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Find video protocols related to scientific articles indexed in Pubmed.
Peripheral DISC1 protein levels as a trait marker for schizophrenia and modulating effects of nicotine.
Behav. Brain Res.
PUBLISHED: 08-27-2014
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The Disrupted-in-Schizophrenia 1 (DISC1) protein plays a key role in behavioral control and vulnerability for mental illnesses, including schizophrenia. In this study we asked whether peripheral DISC1 protein levels in lymphocytes of patients diagnosed with schizophrenia can serve as a trait marker for the disease. Since a prominent comorbidity of schizophrenia patients is nicotine abuse or addiction, we also examined modulation of lymphocyte DISC1 protein levels in smokers, as well as the relationship between nicotine and DISC1 solubility status. We show decreased DISC1 levels in patients diagnosed with schizophrenia independent of smoking, indicating its potential use as a trait marker of this disease. In addition, lymphocytic DISC1 protein levels were decreased in smoking, mentally healthy individuals but not to the degree of overriding the trait level. Since DISC1 protein has been reported to exist in different solubility states in the brain, we also investigated DISC1 protein solubility in brains of rats treated with nicotine. Sub-chronic treatment with progressively increasing doses of nicotine from 0.25mg/kg to 1mg/kg for 15 days led to a decrease of insoluble DISC1 in the medial prefrontal cortex. Our results demonstrate that DISC1 protein levels in human lymphocytes are correlated with the diagnosis of schizophrenia independent of smoking and thus present a potential biomarker. Reduced DISC1 protein levels in lymphocytes of healthy individuals exposed to nicotine suggest that peripheral DISC1 could have potential for monitoring the effects of psychoactive substances.
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Functionally aberrant electrophysiological cortical connectivities in first episode medication-naive schizophrenics from three psychiatry centers.
Front Hum Neurosci
PUBLISHED: 08-20-2014
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Functional dissociation between brain processes is widely hypothesized to account for aberrations of thought and emotions in schizophrenic patients. The typically small groups of analyzed schizophrenic patients yielded different neurophysiological findings, probably because small patient groups are likely to comprise different schizophrenia subtypes. We analyzed multichannel eyes-closed resting EEG from three small groups of acutely ill, first episode productive schizophrenic patients before start of medication (from three centers: Bern N = 9; Osaka N = 9; Berlin N = 12) and their controls. Low resolution brain electromagnetic tomography (LORETA) was used to compute intracortical source model-based lagged functional connectivity not biased by volume conduction effects between 19 cortical regions of interest (ROIs). The connectivities were compared between controls and patients of each group. Conjunction analysis determined six aberrant cortical functional connectivities that were the same in the three patient groups. Four of these six concerned the facilitating EEG alpha-1 frequency activity; they were decreased in the patients. Another two of these six connectivities concerned the inhibiting EEG delta frequency activity; they were increased in the patients. The principal orientation of the six aberrant cortical functional connectivities was sagittal; five of them involved both hemispheres. In sum, activity in the posterior brain areas of preprocessing functions and the anterior brain areas of evaluation and behavior control functions were compromised by either decreased coupled activation or increased coupled inhibition, common across schizophrenia subtypes in the three patient groups. These results of the analyzed three independent groups of schizophrenics support the concept of functional dissociation.
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Postoperative delirium is an independent risk factor for posttraumatic stress disorder in the elderly patient: A prospective observational study.
Eur J Anaesthesiol
PUBLISHED: 07-01-2014
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Posttraumatic stress disorder (PTSD) may appear after hospitalisation for surgery with general anaesthesia in elderly patients. Prevalence and risk factors in this setting are unknown. Postoperative delirium could be a risk factor.
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16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy.
Hum. Mol. Genet.
PUBLISHED: 06-16-2014
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Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65 046 European population controls (5/393 cases versus 32/65 046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.
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Functional polymorphism in the neuropeptide Y gene promoter (rs16147) is associated with serum leptin levels and waist-hip ratio in women.
Ann. Nutr. Metab.
PUBLISHED: 05-04-2013
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The neuropeptide-Y (NP-Y) gene is a strong candidate gene in the pathophysiology of obesity-linked behavior, and several single-nucleotide polymorphisms of NP-Y have already been linked to body weight and appetite. However, the results from current studies remain inconclusive. The aim of the present study was to test whether a certain functional genetic variant (SNP rs16147) in the NP-Y promoter gene is associated with serum leptin levels and body fat distribution.
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The precuneus and the insula in self-attributional processes.
Cogn Affect Behav Neurosci
PUBLISHED: 01-09-2013
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Attributions are constantly assigned in everyday life. A well-known phenomenon is the self-serving bias: that is, peoples tendency to attribute positive events to internal causes (themselves) and negative events to external causes (other persons/circumstances). Here, we investigated the neural correlates of the cognitive processes implicated in self-serving attributions using social situations that differed in their emotional saliences. We administered an attributional bias task during fMRI scanning in a large sample of healthy subjects (n = 71). Eighty sentences describing positive or negative social situations were presented, and subjects decided via buttonpress whether the situation had been caused by themselves or by the other person involved. Comparing positive with negative sentences revealed activations of the bilateral posterior cingulate cortex (PCC). Self-attribution correlated with activation of the posterior portion of the precuneus. However, self-attributed positive versus negative sentences showed activation of the anterior portion of the precuneus, and self-attributed negative versus positive sentences demonstrated activation of the bilateral insular cortex. All significant activations were reported with a statistical threshold of p ? .001, uncorrected. In addition, a comparison of our fMRI task with data from the Internal, Personal and Situational Attributions Questionnaire, Revised German Version, demonstrated convergent validity. Our findings suggest that the precuneus and the PCC are involved in the evaluation of social events with particular regional specificities: The PCC is activated during emotional evaluation, the posterior precuneus during attributional evaluation, and the anterior precuneus during self-serving processes. Furthermore, we assume that insula activation is a correlate of awareness of personal agency in negative situations.
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Lack of association of a functional catechol-O-methyltransferase gene polymorphism with risk of tobacco smoking: results from a multicenter case-control study.
Nicotine Tob. Res.
PUBLISHED: 01-03-2013
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The catechol-O-methyltransferase (COMT) modulates dopaminergic neurotransmission in the prefrontal cortex as well as in the mesolimbic reward system. Since the reward system mediates addictive behavior, the COMT gene is a strong candidate gene regarding the pathophysiology of tobacco dependence and smoking behavior. Because of rather conflicting results in previous studies, the purpose of the present study was to test for association between a functional genetic variant in the COMT gene (single nucleotide polymorphism [SNP] rs4680) and tobacco smoking behavior.
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Dopamine-related genes and spontaneous smoking cessation in ever-heavy smokers.
