Lack of evidence for predictive utility from resting state fMRI data for individual exposure-based cognitive behavioral therapy outcomes: A machine learning study in two large multi-site samples in anxiety disorders.

Data-based predictions of individual Cognitive Behavioral Therapy (CBT) treatment response are a fundamental step towards precision medicine. Past studies demonstrated only moderate prediction accuracy (i.e. ability to discriminate between responders and non-responders of a given treatment) when using clinical routine data such as demographic and questionnaire data, while neuroimaging data achieved superior prediction accuracy. However, these studies may be considerably biased due to very limited sample sizes and bias-prone methodology. Adequately powered and cross-validated samples are a prerequisite to evaluate predictive performance and to identify the most promising predictors. We therefore analyzed resting state functional magnet resonance imaging (rs-fMRI) data from two large clinical trials to test whether functional neuroimaging data continues to provide good prediction accuracy in much larger samples. Data came from two distinct German multicenter studies on exposure-based CBT for anxiety disorders, the Protect-AD and SpiderVR studies. We separately and independently preprocessed baseline rs-fMRI data from n = 220 patients (Protect-AD) and n = 190 patients (SpiderVR) and extracted a variety of features, including ROI-to-ROI and edge-functional connectivity, sliding-windows, and graph measures. Including these features in sophisticated machine learning pipelines, we found that predictions of individual outcomes never significantly differed from chance level, even when conducting a range of exploratory post-hoc analyses. Moreover, resting state data never provided prediction accuracy beyond the sociodemographic and clinical data. The analyses were independent of each other in terms of selecting methods to process resting state data for prediction input as well as in the used parameters of the machine learning pipelines, corroborating the external validity of the results. These similar findings in two independent studies, analyzed separately, urge caution regarding the interpretation of promising prediction results based on neuroimaging data from small samples and emphasizes that some of the prediction accuracies from previous studies may result from overestimation due to homogeneous data and weak cross-validation schemes. The promise of resting-state neuroimaging data to play an important role in the prediction of CBT treatment outcomes in patients with anxiety disorders remains yet to be delivered.

Higher-order comparative reward processing is affected by noninvasive stimulation of the ventromedial prefrontal cortex.

A crucial skill, especially in rapidly changing environments, is to be able to learn efficiently from prior rewards or losses and apply this acquired knowledge in upcoming situations. Often, we must weigh the risks of different options and decide whether an option is worth the risk or whether we should choose a safer option. The ventromedial prefrontal cortex (vmPFC) is suggested as a major hub for basic but also higher-order reward processing. Dysfunction in this region has been linked to cognitive risk factors for depression and behavioral addictions, including reduced optimism and feedback learning. Here, we test whether modulations of vmPFC excitability via noninvasive transcranial direct current stimulation (tDCS) can alter reward anticipation and reward processing. In a financial gambling task, participants chose between a higher and a lower monetary risk option and eventually received feedback whether they won or lost. Simultaneously feedback on the unchosen option was presented as well. Behavioral and magnetoencephalographic correlates of reward processing were evaluated in direct succession of either excitatory or inhibitory tDCS of the vmPFC. We were able to show modulated reward approach behavior (expectancy of greater reward magnitudes) as well as altered reevaluation of received feedback by vmPFC tDCS as indicated by modified choice behavior following the feedback. Thereby, tDCS not only influenced early, rather basic reward processing, but it also modulated higher-order comparative feedback evaluation of gains and losses relative to alternative outcomes. The neural results underline this idea, as stimulation-driven modulations of the basic reward-related effect occurred at rather early time intervals and were followed by stimulation effects related to comparative reward processing. Importantly, behavioral ratings were correlated with neural activity in left frontal areas. Our results imply a dual function of the vmPFC consisting of approaching reward (as indicated by more risky choices) and elaborately evaluating outcomes. In addition, our data suggest that vmPFC activity is associated with adaptive decision-making in the future via modulated behavioral adaptation or reinforcement learning.

Tinnitus-on the interplay between emotion and cognition.

