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It is hypothesized that the ability to discriminate between threat and safety is impaired in individuals with high dispositional negativity, resulting in maladaptive behavior. A large body of research investigated differential learning during fear conditioning and extinction protocols depending on individual differences in intolerance of uncertainty (IU) and trait anxiety (TA), two closely-related dimensions of dispositional negativity, with heterogenous results. These might be due to varying degrees of induced threat/safety uncertainty. Here, we compared two groups with high vs. low IU/TA during periods of low (instructed fear acquisition) and high levels of uncertainty (delayed non-instructed extinction training and reinstatement). Dependent variables comprised subjective (US expectancy, valence, arousal), psychophysiological (skin conductance response, SCR, and startle blink), and neural (fMRI BOLD) measures of threat responding. During fear acquisition, we found strong threat/safety discrimination for both groups. During early extinction (high uncertainty), the low IU/TA group showed an increased physiological response to the safety signal, resulting in a lack of CS discrimination. In contrast, the high IU/TA group showed strong initial threat/safety discrimination in physiology, lacking discriminative learning on startle, and reduced neural activation in regions linked to threat/safety processing throughout extinction training indicating sustained but non-adaptive and rigid responding. Similar neural patterns were found after the reinstatement test. Taken together, we provide evidence that high dispositional negativity, as indicated here by IU and TA, is associated with greater responding to threat cues during the beginning of delayed extinction, and, thus, demonstrates altered learning patterns under changing environments.

Functional Near Infrared Spectroscopy (fNIRS) may be a suitable, simple, and cost-effective brain imaging technique for detecting divergent neuronal patterns at an early stage of neurodegeneration. In course of Mild Cognitive Impairment (MCI) or Alzheimer's disease (AD), a deficit in visual-spatial processing, located in the parietal cortex, is a reliable risk factor. Earlier, we established the application of the clock-hand-angle-discrimination task (ADT) during fNIRS to identify neuronal correlates of the visual-spatial processing in a healthy elderly sample. In this analysis, we aimed to measure and find out differences in the hemodynamic response in MCI participants compared to matched healthy controls. As expected, MCI participants showed more errors over all conditions of pointer length and a higher reaction time in the long and middle pointer length condition. Moreover, results revealed a significant reduction of cortical activation in MCI patients. There was a generally increased activity in both the right as compared to the left hemisphere and the superior parietal brain region as compared to the inferior parietal brain region in both groups. In summary, fNIRS can be implemented in the measurement of visual-spatial processing in MCI patients and healthy elderly based on ADT. MCI participants had difficulties to cope with the ADT. Since neuronal hypoactivity occurs with concomitant behavioral deficits, an additional analysis was performed on a subgroup of MCI patients who performed as well as the control group in behavior. This subgroup analysis also showed a hypoactivation of the parietal cortex, without evidence of a compensatory activation. Therefore, we assume that MCI patients are characterized by a deficit in the parietal cortex. Overall, these findings confirm our hypothesis that hemodynamic deficits in visual-spatial processing, localized in the parietal cortex, are reliable and early diagnostic markers for cognitive decline in risk groups for the development of AD.

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.

It is hypothesized that the ability to discriminate between threat and safety is impaired in individuals with high dispositional negativity, resulting in maladaptive behavior. A large body of research investigated differential learning during fear conditioning and extinction protocols depending on individual differences in intolerance of uncertainty (IU) and trait anxiety (TA), two closely-related dimensions of dispositional negativity, with heterogenous results. These might be due to varying degrees of induced threat/safety uncertainty. Here, we compared two groups with high vs. low IU/TA during periods of low (instructed fear acquisition) and high levels of uncertainty (delayed non-instructed extinction training and reinstatement). Dependent variables comprised subjective (US expectancy, valence, arousal), psychophysiological (skin conductance response, SCR, and startle blink), and neural (fMRI BOLD) measures of threat responding. During fear acquisition we found strong threat/safety discrimination for both groups. During early extinction (high uncertainty), the low IU/TA group showed an increased physiological response to the safety signal, resulting in a lack of CS discrimination. In contrast, the high IU/TA group showed strong initial threat/safety discrimination in physiology, lacking discriminative learning on startle, and reduced neural activation in regions linked to threat/safety processing throughout extinction training indicating sustained but non-adaptive and rigid responding. Similar neural patterns were found after the reinstatement test. Taken together, we provide evidence that high dispositional negativity, as indicated here by IU and TA, is associated with persistent responding to instructed threat cues despite increased ambiguity of the signaled threat and safety and, thus, impaired ability to adapt to changing environments.

