta-analytic principal-components factor analysis demonstrated that these tasks constitute 4 factors (Inattention, Inhibition, Impulsive Decision-Making, and Shifting). Although relations between these 2 measurement models are consistently low to very low, relations between both trait scales and laboratory behavioral tasks and daily-life impulsive behaviors are moderate. That is, both independently predict problematic daily-life impulsive behaviors, such as substance use, gambling, and delinquency; their joint use has incremental predictive power over the use of either type of measure alone and furthers our understanding of these important, problematic behaviors. Future use of confirmatory methods should help to ascertain with greater precision the number of and relations between impulsivity-related components. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
Introduction:
Toxoplasma gondii is the most common protozoan parasite in developed nations. Up to 43% of the French population may be infected, depending on eating habits and exposure to cats, and almost one third of the world human's population may be infected. Two types of infection have been described: a congenital form and an acquired form. Although the medical profession treats these latent cases as asymptomatic and clinically unimportant, results of animal studies and recent studies of personality profiles, behavior, and psychomotor performance have led to reconsider this assumption.
Preclinical data:
Among rats: parasite cysts are more abundant in amygdalar structures than those found in other regions of the brain. Infection does not influence locomotion, anxiety, hippocampal-dependent learning, fear conditioning (or its extinction) and neophobia in rats. Rats' natural predator is the cat, which is also T. gondii's reservoir. Naturally, rats have an aversion to cat urine, but the parasite suppresses this aversion in rats, thus influencing the infection cycle. Tachyzoites may invade different types of nervous cells, such as neurons, astrocytes and microglial cells in the brain, and Purkinje cells in cerebellum. Intracellular tachyzoites manipulate several signs for transduction mechanisms involved in apoptosis, antimicrobial effectors functions, and immune cell maturation. Dopamine levels are 14% higher in mice with chronic infections. These neurochemical changes may be factors contributing to mental and motor abnormalities that accompany or follow toxoplasmosis in rodents and possibly in humans. Moreover, the antipsychotic haloperidol and the mood stabilizer valproic acid most effectively inhibit Toxoplasma growth in vitro with synergistic activity.
Clinical data:
The effects of the parasite are not due to the manipulation in an evolutionary sense but merely due to neuropathological or neuroimmunological effects of the parasite's presence. Toxoplasmosis and schizophrenia: epidemiological studies point to a role for toxoplasmosis in schizophrenia's etiology, probably during pregnancy and early life, this association being congruent with studies in animal models indicating that animal exposures of the developing brain to infectious agents or immune modulating agents can be associated with behavioral changes that do not appear until the animal reaches full maturity. Psychiatric patients have increased rates of toxoplasmic antibodies, the differences between cases and controls being greatest in individuals who are assayed near the time of the onset of their symptoms. The increase of dopamine in the brain of infected subjects can represent the missing link between toxoplasmosis and schizophrenia. Toxoplasmosis and Obsessive Compulsive Disorder (OCD): the seropositivity rate for anti-T. gondii IgG antibodies among OCD patients is found to be significantly higher than the rate in healthy volunteers. Infection of basal ganglia may be implicated in the pathogenesis of OCD among Toxoplasma seropositive subjects. Toxoplasmosis and personality: infected men appear to be more dogmatic, less confident, more jealous, more cautious, less impulsive and more orderly than others. Conversely, infected women seem warmest, more conscientious, more insecure, more sanctimonious and more persistent than others. It is possible that differences in the level of testosterone may be responsible for the observed behavioral differences between Toxoplasma-infected and Toxoplasma-free subjects.
Conclusion:
In the future two major avenues for research seem essential. On one hand, prospective studies and research efforts must still be carried out to understand the mechanisms by which the parasite induces these psychiatric disorders. On the other hand, it has not yet been demonstrated that patients with positive toxoplasmic serology may better respond to haloperidol's or valproic acid's antiparasitic activity. These results may appear as a major issue in the drug's prescribing choices and explain variability in response to the treatment of patients with schizophrenia that is not explained by the genetic polymorphism.