Subjective tinnitus (hereafter tinnitus) is often considered and studied as a perceptual phenomenon. Accordingly, various abnormalities in the area of cognitive processing have been reported in patients with tinnitus. At the same time, the disorder is characterized by considerable emotional distress, which is associated with a high comorbidity of affective disorders. Here, we aim to outline the close link between cognition and emotion, and how current research from the field of cognitive neuroscience examines the processing and acquisition of emotional stimuli. The emotional valence of stimuli can be acquired after brief exposure to learning, leading from neutral to appetitive or aversive evaluation. In contrast to neutral stimuli, emotional stimuli attract attention very early (about 100 ms) during processing, leading to deeper processing and corresponding memory effects. The involved subcortical and cortical network encompasses limbic and sensory areas. In particular, prefrontal regions are involved in the acquisition and evaluation of emotional stimuli as also shown in studies of patients with affect disorders. The interplay of cognitive and emotional processes seems to be central to the development, maintenance, and treatment of tinnitus.

[Tinnitus-on the interplay between emotion and cognition. German version]. / Tinnitus im Wechselspiel zwischen Emotion und Kognition.

Subjective tinnitus (hereafter tinnitus) is often considered and studied as a perceptual phenomenon. Accordingly, various abnormalities in the area of cognitive processing have been reported in patients with tinnitus. At the same time, the disorder is characterized by considerable emotional distress, which is associated with a high comorbidity of affective disorders. Here, we aim to outline the close link between cognition and emotion, and how current research from the field of cognitive neuroscience examines the processing and acquisition of emotional stimuli. The emotional valence of stimuli can be acquired after brief exposure to learning, leading from neutral to appetitive or aversive evaluation. In contrast to neutral stimuli, emotional stimuli attract attention very early (about 100 ms) during processing, leading to deeper processing and corresponding memory effects. The involved subcortical and cortical network encompasses limbic and sensory areas. In particular, prefrontal regions are involved in the acquisition and evaluation of emotional stimuli as also shown in studies of patients with affect disorders. The interplay of cognitive and emotional processes seems to be central to the development, maintenance, and treatment of tinnitus.

Tinnitus and Multimodal Cortical Interaction. / Tinnitus und multimodale kortikale Interaktion.

The term of subjective tinnitus is used to describe a perceived noise without an external sound source. Therefore, it seems to be obvious that tinnitus can be understood as purely auditory, sensory problem. From a clinical point of view, however, this is a very inadequate description, as there are significant comorbidities associated with chronic tinnitus. Neurophysiological investigations with different imaging techniques give a very similar picture, because not only the auditory system is affected in chronic tinnitus patients, but also a widely ramified subcortical and cortical network. In addition to auditory processing systems, networks consisting of frontal and parietal regions are particularly disturbed. For this reason, some authors conceptualize tinnitus as a network disorder rather than a disorder of a circumscribed system. These findings and this concept suggest that tinnitus must be diagnosed and treated in a multidisciplinary and multimodal manner.

Testing the effect of tACS over parietal cortex in modulating endogenous alpha rhythm and temporal integration windows in visual perception.

Neural oscillations in the alpha band (8-12 Hz) have been proposed as a key mechanism for the temporal resolution of visual perception. Higher alpha frequencies have been related to improved segregation of visual events over time, whereas lower alpha frequencies have been related to improved temporal integration. Similarly, also the phase of ongoing alpha has been shown to correlate with temporal integration/segregation. To test a causal relationship between alpha oscillations and perception, we here employed multi-channel transcranial alternating current stimulation (mc-tACS) over the right parietal cortex, whereas participants performed a visual temporal integration/segregation task that used identical stimuli with different instructions. Before and after mc-tACS we recorded the resting-state electroencephalogram (EEG) to extract the individual alpha frequency (IAF) and delivered electrical stimulation at slightly slower and faster frequencies (IAF±2 Hz). We hypothesized that this would not only drive endogenous alpha rhythms, but also affect temporal integration and segregation in an opposite way. However, the mc-tACS protocol used here did not consistently increase or decrease the IAF after the stimulation and did not affect temporal integration/segregation accuracy as expected. Although we found some preliminary evidence for an influence of tACS phase on temporal integration accuracy, the ongoing phase of mc-tACS oscillations did not reliably modulate temporal integration/segregation accuracy in a sinusoidal way as would have been predicted by an effective entrainment of brain oscillations. These findings may guide future studies using different stimulation montages for investigating the role of cortical alpha oscillations for human vision.

