Acute and sustained effects of methylphenidate on cognition and presynaptic dopamine metabolism: an [18F]FDOPA PET study.

Methylphenidate (MPH) inhibits the reuptake of dopamine and noradrenaline. PET studies with MPH challenge show increased competition at postsynaptic D2/3-receptors, thus indirectly revealing presynaptic dopamine release. We used [(18)F]fluorodopamine ([(18)F]FDOPA)-PET in conjunction with the inlet-outlet model (IOM) of Kumakura et al. (2007) to investigate acute and long-term changes in dopamine synthesis capacity and turnover in nigrostriatal fibers of healthy subjects with MPH challenge. Twenty healthy human females underwent two dynamic [(18)F]FDOPA PET scans (124 min; slow bolus-injection; arterial blood sampling), with one scan in untreated baseline condition and the other after MPH administration (0.5 mg/kg, p.o.), in randomized order. Subjects underwent cognitive testing at each PET session. Time activity curves were obtained for ventral putamen and caudate and were analyzed according to the IOM to obtain the regional net-uptake of [(18)F]FDOPA (K; dopamine synthesis capacity) as well as the [(18)F]fluorodopamine washout rate (kloss, index of dopamine turnover). MPH substantially decreased kloss in putamen (-22%; p = 0.003). In the reversed treatment order group (MPH/no drug), K was increased by 18% at no drug follow-up. The magnitude of K at the no drug baseline correlated with cognitive parameters. Furthermore, individual kloss changes correlated with altered cognitive performance under MPH. [(18)F]FDOPA PET in combination with the IOM detects an MPH-evoked decrease in striatal dopamine turnover, in accordance with the known acute pharmacodynamics of MPH. Furthermore, the scan-ordering effect on K suggested that a single MPH challenge persistently increased striatal dopamine synthesis capacity. Attenuation of dopamine turnover by MPH is linked to enhanced cognitive performance in healthy females.

The impact of dopamine on aggression: an [18F]-FDOPA PET Study in healthy males.

Cerebral dopamine (DA) transmission is thought to be an important modulator for the development and occurrence of aggressive behavior. However, the link between aggression and DA transmission in humans has not been investigated using molecular imaging and standardized behavioral tasks. We investigated aggression as a function of DA transmission in a group of (N = 21) healthy male volunteers undergoing 6-[18F]-fluoro-L-DOPA (FDOPA)-positron emission tomography (PET) and a modified version of the Point Subtraction Aggression Paradigm (PSAP). This task measures aggressive behavior during a monetary reward-related paradigm, where a putative adversary habitually tries to cheat. The participant can react in three ways (i.e., money substraction of the putative opponent [aggressive punishment], pressing a defense button, or continuing his money-making behavior). FDOPA-PET was analyzed using a steady-state model yielding estimates of the DA-synthesis capacity (K), the turnover of tracer DA formed in living brain (kloss), and the tracer distribution volume (Vd), which is an index of DA storage capacity. Significant negative correlations between PSAP aggressive responses and the DA-synthesis capacity were present in several regions, most prominently in the midbrain (r = -0.640; p = 0.002). Lower degrees of aggressive responses were associated with higher DA storage capacity in the striatum and midbrain. Additionally, there was a significant positive correlation between the investment into monetary incentive responses on the PSAP and DA-synthesis capacity, notably in the midbrain (r = +0.618, p = 0.003). The results suggest that individuals with low DA transmission capacity are more vulnerable to reactive/impulsive aggression in response to provocation.

A possible brain network for representation of cooperative behavior and its implications for the psychopathology of schizophrenia.

It has been shown that social deficits contribute to psychopathology in schizophrenia, such as the bleulerian autism. A possible dysfunction in the mirror neuron system may be the reason for these deficits in the disorder. We wanted to better characterize the neural networks involved in the perception of social behavior. Fifteen healthy participants were presented with video clips of 8 seconds' duration depicting either (1) one actor manipulating an object, (2) two actors with only one manipulating an object or (3) two actors cooperating in manipulating an object and 2 other control conditions. Functional magnetic resonance imaging data were acquired during watching these videos. We found the perception of social cooperation is supported by a neural network comprising the precuneus, the temporoparietal junction (supramarginal gyrus, angular gyrus, BA 39/40), the middle temporal gyrus (including superior temporal sulcus) and frontal regions (medial frontal gyrus, inferior frontal gyrus). These areas form a complex network also being activated during theory of mind and cooperative behavior tasks. Its nodes overlap with those of the mirror neuron system. Consequently, both theory of mind abilities and mirror mechanisms are relevant in the perception and understanding of social cooperative behavior. We outline the consequences of these results for a further understanding of schizophrenic psychopathology with respect to social deficits and ego disturbances.