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.

The hypothalamus is the main integrator of peripheral and central signals in the control of energy homeostasis. Its functional relevance for the effectivity of bariatric surgery is not entirely elucidated. Studying the effects of bariatric surgery in patients with hypothalamic damage might provide insight.Prospective study to analyze the effects of bariatric surgery in patients with hypothalamic obesity (HO) vs. matched patients with common obesity (CO) with and without bariatric surgery.65 participants were included (HO-surgery: n = 8, HO-control: n = 10, CO-surgery: n = 12, CO-control: n = 12, Lean-control: n = 23). Body weight, levels of anorexic hormones, gut microbiota, as well as subjective well-being/health status, eating behavior, and brain activity (via functional MRI) were evaluated.Patients with HO lost significantly less weight after bariatric surgery than CO-participants (total body weight loss %: 5.5 % vs. 26.2 %, p = 0.0004). After a mixed meal, satiety and abdominal fullness tended to be lowest in HO-surgery and did not correlate with levels of GLP-1 or PYY. Levels of PYY (11,151 ± 1667 pmol/l/h vs. 8099 ± 1235 pmol/l/h, p = 0.028) and GLP-1 (20,975 ± 2893 pmol/l/h vs. 13,060 ± 2357 pmol/l/h, p = 0.009) were significantly higher in the HO-surgery vs. CO-surgery group. Abundance of Enterobacteriaceae and Streptococcus was increased in feces of HO and CO after bariatric surgery. Comparing HO patients with lean-controls revealed an increased activation in insula and cerebellum to viewing high-caloric foods in left insula and cerebellum in fMRI.Hypothalamic integrity is necessary for the effectiveness of bariatric surgery in humans. Peripheral changes after bariatric surgery are not sufficient to induce satiety and long-term weight loss in patients with hypothalamic damage.

Alzheimer's disease (AD) is a growing challenge worldwide, which is why the search for early-onset predictors must be focused as soon as possible. Longitudinal studies that investigate courses of neuropsychological and other variables screen for such predictors correlated to mild cognitive impairment (MCI). However, one often neglected issue in analyses of such studies is measurement invariance (MI), which is often assumed but not tested for. This study uses the absence of MI (non-MI) and latent factor scores instead of composite variables to assess properties of cognitive domains, compensation mechanisms, and their predictability to establish a method for a more comprehensive understanding of pathological cognitive decline.An exploratory factor analysis (EFA) and a set of increasingly restricted confirmatory factor analyses (CFAs) were conducted to find latent factors, compared them with the composite approach, and to test for longitudinal (partial-)MI in a neuropsychiatric test battery, consisting of 14 test variables. A total of 330 elderly (mean age: 73.78 ± 1.52 years at baseline) were analyzed two times (3 years apart).EFA revealed a four-factor model representing declarative memory, attention, working memory, and visual-spatial processing. Based on CFA, an accurate model was estimated across both measurement timepoints. Partial non-MI was found for parameters such as loadings, test- and latent factor intercepts as well as latent factor variances. The latent factor approach was preferable to the composite approach.The overall assessment of non-MI latent factors may pose a possible target for this field of research. Hence, the non-MI of variances indicated variables that are especially suited for the prediction of pathological cognitive decline, while non-MI of intercepts indicated general aging-related decline. As a result, the sole assessment of MI may help distinguish pathological from normative aging processes and additionally may reveal compensatory neuropsychological mechanisms.

Models of anxiety disorders and the rationale of exposure therapy (ET) are grounded on classical fear conditioning. Yet, it is unclear whether lower fear ratings of conditioned safety versus threat cues and corresponding neural markers of safety-learning and/or fear inhibition assessed before treatment would predict better outcomes of behavioral exposure.Sixty-six patients with spider phobia completed pre-treatment clinical and experimental fear conditioning assessments, one session of virtual reality ET, a post-treatment clinical assessment, and a 6-month follow-up assessment. Tilted Gabor gratings served as conditioned stimuli (CS) that were either paired (CS+) or remained unpaired (CS-) with an aversive phobia-related and phobia-unrelated unconditioned stimulus (UCS). CS+/CS- differences in fear ratings and magnetoencephalographic event-related fields (ERFs) were related to percentual symptom reductions from pre- to post-treatment, as assessed via spider phobia questionnaire (SPQ), behavioral avoidance test (BAT), and remission status at 6-month follow-up.We observed no associations between pre-treatment CS+/CS- differences in fear ratings and any treatment outcome. CS+/CS- differences in source estimations of ERFs revealed that higher CS- activity in bilateral dorsolateral prefrontal cortex (dlPFC) was related with SPQ- and BAT-reductions. Associations between CS+/CS- differences and treatment outcomes were also observed in left ventromedial prefrontal cortex (vmPFC) regions, which additionally revealed associations with the follow-up remission status.Results provide initial evidence that neural pre-treatment CS+/CS- differences may hold predictive information regarding outcomes of behavioral exposure. Our findings highlight a key role of neural responses to safety cues with potentially inhibitory effects on affect-generating structures during fear conditioning.

