Genetic polymorphisms of the dopamine and serotonin systems modulate the neurophysiological response to feedback and risk taking in healthy humans.

Genetic differences in the dopamine and serotonin systems have been suggested as potential factors underlying interindividual variability in risk taking and in brain activation during the processing of feedback. Here, we studied the effects of dopaminergic (dopamine transporter [DAT1], catecholamine-O-methyltransferase val158met [COMT]) and serotonergic (serotonin transporter [5HTTLPR]) polymorphisms on risk taking and brain responses following feedback in 60 healthy female subjects. The subjects completed a well-established experimental gambling paradigm while an electroencephalogram was recorded. During the task, risk-taking behavior and prefrontal brain responses (feedback-related negativity [FRN]) following monetary gains and losses were assessed. FRN amplitudes were enhanced for nine-repeat-allele carriers of the DAT1 and short-allele carriers of 5HTTLPR, which are both presumably linked to less transporter activity and higher neurotransmitter levels. Moreover, nine-repeat DAT1 carriers displayed a trend toward increased risk taking in general, whereas 5HTTLPR short-allele carriers showed decreased risk taking following gains. COMT val158met genotype was unrelated to FRN amplitude and average risk taking. However, COMT met/met carriers showed a pronounced feedback P3 amplitude independent of valence, and a gradual increase in risk taking during the gambling task. In sum, the present findings underline the importance of genetic variability in the dopamine and serotonin systems regarding the neurophysiology of feedback processing.

Altered functional connectivity in common resting-state networks in patients with major depressive disorder: A resting-state functional connectivity study.

The neural correlates of major depressive disorder (MDD) remain disputed. In the absence of reliable biological markers, the dysfunction and interaction of neural networks have been proposed as pathophysiological neural mechanisms in depression. Here, we examined the functional connectivity (FC) of brain networks. 51 healthy volunteers (mean age 33.57 ± 7.80) and 55 individuals diagnosed with MDD (mean age 33.89 ± 11.00) participated by performing a resting-state (rs) fMRI scan. Seed to voxel FC analyses were performed. Compared to healthy control (HC), MDD patients showed higher connectivity between the hippocampus and the anterior cingulate cortex (ACC) and lower connectivity between the insula and the ACC. The MDD group displayed lower connectivity between the inferior parietal lobule (IPL) and the superior frontal gyrus (SFG). The current data replicate previous findings regarding the cortico-limbic network (hippocampus - ACC connection) and the salience network (insula - ACC connection) and provide novel insight into altered rsFC in MDD, in particular involving the hippocampus - ACC and the insula - ACC connection. Furthermore, altered connectivity between the IPL and SFG indicates that the processing in higher cognitive processes such as attention and working memory is affected in MDD. These data further support dysfunctional neuronal networks as an interesting pathophysiological marker in depression.

Expression of interleukin (IL)-1 family members upon stimulation with IL-17 differs in keratinocytes derived from patients with psoriasis and healthy donors.

BACKGROUND: A number of studies have challenged the T-cell-centred pathogenetic view of psoriasis by the finding that epithelium-expressed genes are intimately involved in the inflammatory process. Interleukin (IL)-17 is an important inflammatory mediator in skin psoriasis. OBJECTIVE: IL-17 is known to act on keratinocytes and we were interested in its impact on the expression of pro- and anti-inflammatory IL-1 family members. METHODS: We compared human keratinocytes derived from epidermal stem cells of hair follicles plucked from patients with psoriasis and healthy individuals using quantitative reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assays. RESULTS: In the presence of IL-17, psoriasis-derived keratinocytes showed a significantly higher induction of the proinflammatory IL-1 family members IL-1F6 and IL-1F9, but not of anti-inflammatory members IL-1F5, IL-1F7 or IL-1F3 compared with keratinocytes from healthy individuals. Both basal and IL-17-induced levels of IL-1F2 and IL-1F1 were found to be significantly lower in psoriasis keratinocytes. CONCLUSION: As keratinocytes were derived from epidermal stem cells of the hair follicles and were obtained from nonlesional sites, differences found are likely to present an intrinsic feature of psoriasis epithelium. Our data support the significance of IL-1 family members as therapeutic targets in psoriasis conditions.

Epicardial adipose tissue and adrenal gland volume in patients with borderline personality disorder.

