Social support of virtual characters reduces pain perception.

BACKGROUND: Psychosocial factors, such as social support, can reduce pain. Virtual reality (VR) is a powerful tool to decrease pain, but social factors in VR-based pain analgesia have rarely been studied. Specifically, it is unclear whether social support by virtual characters can reduce pain and whether the perceived control behind virtual characters (agency) and varying degrees of social cues impact pain perception. METHODS: Healthy participants (N = 97) received heat pain stimulation while undergoing four within-subject conditions in immersive VR: (1) virtual character with a low number of social cues (virtual figure) provided verbal support, (2) virtual character with a high number of social cues (virtual human) provided verbal support, (3) no social support (hearing neutral words), (4) no social support. Perceived agency of the virtual characters served as between-subjects factor. Participants in the avatar group were led to believe that another participant controlled the virtual characters. Participants in the agent group were told they interacted with a computer. However, in both conditions, virtual characters were computer-controlled. Pain ratings, psychophysiological measurements and presence ratings were recorded. RESULTS: Virtual social support decreased pain intensity and pain unpleasantness ratings but had no impact on electrodermal activity nor heart rate. A virtual character with a high number of social cues led to lower pain unpleasantness and higher feelings of presence. Agency had no significant impact. CONCLUSIONS: Virtual characters providing social support can reduce pain independent of perceived agency. A more human visual appearance can have beneficial effects on social pain modulation by virtual characters. SIGNIFICANCE: Social influences are important factors in pain modulation. The current study demonstrated analgesic effects through verbal support provided by virtual characters and investigated modulating factors. A more human appearance of a virtual character resulted in a higher reduction of pain unpleasantness. Importantly, agency of the virtual characters had no impact. Given the increasing use of digital health interventions, the findings suggest a positive impact of virtual characters for digital pain treatments.

BNST and amygdala activation to threat: Effects of temporal predictability and threat mode.

Recent animal and human studies highlight the uncertainty about the onset of an aversive event as a crucial factor for the involvement of the centromedial amygdala (CM) and bed nucleus of the stria terminalis (BNST) activity. However, studies investigating temporally predictable or unpredictable threat anticipation and confrontation processes are rare. Furthermore, the few existing fMRI studies analyzing temporally predictable and unpredictable threat processes used small sample sizes or limited fMRI paradigms. Therefore, we measured functional brain activity in 109 predominantly female healthy participants during a temporally predictable-unpredictable threat paradigm, which aimed to solve limited aspects of recent studies. Results showed higher BNST activity compared to the CM during the cue indicating that the upcoming confrontation is aversive relative to the cue indicating an upcoming neutral confrontation. Both the CM and BNST showed higher activity during the confrontation with unpredictable and aversive stimuli, but the reaction to aversive confrontation relative to neutral confrontation was stronger in the CM compared to the BNST. Additional modulation analyses by NPSR1 rs324981 genotype revealed higher BNST activity relative to the CM in unpredictable anticipation relative to predictable anticipation in T-carriers compared to AA carriers. Our results indicate that during the confrontation with aversive or neutral stimuli, temporal unpredictability modulates CM and BNST activity. Further, there is a differential activity concerning threat processing, as BNST is more involved when focussing on fear-related anticipation processes and CM is more involved when focussing on threat confrontation.

Treating patients with driving phobia by virtual reality exposure therapy - a pilot study.

