Bodo Warrings

ADORA2A Gene variation, caffeine, and emotional processing: a multi-level interaction on startle reflex.

There is converging evidence for genetic, biochemical, and neuropsychological factors to increase the risk for anxiety and anxiety disorders. The pathogenesis of anxiety disorders is assumed to be influenced by a complex interaction of these individual risk factors on several levels, affecting intermediate phenotypes of anxiety such as the startle reflex. Thus, in the present double-blind, placebo-controlled study we attempted to paradigmatically investigate a multi-level pathogenetic model of anxiety by testing the effect of 300 mg caffeine citrate as an antagonist at the adenosine A2A receptor vs placebo on the emotion-potentiated (unpleasant, neutral, and pleasant International Affective Picture System pictures) startle reflex in 110 healthy individuals (male=56, female=54) stratified for the adenosine A2A receptor (ADORA2A) 1976T>C polymorphism (rs5751876). In addition to the expected main effect of picture category (highest startle amplitude for unpleasant, lowest for pleasant pictures) groups across all ADORA2A 1976T>C genotype and intervention (caffeine vs placebo) groups, an interaction effect of genotype, intervention, and picture category was discerned: In ADORA2A 1976TT risk genotype carriers, highest startle magnitudes were observed after caffeine administration in response to unpleasant pictures, with this effect arising particularly from the female subgroup. Our data point to a complex, multi-level, and potentially gender-specific pathogenetic model of anxiety, with genetic and biochemical factors interactively increasing the risk of maladaptive emotional processing and thereby possibly also anxiety disorders. The present findings may eventually aid in improving primary and secondary prevention by sharpening the risk profiles of anxiety-prone individuals.

Neural correlates of spontaneous panic attacks.

In this report, we present two anxiety disorder patients who spontaneously experienced a panic attack during an fMRI examination and subsequently aborted the measurement. We analyzed the functional data gathered up to that point in relation to the patients’ subsequent verbal reports of the course of the panic attacks. Within prominent structures of the fear network (amygdala, insula, prefrontal cortex) neural dynamics mirrored the description of the attack very well for one of the patients. For the other patient who experienced a less intense attack and who was treated pharmacologically at the time of measurement, the relation was limited to the prefrontal cortex. Investigating the temporal dynamics of neural activation in an ecologically valid situation may point to the potentially different roles of the amygdala and the insula as well as the prefrontal cortex prior to and during a panic attack.

Effects of ADORA2A gene variation and caffeine on prepulse inhibition: A multi-level risk model of anxiety

The complex pathogenesis of anxiety and panic disorder in particular has been suggested to be influenced by genetic factors such as the adenosine A2A receptor gene (ADORA2A) 1976T>C polymorphism (rs5751876) as well as neuropsychological factors such as early information processing deficits. In 114 healthy individuals (males=57, females=57) controlled for anxiety sensitivity (AS), a multi-level risk model of the development of anxiety was applied: Genetic (ADORA2A 1976T>C variant) and biochemical (300 mg of caffeine citrate vs. placebo) factors were hypothesized to influence early information processing as measured by the prepulse inhibition/facilitation paradigm (stimulus onset asynchronies (SOAs) of 60, 120, 240, 480 and 2000ms between prepulses and startle stimuli). A fourfold interaction of genotype, intervention, gender, and SOAs was discerned. Stratification by SOAs revealed that at 120 ms and 240 ms SOAs in the caffeine condition, PPI was impaired in female ADORA2A 1976TT risk genotype carriers as compared to male ADORA2A 1976TT homozygotes, while no significant effects were observed in the ADORA2A 1976CC/CT non-risk genotype or placebo group. Only in high anxiety sensitive probands, a significant intervention effect was discerned with impaired prepulse facilitation (PPF) due to caffeine. The present results point to an impaired ability to selectively process very early information and to gate irrelevant sensory information, respectively, in female ADORA2A 1976TT homozygotes in response to caffeine, providing further evidence for the adenosinergic system to be involved in the pathogenesis of anxiety.

Recovery of cortical functioning in abstinent alcohol-dependent patients: prefrontal brain oxygenation during verbal fluency at different phases during withdrawal.

