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Recent studies indicate differential involvement of the centromedial amygdala (CM) and the bed nucleus of the stria terminalis (BNST) during processing (anticipation and confrontation) of threat stimuli. Here, temporal predictability was shown to be a relevant factor. In this study, we want to investigate the relevance of these effects, which were found in healthy subjects, for anxiety disorders. Therefore, we investigated the differential involvement of CM and BNST in the anticipation and confrontation of phobic stimuli under variation of temporal predictability in spider phobia. 21 patients with spider phobia and 21 healthy controls underwent a temporally predictable/unpredictable phobic and neutral anticipation and confrontation paradigm using functional magnetic resonance imaging (fMRI) and ROI analyses. During the anticipation phase, healthy controls showed higher CM and BNST activity during the predictable compared with the unpredictable condition compared with the anxiety patients. During a confrontation phase that followed the anticipation phase, CM was more activated than BNST during the phobic compared with the neutral confrontation. While this effect was independent of threat predictability in patients, healthy controls showed higher activation in the CM compared with the BNST only during the predictable spider confrontation compared with the predictable bird confrontation. The results contribute to a better understanding of the separate roles of the CM and BNST during phobic processes. The CM was found to be more relevant to phobic confrontation in patients with spider phobia compared with the BNST.

Dementia, including Alzheimer's Disease (AD), is a growing problem worldwide. Prevention or early detection of the disease or a prodromal cognitive decline is necessary. By means of our long-term follow-up "Vogel Study", we aim to predict the pathological cognitive decline of a German cohort (mean age was 73.9 ± 1.55 years at first visit) with three measurement time points within 6 years per participant. Especially in samples of the elderly and subjects with chronic or comorbid diseases, dropouts are one of the biggest problems of long-term studies. In contrast to the large number of research articles conducted on the course of dementia, little research has been done on the completion of treatment. To ensure unbiased and reliable predictors of cognitive decline from study completers, our objective was to determine predictors of dropout. We conducted multivariate analyses of (co-)variance (MANCOVAs) and multinomial logistic regression analyses to compare and predict the subject's dropout behavior at the second visit 3 years after baseline (full participation, partial participation, no participation/dropout) with neuropsychiatric, cognitive, blood, and lifestyle variables. Lower performance in declarative memory, attention, and visual-spatial processing predicted dropout rather than full participation. Lower performance in visual-spatial processing predicted partial participation as opposed to full participation. Furthermore, lower performance in Mini-Mental Status Examination (MMSE) predicted whether subjects dropped out or participated partially instead of full participation. Baseline cognitive parameters are associated with dropouts at follow-up with a loss of impaired participants. We expect a bias into a healthier sample over time.

Fear conditioning and generalization are well-known mechanisms in the pathogenesis of anxiety disorders. Extinction of conditioned fear responses is crucial for the psychotherapeutic treatment of these diseases. Anxious depression as a subtype of major depression shares characteristics with anxiety disorders. We therefore aimed to compare fear learning mechanisms in patients with anxious versus non-anxious depression. Fear learning mechanisms in patients with major depression (n = 79; for subgroup analyses n = 41 patients with anxious depression and n = 38 patients with non-anxious depression) were compared to 48 healthy participants. We used a well-established differential fear conditioning paradigm investigating acquisition, generalization, and extinction. Ratings of valence, arousal and probability of expected threat were assessed as well as skin conductance response as an objective psychophysiological measure. Patients with major depression showed impaired acquisition of conditioned fear. In addition, depressed patients showed impaired extinction of conditioned fear responses after successful fear conditioning. Generalization was not affected. However, there was no difference between patients with anxious and non-anxious depression. Results differed between objective and subjective measures. Our findings show altered fear acquisition and extinction in major depression as compared to healthy controls, but they do not favor differential fear learning and extinction mechanisms in the pathogenesis of anxious versus non-anxious depression. The results of impaired extinction warrant future studies addressing extinction learning elements in the treatment of depression.

Cognitive-behavioral therapy (CBT) has been hypothesized to act by reducing the pathologically enhanced semantic, anxiety-related associations of patients with panic disorder. This study investigated the effects of CBT on the behavioral and neural correlates of the panic-related semantic network in patients with panic disorder.An automatic semantic priming paradigm specifically tailored for panic disorder, in which panic symptoms (e.g., "dizziness") were primed by panic triggers (e.g., "elevator") compared with neutral words (e.g., "bottle"), was performed during functional MRI scanning with 118 patients with panic disorder (compared with 150 healthy control subjects) before and 42 patients (compared with 52 healthy control subjects) after an exposure-based CBT. Neural correlates were investigated by comparing 103 pairs of matched patients and control subjects at the baseline (for patients) or T1 (for control subjects) assessment and 39 pairs at the posttreatment or T2 assessment.At baseline or T1, patients rated panic-trigger/panic-symptom word pairs with higher relatedness and higher negative valence compared with healthy control subjects. Patients made faster lexical decisions to the panic-symptom words when they were preceded by panic-trigger words. This panic-priming effect in patients (compared with control subjects) was reflected in suppressed neural activation in the left and right temporal cortices and insulae and enhanced activation in the posterior and anterior cingulate cortices. After CBT, significant clinical improvements in the patient group were observed along with a reduction in relatedness and negative valence rating and attenuation of neural activation in the anterior cingulate cortex for processing of panic-trigger/panic-symptom word pairs.The findings support a biased semantic network in panic disorder, which is normalized after CBT. Attenuation of anterior cingulate cortex activation for processing of panic-related associations provides a potential mechanism for future therapeutic interventions.