OBJECTIVES: Virtual reality exposure therapy (VRET) is a promising treatment for patients with fear of driving. The present pilot study is the first one focusing on behavioral effects of VRET on patients with fear of driving as measured by a post-treatment driving test in real traffic. METHODS: The therapy followed a standardized manual including psychotherapeutic and medical examination, two preparative psychotherapy sessions, five virtual reality exposure sessions, a final behavioral avoidance test (BAT) in real traffic, a closing session, and two follow-up phone assessments after six and twelve weeks. VRE was conducted in a driving simulator with a fully equipped mockup. The exposure scenarios were individually tailored to the patients' anxiety hierarchy. A total of 14 patients were treated. Parameters on the verbal, behavioral and physiological level were assessed. RESULTS: The treatment was helpful to overcome driving fear and avoidance. In the final BAT, all patients mastered driving tasks they had avoided before, 71% showed an adequate driving behavior as assessed by the driving instructor, and 93% could maintain their treatment success until the second follow-up phone call. Further analyses suggest that treatment reduces avoidance behavior as well as symptoms of posttraumatic stress disorder as measured by standardized questionnaires (Avoidance and Fusion Questionnaire: p < .10, PTSD Symptom Scale-Self Report: p < .05). CONCLUSIONS: VRET in driving simulation is very promising to treat driving fear. Further research with randomized controlled trials is needed to verify efficacy. Moreover, simulators with lower configuration stages should be tested for a broad availability in psychotherapy.

The Influence of Methylphenidate on Hyperactivity and Attention Deficits in Children With ADHD: A Virtual Classroom Test.

Objective: This study compares the performance in a continuous performance test within a virtual reality classroom (CPT-VRC) between medicated children with ADHD, unmedicated children with ADHD, and healthy children. Method:N = 94 children with ADHD (n = 26 of them received methylphenidate and n = 68 were unmedicated) and n = 34 healthy children performed the CPT-VRC. Omission errors, reaction time/variability, commission errors, and body movements were assessed. Furthermore, ADHD questionnaires were administered and compared with the CPT-VRC measures. Results: The unmedicated ADHD group exhibited more omission errors and showed slower reaction times than the healthy group. Reaction time variability was higher in the unmedicated ADHD group compared with both the healthy and the medicated ADHD group. Omission errors and reaction time variability were associated with inattentiveness ratings of experimenters. Head movements were correlated with hyperactivity ratings of parents and experimenters. Conclusion: Virtual reality is a promising technology to assess ADHD symptoms in an ecologically valid environment.

Individual differences in human fear generalization-pattern identification and implications for anxiety disorders.

Previous research indicates that anxiety disorders are characterized by an overgeneralization of conditioned fear as compared with healthy participants. Therefore, fear generalization is considered a key mechanism for the development of anxiety disorders. However, systematic investigations on the variance in fear generalization are lacking. Therefore, the current study aims at identifying distinctive phenotypes of fear generalization among healthy participants. To this end, 1175 participants completed a differential fear conditioning phase followed by a generalization test. To identify patterns of fear generalization, we used a k-means clustering algorithm based on individual arousal generalization gradients. Subsequently, we examined the reliability and validity of the clusters and phenotypical differences between subgroups on the basis of psychometric data and markers of fear expression. Cluster analysis reliably revealed five clusters that systematically differed in mean responses, differentiation between conditioned threat and safety, and linearity of the generalization gradients, though mean response levels accounted for most variance. Remarkably, the patterns of mean responses were already evident during fear acquisition and corresponded most closely to psychometric measures of anxiety traits. The identified clusters reliably described subgroups of healthy individuals with distinct response characteristics in a fear generalization test. Following a dimensional view of psychopathology, these clusters likely delineate risk factors for anxiety disorders. As crucial group characteristics were already evident during fear acquisition, our results emphasize the importance of average fear responses and differentiation between conditioned threat and safety as risk factors for anxiety disorders.

A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety.

Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.

Is prepulse modification altered by continuous theta burst stimulation? DAT1 genotype and motor threshold interact on prepulse modification following brain stimulation.