Pharmacogenomics
PUBLISHED: 08-01-2011
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Several studies have provided evidence for associations of polymorphisms located in and near dopamine-related genes and nicotine dependence and other smoking-related phenotypes, including pharmacogenetic interactions.
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Nicotinic acetylcholine receptor expression on B-lymphoblasts of healthy versus schizophrenic subjects stratified for smoking: [3H]-nicotine binding is decreased in schizophrenia and correlates with negative symptoms.
J Neural Transm
PUBLISHED: 07-11-2011
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Heavy smoking and schizophrenia are diversely associated with nicotinic acetylcholine receptor expression, as was shown for brain and lymphocytes. Most studies so far have not systematically differentiated between schizophrenia smokers and non-smokers and were confined either to in vivo or post-mortem study approaches. In order to avoid variable in vivo influences or post-mortem bias, we used stably transformed B-lymphoblast cultures derived from healthy and schizophrenia subjects stratified for smoking versus non-smoking in order to differentiate these clinical conditions with regard to nicotinic acetylcholine receptor expression and regulation. Receptor quantities were measured using [(3)H]-nicotine and [(3)H]-epibatidine binding. At baseline, [(3)H]-nicotine binding was not statistically different between healthy smokers and never-smokers (1.59 ± 0.73 vs. 1.26 ± 0.91 fmol/10(6) cells), while it was reduced in schizophrenia smokers compared to healthy smokers (1.05 ± 0.69 fmol vs. 1.44 ± 0.84/10(6) cells, P = 0.01). In schizophrenia, baseline [(3)H]-nicotine correlated inversely with higher PANSS negative subscale scores. After long-term nicotine incubation (1 ?M), [3H]-nicotine binding increased in the group of schizophrenia smokers only (from 1.05 ± 0.69 to 1.54 ± 0.77 fmol/106 cells, P = 0.013), while [(3)H]-epibatidine binding decreased in this group (4.52 ± 1.52 to 3.82 ± 1.38 fmol/10(6) cells, P = 0.038). Our data are in further support of a decrease of nicotinic acetylcholine receptor expression in schizophrenia linked to negative psychotic symptoms, which may be counter-regulated by nicotine exposure.
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Smoking, quitting, and psychiatric disease: a review.
Neurosci Biobehav Rev
PUBLISHED: 06-14-2011
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Tobacco smoking among patients with psychiatric disease is more common than in the general population, due to complex neurobiological, psychological, and pharmacotherapeutic mechanisms. Nicotine dependence exposes smokers with co-occurring mental illness to increased risks of smoking-related morbidity, mortality, and to detrimental impacts on their quality of life. The neurobiological and psychosocial links to smoking appear stronger in certain comorbidities, notably depression and schizophrenia. Through its action on the cholinergic system, nicotine may have certain beneficial effects across a range of mental health domains in these patients, including improved concentration and cognition, relief of stress and depressive affect, and feeling pleasurable sensations. Despite the availability of effective smoking cessation pharmacotherapies and psychosocial interventions, as well as increasing evidence that individuals with psychiatric disorders are motivated to quit, nicotine dependence remains an undertreated and under-recognized problem within this patient population. Evidence suggests that provision of flexible and individualized treatment programs may be successful. Furthermore, the complicated relationship observed between nicotine dependence, nicotine withdrawal symptoms, and mental illness necessitates integration of close monitoring in any successful smoking cessation program.
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Brain grey matter deficits in smokers: focus on the cerebellum.
Brain Struct Funct
PUBLISHED: 06-07-2011
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Structural cerebral deficiencies in smokers have been well characterized by morphometric investigations focussing on cortical and subcortical structures. Although the role of the cerebellum is increasingly noted in mental and addiction disorders, no reports exist regarding cerebellar alterations in smokers employing a methodology specifically designed to assess the cerebellar morphology. We acquired high-resolution MRI scans from 33 heavy smokers and 22 never-smokers and used a voxel-based morphometry (VBM) approach utilizing the Spatially Unbiased Infratentorial (SUIT) toolbox (Diedrichsen 2006) to provide an optimized and fine-grained exploration of cerebellar structural alterations associated with smoking. Relative to never-smokers, smokers showed significant reductions of grey matter volume in the right cerebellum Crus I. The grey matter volume in Crus I correlated negatively with the amount of nicotine dependence as assessed by means of the Fagerström scale. Since Crus I has been identified as the cognitive division of the cerebellum, the structural deficit may in part mediate cognitive deficits previously reported in smokers. Of note, the dependence-related magnitude of the volume deficit may support the notion that the cerebellum is substantially involved in core mechanisms of drug dependence.
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The German multi-centre study on smoking-related behavior-description of a population-based case-control study.
Addict Biol
PUBLISHED: 04-26-2011
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Tobacco smoking is a major risk factor for most of the diseases leading in mortality. Nicotine dependence (ND), which sustains regular smoking, is now acknowledged to be under substantial genetic control with some environmental contribution. At present, however, genetic studies on ND are mostly conducted in populations that have been poorly characterized with regard to ND-related phenotypes for the simple reason that the respective populations were not primarily collected to study ND. The German multi-centre study Genetics of Nicotine Dependence and Neurobiological Phenotypes, which is funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) as part of the Priority Program (Schwerpunktprogramm) SPP1226: Nicotine-Molecular and Physiological Effects in CNS, was intended to overcome some of these inherent problems of current genetic studies of ND. The multi-centre study is a population-based case-control study of smokers and never-smokers (n = 2396). The study was unique worldwide because it was the first large-scale genetic study specifically addressing ND with the collection of a wide range of environmental, psychosocial and neurobiological phenotypes. Study design and major population characteristics with emphasis on risk prediction of smoking status were presented in this paper.
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P50 sensory gating and smoking in the general population.
Addict Biol
PUBLISHED: 03-11-2011
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P50 gating is a major functional biomarker in research on schizophrenia and other psychiatric conditions with high smoking prevalence. It is used as endophenotype for studying nicotinic systems genetics and as surrogate endpoint measure for drug development of nicotinic agonists. Surprisingly, little is known about P50 gating in the general population and the relationship to smoking-related characteristics. In this multicenter study at six academic institutions throughout Germany, n=907 never-smokers (NS<20 cigarettes/lifetime), n=463 light smokers (LS) with Fagerström Test for Nicotine Dependence (FTND)?4 and n=353 heavy smokers (HS, FTND<4) were randomly selected from the general population. As part of a standardized protocol for investigating the genetics of nicotine dependence (ND), an auditory P50 paradigm was applied. The main outcome measure was P50-amplitude difference followed by time-frequency analyses and functional imaging (sLORETA). Reduced P50 gating was found in HS compared to NS with LS taking an intermediate position-correlating with the degree of ND. sLORETA and time-frequency analyses indicate that high-frequency oscillations in frontal brain regions are particularly affected. With growing age, P50 gating increased in (heavy) smokers. This is the first large-scale study (normative sample data) on P50 sensory gating and smoking in the general population. Diminished gating of P50 and associated high-frequency oscillations in the frontal brain region are indications of a deficient inhibitory cortical function in nicotine-dependent smokers. The suitability and application of sensory P50 gating as functional biomarker with regard to genetic and pharmacological studies is discussed.