Prediction of phenotype and gene expression for combinations of mutations.

Molecular interactions provide paths for information flows. Genetic interactions reveal active information flows and reflect their functional consequences. We integrated these complementary data types to model the transcription network controlling cell differentiation in yeast. Genetic interactions were inferred from linear decomposition of gene expression data and were used to direct the construction of a molecular interaction network mediating these genetic effects. This network included both known and novel regulatory influences, and predicted genetic interactions. For corresponding combinations of mutations, the network model predicted quantitative gene expression profiles and precise phenotypic effects. Multiple predictions were tested and verified.

The performance of the Health of the Nation Outcome Scales as measures of clinical severity.

The aim of this study was to examine the performance of the Health of the Nation Outcome Scales (HoNOS) against other measures of functioning and mental health in a full three-year cohort of admissions to a psychiatric hospital. A sample of N=1719 patients (35.3% females, aged 17-78 years) was assessed using observer-rated measures and self-reports of psychopathology at admission. Self-reports were available from 51.7% of the sample (34.4% females, aged 17-76 years). Functioning and psychopathology were compared across five ICD-10 diagnostic groups: substance use disorders, schizophrenia and psychotic disorders, affective disorders, anxiety/somatoform disorders and personality disorders. Associations between the measures were examined, stratifying by diagnostic subgroup. The HoNOS were strongly linked to other measures primarily in psychotic disorders (except for the behavioral subscale), while those with substance use disorders showed rather poor links. Those with anxiety/somatoform disorders showed null or only small associations. This study raises questions about the overall validity of the HoNOS. It seems to entail different levels of validity when applied to different diagnostic groups. In clinical practice the HoNOS should not be used as a stand-alone instrument to assess outcome but rather as part of a more comprehensive battery including diagnosis-specific measures.

Effects of Smoking Cessation on Presynaptic Dopamine Function of Addicted Male Smokers.

BACKGROUND: There is evidence of abnormal cerebral dopamine transmission in nicotine-dependent smokers, but it is unclear whether dopaminergic abnormalities are due to acute nicotine abuse or whether they persist with abstinence. We addressed this question by conducting longitudinal positron emission tomography (PET) examination of smokers before and after 3 months of abstinence. METHODS: We obtained baseline 6-[(18)F]fluoro-L-DOPA (FDOPA)-PET scans in 15 nonsmokers and 30 nicotine-dependent smokers, who either smoked as per their usual habit or were in acute withdrawal. All smokers then underwent cessation treatment, and successful abstainers were re-examined by FDOPA-PET after 3 months of abstinence (n = 15). Uptake of FDOPA was analyzed using a steady-state model yielding estimates of the dopamine synthesis capacity (K); the turnover of tracer dopamine formed in living brain (kloss); and the tracer distribution volume (Vd), which is an index of dopamine storage capacity. RESULTS: Compared with nonsmokers, K was 15% to 20% lower in the caudate nuclei of consuming smokers. Intraindividual comparisons of consumption and long-term abstinence revealed significant increases in K in the right dorsal and left ventral caudate nuclei. Relative to acute withdrawal, Vd significantly decreased in the right ventral and dorsal caudate after prolonged abstinence. Severity of nicotine dependence significantly correlated with dopamine synthesis capacity and dopamine turnover in the bilateral ventral putamen of consuming smokers. CONCLUSIONS: The results suggest a lower dopamine synthesis capacity in nicotine-dependent smokers that appears to normalize with abstinence. Further investigations are needed to clarify the role of dopamine in nicotine addiction to help develop smoking prevention and cessation treatments.

Health of the Nation Outcome Scales in a psychiatric inpatient setting: assessing clinical change.