Many previous studies suggest the potential of psychostimulants in improving cognitive functioning. Our earlier pharmacological brain imaging study showed that intravenous methylphenidate (MPH) improves inhibitory control by altering cortico-striato-thalamic activations in cocaine-dependent (CD) individuals. Here we provide additional evidence for the effects of MPH in restoring cerebral activations during cognitive performance. Ten CD individuals performed a stop signal task (SST) during functional magnetic resonance imaging (fMRI) in two sessions, in which either MPH (0.5mg/kg body weight) or saline was administered intravenously. In the SST, a frequent go signal instructs participants to make a speeded response and a less frequent stop signal instructs them to withhold the response. Our previous work described increased activation of the precuneus/posterior cingulate cortex and ventromedial prefrontal cortex-regions of the default mode network (DMN)-before participants committed a stop error in healthy control but not CD individuals (Bednarski et al., 2011). The current results showed that, compared to saline, MPH restored error-preceding activations of DMN regions in CD individuals. The extent of the changes in precuneus activity was correlated with MPH-elicited increase in systolic blood pressure. These findings suggest that the influence of MPH on cerebral activations may extend beyond cognitive control and provide additional evidence warranting future studies to investigate the neural mechanisms and physiological markers of the efficacy of agonist therapy in cocaine dependence.
Objective: Although interleukin (IL)-6 plays a significant role in cardiovascular disease, little is known about its relation to psychological risk factors, such as hostility and severity of depressive symptoms. The current study examined the joint effects of severity of depressive symptoms and hostility on plasma IL-6 in a sample of 90 healthy, nonsmoking men. Methods: After an overnight fast, blood samples for plasma IL-6 and fasting lipids were collected on the same day that the Beck Depression Inventory (BDI) and the Cook-Medley hostility (Ho) scale were administered. Plasma IL-6 was determined using enzymatic-linked immunosorbent assay (ELISA). Results: Analyses of logarithmically normalized plasma IL-6 adjusting for age, body mass index (BMI), fasting total cholesterol, high density lipoprotein (HDL), and resting diastolic blood pressure (DBP) revealed a significant BDI by Ho interaction (p =.026). Post hoc decomposition revealed that Ho was correlated with log-normalized plasma IL-6 (r = 0.59, p =.025) but only among men with BDI scores of 10 and above. Alternatively, BDI was correlated with log-normalized plasma IL-6 (r = 0.61, p =.003) but only among men with Ho scores of 23 and higher. Comparisons among BDI/Ho groups indicated that men with high scores on both the BDI and the Ho exhibited the highest median levels of plasma IL-6. Conclusion: Hostile men who exhibited above normal levels of depressive symptoms had higher plasma levels of IL-6 suggestive of a subpopulation at increased risk for future cardiac events.
Although substantial literature discusses sensation seeking as playing a role in the relationship between baseline heart rate and aggression, few published studies have tested the relationships among these variables. Furthermore, most prior studies have focused on risk factors of aggression in men and have largely ignored this issue in women. Two samples (n = 104; n = 99) of young adult women completed measures of resting heart rate, sensation seeking, and aggression. Across the two samples of females there was no evidence for the relationships of baseline heart rate with sensation seeking or with aggression that has been consistently shown in males. Boredom susceptibility and disinhibition subscales of sensation seeking were consistently significantly correlated with aggression. The lack of significance and the small effect sizes indicate that other mechanisms are also at work in affecting aggression in young adult women. Finally, it is important to consider the type of sensation seeking in relation to aggression, as only boredom susceptibility and disinhibition were consistently replicated across samples. Aggr. Behav. 9999:XX-XX, 2013. © 2013 Wiley Periodicals, Inc.
Variation in dopamine receptor levels has been associated with different facets of impulsivity. To further delineate the neural sub-strates underlying impulsive action (inability to withhold a prepotent motor response) and impulsive choice (delay aversion), we characterised rats in the Differential Reinforcement of Low Rates of Responding task and a delay discounting task. We also measured performance on an effort-based discounting task. We then assessed D1 and D2 dopamine receptor mRNA expression in subregions of the prefrontal cortex and nucleus accumbens using in situ hybridisation, and compared these data with behavioral performance. Expression of D1 and D2 receptor mRNA in distinct brain regions was predictive of impulsive action. A dissociation within the nucleus accumbens was observed between subregions and receptor subtypes; higher D1 mRNA expression in the shell predicted greater impulsive action, whereas lower D2 mRNA expression in the core predicted greater impulsive action. We also observed a negative correlation between impulsive action and D2 mRNA expression in the prelimbic cortex. Interestingly, a similar relationship was present between impulsive choice and prelimbic cortex D2 mRNA, despite the fact that behavioral indices of impulsive action and impulsive choice were uncorrelated. Finally, we found that both high D1 mRNA expression in the insular cortex and low D2 mRNA expression in the infralimbic cortex were associated with willingness to exert effort for rewards. Notably, dopamine receptor mRNA in these regions was not associated with either facet of impulsivity. The data presented here provide novel molecular and neuroanatomical distinctions between different forms of impulsivity, as well as effort-based decision-making.