Obgleich Angsterkrankungen sehr gut mithilfe der kognitiven Verhaltenstherapie (KVT) behandelt werden konnen, profitiert ein Teil der Patienten nicht optimal von der Therapie. In den letzten Jahren wurden nichtinvasive Hirnstimulationsverfahren („noninvasive brain stimulation“, NIBS) als „add-on“ zur Psychotherapie untersucht. Gibt es ausreichende Evidenz fur den Einsatz von NIBS als Erganzung zur Psychotherapie bei Patienten mit Angsterkrankungen? Systematisches Review zu bisherigen Therapiestudien, die NIBS-Verfahren begleitend zur KVT bei Angsterkrankungen uberprufen. Insgesamt konnten 4 randomisierte kontrollierte Therapiestudien gefunden und analysiert werden. Diese Arbeiten verwenden die repetitive transkranielle Magnetstimulation (rTMS) kurz vor oder wahrend einer expositionsbasierten Verhaltenstherapie. Der Einsatz einer aktiven Stimulation im Vergleich zu einer Placebostimulation geht mit einem positiven zusatzlichen Effekt im mittleren Bereich und einer durchschnittlichen Effektstarke von f = 0,3 einher. Erste Arbeiten zeigen einen zusatzlichen Nutzen der rTMS in Kombination mit KVT bei der Behandlung von Angsterkrankungen. In weiteren Studien muss aber gepruft werden, welche genauen Stimulationsparameter am besten geeignet sind, um eine Empfehlung fur die Behandlungspraxis abgeben zu konnen.

BACKGROUND Because overgeneralization of fear is a pathogenic marker of anxiety disorders, we investigated whether pretreatment levels of fear generalization in spider-phobic patients are related to their response to exposure-based treatment to identify pretreatment moderators of treatment success. METHODS A total of 90 patients with spider phobia completed pretreatment clinical and magnetoencephalography assessments, one session of virtual reality exposure therapy, and a posttreatment clinical assessment. Based on the primary outcome (30% symptom reduction in self-reported symptoms), they were categorized as responders or nonresponders. In a pretreatment magnetoencephalography fear generalization paradigm involving fear conditioning with 2 unconditioned stimuli (UCS), we obtained fear ratings, UCS expectancy ratings, and event-related fields to conditioned stimuli (CS: CS-, CS+) and 7 different generalization stimuli on a perceptual continuum from CS- to CS+. RESULTS Before treatment, nonresponders showed behavioral overgeneralization indicated by more linear generalization gradients in fear ratings. Analyses of magnetoencephalography source estimations revealed that nonresponders showed a decline of their (inhibitory) frontal activations to safety-signaling CS- and generalization stimuli compared with CS+ over time, while responders maintained these activations at early (

Pain relief is defined as the ease of pain and is thus highly relevant for clinical applications and everyday life. Given that pain relief is based on the cessation of an aversive pain experience, it is reasonable to assume that pain relief learning would also be shaped by factors that alter subjective and physiological pain responses, such as social presence or a feeling of control. To date, it remains unclear whether and how factors that shape autonomic pain responses might affect pain relief learning. Here, we investigated how pain relief learning is shaped by two important factors known to modulate pain responses, i.e. social influence and controllability of pain. Skin conductance responses (SCRs) were recorded while participants learned to associate a formerly neutral stimulus with pain relief under three different pain conditions. In the social-influence condition (N = 34), the pain stimulation could be influenced by another person’s decisions. In the self-influence condition (N = 31), the participants themselves could influence the pain stimulation. Finally, in the no-influence condition (N = 32), pain stimulation was simply delivered without any influence. According to our results, the SCRs elicited by the stimulus that was associated with pain relief were significantly smaller compared to the SCRs elicited by a neutral control stimulus, indicating pain relief learning. However, there was no significant difference in the pain relief learning effect across the groups. These results suggest that physiological pain relief learning in humans is not significantly influenced by social influence and pain controllability.

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.

Obesity is a major problem in the modern world causing a higher risk for various cerebrovascular diseases causing a profound individual and societal burden. The neurobiological foundation bears potential to understand the complex interaction of individual differences in brain structure and function and ingestive behaviour. This systematic review was performed on the current evidence of structural abnormalities in grey matter volume (GMV) in patients with obesity based on studies published until December 2017, which were selected through search in PubMed, CENTER (Cochrane Library), PsycINFO, Web of Science, and Ovid MEDLINE. Ten studies were included; all of them included patients with obesity and provided a whole-brain analysis of grey matter (GM) distribution. Our findings confirmed the most consistent GM reductions in patients with obesity in the left, middle, and right inferior frontal gyrus (including the insula), the left middle temporal cortex, the left precentral gyrus, and the cerebellum. On the other hand, increased GMV in patients with obesity were found in the left cuneus, left middle frontal gyrus, left inferior occipital gyrus, and corpus callosum.

While being highly effective on average, exposure-based treatments are not equally effective in all patients. The a priori identification of patients with a poor prognosis may enable the application of more personalized psychotherapeutic interventions. We aimed at identifying sociodemographic and clinical pre-treatment predictors for treatment response in spider phobia (SP). N = 174 patients with SP underwent a highly standardized virtual reality exposure therapy (VRET) at two independent sites. Analyses on group-level were used to test the efficacy. We applied a state-of-the-art machine learning protocol (Random Forests) to evaluate the predictive utility of clinical and sociodemographic predictors for a priori identification of individual treatment response assessed directly after treatment and at 6-month follow-up. The reliability and generalizability of predictive models was tested via external cross-validation. Our study shows that one session of VRET is highly effective on a group-level and is among the first to reveal long-term stability of this treatment effect. Individual short-term symptom reductions could be predicted above chance, but accuracies dropped to non-significance in our between-site prediction and for predictions of long-term outcomes. With performance metrics hardly exceeding chance level and the lack of generalizability in the employed between-site replication approach, our study suggests limited clinical utility of clinical and sociodemographic predictors. Predictive models including multimodal predictors may be more promising.