RATIONALE, AIMS AND OBJECTIVES: The aim of this study was to examine the validity of the Health of the Nation Outcome Scales (HoNOS) in terms of change in relation to sex, clinical characteristics and level of clinical change as assessed using other measures. METHODS: The sample consisted of N = 690 admissions from one Swiss psychiatric hospital who were assessed at admission and discharge using the HoNOS and the clinical global impression (CGI) scale. Repeated measures analyses of variance were conducted to compare changes in HoNOS scores over time stratified by sex, diagnostic category and CGI level of change, controlled for age and previous hospitalizations. Two-way interactions between time and these factors were calculated and post hoc t-tests were conducted to compare changes in HoNOS scores between admission and discharge at factor levels. RESULTS: HoNOS scores significantly decreased from admission to discharge in bivariate analyses although no main effect of time was found in multivariate models. Sex was found to moderate change in HoNOS behavioural subscale scores; primary diagnosis at admission moderated change in HoNOS total scores, the behavioural subscale and the social subscale; and CGI level of change moderated the change in all HoNOS scales. CONCLUSIONS: Our findings confirmed the sensitivity to change of the HoNOS in psychiatric settings from admission to discharge. Furthermore, we found that this change reflected similar changes in the CGI, a well-established measure for the evaluation of clinical outcomes, which, in turn supports the validity of the HoNOS.

[Identification and assessment of suicidality]. / Suizidalität erkennen und beurteilen.

Suicidality is a frequently observed but unfortunately frequently overlooked phenomenon. Every year over 1000 persons in Switzerland commit suicide; the number of attempted suicides is much higher. If suicidality is recognized promptly, appropriately assessed and adequate therapy initiated, suicides can be prevented. The assessment of suicidality can be facilitated by knowledge of the most important risk groups and factors, but also of protective factors. Various instruments are available which provide an overview of the influential factors, whereby some risk factors, e.g. access to suicidal methods or concrete suicide plans, involve a greater suicide risk than others. Such instruments, however, can never replace the overall assessment of a clinician which ought to arise from a dialogue characterized by empathy and transparency.

Chaque année, plus de 1000 personnes meurent par suicide en Suisse. Les tentatives de suicide sont beaucoup plus fréquentes. Si le risque de suicide est reconnu à temps et convenablement soigné, le taux de suicide peut-être diminué. Connaissant les principaux facteurs de risque et de protection, on peut mieux évaluer les tendances suicidaires. Il existe différents outils qui peuvent fournir un aperçu général sur le risque de suicide. Certains facteurs de risque, tels que l'accès à des méthodes ou une planification concrète de suicide, entraînent par exemple un risque de suicide plus élevé que d'autres. Toutefois, ces outils ne peuvent pas remplacer le jugement du médecin, qui devrait naître d'une conversation marquée par empathie et transparence.

Impact of personal economic environment and personality factors on individual financial decision making.

This study on healthy young male students aimed to enlighten the associations between an individual's financial decision making and surrogate makers for environmental factors covering long-term financial socialization, the current financial security/responsibility, and the personal affinity to financial affairs as represented by parental income, funding situation, and field of study. A group of 150 male young healthy students underwent two versions of the Holt and Laury (2002) lottery paradigm (matrix and random sequential version). Their financial decision was mainly driven by the factor "source of funding": students with strict performance control (grants, scholarships) had much higher rates of relative risk aversion (RRA) than subjects with support from family (ΔRRA = 0.22; p = 0.018). Personality scores only modestly affected the outcome. In an ANOVA, however, also the intelligence quotient significantly and relevantly contributed to the explanation of variance; the effects of parental income and the personality factors "agreeableness" and "openness" showed moderate to modest - but significant - effects. These findings suggest that environmental factors more than personality factors affect risk aversion.

Perinatal lead and mercury exposure in Austria.

OBJECTIVE: The heavy metals lead (Pb) and mercury (Hg) are ubiquitous environmental pollutants with high neurotoxic potential. We aimed to compare perinatal Pb and Hg concentrations and to explore the potential association between Pb and Hg exposure and newborn anthropometry. STUDY DESIGN: Pregnant women were recruited in 2005 at the General Hospital Vienna for participation in this longitudinal study. Pb and Hg concentrations were measured in maternal blood and hair, placenta, cord blood, meconium, and breast milk of 53 mother-child pairs by CV-AAS, GF-AAS, and HPLC-CV-ICPMS. We conducted bivariate analyses and categorical regression analysis (CATREG) to evaluate the determinants of Pb and Hg exposure, and of infant anthropometry. RESULTS: Median Pb and total Hg contents were low, i.e., 25 µg/L (maternal blood-Pb), 13 µg/L (cord blood-Pb), 0.7 µg/L (maternal blood-Hg), and 1.1 µg/L (cord blood-Hg). Hg levels in maternal and fetal tissues were frequently correlated (r>0.3, P<0.05, respectively). Regarding Pb, only maternal blood and cord blood concentrations correlated (P=0.043). Cord blood levels indicated higher Hg exposure but lower Pb exposure relative to maternal blood contents. Adjusted CATREG models indicated the significant predictors of birth length (placenta-Pb, gestational length, meconium-Pb), birth weight (placenta-Pb, gestational length, maternal blood-Pb), and head circumference (maternal education, maternal height). Besides one significant correlation between maternal hair Hg and birth length, the mercury levels were not associated with newborn anthropometry. CONCLUSIONS: Our data implicate that different modes of action may exist for placentar transfer of Pb and Hg as well as that low Pb exposure levels can result in lower birth weight. The findings related to newborn anthropometry need to be confirmed by the examination of larger study groups. Further research is needed to clarify the mechanisms of Pb and Hg transfer via the placenta, and to explore how prenatal Pb exposure is related to intrauterine growth.