Abstract Objectives. Neurotoxic effects of alcohol consumption are well-known. There is plenty of literature on frontal lobe impairment on the behavioural and structural brain imaging level. However, only few functional imaging studies investigated altered neural patterns and even less abstinence-related neural recovery. Methods. In a cross-sectional design three patient groups (acute withdrawal, detoxified, abstinent) and healthy controls (each n = 20) performed a phonological and semantic verbal fluency task (VFT) while brain activity was measured with near-infrared spectroscopy (NIRS). Results. First, for the phonological condition withdrawal patients and detoxified patients showed less fluency-related frontal lobe activation compared to controls despite equal performance. Second, significant linear trend effects from withdrawal patients over detoxified and abstinent patients up to healthy controls indicated more normal activation patterns in the abstinent group that did not differ significantly from the controls. In the detoxified group brain activation increased with time since detoxification. Conclusions. Our results are compatible with an increase in frontal brain activity from alcohol dependence over abstinence up to normal functioning. However, as cross-sectional designs do not allow to assess causal relations, results have to be considered preliminary and longitudinal studies are needed to further elucidate recovery processes in alcohol dependence.

Affect-modulated startle: interactive influence of catechol-O-methyltransferase Val158Met genotype and childhood trauma.

The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system – partly conferred by catechol-O-methyltransferase (COMT) gene variation – for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design) and childhood maltreatment (CTQ) as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders.

Genetics of panic disorder: focus on association studies and therapeutic perspectives.

There is evidence for either genetic heterogeneity or complex inheritance with an interaction of environmental factors and multiple single genes in the etiology of panic disorder. Although linkage analyses of panic disorder have implicated several chromosomal regions including 1q, 2q, 4q, 7p, 9q, 12q, 13q, 15q and 22q, they so far have not been able to identify a major gene responsible for panic disorder. Several genes of classical candidate neurotransmitter systems have been reported to be associated with panic disorder. Genetic variation in genes of monoamine oxidase A, catechol-O-methyltransferase, adenosine receptor (ADORA2A) and cholecystokinin B receptor have been inconsistently replicated. There are multiple lines of evidence for highly relevant effects of gender and ethnicity. Future research strategies might focus on broad phenotypes defined by comorbidity or intermediate phenotypes and include the use of animal models for identifying candidate genes, such as the regulator of G-protein signaling (RGS2) gene, genome-wide association studies in large samples, studies of gene–gene and gene–environment interactions and pharmacogenetic studies. The identification of novel pathophysiological pathways may provide the basis for the development of novel therapeutic interventions.

Vagus somatosensory evoked potentials are delayed in Alzheimer’s disease, but not in major depression

In Alzheimer’s disease (AD), the degeneration of brainstem nuclei is different from major depression (MD). Thus, vagus somatosensory evoked potentials (VSEP) proposed for the functional assessment of brainstem nuclei should show prolonged latencies in AD but not in MD. In 55 AD patients, 57 MD patients and two age-matched control groups evoked potentials were recorded upon stimulation of the auricular branch of the vagus nerve. In the AD, not in the MD group, latencies were significantly longer as compared to controls. Thus, the method of VSEP could contribute to the important differential diagnosis of AD and MD in elderly patients.

Monoamine Oxidase A Gene Methylation and Its Role in Posttraumatic Stress Disorder: First Evidence from the South Eastern Europe (SEE)- PTSD Study

Abstract Background Posttraumatic stress disorder is characterized by an overactive noradrenergic system conferring core posttraumatic stress disorder symptoms such as hyperarousal and reexperiencing. Monoamine oxidase A is one of the key enzymes mediating the turnover of noradrenaline. Here, DNA methylation of the monoamine oxidase A gene exonI/intronI region was investigated for the first time regarding its role in posttraumatic stress disorder risk and severity. Methods Monoamine oxidase A methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells in a total sample of N=652 (441 male) patients with current posttraumatic stress disorder, patients with remitted posttraumatic stress disorder, and healthy probands (comparison group) recruited at 5 centers in Bosnia-Herzegovina, Croatia, and the Republic of Kosovo. Posttraumatic stress disorder severity was measured by means of the Clinician-Administered Posttraumatic Stress Disorder Scale and its respective subscores representing distinct symptom clusters. Results In the male, but not the female sample, patients with current posttraumatic stress disorder displayed hypermethylation of 3 CpGs (CpG3=43656362; CpG12=43656514; CpG13=43656553, GRCh38.p2 Assembly) as compared with remitted Posttraumatic Stress Disorder patients and healthy probands. Symptom severity (Clinician-Administered Posttraumatic Stress Disorder Scale scores) in male patients with current posttraumatic stress disorder significantly correlated with monoamine oxidase A methylation. This applied particularly to symptom clusters related to reexperiencing of trauma (cluster B) and hyperarousal (cluster D). Conclusions The present findings suggest monoamine oxidase A gene hypermethylation, potentially resulting in enhanced noradrenergic signalling, as a disease status and severity marker of current posttraumatic stress disorder in males. If replicated, monoamine oxidase A hypermethylation might serve as a surrogate marker of a hyperadrenergic subtype of posttraumatic stress disorder guiding personalized treatment decisions on the use of antiadrenergic agents.