Adapting threat-related memories towards changing environments is a fundamental ability of organisms. One central process of fear reduction is suggested to be extinction learning, experimentally modeled by extinction training that is repeated exposure to a previously conditioned stimulus (CS) without providing the expected negative consequence (unconditioned stimulus, US). Although extinction training is well investigated, evidence regarding process-related changes in neural activation over time is still missing. Using optimized delayed extinction training in a multicentric trial we tested whether: 1) extinction training elicited decreasing CS-specific neural activation and subjective ratings, 2) extinguished conditioned fear would return after presentation of the US (reinstatement), and 3) results are comparable across different assessment sites and repeated measures. We included 100 healthy subjects (measured twice, 13-week-interval) from six sites. 24h after fear acquisition training, extinction training, including a reinstatement test, was applied during fMRI. Alongside, participants had to rate subjective US-expectancy, arousal and valence. In the course of the extinction training, we found decreasing neural activation in the insula and cingulate cortex as well as decreasing US-expectancy, arousal and negative valence towards CS+. Re-exposure to the US after extinction training was associated with a temporary increase in neural activation in the anterior cingulate cortex (exploratory analysis) and changes in US-expectancy and arousal ratings. While ICCs-values were low, findings from small groups suggest highly consistent effects across time-points and sites. Therefore, this delayed extinction fMRI-paradigm provides a solid basis for the investigation of differences in neural fear-related mechanisms as a function of anxiety-pathology and exposure-based treatment.Clinical Trials RegistrationRegistry names: Deutsches Register Klinischer Studien (DRKS) – German Clinical Trails RegisterClinicalTrials.govRegistration ID-numbers: DRKS00008743DRKS00009687ClinicalTrials.gov Identifier: NCT02605668URLs: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00008743https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00009687https://clinicaltrials.gov/ct2/show/NCT02605668

Non-invasive brain stimulation is widely used to investigate and manipulate specific brain functions to broaden knowledge about healthy people, and also to provide for a potential treatment option for people with various psychopathological disorders that do not adequately benefit from traditional treatments. Nevertheless, the underlying mechanisms have not been fully investigated yet. The aim of the present study was to investigate whether we could alter the brain activity during a test for executive functioning. Therefore, we measured the activity in the prefrontal cortex (PFC) using near-infrared spectroscopy (NIRS) while applying bilateral anodal and cathodal transcranial direct current stimulation (tDCS, 1 mA) to the left and right dorsolateral PFC (dlPFC) during the phonemic part of the verbal fluency test (VFT). A total of 61 young and healthy participants were divided into three groups: left anodal/right cathodal, left cathodal/right anodal stimulation or sham. All participants performed the letter-cued part of the VFT and a control task. Brain activation was simultaneously measured using NIRS. We found only the frontotemporal cortex (FTC) but not the dorsolateral prefrontal cortex (DLPFC) to be activated. Furthermore, stimulating the DLPFC bilaterally by tDCS showed no significant differences between the three different groups when performing the VFT, neither in performance nor in cortical activation. Instead, we found a significant increase in deoxygenated hemoglobin [HHb] while performing the control task in the left anodal/right cathodal stimulation group compared to sham. Interestingly, also an influence on the mood of our participants was observed. These results are of importance especially regarding a better understanding of the influence of the dlPFC on the VFT.

Abstract. Conditioning and generalization of fear are assumed to play central roles in the pathogenesis of anxiety disorders. Here we investigate the influence of a psychometric anxiety-specific factor on these two processes, thus try to identify a potential risk factor for the development of anxiety disorders. To this end, 126 healthy participants were examined with questionnaires assessing symptoms of anxiety and depression and with a fear conditioning and generalization paradigm. A principal component analysis of the questionnaire data identified two factors representing the constructs anxiety and depression. Variations in fear conditioning and fear generalization were solely associated with the anxiety factor characterized by anxiety sensitivity and agoraphobic cognitions; high-anxious individuals exhibited stronger fear responses (arousal) during conditioning and stronger generalization effects for valence and UCS-expectancy ratings. Thus, the revealed psychometric factor “anxiety” was associated with enhanced fear generalization, an assumed risk factor for anxiety disorders. These results ask for replication with a longitudinal design allowing to examine their predictive validity.

BackgroundPanic disorder (PD) patients are constantly concerned about future panic attacks and exhibit general hypersensitivity to unpredictable threat. We aimed to reveal phasic and sustained brain responses and functional connectivity of the amygdala and the bed nucleus of the stria terminalis (BNST) during threat anticipation in PD.MethodsUsing functional magnetic resonance imaging (fMRI), we investigated 17 PD patients and 19 healthy controls (HC) during anticipation of temporally unpredictable aversive and neutral sounds. We used a phasic and sustained analysis model to disentangle temporally dissociable brain activations.ResultsPD patients compared with HC showed phasic amygdala and sustained BNST responses during anticipation of aversive v. neutral stimuli. Furthermore, increased phasic activation was observed in anterior cingulate cortex (ACC), insula and prefrontal cortex (PFC). Insula and PFC also showed sustained activation. Functional connectivity analyses revealed partly distinct phasic and sustained networks.ConclusionsWe demonstrate a role for the BNST during unpredictable threat anticipation in PD and provide first evidence for dissociation between phasic amygdala and sustained BNST activation and their functional connectivity. In line with a hypersensitivity to uncertainty in PD, our results suggest time-dependent involvement of brain regions related to fear and anxiety.

Feelings of uncontrollability and anxiety regarding possibly harmful events are key features of post-traumatic stress disorder (PTSD) symptomatology. Due to a lack of studies, the neural correlates of anticipatory anxiety in PTSD are still poorly understood. During functional magnetic resonance imaging, female PTSD patients with interpersonal violence trauma and healthy controls (HC) anticipated the temporally unpredictable presentation of aversive (human scream) or neutral sounds. Based on separate analysis models, we investigated phasic and sustained brain activations. PTSD patients reported increased anxiety during anticipation of aversive versus neutral sounds. Furthermore, we found both increased initial, phasic amygdala activation and increased sustained activation of the bed nucleus of the stria terminalis (BNST) during anticipation of aversive versus neutral sounds in PTSD patients in comparison to HC. PTSD patients as compared with HC also showed increased phasic responses in mid-cingulate cortex (MCC), posterior cingulate cortex (PCC), mid-insula and lateral prefrontal cortex (PFC) as well as increased sustained responses in MCC, PCC, anterior insula and lateral and medial PFC. Our results demonstrate a relationship between anticipatory anxiety in PTSD patients and hyperresponsiveness of brain regions that have previously been associated with PTSD symptomatology. Additionally, the dissociation between amygdala and BNST indicates distinct temporal and functional characteristics and suggests that phasic fear and sustained anxiety responses are enhanced during unpredictable anticipation of aversive stimuli in PTSD. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.