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Attention shift towards smoking cues relates to severity of dependence, smoking behavior and breath carbon monoxide.
Eur Addict Res
PUBLISHED: 03-08-2011
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The aim of this study was to assess the severity of dependence as a factor affecting the attentional bias of smokers towards smoking-related stimuli and to clarify contradictory results of previous studies. A visual dot probe task was administered to 51 smokers and 41 nonsmokers to assess the attentional bias. Smokers were classified into a group of less severely dependent and a group of more severely dependent smokers according to the Fagerström Test for Nicotine Dependence, the number of cigarettes smoked per day or the CO concentration in the expired air. Nicotine craving was assessed as well. The more severely dependent smokers displayed an attentional bias towards smoking-related stimuli, while smokers with less severe nicotine dependence showed a negative attentional bias which was also observed in nonsmokers. A multiple linear regression indicated that CO concentration was the only significant predictor of attentional bias. In the total group of smokers we found a positive association between attentional bias and craving for the rewarding effects of nicotine. Future studies are warranted to further enhance our understanding of factors that affect attentional bias as appetitive responses towards smoking-related stimuli might be an important target for therapeutic interventions.
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Spatial and sustained attention in relation to smoking status: behavioural performance and brain activation patterns.
J. Psychopharmacol. (Oxford)
PUBLISHED: 02-07-2011
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Nicotine enhances attentional functions. Since chronic nicotine exposure through smoking induces neuroadaptive changes in the brain at a structural and molecular level, the present functional MRI (fMRI) study aimed at investigating the neural mechanisms underlying visuospatial and sustained attention in smokers and non-smokers. Visuospatial attention was assessed with a location-cueing paradigm, while sustained attention was measured by changes in response speed over time. During invalid trials, neural activity within the basal forebrain was selectively enhanced in smokers and higher basal forebrain activity was associated with increased parietal cortex activation. Moreover, higher levels of expired carbon monoxide in smokers before scanning were associated with higher parietal cortex activation and faster responses to invalidly cued targets. Smokers showed a slowing of responses and additionally recruited an area within the right supramarginal gyrus with increasing time on task. Activity decreases over time were observed in visual areas in smokers. The data provide evidence for altered attentional functions in smokers as compared with non-smokers, which were partly modulated by residual nicotine levels and were observed at a behavioural level for sustained and at a neural level for spatial and sustained attention.
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Ketamine effects on brain function--simultaneous fMRI/EEG during a visual oddball task.
Neuroimage
PUBLISHED: 01-31-2011
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Behavioral and electrophysiological human ketamine models of schizophrenia are used for testing compounds that target the glutamatergic system. However, corresponding functional neuroimaging models are difficult to reconcile with functional imaging and electrophysiological findings in schizophrenia. Resolving the discrepancies between different observational levels is critical to understand the complex pharmacological ketamine action and its usefulness for modeling schizophrenia pathophysiology.
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Direction and magnitude of nicotine effects on the fMRI BOLD response are related to nicotine effects on behavioral performance.
Psychopharmacology (Berl.)
PUBLISHED: 01-18-2011
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Considerable variability across individuals has been reported in both the behavioral and fMRI blood oxygen level-dependent (BOLD) response to nicotine. We aimed to investigate (1) whether there is a heterogeneous effect of nicotine on behavioral and BOLD responses across participants and (2) if heterogeneous BOLD responses are associated with behavioral performance measures. In this double-blind, placebo-controlled, cross-over study, 41 healthy participants (19 smokers)--drawn from a larger population-based sample--performed a visual oddball task after acute challenge with 1 mg nasal nicotine. fMRI data and reaction time were recorded during performance of the task. Across the entire group of subjects, we found increased activation in the anterior cingulate cortex, middle frontal gyrus, superior temporal gyrus, post-central gyrus, planum temporal and frontal pole in the nicotine condition compared with the placebo condition. However, follow-up analyses of this difference in activation between the placebo and nicotine conditions revealed that some participants showed an increase in activation while others showed a decrease in BOLD activation from the placebo to the nicotine condition. A reduction of BOLD activation from placebo to nicotine was associated with a decrease in reaction time and reaction time variability and vice versa, suggesting that it is the direction of BOLD response to nicotine which is related to task performance. We conclude that the BOLD response to nicotine is heterogeneous and that the direction of response to nicotine should be taken into account in future pharmaco-fMRI research on the central action of nicotine.
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The effect of pictorial warnings on cigarette packages on attentional bias of smokers.
Pharmacol. Biochem. Behav.
PUBLISHED: 01-13-2011
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Given that previous studies demonstrated that smoking-related cues (like cigarette packages) grab the attention of smokers and thereby contribute to craving and tobacco seeking we investigated how pictorial health warnings presented on cigarette packages affect attention allocation towards cigarette packages. The WHO advises the use of pictorial health warnings on cigarette packages. However, at present no experimental studies are available investigating if pictorial warnings modulate incentive properties of cigarette packages. Fifty-nine tobacco smokers and 55 non-smokers performed a visual dot probe task to assess attention allocation towards cigarette packages with and without health warnings. Smokers were divided a priori in a group of light smokers (<20 cigarettes/day; n=39) and heavy smokers (?20 cigarettes/day; n=20). Psychometric measures on anxiety and nicotine craving were administered. Light smokers showed an attentional bias towards packages without pictorial warnings while no effects were observed in the other groups. In heavy smokers attention allocation towards pictorial health warnings was associated with an increase of craving and anxiety. The results have a potential public health perspective as pictorial health warnings might be an effective strategy to reduce attentional bias towards cigarette packages of light smokers, while counterproductive effects in heavy smokers warrant further investigation.
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NACP-Rep1 relates to Beck Depression Inventory scores in healthy humans.
J. Mol. Neurosci.
PUBLISHED: 01-11-2011
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Alpha-synuclein (SNCA) is associated with a range of psychiatric diseases including neurodegeneration, alcohol craving, and depression. It regulates cellular homeostasis by virtue of its ability to interfere in dopaminergic, serotonergic, and noradrenergic pathways. To date, it is unclear whether the previously described association between SNCA and depressive symptomatology is limited to females with eating disorders or whether it could be extended to include healthy individuals. We included 105 women and 108 men. Genetic data and mRNA expression analyses were drawn from peripheral blood and the severity of depressive symptoms was quantified by the Becks Depression Inventory (BDI). We found a significant association between the NACP-Rep1 length polymorphism and the BDI score (p?=?0.004). Moreover, there was a significant gender dimorphism regarding mRNA expression of SNCA (p?=?0.011). Our analysis revealed no further association between the In4 polymorphism or between the mRNA expression of SNCA and the BDI score. Since this investigation was limited to healthy individuals, conclusions concerning depression according to ICD-10 or DSM-IV cannot be drawn. The reported results may contribute to a better understanding of the molecular mechanisms linked to depressive symptoms.