Previous studies suggest an inhibitory top-down control of the amygdala by the prefrontal cortex (PFC). Both brain regions play a role in the modulation of prepulse modification (PPM) of the acoustic startle response by a pre-stimulus. Repetitive transcranial magnetic stimulation (rTMS) can modulate the activity of the PFC and might thus affect PPM. This study tested the effect of inhibitory rTMS on PPM accounting for a genetic variant of the dopamine transporter gene (DAT1). Healthy participants (N = 102) were stimulated with continuous theta burst stimulation (cTBS, an intense form of inhibitory rTMS) or sham treatment over the right PFC. Afterwards, during continuous presentation of a background white noise a louder noise burst was presented either alone (control startle) or preceded by a prepulse. Participants were genotyped for a DAT1 variable number tandem repeat (VNTR) polymorphism. Two succeeding sessions of cTBS over the right PFC (2 × 600 stimuli with a time lag of 15 min) attenuated averaged prepulse inhibition (PPI) in participants with a high resting motor threshold. An attenuation of PPI induced by prepulses with great distances to the pulse (480, 2000 ms) was observed following active cTBS in participants that were homozygous carriers of the 10-repeat-allele of the DAT1 genotype and had a high resting motor threshold. Our results confirm the importance of the prefrontal cortex for the modulation of PPM. The effects were observed in participants with a high resting motor threshold only, probably because they received a higher dose of cTBS. The effects in homozygous carriers of the DAT1 10-repeat allele confirm the relevance of dopamine for PPM. Conducting an exploratory study we decided against the use of a correction for multiple testing.

GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder.

The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG-related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, P=3.3 × 10-8; rs191260602, P=3.9 × 10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3845) and a case-control sample with the categorical phenotype PD/AG (Ncombined =1012) obtaining highly significant P-values also for GLRB single-nucleotide variants rs17035816 (P=3.8 × 10-4) and rs7688285 (P=7.6 × 10-5). GLRB gene expression was found to be modulated by rs7688285 in brain tissue, as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network, as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout mice demonstrated an agoraphobic phenotype. In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, although functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.

MAOA gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy.

Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0-T1: +3.37±2.17%), while non-responders further decreased in methylation (-2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02-0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.

Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing.

Corticotropin-releasing hormone (CRH) is a major regulator of the hypothalamic-pituitary-adrenal axis. Binding to its receptor CRHR1 triggers the downstream release of the stress response-regulating hormone cortisol. Biochemical, behavioral and genetic studies revealed CRHR1 as a possible candidate gene for mood and anxiety disorders. Here we aimed to evaluate CRHR1 as a risk factor for panic disorder (PD). Allelic variation of CRHR1 was captured by 9 single-nucleotide polymorphisms (SNPs), which were genotyped in 531 matched case/control pairs. Four SNPs were found to be associated with PD, in at least one sub-sample. The minor allele of rs17689918 was found to significantly increase risk for PD in females after Bonferroni correction and furthermore decreased CRHR1 mRNA expression in human forebrains and amygdalae. When investigating neural correlates underlying this association in patients with PD using functional magnetic resonance imaging, risk allele carriers of rs17689918 showed aberrant differential conditioning predominantly in the bilateral prefrontal cortex and safety signal processing in the amygdalae, arguing for predominant generalization of fear and hence anxious apprehension. Additionally, the risk allele of rs17689918 led to less flight behavior during fear-provoking situations but rather increased anxious apprehension and went along with increased anxiety sensitivity. Thus reduced gene expression driven by CRHR1 risk allele leads to a phenotype characterized by fear sensitization and hence sustained fear. These results strengthen the role of CRHR1 in PD and clarify the mechanisms by which genetic variation in CRHR1 is linked to this disorder.

Attachment style and oxytocin receptor gene variation interact in influencing social anxiety.