Neural processing of emotional facial stimuli in specific phobia: An fMRI study.

BACKGROUND: Patients with specific phobia (SP) show altered brain activation when confronted with phobia-specific stimuli. It is unclear whether this pathogenic activation pattern generalizes to other emotional stimuli. This study addresses this question by employing a well-powered sample while implementing an established paradigm using nonspecific aversive facial stimuli. METHODS: N = 111 patients with SP, spider subtype, and N = 111 healthy controls (HCs) performed a supraliminal emotional face-matching paradigm contrasting aversive faces versus shapes in a 3-T magnetic resonance imaging scanner. We performed region of interest (ROI) analyses for the amygdala, the insula, and the anterior cingulate cortex using univariate as well as machine-learning-based multivariate statistics based on this data. Additionally, we investigated functional connectivity by means of psychophysiological interaction (PPI). RESULTS: Although the presentation of emotional faces showed significant activation in all three ROIs across both groups, no group differences emerged in all ROIs. Across both groups and in the HC > SP contrast, PPI analyses showed significant task-related connectivity of brain areas typically linked to higher-order emotion processing with the amygdala. The machine learning approach based on whole-brain activity patterns could significantly differentiate the groups with 73% balanced accuracy. CONCLUSIONS: Patients suffering from SP are characterized by differences in the connectivity of the amygdala and areas typically linked to emotional processing in response to aversive facial stimuli (inferior parietal cortex, fusiform gyrus, middle cingulate, postcentral cortex, and insula). This might implicate a subtle difference in the processing of nonspecific emotional stimuli and warrants more research furthering our understanding of neurofunctional alteration in patients with SP.

Ratings of Emotional Expressions in Static and Dynamic Facial Recordings Before and After Upper Face Botulinum Injections-An Observational Prospective Study.

BACKGROUND: Botulinum toxin A (BTX), a neurotoxin widely used for facial aesthetics, causes dose-dependent muscle paralysis. It was hypothesized that treatment of mimic muscles with BTX might have a positive impact on emotional expression in static images (photographs), but a negative impact in dynamic recordings (videos). OBJECTIVES: The aim of this study was to compare of emotional expression recorded in photographs and videos before and after treatment with BTX. METHODS: Twenty healthy women (mean age, 45 years) received a dose of 19 mouse units of XEOMIN (Merz, Frankfurt am Main, Germany) into the procerus, occipitofrontalis, and orbicularis oculi muscles. Photographs and videos of the participants' faces with neutral and happy expressions were recorded before treatment and 2 weeks later. Recordings were rated by naive raters blind to the conditions and in balanced order. RESULTS: Videos were generally rated as more pleasant, arousing, attractive, and genuine than photographs (all Ps > 0.001). This was especially the case for videos with neutral expression (P = 0.003). Independent of presentation mode and facial expression, women were rated as more attractive after BTX treatment (P = 0.03). CONCLUSIONS: In contrast to the hypothesis, the reduced mobility had no detectable negative impact on dynamic emotional expression, but videos received more positive ratings, particularly for neutral expressions. It is thus recommended to assess emotional expression with dynamic recordings to evaluate the effects of treatment with BTX. BTX seems to improve perceived attractiveness, although the cause of this effect remains unclear.

Contextual information resolves uncertainty about ambiguous facial emotions: Behavioral and magnetoencephalographic correlates.