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Psychological and hormonal features of smokers at risk to gain weight after smoking cessation--results of a multicenter study.
Horm Behav
PUBLISHED: 01-10-2011
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Preclinical and clinical data suggest modulating effects of appetite-regulating hormones and stress perception on food intake. Nicotine intake also interferes with regulation of body weight. Especially following smoking cessation gaining weight is a common but only partially understood consequence. The aim of this study was to examine the interaction between smoking habits, the appetite regulating hormone leptin, negative affectivity, and stress vulnerability on eating behavior in a clinical case-control study under standardized conditions. In a large population-based study sample, we compared leptin and cortisol plasma concentrations (radioimmunoassay) between current tobacco smokers with high cognitive restraint and disinhibition in eating behavior and smokers scoring low in both categories as assessed with the Three Factor Eating Questionnaire (TFEQ; Stunkard & Messick, 1985). As a measure for smoking effects on the stress axis, the saliva cortisol concentrations were compared before and after nicotine smoking. Additionally, stress perception was assessed with the Perceived Stress Scale (PSS), symptoms of depression and anxiety with the Beck Depression Inventory (BDI) and the State Trait Anxiety Inventory (STAI). In smokers showing high cognitive restraint and disinhibition we found significantly higher leptin concentrations than in the group of smokers scoring low in both categories. Furthermore there was a significant group difference in saliva cortisol concentrations after nicotine intake. Smokers showing high cognitive restraint and disinhibition were also characterized by significantly higher scores in the STAI, the PSS and the BDI. Our results suggest that smokers with a pathological eating behavior show an impaired neuroendocrine regulation of appetite and are prone to experience higher levels of stress and negative affectivity. This interaction of behavioral and neuroendocrinological factors may constitute a high risk condition for gaining weight following smoking cessation.
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White matter abnormalities and their impact on attentional performance in adult attention-deficit/hyperactivity disorder.
Eur Arch Psychiatry Clin Neurosci
PUBLISHED: 01-03-2011
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Inattention is the most important behavioral feature of adult patients with attention-deficit/hyperactivity disorder (ADHD). Neuroimaging studies in ADHD have demonstrated abnormalities primarily in the frontostriatal circuitry and were mostly conducted in children. We investigated white matter (WM) integrity in adult ADHD patients and the correlation of WM microstructure and neuropsychological parameters in 37 (21 men) never-medicated adult ADHD patients and 34 age- and gender-matched healthy controls. All subjects underwent clinical interviews, rating scales, and neuropsychological tests of attentional performance. Diffusion tensor imaging (DTI) was acquired, and 12 WM regions-of-interest (ROIs) within the attentional network were chosen. Group differences of mean fractional anisotropy (FA) and mean diffusivity (MD) values were calculated for each ROI, and patients DTI measures were then correlated with measures of attentional performance. FA values in ADHD patients were significantly reduced in the left inferior longitudinal fasciculus (ILF), while MD values were significantly increased in ADHD patients in the frontal portion of the left frontooccipital fasciculus (IFO). In ADHD patients, MD values were negatively correlated with attentional performance in the left ILF. Our findings provide further support for disturbed frontostriatal structural connectivity and also point to an involvement of the left temporal white matter with an impact on attentional performance.
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ERK1/2 protein and mRNA levels in human blood are linked to smoking behavior.
Addict Biol
PUBLISHED: 11-11-2010
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From studies in cultured cells and animal models, nicotine and alcohol are known to regulate extracellular signal-regulated kinase 1 and 2 (ERK1/2). Alterations of ERK1/2 are thought to contribute to the drugs rewarding effects. Accumulating evidence supports the importance of ERK1/2 in the molecular pathophysiology of depression and affective regulation in the hippocampus. We recently showed that the expression and phosphorylation of cyclic adenosine monophosphate response element (CRE)-binding protein (CREB) in human buffy coat were associated with smoking behavior. Because ERK1/2 is known to effect phosphorylation of CREB, the aim of the present study was to further elucidate whether cigarette smoking leads to alterations in terms of ERK1/2 in human buffy coat as well. In a comparison of 53 smokers with 146 non-smoking controls, we found significantly higher levels of ERK1/2 protein (P=0.004). In contrast, phospho-ERK1/2, phospho-/total-ERK1/2 ratio, mRNA-ERK1 and mRNA-ERK2 were not significantly different. Multiple regression analysis revealed a significant relation among the number of cigarettes smoked daily (R(2)=0.266, P=0.003), the Fagerström Test for Nicotine Dependence score (R(2)=0.149, P=0.032) and the mRNA expression of ERK1. Moreover, our analysis suggests that the mRNA expression of ERK2 might be linked to mood (model summary: R(2)=0.087, P=0.019; mRNA-ERK2: P=0.026). Given that the ERK1/2 signaling pathway plays an important role in the physiology and pathophysiology of affective and addictive behavior, our findings provide a rationale basis for additional mechanistic studies that may lead to the development of novel signaling pathway selective therapeutics in humans.
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COMT Val108/158Met genotype modulates human sensory gating.
Neuroimage
PUBLISHED: 08-07-2010
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The catechol-O-methyltransferase (COMT) Val(108/158)Met polymorphism of the dopamine system is essential for prefrontal cortex processing capacity and efficiency. In addition, dopaminergic neurotransmission is also associated with the sensory gating phenomenon protecting the cerebral cortex from information overload. It is however unclear if COMT genotype as a predictor of prefrontal efficiency modulates sensory gating on the level of the auditory cortex, i.e. the gating of the auditory evoked P50 and N100 components.
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Haplotypes of dopamine and serotonin transporter genes are associated with antisocial personality disorder in alcoholics.
Psychiatr. Genet.
PUBLISHED: 05-28-2010
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A different genetic background is postulated for alcoholics with early onset and with antisocial personality disorder (type 2 alcoholics) compared with those with late onset and without antisocial personality disorder (type 1 alcoholics). The dopamine transporter (DAT) and the serotonin transporter (SERT) are involved in endophenotypes that are associated with these subtypes. Our study was aimed at investigating whether distinct haplotypes, defined by polymorphisms associated with the expressions of DAT and SERT, were associated with subgroups of alcohol dependence.
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Risk gene variants for nicotine dependence in the CHRNA5-CHRNA3-CHRNB4 cluster are associated with cognitive performance.