Hypermethylation of the monoamine oxidase A gene – a new epigenetic marker for posttraumatic stress disorder?

Posttraumatic Stress Disorder (PTSD) can develop after experiencing or witnessing any severe traumatic event such as combat. Point prevalence rates in war-affected regions, e.g. Bosnia-Herzegovina and Kosovo, range from 18% to 35%. Noradrenergic dysfunction as represented by e.g. elevated noradrenaline concentrations in the cerebrospinal fluid of PTSD patients is known to play a substantial role in the pathogenesis of PTSD symptoms [1]. Epigenetic regulation (i.e. DNA methylation) is strongly suggested to moderate the interaction between environmental influences and a genetic predisposition. Therefore, differential methylation of genes involved in the noradrenergic system such as the monoamine oxidase A (MAOA) gene might be part of the complex biological underpinnings of a dysregulated noradrenergic system and thereby contribute to PTSD risk. The present study aimed at investigating MAOA gene methylation as a possible epigenetic marker of PTSD status and severity in a sample comprising patients with PTSD and healthy controls recruited from war-affected regions in Bosnia-Herzegovina, Croatia and Kosovo. DNA methylation levels of MAOA (exonI/intronI region) were analyzed in PTSD patients [N=216; m=157, age (mean±s.d.): 50.08±6.74 years], remitted PTSD patients [N=151; m=98, age (mean±s.d.): 49.48±8.20 years] and healthy controls [N=349, m=232, age (mean±s.d.): 48.81±8.50 years] by direct sequencing of sodium bisulfite-treated DNA followed by semi-quantitative analysis of the sequencing results via the Epigenetic Sequencing Methylation software. Severity of PTSD symptoms was assessed by the Clinician-Administered PTSD Scale (CAPS). All participants were assessed for potential confounders of methylation (sex, age, or smoking status). Possible categorical differences were analyzed by (M)ANCOVAs with age and smoking status as covariates. Post-hoc tests (Bonferroni) were performed to test individual differences in methylation across groups. Associations between dimensional measures were analyzed performing partial correlation analyses controlled for age and smoking status. In the male subsample, analyses revealed significant methylation differences at three out of 13 CpG sites between patients with current PTSD, remitted PTSD patients, and healthy controls. Post-hoc tests showed trend-wise significant (padjusted In the female subsample, we failed to observe association of MAOA methylation with either current or remitted PTSD, while there was a positive correlation between MAOA methylation and symptom severity (r=0.294, p=0.033). The results of the present study for the first time suggest MAOA hypermethylation – possibly resulting in an increased noradrenergic tonus – as a disease status and severity marker of PTSD particularly in male patients. Given robust replication, MAOA hypermethylation might thus serve as an epigenetic marker within the complex risk factor constellation of PTSD. Furthermore, applying a personalized pharmaco-therapeutic approach, anti-adrenergic agents might prove to be beneficial in counterbalancing increased noradrenergic signalling specifically in male PTSD patients displaying MAOA hypermethylation.

Unterschiede zwischen Patienten im psychiatrischen Konsildienst und stationär-psychiatrischen Patienten

Ziel: Zur Optimierung des psychiatrischen Konsildienstes mussen epidemiologische Daten berucksichtigt werden. Methode: Es wurden Geschlecht, Alter und Diagnosen von Patienten im Konsildienst mit stationar-psychiatrischen Patienten verglichen. Ergebnisse: Patienten im Konsildienst waren deutlich alter (p  Schlussfolgerung: Das unterschiedliche Spektrum im Konsildienst erfordert angepasste diagnostische und therapeutische Masnahmen.