OBJECTIVES: Social anxiety has been suggested to be promoted by an insecure attachment style. Oxytocin is discussed as a mediator of trust and social bonding as well as a modulator of social anxiety. Applying a gene-environment (G × E) interaction approach, in the present pilot study the main and interactive effects of attachment styles and oxytocin receptor (OXTR) gene variation were probed in a combined risk factor model of social anxiety in healthy probands. METHODS: Participants (N = 388; 219 females, 169 males; age 24.7 ± 4.7 years) were assessed for anxiety in social situations (Social Phobia and Anxiety Inventory) depending on attachment style (Adult Attachment Scale, AAS) and OXTR rs53576 A/G genotype. RESULTS: A less secure attachment style was significantly associated with higher social anxiety. This association was partly modulated by OXTR genotype, with a stronger negative influence of a less secure attachment style on social anxiety in A allele carriers as compared to GG homozygotes. CONCLUSIONS: The present pilot data point to a strong association of less secure attachment and social anxiety as well as to a gene-environment interaction effect of OXTR rs53576 genotype and attachment style on social anxiety possibly constituting a targetable combined risk marker of social anxiety disorder.

The functional -1019C/G HTR1A polymorphism and mechanisms of fear.

Serotonin receptor 1A gene (HTR1A) knockout mice show pronounced defensive behaviour and increased fear conditioning to ambiguous conditioned stimuli. Such behaviour is a hallmark of pathological human anxiety, as observed in panic disorder with agoraphobia (PD/AG). Thus, variations in HTR1A might contribute to neurophysiological differences within subgroups of PD/AG patients. Here, we tested this hypothesis by combining genetic with behavioural techniques and neuroimaging. In a clinical multicentre trial, patients with PD/AG received 12 sessions of manualized cognitive-behavioural therapy (CBT) and were genotyped for HTR1A rs6295. In four subsamples of this multicentre trial, exposure behaviour (n=185), defensive reactivity measured using a behavioural avoidance test (BAT; before CBT: n=245; after CBT: n=171) and functional magnetic resonance imaging (fMRI) data during fear conditioning were acquired before and after CBT (n=39). HTR1A risk genotype (GG) carriers more often escaped during the BAT before treatment. Exploratory fMRI results suggest increased activation of the amygdala in response to threat as well as safety cues before and after treatment in GG carriers. Furthermore, GG carriers demonstrated reduced effects of CBT on differential conditioning in regions including the bilateral insulae and the anterior cingulate cortex. Finally, risk genotype carriers demonstrated reduced self-initiated exposure behaviour to aversive situations. This study demonstrates the effect of HTR1A variation on defensive behaviour, amygdala activity, CBT-induced neural plasticity and normalization of defence behaviour in PD/AG. Our results, therefore, translate evidence from animal studies to humans and suggest a central role for HTR1A in differentiating subgroups of patients with anxiety disorders.

MAOA and mechanisms of panic disorder revisited: from bench to molecular psychotherapy.

Panic disorder with agoraphobia (PD/AG) is a prevalent mental disorder featuring a substantial complex genetic component. At present, only a few established risk genes exist. Among these, the gene encoding monoamine oxidase A (MAOA) is noteworthy given that genetic variation has been demonstrated to influence gene expression and monoamine levels. Long alleles of the MAOA-uVNTR promoter polymorphism are associated with PD/AG and correspond with increased enzyme activity. Here, we have thus investigated the impact of MAOA-uVNTR on therapy response, behavioral avoidance and brain activity in fear conditioning in a large controlled and randomized multicenter study on cognitive behavioral therapy (CBT) in PD/AG. The study consisted of 369 PD/AG patients, and genetic information was available for 283 patients. Carriers of the risk allele had significantly worse outcome as measured by the Hamilton Anxiety scale (46% responders vs 67%, P=0.017). This was accompanied by elevated heart rate and increased fear during an anxiety-provoking situation, that is, the behavioral avoidance task. All but one panic attack that happened during this task occurred in risk allele carriers and, furthermore, risk allele carriers did not habituate to the situation during repetitive exposure. Finally, functional neuroimaging during a classical fear conditioning paradigm evidenced that the protective allele is associated with increased activation of the anterior cingulate cortex upon presentation of the CS+ during acquisition of fear. Further differentiation between high- and low-risk subjects after treatment was observed in the inferior parietal lobes, suggesting differential brain activation patterns upon CBT. Taken together, we established that a genetic risk factor for PD/AG is associated with worse response to CBT and identify potential underlying neural mechanisms. These findings might govern how psychotherapy can include genetic information to tailor individualized treatment approaches.