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 04-12-2010
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Recent studies strongly support an association of the nicotinic acetylcholine receptor gene cluster CHRNA5-CHRNA3-CHRNB4 with nicotine dependence (ND). However, the precise genotype-phenotype relationship is still unknown. Clinical and epidemiological data on smoking behavior raise the possibility that the relevant gene variants may indirectly contribute to the development of ND by affecting cognitive performance in some smokers who consume nicotine for reasons of "cognition enhancement." Here, we tested seven single nucleotide polymorphisms (SNPs) rs684513, rs637137, rs16969968, rs578776, rs1051730, rs3743078, rs3813567 from the CHRNA5-CHRNA3-CHRNB4 gene cluster for association with ND, measures of cognitive performance and gene expression. As expected, we found all SNPs being associated with ND in three independent cohorts (KORA, NCOOP, ESTHER) comprising 5,561 individuals. In an overlapping sample of 2,186 subjects we found three SNPs (rs16969968, rs1051730, rs3743078) being associated with cognitive domains from the Wechsler-Adult-Intelligence Scale (WAIS-R)-most notably in the performance subtest "object assembly" and the verbal subtest "similarities." In a refined analysis of a subsample of 485 subjects, two of these three SNPs (rs16969968, rs1051730) were associated with n-back task performance/Continuous Performance Test. Furthermore, two CHRNA5 risk alleles (rs684513, rs637137) were associated with CHRNA5 mRNA expression levels in whole blood in a subgroup of 190 subjects. We here report for the first time an association of CHRNA5-CHRNA3-CHRNB4 gene variants with cognition possibly mediating in part risk for developing ND. The observed phenotype-genotype associations may depend on altered levels of gene expression. © 2010 Wiley-Liss, Inc.
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Disturbed structural connectivity is related to inattention and impulsivity in adult attention deficit hyperactivity disorder.
Eur. J. Neurosci.
PUBLISHED: 04-09-2010
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Inattention and impulsivity are the most prominent clinical features of attention deficit hyperactivity disorder (ADHD) in adulthood. Structural and functional neuroimaging studies of subjects with ADHD have demonstrated abnormalities in several brain areas, including fronto-striatal and fronto-cerebellar networks. Mostly, these studies were based on volumetric measurements and have been conducted in children. We investigated white matter (WM) integrity and correlation with measures of attention and impulsivity in adult patients with ADHD adopting diffusion tensor imaging (DTI). N = 37 (21 males) never-medicated adult patients with ADHD combined subtype and N = 34 (16 males) healthy controls were investigated. ADHD diagnosis (DSM-IV) was assessed with clinical interviews and rating scales, subjects also underwent a large neuropsychological test battery including tests of attention and impulsivity. DTI was acquired, and group differences of fractional anisotropy (FA) and mean diffusivity (MD) as well as correlation analyses with measures of attentional performance and impulsivity were calculated using voxel-based analyses. In adult patients with ADHD, we found reduced FA as well as higher MD bilaterally in orbitomedial prefrontal WM and in the right anterior cingulate bundle, while elevated FA was present bilaterally in temporal WM structures. Measures of attention were correlated with DTI parameters in the right superior longitudinal fasciculus, whereas measures of impulsivity were correlated with FA in right orbitofrontal fibre tracts. This is the first DTI study demonstrating disturbed structural connectivity of the frontal-striatal circuitry in adult patients with ADHD. Moreover, a direct correlation between WM integrity and measures of attention and impulsivity is shown.
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Effects of 10 Hz repetitive transcranial magnetic stimulation (rTMS) on clinical global impression in chronic schizophrenia.
Psychiatry Res
PUBLISHED: 04-08-2010
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We conducted a randomized, sham-controlled repetitive transcranial magnetic stimulation (rTMS) study in chronic schizophrenia in-patients (n=35) to evaluate the therapeutic efficacy of 10 Hz stimulation. Patients, who were on stable antipsychotic treatment, were randomly assigned to the active or sham condition. In the active rTMS group, ten sessions with a total of 10,000 stimuli were applied over the left dorsolateral prefrontal cortex at 110% of motor threshold. The sham group received corresponding sham stimulation. Clinical improvement was measured by the Clinical Global Impression scale (primary outcome measure), the Global Assessment of Functioning Scale (GAF) and the Positive and Negative Symptom Scale (PANSS; secondary outcome measures). Between-group comparisons revealed no significant differences in clinical outcome variables. Only a subgroup of patients with pronounced negative symptoms developed some clinical improvement as indicated by significant changes in the GAF-scale. Besides there is some evidence for a more favourable clinical outcome within this subgroup after rTMS in the CGI-S and PANSS negative scale, too. In line with earlier investigations, our results suggest a moderate - potentially clinically relevant - treatment effect of prefrontal 10 Hz rTMS stimulation in chronic patients. However, in our study this beneficial effect was restricted to subjects with pronounced negative symptoms.
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Dynamic EEG-informed fMRI modeling of the pain matrix using 20-ms root mean square segments.
Hum Brain Mapp
PUBLISHED: 02-18-2010
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Previous studies on the spatio-temporal dynamics of cortical pain processing using electroencephalography (EEG), magnetoencephalography (MEG), or intracranial recordings point towards a high degree of parallelism, e.g. parallel instead of sequential activation of primary and secondary somatosensory areas or simultaneous activation of somatosensory areas and the mid-cingulate cortex. However, because of the inverse problem, EEG and MEG provide only limited spatial resolution and certainty about the generators of cortical pain-induced electromagnetic activity, especially when multiple sources are simultaneously active. On the other hand, intracranial recordings are invasive and do not provide whole-brain coverage. In this study, we thought to investigate the spatio-temporal dynamics of cortical pain processing in 10 healthy subjects using simultaneous EEG/functional magnetic resonance imaging (fMRI). Voltages of 20 ms segments of the EEG root mean square (a global, largely reference-free measure of event-related EEG activity) in a time window 0-400 ms poststimulus were used to model trial-to-trial fluctuations in the fMRI blood oxygen level dependent (BOLD) signal. EEG-derived regressors explained additional variance in the BOLD signal from 140 ms poststimulus onward. According to this analysis, the contralateral parietal operculum was the first cortical area to become activated upon painful laser stimulation. The activation pattern in BOLD analyses informed by subsequent EEG-time windows suggests largely parallel signal processing in the bilateral operculo-insular and mid-cingulate cortices. In that regard, our data are in line with previous reports. However, the approach presented here is noninvasive and bypasses the inverse problem using only temporal information from the EEG.
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The val158met polymorphism of human catechol-O-methyltransferase (COMT) affects anterior cingulate cortex activation in response to painful laser stimulation.