Blood-injection-injury (BII) phobia differs from other subtypes of specific phobia in that it is associated with elevated disgust-sensitivity as well as specific autonomic and brain responses during processing of phobia-relevant stimuli. To what extent these features play a role already during threat anticipation is unclear. In the current fMRI experiment, 16 female BII phobics and 16 female healthy controls anticipated the presentation of phobia-specific and neutral pictures. On the behavioral level, anxiety dominated the anticipatory period in BII phobics relative to controls, while both anxiety and disgust were elevated during picture presentation. By applying two different models for the analysis of brain responses to anticipation of phobia-specific versus neutral stimuli, we found initial and sustained increases of activation in anterior cingulate cortex (ACC), insula, lateral and medial prefrontal cortex (PFC), thalamus and visual areas, as well as initial activation in the amygdala for BII phobics as compared to healthy controls. These results suggest that BII phobia is characterized by activation of a typical neural defense network during threat anticipation, with anxiety as the predominant emotion., Highlights • Anxiety, but not disgust, during threat anticipation in blood-injection-injury phobics. • Distinct temporal characteristics of brain regions involved in threat anticipation. • Initial and sustained activation in subregions of a neural defense network.

Objectives Embedded in the Collaborative Research Center “Fear, Anxiety, Anxiety Disorders” (CRC‐TRR58), this bicentric clinical study aims at identifying biobehavioral markers of treatment (non‐)response by applying machine learning methodology with an external cross‐validation protocol. We hypothesize that a priori prediction of treatment (non‐)response is possible in a second, independent sample based on multimodal markers. Methods One‐session virtual reality exposure treatment (VRET) with patients with spider phobia was conducted on two sites. Clinical, neuroimaging, and genetic data were assessed at baseline, post‐treatment and after 6 months. The primary and secondary outcomes defining treatment response are as follows: 30% reduction regarding the individual score in the Spider Phobia Questionnaire and 50% reduction regarding the individual distance in the behavioral avoidance test. Results N = 204 patients have been included (n = 100 in Würzburg, n = 104 in Münster). Sample characteristics for both sites are comparable. Discussion This study will offer cross‐validated theranostic markers for predicting the individual success of exposure‐based therapy. Findings will support clinical decision‐making on personalized therapy, bridge the gap between basic and clinical research, and bring stratified therapy into reach. The study is registered at ClinicalTrials.gov (ID: NCT03208400).

Both functional imaging or EEG studies and studies including neurological patients found the dorsolateral prefrontal cortex (dLPFC) to be an important brain area for the processing of emotion and attention. The aim of the present study was to investigate whether emotion and attention can be modulated through bilateral transcranial direct current stimulation (tDCS) of the dLPFC. Therefore, we measured electroencephalographic occipital (early posterior negativity, EPN) and parietal ERPs (late positive potential, LPP) during an emotional picture viewing paradigm with an additional attentional instruction while applying bilateral anodal and cathodal tDC-stimulation to the left and right dLPFC. Beyond the well-known emotion and attention effects for both EPN and LPP, we found that left cathodal/right anodal tDCS leads to increased LPP amplitudes to target stimuli. In contrast to our hypothesis bilateral tDCS over the dLPFC did not influence emotional processing.

Alcohol craving has been shown to be an important factor for relapses in alcohol-dependent patients. Furthermore, brain activity in reward-related areas in response to alcohol-related cues is positively related to the amount of post-relapse alcohol consumption. On the other hand, it has been shown that cue-exposure based extinction training (CET) leads to larger decrease of striatal and left dorsolateral prefrontal cortex (dLPFC) cue-induced activation compared to standard clinical day-care treatment, but the effect sizes are relatively small. The question of this study was, whether it is possible to change cue-reactivity and subjective craving by applying bilateral prefrontal transcranial direct current stimulation (tDCS). We stimulated 30 detoxified alcohol-dependent patients (50 % with a sham and 50 % with left cathodal/right anodal stimulation) and presented emotional as well as alcohol-related pictures. We measured the emotional startle modulation and found significantly increased startle amplitudes in the verum stimulation condition for alcohol-related cues, indicating a more negative processing of this cues in alcohol-dependent patients after verum tDCS stimulation. Additionally we found tendencies for stronger reduction in subjective craving in verum-stimulated patients. Therefore our study underscores the positive value of DCS in reducing craving and might help to improve the understanding and therapy of alcohol dependence.

Individuals with high anxiety sensitivity (AS) have an increased risk of developing anxiety disorders and are more biased in how they process fear-related stimuli. This study investigates the neural correlates of fear-related words and word associations in high- and low-AS individuals. We used a semantic priming paradigm during functional magnetic resonance imaging in which three types of target words (fear symptoms, e.g. 'dizziness'; neutral, e.g. 'drink'; and pseudowords, e.g. 'salkom') were preceded by two types of prime words (fear-triggers, e.g. 'elevator'; and neutral, e.g. 'bottle'). Subjects with high AS rated fear-symptom words (vs neutral words) as more unpleasant than low-AS individuals; they also related these words more strongly to fear-triggers and showed prolonged reaction times. During the processing of fear-symptom words, greater activation in the left anterior insula was observed in high-AS subjects than in low-AS subjects. Lower activation in the left inferior frontal gyrus, angular gyrus, fusiform gyrus and bilateral amygdalae was found in high-AS subjects when fear-symptom words were preceded by fear-trigger words. The findings suggest that cognitive biases and the anterior insula play a crucial role in high-AS individuals. Furthermore, semantic processes may contribute to high AS and the risk of developing anxiety disorders.

Spontaneous low frequency oscillations (LFO) in functional imaging data have gained increased interest in the study of cognitive decline. Persons diagnosed with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) display alterations in their amount of LFO in various brain regions. This is commonly interpreted as disruptions in the autoregulation of the cerebral microvascular system. In the present study LFO (0,07–0,11 Hz) were measured with 52-channel near-infrared spectroscopy (NIRS) in 61 healthy elderly persons (70–76 years), 54 MCI subjects (70–76 years) and 25 healthy young controls (21–48 years) during rest over the frontal and the parietal cortex. Both MCI and healthy elderly controls showed less LFO in the frontal cortex as compared to young subjects. For the parietal cortex a decrease in LFO could be observed for the MCI group in comparison to healthy elderly subjects. Correlations of more LFO with worse performance in neuropsychological tests point to compensatory processes. LFO measured with NIRS might be especially suited for longitudinal studies aiming at predicting cognitive decline.