Borderline personality disorder (BPD) is associated with an elevated mortality risk that is partially attributed to suicide, but few studies examined other possible causes of premature death. The present study compared epicardial adipose tissue (EAT) volume as a known early predictor of premature cardiovascular morbidity, cardiovascular risk indices, and adrenal gland volume (AGV) as an indicator for chronic hypothalamus-pituitary-adrenal (HPA) axis activation in females with borderline personality disorder (BPD), major depressive disorder (MDD) and in healthy individuals. Twenty-eight patients with BPD comorbid with MDD (BPD/MDD), 22 MDD patients and 26 healthy females (CTRL) of comparable age were included. EAT and AGV were assessed by magnetic resonance tomography; 10-year cardiovascular risk and diabetes risk were determined by PROCAM and FINDRISK score; metabolic syndrome was defined following National Cholesterol Education Adult Treatment Panel III R (NCEP/ATP III) criteria. MADRS was used to assess depression severity. After adjustment for age, body mass index (BMI), and physical activity, EAT and AGV were significantly increased in BPD/MDD compared to MDD and CTRL. EAT and AGV displayed a positive correlation. Finally, diabetes risk in BPD/MDD was elevated compared to CTRL and MDD. The present study highlights the increased cardiometabolic risk of BPD patients. We identify EAT accumulation as an early predictor and potential mediator of cardiovascular disease in BPD that appears to be driven at least in part by HPA axis dysregulation. Therefore, interventions that reduce EAT volume (i.e. exercise and diet) should be considered in the clinical management of BPD.

In vivo magnetic resonance spectrometry imaging demonstrates comparable adaptation of brain energy metabolism to metabolic stress induced by 72 h of fasting in depressed patients and healthy volunteers.

Major depressive disorder (MDD) is characterized by dysregulation of stress systems and by abnormalities in cerebral energy metabolism. Stress induction has been shown to impact neurometabolism in healthy individuals. Contrarily, neurometabolic changes in response to stress are insufficiently investigated in MDD patients. Metabolic stress was induced in MDD patients (MDD, N = 24) and in healthy individuals (CTRL, N = 22) by application of an established fasting protocol in which calorie intake was omitted for 72 h. Both study groups were comparable regarding age, gender distribution, and body mass index (BMI). Fasting-induced effects on brain high-energy phosphate levels and membrane phospholipid metabolism were assessed using phosphorus-31 magnetic resonance spectroscopy (31P-MRS). Two-way repeated measures ANOVAs did not reveal significant interaction effects (group x fasting) or group differences in adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi), phosphomonoesters (PME), phosphodiesters (PDE), or pH levels between MDD and CTRL. Fasting, independent of group, significantly increased ATP and decreased Pi levels and an overall increase in PME/PDE ratio as marker for membrane turnover was observed. Overall these results indicate reactive changes in cerebral energetics and in membrane phospholipid metabolism in response to fasting. The observed effects did not significantly differ between CTRL and MDD, indicating that neurometabolic adaptation to metabolic stress is preserved in MDD patients.

Human fear acquisition deficits in relation to genetic variants of the corticotropin-releasing hormone receptor 1 and the serotonin transporter--revisited.

We recently showed that a genetic polymorphism (rs878886) in the human corticotropin-releasing hormone receptor 1 (CRHR1) is associated with reduced fear-conditioned responses to a threat cue. This is a potentially important finding considering that the failure to acquire fear contingencies can leave an individual in a maladaptive state of more generalized anxiety. Consistent with that idea, the CRHR1-dependent fear acquisition deficit translated into heightened contextual anxiety when taking genetic variability within the serotonin transporter long polymorphic region (5-HTTLPR) into account. To replicate our previous findings, we conducted a replication study in 224 healthy medication-free human subjects using the exact same cue and context virtual reality fear-conditioning procedure as in study by Heitland et al. (2013). In the replication study, consistent with the original findings, CRHR1 rs878886 G-allele carriers showed reduced acquisition of cue-specific fear-conditioned responses compared with C/C homozygotes. Also, in this larger sample the cue acquisition deficit of G-allele carriers translated into heightened contextual anxiety, even independent of 5-HTT gene variation. In contrast to our earlier findings, there was an additional interaction effect of CRHR1 rs878886 and the triallelic 5-HTTLPR/rs25531 variant on cued fear acquisition. In summary, this study replicated the initially reported association of the CRHR1 rs878886 G-allele with cued fear acquisition deficits, albeit with a different pattern of results regarding the interaction with 5-HTT variation. This further supports the notion that the human corticotropin-releasing hormone plays a role in the acquisition of fears.

Genetic variability in the human cannabinoid receptor 1 is associated with resting state EEG theta power in humans.