Control of signaling in a MAP-kinase pathway by an RNA-binding protein.

Signaling-protein mRNAs tend to have long untranslated regions (UTRs) containing binding sites for RNA-binding proteins regulating gene expression. Here we show that a PUF-family RNA-binding protein, Mpt5, represses the yeast MAP-kinase pathway controlling differentiation to the filamentous form. Mpt5 represses the protein levels of two pathway components, the Ste7 MAP-kinase kinase and the Tec1 transcriptional activator, and negatively regulates the kinase activity of the Kss1 MAP kinase. Moreover, Mpt5 specifically inhibits the output of the pathway in the absence of stimuli, and thereby prevents inappropriate cell differentiation. The results provide an example of what may be a genome-scale level of regulation at the interface of signaling networks and protein-RNA binding networks.

Mnd2, an essential antagonist of the anaphase-promoting complex during meiotic prophase.

Meiotic cohesin serves in sister chromatid linkage and DNA repair until its subunit Rec8 is cleaved by separase. Separase is activated when its inhibitor, securin, is polyubiquitinated by the Cdc20 regulated anaphase-promoting complex (APC(Cdc20)) and consequently degraded. Differently regulated APCs (APC(Cdh1), APC(Ama1)) have not been implicated in securin degradation at meiosis I. We show that Mnd2, a factor known to associate with APC components, prevents premature securin degradation in meiosis by APC(Ama1). mnd2Delta cells lack linear chromosome axes and exhibit precocious sister chromatid separation, but deletion of AMA1 suppresses these defects. Besides securin, Sgo1, a protein essential for protection of centromeric cohesion during anaphase I, is also destabilized in mnd2delta cells. Mnd2's disappearance prior to anaphase II may activate APC(Ama1). Human oocytes may spend many years in meiotic prophase before maturation. Inhibitors of meiotic APC variants could prevent loss of chiasmata also in these cells, thereby guarding against aberrant chromosome segregation.

Spo13 regulates cohesin cleavage.

A key aspect of meiotic chromosome segregation is that cohesin, the protein complex that holds sister chromatids together, dissociates from chromosome arms during meiosis I and from centromeric regions during meiosis II. The budding yeast protein Spo13 plays a key role in preventing centromeric cohesin from being lost during meiosis I. We have determined the molecular basis for the metaphase arrest obtained when SPO13 is overexpressed during the mitotic cell cycle. Overexpression of SPO13 inhibits anaphase onset by at least two mechanisms. First, Spo13 causes a transient delay in degradation of the anaphase inhibitor Pds1. Second, Spo13 inhibits cleavage of the cohesin subunit Scc1/Mcd1 or its meiosis-specific homolog, Rec8, by the separase Esp1. The finding that Spo13 did not prevent cleavage of another Esp1 substrate, Slk19, suggests that overexpression of SPO13 is sufficient to prevent cohesin cleavage by protecting specific substrates from separase activity.

Control of yeast filamentous-form growth by modules in an integrated molecular network.

On solid growth media with limiting nitrogen source, diploid budding-yeast cells differentiate from the yeast form to a filamentous, adhesive, and invasive form. Genomic profiles of mRNA levels in Saccharomyces cerevisiae yeast-form and filamentous-form cells were compared. Disparate data types, including genes implicated by expression change, filamentation genes known previously through a phenotype, protein-protein interaction data, and protein-metabolite interaction data were integrated as the nodes and edges of a filamentation-network graph. Application of a network-clustering method revealed 47 clusters in the data. The correspondence of the clusters to modules is supported by significant coordinated expression change among cluster co-member genes, and the quantitative identification of collective functions controlling cell properties. The modular abstraction of the filamentation network enables the association of filamentous-form cell properties with the activation or repression of specific biological processes, and suggests hypotheses. A module-derived hypothesis was tested. It was found that the 26S proteasome regulates filamentous-form growth.