Epigenetic mechanisms have been proposed to mediate fear extinction in animal models. Here, MAOA methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells before and after a 2-week exposure therapy in a sample of n = 28 female patients with acrophobia as well as in n = 28 matched healthy female controls. Clinical response was measured using the Acrophobia Questionnaire and the Attitude Towards Heights Questionnaire. The functional relevance of altered MAOA methylation was investigated by luciferase-based reporter gene assays. MAOA methylation was found to be significantly decreased in patients with acrophobia compared with healthy controls. Furthermore, MAOA methylation levels were shown to significantly increase after treatment and correlate with treatment response as reflected by decreasing Acrophobia Questionnaire/Attitude Towards Heights Questionnaire scores. Functional analyses revealed decreased reporter gene activity in presence of methylated compared with unmethylated pCpGfree_MAOA reporter gene vector constructs. The present proof-of-concept psychotherapy-epigenetic study for the first time suggests functional MAOA methylation changes as a potential epigenetic correlate of treatment response in acrophobia and fosters further investigation into the notion of epigenetic mechanisms underlying fear extinction.

The neuropeptide S (NPS) and its receptor NPSR have captured attention in the pathogenesis of anxiety disorders. Here, a functional polymorphism in the NPSR1 gene has been linked to deviant cortico-limbic interactions in response to negative stimuli. While healthy T allele carriers exhibited increased amygdala and prefrontal cortex activity, panic disorder patients carrying the T risk allele displayed hypofrontality possibly reflecting insufficient prefrontal inhibition of limbic reactivity. In order to study multi-level effects of genotype and anxiety, prefrontal cortex activity during an emotional n-back task was measured in 66 volunteers genotyped for the NPSR1 rs324981 A/T variant (AA homozygotes vs. T allele carriers) by means of functional near-infrared spectroscopy. For a high working memory load (3-back), T allele carriers showed a signal increase to negative pictures in the dorsolateral and medial prefrontal cortex while AA homozygotes displayed a signal decrease. Since groups did not differ on skin conductance level and behavioral parameters, this effect in the risk group in line with results from fMRI studies is speculated to represent an adaptive mechanism to compensate for presumably increased subcortical activity driven by an overactive NPS system. However, anxiety sensitivity correlated negatively with prefrontal activity in T allele carriers possibly suggesting a decompensation of the adaptive compensatory upregulation.

Patients suffering from bipolar disorder often report negative thoughts and a bias towards negative environmental stimuli. Previous studies show that this mood-congruent attentional bias could mediated by dysfunctions in anterior limbic regions. The Error-Related Negativity (ERN), which originates in the anterior cingulate cortex (ACC), has been used to research this negativity bias in depressed patients, and could also help to better understand the underlying mechanisms causing the negativity bias in bipolar patients. In this study we investigated error processing in patients with bipolar disorder. Acute depressive bipolar patients (n = 20) and age-matched healthy controls (n = 20) underwent a modified Eriksen Flanker Task to assess test performance and two error-related event-related potentials (ERPs), i.e., the ERN and Error Positivity (Pe) were measured by EEG. Half of the patients were measured again in a euthymic state. We found similar ERN amplitudes in bipolar patients as compared to healthy controls, but significantly reduced Pe amplitudes. Moreover, acutely depressed bipolar patients displayed an ERN and Pe even if they responded accurately or too slow, which indicates that correct responses are processed in a way similar to wrong responses. This can be interpreted as a psychophysiological correlate of typical cognitive distortions in depression, i.e., an erroneous perception of personal failures. This biased error perception partially remained when patients were in a euthymic state. Together, our data indicate that aberrant error processing of bipolar patients may be regarded a trait marker possibly reflecting a risk factor for depressive relapses in bipolar disorder.

A functional polymorphism (5-HTTLPR) within the serotonin transporter gene (SERT) has been associated with personality dimensions such as neuroticism, with emotional reactivity to negative events, and with an increased risk of affective disorders. More specifically, the short (S) allele of 5-HTTLPR has been linked to increased amygdala activity and has been identified as a risk allele for depressive disorders. Recently, Homberg and Lesch (2011) urged for a conceptual change in the current deficit-oriented connotation of the 5-HTTLPR S-allele and argued that the S-allele could be considered adaptive in certain contexts. They postulated that S-allele carriers show hypervigilant behavior in social situations and should thus show increased social conformity. Therefore, we tested whether 5-HTTLPR modulates the neural correlates of real-life social joint action through functional near-infrared spectroscopy (fNIRS). Thirty participants, homozygote for 5-HTTLPR, were measured and analyzed while they were involved in a previously published joint-action paradigm, which reliably leads to an activation of the left parietal cortex. We found that homozygote S-allele carriers showed increased inferior parietal lobe activation, compared to the LL-allele carriers for the contrast "joint action greater solo action". Therefore, our results provide evidence for beneficial effects of the S-allele on the neural correlates of social interactions.

An influential framework suggests that the central nucleus of the amygdala (CeA) is involved in phasic responses to threat, while the bed nucleus of the stria terminalis (BNST) mediates sustained anxiety. However, this model has been questioned, proposing that the role of the BNST is not limited to sustained threat contexts. Rather, amygdala and BNST also seem to work in concert in the processing of discrete and briefly presented threat-related stimuli, likely dependent on inter-individual differences in anxiety. A direct test of this assumption with sufficient experimental power is missing in human research and the degree to which individual differences in trait anxiety moderate phasic responses and functional connectivity of amygdala and BNST during threat processing remains unclear. The current event-related functional magnetic resonance imaging (fMRI) study investigated activation and connectivity of amygdala and BNST, as well as modulating effects of trait anxiety, during processing of briefly presented threat-related relative to neutral standardized pictures in 93 psychiatrically healthy individuals. Both amygdala and BNST activation was increased during presentation of threat-related relative to neutral pictures. Furthermore, functional connectivity between BNST and amygdala in response to threat was positively associated with trait anxiety. These findings suggest that amygdala and BNST form a functional unit during phasic threat processing whereby their connectivity is shaped by inter-individual differences in trait anxiety.