It has long been postulated that exogenous cannabinoids have a profound effect on human cognitive functioning. These cannabinoid effects are thought to depend, at least in parts, on alterations of phase-locking of local field potential neuronal firing. The latter can be measured as activity in the theta frequency band (4-7Hz) by electroencephalogram. Theta oscillations are supposed to serve as a mechanism in neural representations of behaviorally relevant information. However, it remains unknown whether variability in endogenous cannabinoid activity is involved in theta rhythms and therefore, may serve as an individual differences index of human cognitive functioning. To clarify this issue, we recorded resting state EEG activity in 164 healthy human subjects and extracted EEG power across frequency bands (δ, θ, α, and ß). To assess variability in the endocannabinoid system, two genetic polymorphisms (rs1049353, rs2180619) within the cannabinoid receptor 1 (CB1) were determined in all participants. As expected, we observed significant effects of rs1049353 on EEG power in the theta band at frontal, central and parietal electrode regions. Crucially, these effects were specific for the theta band, with no effects on activity in the other frequency bands. Rs2180619 showed no significant associations with theta power after Bonferroni correction. Taken together, we provide novel evidence in humans showing that genetic variability in the cannabinoid receptor 1 is associated with resting state EEG power in the theta frequency band. This extends prior findings of exogenous cannabinoid effects on theta power to the endogenous cannabinoid system.

Auditory event-related potentials (P3a, P3b) and genetic variants within the dopamine and serotonin system in healthy females.

The late positive components of the human event-related brain potential comprise electrocortical reflections of stimulus-driven attentional capture (the anteriorly distributed P3a) and top-down control detection of relevant events (the posteriorly distributed P3b). As of yet, the neuropharmacologic and neurogenetic origin of the P3a and P3b is not fully understood. In this study, we address the contribution of dopaminergic and serotoninergic mechanisms. Sixty healthy females completed an active auditory novelty oddball paradigm while EEG was recorded. In all subjects, genetic polymorphisms within the dopamine system (dopamine transporter [DAT1], catecholamine-O-methyltransferase val158met [COMT val158met]) and the serotonin system (serotonin transporter [5HTTLPR]) were assessed. Across genotypes, novels (relative to standards) elicited a fronto-centrally distributed P3a, and targets (relative to standards) a parieto-centrally distributed P3b. Genotypes effects were observed for both P3a (COMT, 5HTTPLR) and P3b (DAT1, COMT, 5HTTLPR) only at prefrontal electrode location (Fz). Specifically, the frontal P3a was enhanced in COMT met/met homozygotes, but not in DAT1 9R. The target-related P3b was enhanced in COMT met/met and DAT1 9R relative to its genetic counterparts, but only at frontal electrodes. This 'anteriorized' enhancement may reflect either an additional frontal component in the target-related P3 dependent on dopamine, or a more subtle shift in the neural ensemble that generates the target-related P3. Results for 5HTTLPR short allele homozygotes mimicked those in COMT met/met homozygotes. In all, the present findings suggest involvement of frontal-cortical dopaminergic and serotoninergic mechanisms in bottom-up attentional capture (COMT val158met, 5HTTLPR), with an additional top-down component sensitive to striatal signals (DAT1).

Failure to extinguish fear and genetic variability in the human cannabinoid receptor 1.

Failure to extinguish fear can lead to persevering anxiety and has been postulated as an important mechanism in the pathogenesis of human anxiety disorders. In animals, it is well documented that the endogenous cannabinoid system has a pivotal role in the successful extinction of fear, most importantly through the cannabinoid receptor 1. However, no human studies have reported a translation of this preclinical evidence yet. Healthy medication-free human subjects (N=150) underwent a fear conditioning and extinction procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex was measured to assess fear-conditioned responding, and subjective fear ratings were collected. Participants were genotyped for two polymorphisms located within the promoter region (rs2180619) and the coding region (rs1049353) of cannabinoid receptor 1. As predicted from the preclinical literature, acquisition and expression of conditioned fear did not differ between genotypes. Crucially, whereas both homozygote (G/G, N=23) and heterozygote (A/G, N=68) G-allele carriers of rs2180619 displayed robust extinction of fear, extinction of fear-potentiated startle was absent in A/A homozygotes (N=51). Additionally, this resistance to extinguish fear left A/A carriers of rs2180619 with significantly higher levels of fear-potentiated startle at the end of the extinction training. No effects of rs1049353 genotype were observed regarding fear acquisition and extinction. These results suggest for the first time involvement of the human endocannabinoid system in fear extinction. Implications are that genetic variability in this system may underlie individual differences in anxiety, rendering cannabinoid receptor 1 a potential target for novel pharmacological treatments of anxiety disorders.