The interaction of early life experiences with COMT val158met affects anxiety sensitivity.

The pathogenesis of anxiety disorders is considered to be multifactorial with a complex interaction of genetic factors and individual environmental factors. Therefore, the aim of this study was to examine gene-by-environment interactions of the genes coding for catechol-O-methyltransferase (COMT) and monoamine oxidase A (MAOA) with life events on measures related to anxiety. A sample of healthy subjects (N = 782; thereof 531 women; mean age M = 24.79, SD = 6.02) was genotyped for COMT rs4680 and MAOA-uVNTR (upstream variable number of tandem repeats), and was assessed for childhood adversities [Childhood Trauma Questionnaire (CTQ)], anxiety sensitivity [Anxiety Sensitivity Index (ASI)] and anxious apprehension [Penn State Worry Questionnaire (PSWQ)]. Main and interaction effects of genotype, environment and gender on measures related to anxiety were assessed by means of regression analyses. Association analysis showed no main gene effect on either questionnaire score. A significant interactive effect of childhood adversities and COMT genotype was observed: Homozygosity for the low-active met allele and high CTQ scores was associated with a significant increment of explained ASI variance [R(2) = 0.040, false discovery rate (FDR) corrected P = 0.04]. A borderline interactive effect with respect to MAOA-uVNTR was restricted to the male subgroup. Carriers of the low-active MAOA allele who reported more aversive experiences in childhood exhibited a trend for enhanced anxious apprehension (R(2) = 0.077, FDR corrected P = 0.10). Early aversive life experiences therefore might increase the vulnerability to anxiety disorders in the presence of homozygosity for the COMT 158met allele or low-active MAOA-uVNTR alleles.

[Internet therapy for ICD-patients]. / Internettherapie für ICD-Patienten.

Implantable cardioverter-defibrillators (ICD) are increasingly used for the prevention of potentially lethal cardiac arrhythmias due to their confirmed superior medical efficiency. Nevertheless, ICD-patients often suffer from psychosocial problems, e.g., anxiety and depression. These issues are rarely addressed in routine medical follow-up care. Due to the limited mobility of many ICD-patients, Internet-based care may be ideal for delivering psychosocial care to patients in their homes. Our pilot study and case studies illustrate prospects and challenges of this approach. We developed icd-forum.de, a 6-week internet-based prevention program that provides a platform for information, a virtual self-help group, and a professionally moderated chat room in order to help decrease anxiety and to improve quality of life. A critical evaluation in the context of other published studies on the subject allows recommendations for the implementation of future internet-based psychosocial programs for ICD-patients to be deduced. It is the authors' opinion that such programs offer advantages specifically for heart failure patients and they recommend their broader use. Prior to this, conclusive evaluation studies are needed.

Neuropeptide S receptor gene -- converging evidence for a role in panic disorder.

Animal studies have suggested neuropeptide S (NPS) and its receptor (NPSR) to be involved in the pathogenesis of anxiety-related behavior. In this study, a multilevel approach was applied to further elucidate the role of NPS in the etiology of human anxiety. The functional NPSR A/T (Asn¹°7Ile) variant (rs324981) was investigated for association with (1) panic disorder with and without agoraphobia in two large, independent case-control studies, (2) dimensional anxiety traits, (3) autonomic arousal level during a behavioral avoidance test and (4) brain activation correlates of anxiety-related emotional processing in panic disorder. The more active NPSR rs324981 T allele was found to be associated with panic disorder in the female subgroup of patients in both samples as well as in a meta-analytic approach. The T risk allele was further related to elevated anxiety sensitivity, increased heart rate and higher symptom reports during a behavioral avoidance test as well as decreased activity in the dorsolateral prefrontal, lateral orbitofrontal and anterior cingulate cortex during processing of fearful faces in patients with panic disorder. The present results provide converging evidence for a female-dominant role of NPSR gene variation in panic disorder potentially through heightened autonomic arousal and distorted processing of anxiety-relevant emotional stimuli.