Apolipoprotein-E4 (APOE-E4) is a major genetic risk factor for developing Alzheimer’s disease (AD). The verbal fluency task (VFT), especially the subtask category fluency, has shown to provide a good discrimination between cognitively normal controls and subjects with AD. Interestingly, APOE-E4 seems to have no effect on the behavioral performance during a VFT in healthy elderly. Thus, the purpose of the present study was to reveal possible compensation mechanisms by investigating the effect of APOE-E4 on the hemodynamic response in non-demented elderly during a VFT by using functional near-infrared spectroscopy (fNIRS). We compared performance and hemodynamic response of high risk APOE-E4/E4, -E3/E4 carriers with neutral APOE-E3/E3 non-demented subjects (N = 288; 70–77 years). No difference in performance was found. APOE-E4/E4, -E3/E4 carriers had a decreased hemodynamic response in the right inferior frontal junction (IFJ) with a corresponding higher response in the left middle frontal gyrus (MFG) during category fluency. Performance was correlated with the hemodynamic response in the MFG. We assume a compensation of decreased IFJ brain activation by utilizing the MFG during category fluency and thus resulting in no behavioral differences between APOE-groups during the performance of a VFT.

Functional near-infrared spectroscopy (fNIRS) and vagus somatosensory evoked potentials (VSEP) show deviant patterns in subjects with Alzheimer’s disease (AD) compared to healthy controls. We now aimed at testing the predictive value of these methods in the early diagnosis of AD. The Vogel study is a prospective, observational, long-term follow-up study with three time points of investigation within 6 years. Residents of the city of Wurzburg born between 1936 and 1941 were recruited. Every participant underwent physical, psychiatric, and laboratory examinations, and performed an intense neuropsychological testing as well as VSEP and NIRS according to the published procedures. 604 subjects were included. Mean age of the participants was 73.9 ± 1.55 years. The most frequent pathological physical and laboratory examination results were observed for blood pressure (62%), body weight (54%), HbA1c (16%), cholesterol (42%), and homocysteine (69%). Comprehensive analysis of cognitive testing showed mild cognitive impairment (MCI) in 12.3% of the patients. Concurrent major depression was found in 6.6% of the patients. We observed a high rate of MCI and somatic comorbidity in our cohort. The high rate of vascular risk factors and depressive symptoms, all of which are known risk factors of AD, is consistent with the notion that there are multiple options to prevent or postpone the onset of AD in a geriatric population like the one of the Vogel studies.

Downregulation of emotional responses to threat is strongly associated with frontal cortex functions. Additionally pathological anxiety has been proposed to be associated with the altered frontal control. Understanding the frontal regulation of both initial and sustained fear responses seems to be crucial for further research on the treatment of anxiety disorders. Therefore, this study aims to examine the effects of transcranial direct current stimulation (tDCS) over the right inferior frontal cortex (rIFC) on the subjects' psychophysiological responses as measured by skin conductance reaction (SCR) during a sustained threat paradigm. 80 participants were randomly assigned to an anodal and sham stimulation group in a double-blinded manner. Indicated by visual cues, participants anticipated the temporally unpredictable occurrence of aversive or neutral auditory stimuli. We found a significant interaction effect of condition x tDCS for SCR during the sustained threat. Post-hoc tests revealed a significant reduction in SCR during sustained fear in verum stimulated group. The results confirm that tDCS of the rIFC attenuates sustained fear. This supports the suggested role of the rIFC in psychophysiological emotional regulation and the potential use of tDCS to enhance these effects.

Sustained anticipatory anxiety is central to Generalized Anxiety Disorder (GAD). During anticipatory anxiety, phasic threat responding appears to be mediated by the amygdala, while sustained threat responding seems related to the bed nucleus of the stria terminalis (BNST). Although sustained anticipatory anxiety in GAD patients was proposed to be associated with BNST activity alterations, firm evidence is lacking. We aimed to explore temporal characteristics of BNST and amygdala activity during threat anticipation in GAD patients. Nineteen GAD patients and nineteen healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) during a temporally unpredictable threat anticipation paradigm. We defined phasic and a systematic variation of sustained response models for blood oxygen level-dependent responses during threat anticipation, to disentangle temporally dissociable involvement of the BNST and the amygdala. GAD patients relative to HC responded with increased phasic amygdala activity to onset of threat anticipation and with elevated sustained BNST activity that was delayed relative to the onset of threat anticipation. Both the amygdala and the BNST displayed altered responses during threat anticipation in GAD patients, albeit with different time courses. The results for the BNST activation hint towards its role in sustained threat responding, and contribute to a deeper understanding of pathological sustained anticipatory anxiety in GAD.

Efficient emotion regulation is essential for social interaction and functioning in human society and often happens without direct intention and conscious awareness. Cognitive labeling of stimuli based on certain characteristics has been assumed to represent an effective strategy of implicit emotional regulation whereas processing based on simple perceptual characteristics (e.g., matching) has not. Evidence exists that the ventrolateral prefrontal cortex (VLPFC) might be of functional relevance during labeling by down-regulating limbic activity in the presence of threatening stimuli. However, it remained unclear whether this VLPFC activation was particularly specific to threat because previous studies focused exclusively on threatening stimuli. In the current study, 35 healthy participants labeled or matched both threatening and neutral pictures while undergoing 52-channel functional near-infrared spectroscopy. Results showed increased VLPFC activation during labeling of threatening but not neutral pictures. No increase in prefrontal activation was detected during matching. Moreover, skin conductance increased equally for both valence conditions during initial phases of labeling whereas during matching stronger increases were found for threatening stimuli. Although a general inverse relationship between VLPFC function and skin conductance was not confirmed, both were negatively correlated during matching of threatening pictures in subjects with high state anxiety. It was concluded that the VLPFC plays an essential role during implicit emotion regulation. Further, even simple perceptual processing seems to engage regulatory top-down activation in anxious individuals.