Mol Pain
PUBLISHED: 02-03-2010
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Pain is a complex experience with sensory, emotional and cognitive aspects. Genetic and environmental factors contribute to pain-related phenotypes such as chronic pain states. Genetic variations in the gene coding for catechol-O-methyltransferase (COMT) have been suggested to affect clinical and experimental pain-related phenotypes including regional mu-opioid system responses to painful stimulation as measured by ligand-PET (positron emission tomography). The functional val158met single nucleotide polymorphism has been most widely studied. However, apart from its impact on pain-induced opioid release the effect of this genetic variation on cerebral pain processing has not been studied with activation measures such as functional magnetic resonance imaging (fMRI), PET or electroencephalography. In the present fMRI study we therefore sought to investigate the impact of the COMT val158met polymorphism on the blood oxygen level-dependent (BOLD) response to painful laser stimulation.
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Why do patients with schizophrenia smoke?
Curr Opin Psychiatry
PUBLISHED: 01-07-2010
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Among the mentally ill, smoking prevalence is highest in patients with schizophrenia ( approximately 70-80%). This can impose a significant financial burden on patients, not to speak of increased smoking-related morbidity and mortality. Therefore, it is critical for clinicians to understand why patients with schizophrenia smoke in order to adapt treatment schemes. Understanding the reasons may also help to develop new drugs that target the nicotinic system in the brain as well as smoking cessation programs that are specifically designed for this particular patient population.
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Smoking behaviour is associated with expression and phosphorylation of CREB in human buffy coat.
Int. J. Neuropsychopharmacol.
PUBLISHED: 01-05-2010
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Nicotine induces various acute und chronic pharmacological effects which can be long lasting and might lead to nicotine dependence. Nicotinic acetylcholine receptors (nAChRs) are involved in nicotine-induced phosphorylation of CREB (cyclic AMP response element-binding protein) in PC12h cells. Several studies, mainly done in animal models, report that CREB plays a role in anxiety, memory and substance abuse as well as in affective disorders. Information regarding nicotine effects on gene expression in humans in vivo is rare. The aim of our study was to determine whether or not there are differences between smokers and non-smoking controls in terms of CREB expression and phosphorylation in human buffy coat. Comparing 32 smokers with 76 non-smoking controls we found significantly elevated relative (p=0.043) and absolute (p=0.040) CREB phosphorylation in the blood of smokers who had smoked two cigarettes in the past 6 h. In contrast, the score of the State and Trait Anxiety Inventory, total-CREB and mRNA-CREB were not significantly different. Multiple regression analysis revealed a significant relation between the number of cigarettes smoked daily (R2=0.143, p=0.023), the Fagerström Test for Nicotine Dependence score (R2=0.145, p=0.022) and the expression of CREB. Moreover, in accord with previously published data our analysis suggests gender and age as factors that significantly influence expression and phosphorylation of CREB. It appears that human buffy coat is suitable for studying pharmacological effects of substances such as nicotine on selected signal transduction pathways in humans in vivo. This kind of study may be helpful for translating findings from animal models and cell cultures.
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Association of the dopamine D2 receptor gene with alcohol dependence: haplotypes and subgroups of alcoholics as key factors for understanding receptor function.
Pharmacogenet. Genomics
PUBLISHED: 07-16-2009
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The dopamine D2 receptor (DRD2) plays an important role in the reinforcing and motivating effects of ethanol. Several polymorphisms have been reported to affect receptor expression. The amount of DRD2, expressed in a given individual, is the result of the expression of both alleles, each representing a distinct haplotype. We examined the hypothesis that haplotypes composed of polymorphisms, associated with reduced receptor expression, are more frequent in alcoholics compared with healthy individuals.
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Variants in COMT and spontaneous smoking cessation: retrospective cohort analysis of 925 cessation events.
Pharmacogenet. Genomics
PUBLISHED: 07-09-2009
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Genome-wide studies have identified single nucleotide polymorphisms associated with smoking behaviour and nicotine dependence. Less is known about genetic determinants of smoking cessation, but rs4680 in COMT has recently been shown to explain a substantial proportion of the variation in cessation in the general population. We attempted to replicate the reported, clinically relevant effect in a population-based retrospective cohort analysis of 1443 ever-heavy smokers, of whom 925 had reached abstinence. In Cox regression models, neither rs4680 nor two polymorphisms nearby were associated with smoking cessation. The adjusted relative cessation rate (95% confidence interval) in rs4680 methionine carriers in reference to valine homozygotes was 0.97 (0.83-1.12). The absence of a significant effect of rs4680 in this statistically well-powered study - the 95% confidence interval even excluding the previously reported effect - highlights the need for rigorous replication efforts and suggests that rs4680 genotype should not yet be considered informative for smoking patient care.
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Correlation of brain white matter diffusion anisotropy and mean diffusivity with reaction time in an oddball task.
Neuropsychobiology
PUBLISHED: 05-20-2009
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Reaction time (RT) is a frequently used measure of information processing speed, but the underlying physiological and anatomical conditions are not yet fully understood. A correlation between measures of white matter (WM) ultrastructural properties and RT is expected--particularly for those WM tracts that are involved in the attentional system of the brain.
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Smoking cessation and variations in nicotinic acetylcholine receptor subunits alpha-5, alpha-3, and beta-4 genes.
Biol. Psychiatry
PUBLISHED: 05-20-2009
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Evidence has recently accumulated that single nucleotide polymorphisms in the genetic region encoding the nicotinic acetylcholine receptor subunits alpha-5, alpha-3, and beta-4 are associated with smoking and nicotine dependence. We aimed to determine whether these genetic variations are also predictive of smoking cessation.
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Orexin and leptin are associated with nicotine craving: a link between smoking, appetite and reward.
Psychoneuroendocrinology
PUBLISHED: 05-06-2009
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Preclinical data suggest modulating effects of both orexin/hypocretin and leptin on dopaminergic transmission in mesolimbic reward pathways. This indicates a possible role of both peptides in reward function and motivation, and thus in addictive diseases. The aim of this study was to examine the possible association between orexin and leptin, and nicotine craving in smokers in a clinical case-control study under standardized conditions.
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ErbB4 genotype predicts left frontotemporal structural connectivity in human brain.
Neuropsychopharmacology
PUBLISHED: 03-31-2009
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Diminished left frontotemporal connectivity is among the most frequently reported findings in schizophrenia and there is evidence that altered neuronal myelination may in part account for this deficit. Several investigations have suggested that variations of the genes that encode the Neuregulin 1 (NRG1)-ErbB4 receptor complex are associated with schizophrenia illness. As NRG1--ErbB4 has been implicated in neuronal myelination, we investigated with diffusion tensor imaging (DTI) whether fractional anisotropy (FA)--a putative measure of neuronal myelination--is predicted by a risk haplotype of the ErbB4 gene. The effects of the ErbB4 genotype were investigated in healthy subjects (N=59; mean age: 22.6+/-1.8 years). We also measured reaction time (RT) during a selective attention/working memory paradigm (visual oddball). In the schizophrenia risk genotype group, we found lower FA in the temporal lobe white matter (WM) including frontotemporal fiber tracts, predominantly in the left hemisphere. RT was increased in the risk genotype group and correlated with FA in the affected brain region. As FA is considered to index structural integrity of WM, to which neuronal fiber myelination is contributing, our results suggest that variations of the ErbB4 genotype may confer risk for schizophrenia illness via its impact on left frontotemporal connectivity in human brain. Reliability and validity of the result is suggested by our observation that (1) the FA-genotype association was not only obtained in the entire sample but also in both the split halves and (2) a statistical relationship was found among RT, genotype and FA.