Environmental conditions bias our perception of other peoples' facial emotions. This becomes quite relevant in potentially threatening situations, when a fellow's facial expression might indicate potential danger. The present study tested the prediction that a threatening environment biases the recognition of facial emotions. To this end, low- and medium-expressive happy and fearful faces (morphed to 10%, 20%, 30%, or 40% emotional) were presented within a context of instructed threat-of-shock or safety. Self-reported data revealed that instructed threat led to a biased recognition of fearful, but not happy facial expressions. Magnetoencephalographic correlates revealed spatio-temporal clusters of neural network activity associated with emotion recognition and contextual threat/safety in early to mid-latency time intervals in the left parietal cortex, bilateral prefrontal cortex, and the left temporal pole regions. Early parietal activity revealed a double dissociation of face-context information as a function of the expressive level of facial emotions: When facial expressions were difficult to recognize (low-expressive), contextual threat enhanced fear processing and contextual safety enhanced processing of subtle happy faces. However, for rather easily recognizable faces (medium-expressive) the left hemisphere (parietal cortex, PFC, and temporal pole) showed enhanced activity to happy faces during contextual threat and fearful faces during safety. Thus, contextual settings reduce the salience threshold and boost early face processing of low-expressive congruent facial emotions, whereas face-context incongruity or mismatch effects drive neural activity of easier recognizable facial emotions. These results elucidate how environmental settings help recognize facial emotions, and the brain mechanisms underlying the recognition of subtle nuances of fear.

Acute aerobic exercise enhances pleasant compared to unpleasant visual scene processing.

Although acute aerobic exercise benefits different aspects of emotional functioning, it is unclear how exercise influences the processing of emotional stimuli and which brain mechanisms support this relationship. We assessed the influence of acute aerobic exercise on valence biases (preferential processing of negative/positive pictures) by performing source reconstructions of participants' brain activity after they viewed emotional scenes. Twenty-four healthy participants (12 women) were tested in a randomized and counterbalanced design that consisted of three experimental protocols, each lasting 30 min: low-intensity exercise (Low-Int); moderate-intensity exercise (Mod-Int); and a seated rest condition (REST). After each of the protocols, participants viewed negative and positive pictures, during which event-related magnetic fields were recorded. Analyses revealed that exercise strongly impacted the valence processing of emotional scenes within a widely distributed left hemispheric spatio-temporal cluster between 190 and 310 ms after picture onset. Brain activity in this cluster showed that a negativity bias at REST (negative > positive picture processing) diminished after the Low-Int condition (positive = negative) and even reversed to a positivity bias after the Mod-Int condition (positive > negative). Thus, acute aerobic exercise of low and moderate intensities induces a positivity bias which is reflected in early, automatic processes.

Biased emotional attention in patients with dental phobia.

Biased motivated attention towards phobia-relevant pictures is a typical finding in specific phobia. In the visual system, the allocation of motivated attention is indexed by two event-related potential components - the Early Posterior Negativity and the Late Positive Potential. Enhanced Early Posterior Negativity and Late Positive Potential amplitudes are reliably observed in specific phobia such as, for instance, snake, spider, or blood-injection-injury phobia and to some extent also in dental phobia. However, regarding dental phobia results are sparse and its theoretical concept is not undisputed. To further elucidate the electrophysiological characteristics of dental phobia, we investigated visual emotional processing in dental phobia patients and controls. Subjects viewed neutral, phobia-irrelevant and phobia-relevant pictures while magnetoencephalographic and behavioural measures were recorded. All patients reported a history of traumatic experiences and depressive and anxiety symptoms, as well as dissociative and posttraumatic symptoms. In the magnetoencephalography, patients showed generally less evoked neural activation at parietal and temporal regions and a reduced differentiation between picture categories compared to controls. At the behavioural level, patients rated phobia-relevant pictures as clearly more negative as did controls. In contrast to previous reports, our results suggest that dental phobia cannot be associated with the typical effects of biased motivated attention seen in other specific phobias. Instead, results indicate that dental phobia shares typical characteristics with mild forms of posttraumatic stress disorder.

Noninvasive stimulation of the ventromedial prefrontal cortex modulates emotional face processing.