Cognitive decline is very common in age and particularly in subjects with neurodegenerative conditions. Besides memory and language, executive functions are very often affected in elderly and patients with Alzheimer's disease or Parkinson's disease. However, the neural alterations associated with these executive deficits are still not fully understood. Therefore, we measured cortical activation using functional near-infrared spectroscopy (fNIRS) in 16 healthy elderly subjects (50-75 years) performing the Trail Making Test (TMT), a widely used neuropsychological instrument measuring executive function. In line with previous studies focusing on younger subjects, the results showed frontal activation during the TMT A and the TMT B in the dorsolateral prefrontal cortex, the frontopolar area and also Broca's area. Furthermore, significant activation in the left motor, somatosensory cortices and somatosensory association cortices was demonstrated. Additionally, after a median split the differences between younger (58 years) and older (58 years) subjects were analyzed with the older subjects showing a less focused prefrontal activation. Altogether, fNIRS was found to be suitable to detect cortical activation in elderly subjects during performance of the TMT as well as aging-related differences in prefrontal activation topography. These neural correlates of executive functions should be further investigated as a potential prodromal neural marker of executive deficits and neurodegenerative processes.

Smoking is among the leading causes of mortality worldwide. Discontinuing smoking can increase life expectancy to the presmoking level. Unaided attempts are often ineffective, strengthening the necessity of cognitive-behavioral therapy (CBT), nicotine replacement or pharmacotherapy. Still, relapse rates are high. Recently, a modulation of nicotine craving, which predicts relapse, through transcranial magnetic stimulation to the prefrontal cortex was shown. In a pilot study, we investigated whether 4 sessions of intermittent theta burst stimulation (iTBS) as add-on treatment to CBT reduces nicotine craving and improves long-term abstinence (at 3, 6 and 12 months). Smokers were randomly assigned to a treatment (n = 38) or a sham group (n = 36). Although we did not find reduced craving, we could show higher abstinence rates in the treatment group at 3 months. At 6 and 12 months abstinence rates did not differ significantly. Results at 12 months, however, have to be interpreted cautiously due to significant differences in the dropout rates between the two groups at this time point. We provide first evidence for a beneficial effect of additional iTBS on intermediate nicotine abstinence; however, the low number of iTBS sessions might have prevented longer effects. More lasting effects might be achieved by iTBS maintenance sessions in analogy to the treatment of depression.

Anticipation of potentially threatening social situations is a key process in social anxiety disorder (SAD). In other anxiety disorders, recent research of neural correlates of anticipation of temporally unpredictable threat suggests a temporally dissociable involvement of amygdala and bed nucleus of the stria terminalis (BNST) with phasic amygdala responses and sustained BNST activation. However, the temporal profile of amygdala and BNST responses during temporal unpredictability of threat has not been investigated in patients suffering from SAD. We used functional magnetic resonance imaging (fMRI) to investigate neural activation in the central nucleus of the amygdala (CeA) and the BNST during anticipation of temporally unpredictable aversive (video camera observation) relative to neutral (no camera observation) events in SAD patients compared to healthy controls (HC). For the analysis of fMRI data, we applied two regressors (phasic/sustained) within the same model to detect temporally dissociable brain responses. The aversive condition induced increased anxiety in patients compared to HC. SAD patients compared to HC showed increased phasic activation in the CeA and the BNST for anticipation of aversive relative to neutral events. SAD patients as well as HC showed sustained activity alterations in the BNST for aversive relative to neutral anticipation. No differential activity during sustained threat anticipation in SAD patients compared to HC was found. Taken together, our study reveals both CeA and BNST involvement during threat anticipation in SAD patients. The present results point towards potentially SAD-specific threat processing marked by elevated phasic but not sustained CeA and BNST responses when compared to HC., Highlights • fMRI in SAD during anticipation of temporally unpredictable aversive events. • Anticipation of social observation induces increased anxiety in SAD patients. • SAD patients show elevated phasic activity in fundamental anxiety network regions. • Evidence of SAD-specific threat processing.

Highlights • Higher amygdala activation in T risk allele carriers during the perception of agoraphobia-specific stimuli • Amygdala activation correlated negatively trendwise with the trait neuroticism in healthy controls carrying A/A genotype • A diagnosis x genotype interaction as a trend in the inferior orbitofrontal cortex during the perception of agoraphobia-specific stimuli, Introduction The neurobiological mechanisms behind panic disorder with agoraphobia (PD/AG) are not completely explored. The functional A/T single nucleotide polymorphism (SNP) rs324981 in the neuropeptide S receptor gene (NPSR1) has repeatedly been associated with panic disorder and might partly drive function respectively dysfunction of the neural “fear network”. We aimed to investigate whether the NPSR1 T risk allele was associated with malfunctioning in a fronto-limbic network during the anticipation and perception of agoraphobia-specific stimuli. Method 121 patients with PD/AG and 77 healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) using the disorder specific “Westphal-Paradigm”. It consists of neutral and agoraphobia-specific pictures, half of the pictures were cued to induce anticipatory anxiety. Results Risk allele carriers showed significantly higher amygdala activation during the perception of agoraphobia-specific stimuli than A/A homozygotes. A linear group x genotype interaction during the perception of agoraphobia-specific stimuli showed a strong trend towards significance. Patients with the one or two T alleles displayed the highest and HC with the A/A genotype the lowest activation in the inferior orbitofrontal cortex (iOFC). Discussion The study demonstrates an association of the NPSR1rs324981 genotype and the perception of agoraphobia-specific stimuli. These results support the assumption of a fronto-limbic dysfunction as an intermediate phenotype of PD/AG.

Background. In order to prevent future errors, we constantly control our behavior for discrepancies between the expected (i.e., intended) and the real action outcome and continuously adjust our behavior accordingly. Neurophysiological correlates of this action-monitoring process can be studied with event-related potentials (error-related negativity (ERN) and error positivity (Pe)) originating from the medial prefrontal cortex (mPFC). Patients with neuropsychiatric diseases often show performance monitoring dysfunctions potentially caused by pathological changes of cortical excitability; therefore, a modulation of the underlying neuronal activity might be a valuable therapeutic tool. One technique which allows us to explore cortical modulation of neural networks is transcranial direct current stimulation (tDCS). Therefore, we tested the effect of medial-prefrontal tDCS on error-monitoring potentials in 48 healthy subjects randomly assigned to anodal, cathodal, or sham stimulation. Results. We found that cathodal stimulation attenuated Pe amplitudes compared to both anodal and sham stimulation, but no effect for the ERN. Conclusions. Our results indicate that cathodal tDCS over the mPFC results in an attenuated cortical excitability leading to decreased Pe amplitudes. We therefore conclude that tDCS has a neuromodulatory effect on error-monitoring systems suggesting a future approach to modify the sensitivity of corresponding neural networks in patients with action-monitoring deficits.