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Epoch versus impulse models in the analysis of parametric fMRI studies.
Clin Neurophysiol
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In parametric fMRI studies the relationship between the amplitude of the hemodynamic response and electrophysiological or behavioral parameters is commonly analyzed using the general linear model (GLM). We examined ways of using single-trial response time (RT) in the analysis of a decision-making task to better isolate task-specific activation.
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Nicotine effects on anterior cingulate cortex in schizophrenia and healthy smokers as revealed by EEG-informed fMRI.
Psychiatry Res
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Nicotine can have beneficial effects on attention performance and corresponding brain function in both schizophrenia patients and healthy controls, but it remains controversial whether nicotine affects brain function differentially in patients vs. controls. The effects of nicotine on brain activity elicited by attention-requiring oddball-type tasks have not been studied in schizophrenia patients. In this study we sought to investigate the impact of nicotine on the p300 evoked potential component and corresponding fMRI (functional magnetic resonance imaging) activation measures in schizophrenia patients and controls. Applying a double-blind, placebo-controlled cross-over design, the effects of 1mg nasal nicotine on brain activity elicited by a visual oddball-type task in N=14 schizophrenia and N=15 control smokers were studied with simultaneous EEG-fMRI. EEG single trial amplitudes were used to inform the fMRI analysis. We found a nicotine-associated increase in P300-informed fMRI activation in schizophrenia patients and controls, mainly in the anterior cingulate and adjacent medial frontal cortex. No group differences in the response to nicotine were found. Remarkably, averaged EEG and fMRI activation measures considered in isolation were largely unaffected by nicotine. Taken together, the effects of nicotine on P300 amplitude-associated brain activation do not seem to be fundamentally different in schizophrenic smokers and healthy controls.
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Effects of nicotine on social cognition, social competence and self-reported stress in schizophrenia patients and healthy controls.
Eur Arch Psychiatry Clin Neurosci
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More than 80 % of patients diagnosed with schizophrenia are nicotine-dependent. Self-medication of cognitive deficits and an increased vulnerability to stress are discussed as promoting factors for the development of nicotine dependence. However, the effects of nicotine on social cognition and subjective stress responses in schizophrenia are largely unexplored. A 2 × 2-factorial design (drug × group) was used to investigate the effects of nicotine versus placebo in smoking schizophrenia patients and healthy controls after 24 h of abstinence from smoking. Participants performed a facial affect recognition task and a semi-standardized role-play task, after which social competence and self-reported stress during social interaction were assessed. Data analysis revealed no significant group differences in the facial affect recognition task. During social interaction, healthy controls showed more non-verbal expressions and a lower subjective stress level than schizophrenia patients. There were no significant effects of nicotine in terms of an enhanced recognition of facial affect, more expressive behaviour or reduced subjective stress during social interaction. While schizophrenia patients unexpectedly recognized facial affect not significantly worse than healthy controls, the observed group differences in subjective stress and non-verbal expression during social interaction in the role-play situation are in line with previous findings. Contrary to expectations derived from the self-medication hypothesis, nicotine showed no significant effects on the dependent variables, perhaps because of the dosage used and the delay between the administration of nicotine and the performance of the role-play.
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Impaired sleep quality and sleep duration in smokers-results from the German Multicenter Study on Nicotine Dependence.
Addict Biol
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Cigarette smoking is a severe health burden being related to a number of chronic diseases. Frequently, smokers report about sleep problems. Sleep disturbance, in turn, has been demonstrated to be involved in the pathophysiology of several disorders related to smoking and may be relevant for the pathophysiology of nicotine dependence. Therefore, determining the frequency of sleep disturbance in otherwise healthy smokers and its association with degree of nicotine dependence is highly relevant. In a population-based case-control study, 1071 smokers and 1243 non-smokers without lifetime Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I disorder were investigated. Sleep quality (SQ) of participants was determined by the Pittsburgh Sleep Quality Index. As possible confounders, age, sex and level of education and income, as well as depressiveness, anxiety, attention deficit hyperactivity, alcohol drinking behaviour and perceived stress, were included into multiple regression analyses. Significantly more smokers than non-smokers (28.1% versus 19.1%; P?
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An investigation of a genomewide supported psychosis variant in ZNF804A and white matter integrity in the human brain.
Magn Reson Imaging
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ZNF804A, a genomewide supported susceptibility gene for schizophrenia and bipolar disorder, has been associated with task-independent functional connectivity between the left and right dorsolateral prefrontal cortices. Several lines of evidence have converged on the hypothesis that this effect may be mediated by structural connectivity. We tested this hypothesis using diffusion tensor magnetic resonance imaging in three samples: one German sample of 50 healthy individuals, one Scottish sample of 83 healthy individuals and one Scottish sample of 84 unaffected relatives of bipolar patients. Voxel-based analysis and tract-based spatial statistics did not detect any fractional anisotropy (FA) differences between minor allele carriers and individuals homozygous for the major allele at rs1344706. Similarly, region-of-interest analyses and quantitative tractography of the genu of the corpus callosum revealed no significant FA differences between the genotype groups. Examination of effect sizes and confidence intervals indicated that this negative finding is very unlikely to be due to a lack of statistical power. In summary, despite using various analysis techniques in three different samples, our results were strikingly and consistently negative. These data therefore suggest that it is unlikely that the effects of genetic variation at rs1344706 on functional connectivity are mediated by structural integrity differences in large, long-range white matter fiber connections.
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Allosteric alpha-7 nicotinic receptor modulation and P50 sensory gating in schizophrenia: a proof-of-mechanism study.
Neuropharmacology
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In this multicenter, double-blind, placebo-controlled, randomized, four way cross-over proof-of-mechanism study, we tested the effect of the positive allosteric ?7 nicotinic acetylcholine receptor (nAChR) modulator JNJ-39393406 in a key translational assay (sensory P50 gating) in 39 regularly smoking male patients with schizophrenia. All patients were clinically stable and JNJ-39393406 was administered as an adjunct treatment to antipsychotics. No indication was found that JNJ-39393406 has the potential to reverse basic deficits of information processing in schizophrenia (sensory P50 gating) or has a significant effect on other tested electrophysiological markers (MMN, P300 and quantitative resting EEG). Sensitivity analyses including severity of disease, baseline P50 gating, medication and gene variants of the CHRNA7 gene did not reveal any subgroups with consistent significant effects. It is discussed that potential positive effects in subgroups not present or not large enough in the current study or upon chronic dosing are possible, but unlikely to be developed. This article is part of a Special Issue entitled Cognitive Enhancers.