ZUSAMMENFASSUNGGegenstand und Ziel: Obwohl stress- und angstbedingte Störungen weit verbreitet sind, ist die Wirksamkeit entsprechender therapeutischer Maßnahmen nicht optimal. In jüngster Zeit wurde in einer Reihe von Studien der zusätzliche Nutzen einer nicht invasiven Hirnstimulation (NIBS) bei der Psychotherapie von Angsterkrankungen untersucht. Um die Effektivität der Hirnstimulation in Kombination mit einer Psychotherapieweiter zu verbessern, ist es notwendig, die Modulation von therapierelevanten Lernprozessen besser zu verstehen.Material und Methode: In diesem systematischen Review werden die Studien dargestellt, die eine Modulation der Furchtextinktion beim Menschen mittels NIBS untersuchen.Ergebnisse: Insgesamt konnten 7 Studien identifiziert und analysiert werden, die entweder die repetitive transkranielle Magnetstimulation (rTMS) oder die transkranielle Gleichstromstimulation (tDCS) bei der Furchtextinktion verwenden.Schlussfolgerungen: Das Review zeigt, dass mittels NIBS das Extinktionslernen verbessert werden kann. Die Übertragung dieser Ergebnisse in klinische Studien wurde bereits begonnen, sodass damit zu rechnen ist, dass in den nächsten Jahren genauere Informationen zu den optimalen Stimulationsparametern vorliegen.

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.

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.

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.

Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) are a globally rising issue. It is necessary to detect such diseases early to find strategies for prevention. Typically, patients with MCI or AD show deviant neuronal patterns, which could be detected early through brain imaging techniques enabling assumptions about pre-existing diseases. Functional Near-Infrared Spectroscopy (fNIRS) is an appropriate imaging method because of its easy and economical nature with hardly any drawbacks. An early measurable risk factor indicating neurodegenerative processes could be a deficit in visual-spatial processing, which is localized in the parietal cortex. In this study, we aimed to measure the hemodynamic response of the visual-spatial processing in the healthy elderly participants of our long-term Vogel Study with fNIRS during the clock-hand-angle-discrimination task (ADT) to deepen our understanding of healthy brain mechanisms. Our results revealed for our healthy sample a significantly increased neuronal brain activity with increasing task difficulties, namely from the long to the middle to the short clock hand during ADT and significantly higher activation in the right hemisphere compared to the left hemisphere as well as in the superior parietal cortex compared to the inferior parietal cortex. Additionally, our behavioral data demonstrated longer reaction times and more errors with an increasing task requirement. We, therefore, assume that visual-spatial processing can successfully be operationalized with fNIRS for healthy elderly people based on ADT. Further fNIRS analyses are planned to investigate pathological neuronal correlates of visual-spatial function in MCI or AD study participants.

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).

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.

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

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.

International audience; There is growing interest in non-invasive brain stimulation (NIBS) as a novel treatment option for substance-use disorders (SUDs). Recent momentum stems from a foundation of preclinical neuroscience demonstrating links between neural circuits and drug consuming behavior, as well as recent FDA-approval of NIBS treatments for mental health disorders that share overlapping pathology with SUDs. As with any emerging field, enthusiasm must be tempered by reason; lessons learned from the past should be prudently applied to future therapies. Here, an international ensemble of experts provides an overview of the state of transcranial-electrical (tES) and transcranial-magnetic (TMS) stimulation applied in SUDs. This consensus paper provides a systematic literature review on published data - emphasizing the heterogeneity of methods and outcome measures while suggesting strategies to help bridge knowledge gaps. The goal of this effort is to provide the community with guidelines for best practices in tES/TMS SUD research. We hope this will accelerate the speed at which the community translates basic neuroscience into advanced neuromodulation tools for clinical practice in addiction medicine.

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.