The ventromedial prefrontal cortex (vmPFC) is associated with emotional states that can be characterized as positive affect. Moreover, a variety of psychiatric disorders that are associated with disturbed reactions toward reward- or safety-signaling stimuli reveal functional or structural anomalies within this area. Thus, neuromodulation of this region via transcranial direct current stimulation (tDCS) offers an attractive opportunity to noninvasively influence pleasant emotional and reward processing. Recent experiments revealed hemodynamic and electrophysiological evidence for valence specific modulations of emotional scene processing after excitatory and inhibitory tDCS of the vmPFC. Here, we identified that tDCS modulation of vmPFC during emotional face processing results in effects convergent with scene processing, in that excitatory tDCS increased neural reactivity during happy compared to fearful face perception, whereas inhibitory stimulation led to a converse effect. In addition, behavioral data (affect identification of ambiguous expressive faces) revealed a bias toward preferential processing of happy compared to fearful faces after excitatory compared to after inhibitory stimulation. These results further support the vmPFC as an appropriate target for noninvasive neuromodulation of an appetitive processing network in patients suffering from disturbed cognition of reward- and safety-signaling stimuli. It should however be noted that electrophysiological pre-tDCS differences at earlier time intervals of emotional face and scene processing appeared amplified by tDCS, which remains to be investigated.

Noninvasive Stimulation of the Ventromedial Prefrontal Cortex Enhances Pleasant Scene Processing.

Depressive patients typically show biased attention towards unpleasant and away from pleasant emotional material. Imaging studies suggest that dysfunctions in a distributed neural network, including the ventromedial prefrontal cortex (vmPFC), are associated with this processing bias. Accordingly, changes in vmPFC activation should mediate changes in processing of emotional stimuli. Here, we investigated the effect of inhibitory and excitatory transcranial direct current stimulation (tDCS) of the vmPFC on emotional scene processing in two within-subject experiments using functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). Both studies showed that excitatory relative to inhibitory tDCS amplifies processing of pleasant compared to unpleasant scenes in healthy participants. This modulatory effect occurred in a distributed network including sensory and prefrontal cortex regions and was visible during very early to late processing stages. Findings are discussed with regard to neurophysiological models of emotional processing. The convergence of stimulation effects across independent groups of healthy participants and complementary neuroimaging methods (fMRI, MEG) provides a basis for further investigation of a potentially therapeutic use of this novel stimulation approach in patients with depression or other affective disorders.

No differential effects to facial expressions under continuous flash suppression: An event-related potentials study.

In recent years continuous flash suppression (CFS) has become a popular "blinding" technique for the investigation of nonconscious affective processing since it elicits potent and long-lasting suppression of conscious visual perception. While the majority of studies provides some positive evidence for nonconscious affective processing, there are also studies reporting their absence. Several methodological variations may give rise to this discrepancy: with respect to the experimental paradigm these variations pertain to the likelihood of residual stimulus visibility on the level of individual participants and single trials. Concerning the statistical analysis they relate to the procedures applied to assess whether detection performance is at chance level and whether the outcome measure does or does not depend on the affective stimulus category. In the present study we determined individual eye dominance and individual stimulus contrast in pretests, measured objective and subjective awareness online and applied Bayesian statistics to estimate the likelihood for the null hypothesis. Event-related potentials (ERPs) were measured while participants were subjected to fearful, happy, and neutral faces in a conscious as well as in a nonconscious CFS condition. In the conscious condition, expected emotion effects were observed in the ERP components N170/EPN and LPP. However, despite high statistical power, no effects of emotional expression were found in the nonconscious condition and the absence of nonconscious affective processing under the tested conditions was substantially more likely than its presence. We discuss whether CFS disrupts affective processing completely if thoroughly applied or whether positive and negative findings should be integrated under a two-threshold framework of nonconscious processing.

Hypervigilance-avoidance in children with anxiety disorders: magnetoencephalographic evidence.

BACKGROUND: An altered pattern of threat processing is deemed critical for the development of anxiety disorders (AD). According to the hypervigilance-avoidance hypothesis, AD patients show hypervigilance to threat cues at early stages of processing but avoid threat cues at later stages of processing. Consistently, adults with AD show enhanced neurophysiological responses to threat in early time windows and reduced responses to threat in late time windows. The presence of such a hypervigilance-avoidance effect and its underlying neural sources remain to be determined in clinically anxious children. METHODS: Twenty-three children diagnosed with an AD and 23 healthy control children aged 8-14 years saw faces with angry and neutral expressions while whole-head magnetoencephalography (MEG) was recorded. Neural sources were estimated based on L2-Minimum Norm inverse source modeling and analyzed in early, midlatency, and late time windows. RESULTS: In visual cortical regions, early threat processing was relatively enhanced in patients compared to controls, whereas this relation was inverted in a late interval. Consistent with the idea of affective regulation, the right dorsolateral prefrontal cortex revealed relatively reduced inhibition of early threat processing but revealed enhanced inhibition at a late interval in patients. Both visual-sensory and prefrontal effects were correlated with individual trait anxiety. CONCLUSIONS: These results support the hypothesis of early sensory hypervigilance followed by later avoidance of threat in anxiety disordered children, presumably modulated by early reduced and later enhanced prefrontal inhibition. This neuronal hypervigilance-avoidance pattern unfolds gradually with increasing trait anxiety, reflecting a progressively biased allocation of attention to threat.