Tph2 gene variants modulate response control processes in adult ADHD patients and healthy individuals.

Although therapeutic interventions in attention-deficit/hyperactivity disorder (ADHD) still focus on the dopaminergic system, recent studies indicate a serotonergic dysfunction in this disease as well. In that respect, several variants of the tryptophan hydroxylase gene (TPH2), which codes for the rate-limiting enzyme in the biosynthesis of serotonin (5-HT), have been associated with ADHD. The rs4570625 G-allele polymorphisms of the TPH2 gene have already been related to altered reactivity of the brain during perception tasks with emotional stimuli in healthy adults. Here we investigated the influence of the ADHD related risk alleles for rs4570625 and for rs11178997 on prefrontal brain function during cognitive response control in large samples of adult ADHD patients (n=124) and healthy controls (n=84). Response control was elicited with a Go-NoGo task (continuous performance test; CPT) performed during recording of an ongoing EEG. From the resulting event-related potentials in the Go- and NoGo conditions of the CPT, the NoGo-anteriorization (NGA) has been calculated as a valid neurophysiological parameter for prefrontal brain function. In the current study, ADHD risk alleles of both polymorphisms were found to be associated with a reduction in the NGA in both healthy controls and ADHD patients. These findings are in line with the notion that genetic variations associated with altered serotonergic neurotransmission are also associated with the function of the prefrontal cortex during response inhibition. This mechanism might also be relevant in the pathophysiology of ADHD.

The impact of prefrontal cortex for selective attention in a visual working memory task.

In this study, a variant of the n-back task was used to investigate electrophysiological correlates of top-down processes in visual-object working memory. Event-related potentials were used to replicate results concerning an attention related modulation of neural processes and to investigate the involvement of prefrontal cortex in this modulation. 16 healthy subjects executed an n-back task with sequentially presented faces and scenes. Attention was selectively directed to only one stimulus category. We found an enhancement of the N170 amplitudes for relevant stimuli compared to irrelevant or neutral stimuli. Late frontal amplitudes were stronger positive for relevant compared to neutral stimuli indicating selective attention processes of working memory. Evidence for selective inhibition was not found.

D4 receptor gene variation modulates activation of prefrontal cortex during working memory.

It has been shown that dopamine (DA) influences performance on neurocognitive tests, which are thought to rely on prefrontal activity. The purpose of this study was to explore the effects of gene polymorphisms related to DA activity, namely the D4 DA receptor (DRD4) gene exon III polymorphisms, on prefrontal cortex (PFC) activation. In this study we measured the brain oxygenation of the PFC during an n-back task with near-infrared spectroscopy (NIRS). We investigated 40 young healthy subjects, 12 of which carried the DRD4 exon III 7-repeat allele (group 7). These were compared with subjects without a 7-repeat allele (n=28, group 4). Additionally, we compared good and bad performers with respect to brain activation. As expected, we found significant increases in the concentration of oxygenated haemoglobin [O2Hb] during the 1-back and 2-back condition compared with baseline, and a corresponding significant decrease of deoxyhaemoglobin concentration. As a main result of this study we also found an interaction effect between task condition and DRD4 genotype with higher increases of [O2Hb] during the 2-back version compared with the 1-back version for the subjects of the 7-repeat allele group only. The same effect was seen as a statistical trend, when we compared bad performers with good performers. Therefore, we interpret the effects of the 7-repeat allele group of DRD4 as a sign of ineffective brain activity, perhaps even as a sign of prefrontal noise.