Replicating thought suppression effects with the Think/No-Think paradigm (TNT) has failed in some studies investigating the phenomenon of below-baseline recall of suppressed stimuli. Attempts have been made to isolate factors that might explain inter-individual differences in suppression performance. Certain personality traits, whether associated with a pathological state or investigated in a community sample, have been shown to interfere with successful thought suppression and might be responsible for some of the negative results obtained in TNT studies. In the present study we investigate the influence of psychometric measures of depression and anxiety in a fairly large sample of healthy volunteers. We show that high brooding and anxious tendencies predict worse suppression performance. While no suppression was shown when investigating the TNT not taking the psychometric measures into account, including these two traits in the analysis resulted in a pattern of below-baseline recall only for low brooders and low anxious participants. We argue that inclusion of variables measuring personality traits is warranted using the TNT and that these variables already exert their influence at minimal levels of variance, significantly improving the interpretability of the results. Future research should therefore cautiously investigate potential confounding personality characteristics before analysing their data.

Background: Animal as well as human research indicated that the ventral medial prefrontal cortex (vmPFC) is highly relevant for fear extinction learning. Recently, we showed that targeting the vmPFC with high-frequency repetitive transcranial magnetic stimulation (rTMS) in a placebo-controlled study with 45 healthy controls induced higher prefrontal activity during extinction of conditioned stimuli (CS+) in the active compared to the sham stimulated group and better extinction learning as indicated by ratings, fear potentiated startles and skin conductance responses. Objective: In this study, we aimed to proof our concept of accelerating extinction learning using rTMS of the mPFC in a group of anxiety disorder patients. Methods: To specifically evaluate the impact of rTMS on exposure-based therapy, we applied a sham-controlled protocol over the vmPFC (FPz) succeeded by a virtual reality exposure therapy (VRET) in n = 20 participants with acrophobia and n = 19 controls. Results: We found a significantly higher reduction in active compared to sham stimulated group for anxiety (t[37] = 2.33, p < 0.05) as well as avoidance ratings t[37] = 2.34, p < 0.05) from pre to post therapy. Conclusion: This study provides first clinical evidence that high-frequency rTMS over the vmPFC improves exposure therapy response of acrophobia symptoms.

Emotional processing is probably the most crucial tool for orienting oneself in our everyday social life and has been considered to be highly automatic for a long time. Dual task (DT) research shows that information competing for working memory resources impairs the identification of emotional facial expressions. Effects of cognitive load in DT paradigms have been confirmed in numerous neuroimaging studies. However, interference occurring during a DT comprised of decoding emotional facial expressions and a visuo-spatial working memory task has yet to be visualized. To investigate the DT interference effect on brain areas associated not only with working memory, but also emotional and visuo-spatial processing, we recorded brain activation within the prefrontal cortex and parietal-occipital sensory areas using functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG) simultaneously. Our study consisted of N = 36 participants (27 female) performing the following tasks: a) Corsi blocks, b) identification of emotional facial expressions or c) DT comprising of tasks a) and b). We predicted higher activation of the prefrontal cortex during DT and corresponding reduced P100 and P300 amplitudes. As expected, fNIRS measurements revealed significantly higher neuronal activation within the prefrontal cortex in the DT condition. When comparing DT to the single tasks, the P100 amplitude was reduced, but the P300 amplitude did not show the expected reduction. Our findings underline that at least some aspects of emotional processing are not entirely automatic, but depend on prefrontal control and are therefore affected by cognitive load, in particular visuo-spatial working memory resources.

Purpose: Clinical effects of repetitive transcranial magnetic stimulation (rTMS) in chronic tinnitus are moderate. More precise coil localisation strategies, innovative stimulation protocols, and identification of predictors for treatment response were proposed as promising attempts to enhance treatment efficacy. In this pilot study we investigated neuronavigated continuous theta burst TMS (cTBS). Methods: Twenty-three patients received neuronavigated cTBS over the left primary auditory cortex in a randomized sham-controlled trial (verum = 12; sham = 11). Treatment response was evaluated with tinnitus questionnaires and numeric rating scales. Immediate change in numeric rating scales during the first session was used as predictor for treatment response. Results: Tinnitus was significantly reduced after treatment, but there were no superior effects between verum vs. sham treatment. Immediate change in the first treatment session predicted the response to treatment only in the verum group. Conclusions: In our study, verum cTBS was not superior to sham which highlights the persistent need for improving non-invasive brain stimulation techniques for the treatment of tinnitus. Future research should focus on the transfer of positive single session effects to daily treatment trials.

Both the neuropeptide S (NPS) system and antagonism at the adenosine A2A receptor (e.g., by caffeine) were found to play a crucial role in the mediation of arousal and anxiety/panic in animal and human studies. Furthermore, a complex interaction of the neuropeptide S and the adenosinergic system has been suggested with administration of the adenosine A2A receptor antagonist caffeine downregulating NPS levels (Lage et al., 2006) and attenuating the stimulatory effects of NPS in rodents (Boeck et al., 2010).Thus, in the present study, the impact of the functional neuropeptide S receptor (NPSR) A/T (Asn(107)Ile; rs324981) variant on affect-modulated (neutral, unpleasant, and pleasant IAPS pictures) startle response depending on the administration of 300 mg caffeine citrate was investigated in a sample of 124 (m = 58, f = 66) healthy probands using a double-blind, placebo-controlled design.ANOVA revealed a significant interaction between NPSR genotype, challenge condition, and picture valence. Comparing startle magnitudes upon stimulation with neutral or emotional pictures between the placebo and caffeine condition, in AA/AT non-risk genotype carriers no significant difference was discerned, while TT risk genotype carriers showed a significantly increased startle magnitude in response to neutral stimuli (p = .02) and a significantly decreased startle magnitude in response to unpleasant stimuli (p = .02) in the caffeine condition as compared to the placebo condition.In summary, the present findings - extending previous evidence from rodent studies - for the first time provide support for a complex, non-linear interaction of the neuropeptide S and adenosinergic systems affecting the affect-modulated startle response as an intermediate phenotype of anxiety in humans.