Healthy individuals maintain adaptive stimulus evaluation under predictable and unpredictable threat.

The anxiety inducing paradigms such as the threat-of-shock paradigm have provided ample data on the emotional processing of predictable and unpredictable threat, but little is known about the processing of aversive, threat-irrelevant stimuli in these paradigms. We investigated how the predictability of threat influences the neural visual processing of threat-irrelevant fearful and neutral faces. Thirty-two healthy individuals participated in an NPU-threat test, consisting of a safe or neutral condition (N) and a predictable (P) as well as an unpredictable (U) threat condition, using audio-visual threat stimuli. In all NPU-conditions, we registered participants' brain responses to threat-irrelevant faces via magnetoencephalography. The data showed that increasing unpredictability of threat evoked increasing emotion regulation during face processing predominantly in dorsolateral prefrontal cortex regions during an early to mid-latency time interval. Importantly, we obtained only main effects but no significant interaction of facial expression and conditions of different threat predictability, neither in behavioral nor in neural data. Healthy individuals with average trait anxiety are thus able to maintain adaptive stimulus evaluation processes under predictable and unpredictable threat conditions.

Magnetoencephalographic Correlates of Emotional Processing in Major Depression Before and After Pharmacological Treatment.

BACKGROUND: In major depressive disorder (MDD), electrophysiological and imaging studies suggest reduced neural activity in the parietal and dorsolateral prefrontal cortex regions. In the present study, neural correlates of emotional processing in MDD were analyzed for the first time in a pre-/post-treatment design by means of magnetoencephalography (MEG), allowing for detecting temporal dynamics of brain activation. METHODS: Twenty-five medication-free Caucasian in-patients with MDD and 25 matched controls underwent a baseline MEG session with passive viewing of pleasant, unpleasant, and neutral pictures. Fifteen patients were followed-up with a second MEG session after 4 weeks of antidepressant monopharmacotherapy with mirtazapine. The corresponding controls received no intervention between the measurements. The clinical course of depression was assessed using the Hamilton Depression scale. RESULTS: Prior to treatment, an overall neocortical hypoactivation during emotional processing, particularly at the parietal regions and areas at the right temporoparietal junction, as well as abnormal valence-specific reactions at the right parietal and bilateral dorsolateral prefrontal cortex (dlPFC) regions were observed in patients compared to controls. These effects occurred <150 ms, suggesting dysfunctional processing of emotional stimuli at a preconscious level. Successful antidepressant treatment resulted in a normalization of the hypoactivation at the right parietal and right temporoparietal regions. Accordingly, both dlPFC regions revealed an increase of activity after therapy. CONCLUSIONS: The present study provides neurophysiological evidence for dysfunctional emotional processing in a fronto-parieto-temporal network, possibly contributing to the pathogenesis of MDD. These activation patterns might have the potential to serve as biomarkers of treatment success.

Inhibitory repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex modulates early affective processing.