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Genetic variation in the neuropeptide Y gene promoter is associated with increased risk of tobacco smoking.
Eur Addict Res
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Neuropeptide Y (NPY) is a strong candidate gene regarding the pathophysiology of tobacco dependence. It has been associated with various addictive and psychiatric disorders, and closely interacts with the brain reward system. The aim of the present study was to test for association between a functional genetic variant in the NP-Y promoter gene (SNP rs16147) and tobacco smoking.
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Nicotine effects on brain function during a visual oddball task: a comparison between conventional and EEG-informed fMRI analysis.
J Cogn Neurosci
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In a previous oddball task study, it was shown that the inclusion of electrophysiology (EEG), that is, single-trial P3 ERP parameters, in the analysis of fMRI responses can detect activation that is not apparent with conventional fMRI data modeling strategies [Warbrick, T., Mobascher, A., Brinkmeyer, J., Musso, F., Richter, N., Stoecker, T., et al. Single-trial P3 amplitude and latency informed event-related fMRI models yield different BOLD response patterns to a target detection task. Neuroimage, 47, 1532-1544, 2009]. Given that P3 is modulated by nicotine, including P3 parameters in the fMRI analysis might provide additional information about nicotine effects on brain function. A 1-mg nasal nicotine spray (0.5 mg each nostril) or placebo (pepper) spray was administered in a double-blind, placebo-controlled, within-subject, randomized, cross-over design. Simultaneous EEG-fMRI and behavioral data were recorded from 19 current smokers in response to an oddball-type visual choice RT task. Conventional general linear model analysis and single-trial P3 amplitude informed general linear model analysis of the fMRI data were performed. Comparing the nicotine with the placebo condition, reduced RTs in the nicotine condition were related to decreased BOLD responses in the conventional analysis encompassing the superior parietal lobule, the precuneus, and the lateral occipital cortex. On the other hand, reduced RTs were related to increased BOLD responses in the precentral and postcentral gyri, and ACC in the EEG-informed fMRI analysis. Our results show how integrated analyses of simultaneous EEG-fMRI data can be used to detect nicotine effects that would not have been revealed through conventional analysis of either measure in isolation. This emphasizes the significance of applying multimodal imaging methods to pharmacoimaging.
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Schizophrenia risk polymorphisms in the TCF4 gene interact with smoking in the modulation of auditory sensory gating.
Proc. Natl. Acad. Sci. U.S.A.
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Several polymorphisms of the transcription factor 4 (TCF4) have been shown to increase the risk for schizophrenia, particularly TCF4 rs9960767. This polymorphism is associated with impaired sensorimotor gating measured by prepulse inhibition--an established endophenotype of schizophrenia. We therefore investigated whether TCF4 polymorphisms also affect another proposed endophenotype of schizophrenia, namely sensory gating assessed by P50 suppression of the auditory evoked potential. Although sensorimotor gating and sensory gating are not identical, recent data suggest that they share genetic fundamentals. In a multicenter study at six academic institutions throughout Germany, we applied an auditory P50 suppression paradigm to 1,821 subjects (1,023 never-smokers, 798 smokers) randomly selected from the general population. Samples were genotyped for 21 TCF4 polymorphisms. Given that smoking is highly prevalent in schizophrenia and affects sensory gating, we also assessed smoking behavior, cotinine plasma concentrations, exhaled carbon monoxide, and the Fagerström Test (FTND). P50 suppression was significantly decreased in carriers of schizophrenia risk alleles of the TCF4 polymorphisms rs9960767, rs10401120rs, rs17597926, and 17512836 (P < 0.0002-0.00005). These gene effects were modulated by smoking behavior as indicated by significant interactions of TCF4 genotype and smoking status; heavy smokers (FTND score ? 4) showed stronger gene effects on P50 suppression than light smokers and never-smokers. Our finding suggests that sensory gating is modulated by an interaction of TCF4 genotype with smoking, and both factors may play a role in early information processing deficits also in schizophrenia. Consequently, considering smoking behavior may facilitate the search for genetic risk factors for schizophrenia.
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Neurocognitive impairments in non-deprived smokers--results from a population-based multi-center study on smoking-related behavior.
Addict Biol
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The aim of the present study was to examine neurocognitive function associated with chronic nicotine use. A total of 2163 healthy participants (1002 smokers, 1161 never-smoking controls) participated in a population-based case-control design. The main outcome measures were six cognitive domain factors derived from a neuropsychological test battery. In smokers, the battery was administered after controlled smoking of one cigarette. Analyses included age, sex and education as covariates. Results demonstrated small, but significant deficits in smokers for visual attention (P<0.001) and cognitive impulsivity (P<0.006), while verbal episodic memory, verbal fluency, verbal working memory, and Stroop-interference did not differ between groups. These attention/impulsivity deficits were also present in smokers with only a low amount of cigarette consumption. Lifetime nicotine use (pack-years) was not correlated with cognition in smokers. In conclusion, this study confirmed subtle and specific cognitive deficits in non-deprived smokers. The independence of these deficits from consumption intensity may argue for an a priori deficit of some cognitive abilities in smokers. These specific deficits may constitute intermediate phenotypes for genetic research on nicotine use.
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VBM-DTI correlates of verbal intelligence: a potential link to Brocas area.
J Cogn Neurosci
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Human brain lesion studies first investigated the biological roots of cognitive functions including language in the late 1800s. Neuroimaging studies have reported correlation findings with general intelligence predominantly in fronto-parietal cortical areas. However, there is still little evidence about the relationship between verbal intelligence and structural properties of the brain. We predicted that verbal performance is related to language regions of Brocas and Wernickes areas. Verbal intelligence quotient (vIQ) was assessed in 30 healthy young subjects. T1-weighted MRI and diffusion tensor imaging data sets were acquired. Voxel-wise regression analyses were used to correlate fractional anisotropy (FA) and mean diffusivity values with vIQ. Moreover, regression analyses of regional brain volume with vIQ were performed adopting voxel-based morphometry (VBM) and ROI methodology. Our analyses revealed a significant negative correlation between vIQ and FA and a significant positive correlation between vIQ and mean diffusivity in the left-hemispheric Brocas area. VBM regression analyses did not show significant results, whereas a subsequent ROI analysis of Brocas area FA peak cluster demonstrated a positive correlation of gray matter volume and vIQ. These findings suggest that cortical thickness in Brocas area contributes to verbal intelligence. Diffusion parameters predicted gray matter ratio in Brocas area more sensitive than VBM methodology.
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