The dorsolateral prefrontal cortex (dlPFC) has often been suggested as a key modulator of emotional stimulus appraisal and regulation. Therefore, in clinical trials, it is one of the most frequently targeted regions for non-invasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS). In spite of various encouraging reports that demonstrate beneficial effects of rTMS in anxiety disorders, psychophysiological studies exploring the underlying neural mechanisms are sparse. Here we investigated how inhibitory rTMS influences early affective processing when applied over the right dlPFC. Before and after rTMS or sham stimulation, subjects viewed faces with fearful or neutral expressions while whole-head magnetoencephalography (MEG) was recorded. Due to the disrupted functioning of the right dlPFC, visual processing in bilateral parietal, temporal, and occipital areas was amplified starting at around 90 ms after stimulus onset. Moreover, increased fear-specific activation was found in the right TPJ area in a time-interval between 110 and 170 ms. These neurophysiological effects were reflected in slowed reaction times for fearful, but not for neutral faces in a facial expression identification task while there was no such effect on a gender discrimination control task. Our study confirms the specific and important role of the dlPFC in regulation of early emotional attention and encourages future clinical research to use minimal invasive methods such as transcranial magnetic (TMS) or direct current stimulation (tDCS).

How 'love' and 'hate' differ from 'sleep': using combined electro/magnetoencephalographic data to reveal the sources of early cortical responses to emotional words.

Emotional words--as symbols for biologically relevant concepts--are preferentially processed in brain regions including the visual cortex, frontal and parietal regions, and a corticolimbic circuit including the amygdala. Some of the brain structures found in functional magnetic resonance imaging are not readily apparent in electro- and magnetoencephalographic (EEG; MEG) measures. By means of a combined EEG/MEG source localization procedure to fully exploit the available information, we sought to reduce these discrepancies and gain a better understanding of spatiotemporal brain dynamics underlying emotional-word processing. Eighteen participants read high-arousing positive and negative, and low-arousing neutral nouns, while EEG and MEG were recorded simultaneously. Combined current-density reconstructions (L2-minimum norm least squares) for two early emotion-sensitive time intervals, the P1 (80-120 ms) and the early posterior negativity (EPN, 200-300 ms), were computed using realistic individual head models with a cortical constraint. The P1 time window uncovered an emotion effect peaking in the left middle temporal gyrus. In the EPN time window, processing of emotional words was associated with enhanced activity encompassing parietal and occipital areas, and posterior limbic structures. We suggest that lexical access, being underway within 100 ms, is speeded and/or favored for emotional words, possibly on the basis of an "emotional tagging" of the word form during acquisition. This gives rise to their differential processing in the EPN time window. The EPN, as an index of natural selective attention, appears to reflect an elaborate interplay of distributed structures, related to cognitive functions, such as memory, attention, and evaluation of emotional stimuli.

Association between resting-state connectivity patterns in the defensive system network and treatment response in spider phobia-a replication approach.

Although highly effective on average, exposure-based treatments do not work equally well for all patients with anxiety disorders. The identification of pre-treatment response-predicting patient characteristics may enable patient stratification. Preliminary research highlights the relevance of inhibitory fronto-limbic networks as such. We aimed to identify pre-treatment neural signatures differing between exposure treatment responders and non-responders in spider phobia and to validate results through rigorous replication. Data of a bi-centric intervention study comprised clinical phenotyping and pre-treatment resting-state functional connectivity (rsFC) data of n = 79 patients with spider phobia (discovery sample) and n = 69 patients (replication sample). RsFC data analyses were accomplished using the Matlab-based CONN-toolbox with harmonized analyses protocols at both sites. Treatment response was defined by a reduction of >30% symptom severity from pre- to post-treatment (Spider Phobia Questionnaire Score, primary outcome). Secondary outcome was defined by a reduction of >50% in a Behavioral Avoidance Test (BAT). Mean within-session fear reduction functioned as a process measure for exposure. Compared to non-responders and pre-treatment, results in the discovery sample seemed to indicate that responders exhibited stronger negative connectivity between frontal and limbic structures and were characterized by heightened connectivity between the amygdala and ventral visual pathway regions. Patients exhibiting high within-session fear reduction showed stronger excitatory connectivity within the prefrontal cortex than patients with low within-session fear reduction. Whereas these results could be replicated by another team using the same data (cross-team replication), cross-site replication of the discovery sample findings in the independent replication sample was unsuccessful. Results seem to support negative fronto-limbic connectivity as promising ingredient to enhance response rates in specific phobia but lack sufficient replication. Further research is needed to obtain a valid basis for clinical decision-making and the development of individually tailored treatment options. Notably, future studies should regularly include replication approaches in their protocols.