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Background Individuals with bipolar disorder are commonly correctly diagnosed a decade after symptom onset. Machine learning techniques may aid in early recognition and reduce the disease burden. As both individuals at risk and those with a manifest disease display structural brain markers, structural magnetic resonance imaging may provide relevant classification features. Methods Following a pre-registered protocol, we trained linear support vector machine (SVM) to classify individuals according to their estimated risk for bipolar disorder using regional cortical thickness of help-seeking individuals from seven study sites (N = 276). We estimated the risk using three state-of-the-art assessment instruments (BPSS-P, BARS, EPIbipolar). Results For BPSS-P, SVM achieved a fair performance of Cohen's κ of 0.235 (95% CI 0.11–0.361) and a balanced accuracy of 63.1% (95% CI 55.9–70.3) in the 10-fold cross-validation. In the leave-one-site-out cross-validation, the model performed with a Cohen's κ of 0.128 (95% CI −0.069 to 0.325) and a balanced accuracy of 56.2% (95% CI 44.6–67.8). BARS and EPIbipolar could not be predicted. In post hoc analyses, regional surface area, subcortical volumes as well as hyperparameter optimization did not improve the performance. Conclusions Individuals at risk for bipolar disorder, as assessed by BPSS-P, display brain structural alterations that can be detected using machine learning. The achieved performance is comparable to previous studies which attempted to classify patients with manifest disease and healthy controls. Unlike previous studies of bipolar risk, our multicenter design permitted a leave-one-site-out cross-validation. Whole-brain cortical thickness seems to be superior to other structural brain features.

Laughter plays an important role in group formation, signaling social belongingness by indicating a positive or negative social intention towards the receiver. In adults without autism, the intention of laughter can be correctly differentiated without further contextual information. In autism spectrum disorder (ASD), however, differences in the perception and interpretation of social cues represent a key characteristic of the disorder. Studies suggest that these differences are associated with hypoactivation and altered connectivity among key nodes of the social perception network. How laughter, as a multimodal nonverbal social cue, is perceived and processed neurobiologically in association with autistic traits has not been assessed previously. We investigated differences in social intention attribution, neurobiological activation, and connectivity during audiovisual laughter perception in association with the degree of autistic traits in adults [N = 31, Mage (SD) = 30.7 (10.0) years, nfemale = 14]. An attenuated tendency to attribute positive social intention to laughter was found with increasing autistic traits. Neurobiologically, autistic trait scores were associated with decreased activation in the right inferior frontal cortex during laughter perception and with attenuated connectivity between the bilateral fusiform face area with bilateral inferior and lateral frontal, superior temporal, mid-cingulate and inferior parietal cortices. Results support hypoactivity and hypoconnectivity during social cue processing with increasing ASD symptoms between socioemotional face processing nodes and higher-order multimodal processing regions related to emotion identification and attribution of social intention. Furthermore, results reflect the importance of specifically including signals of positive social intention in future studies in ASD.

Objectives: In bipolar disorder (BD), the alternation of extreme and sustained positive and negative mood states indicates deficits in emotion processing. These alterations in emotion processing are accompanied by aberrant neural function of the emotion network. Focusing on the amygdala as the central node of this network, the present study aimed to investigate the effects of an emotion-centered psychotherapeutic intervention on amygdala responsivity and connectivity during emotional face processing in BD.Methods: In a randomized controlled trial within the multicentric BipoLife project, euthymic BD patients received one of two interventions over six months: an emotion-focused intervention where patients were guided to adequately perceive and label their emotions (FEST, n = 28) or a specific, cognitive-behavioral intervention (SEKT, n = 31). Before and after interventions, patients completed an established emotional face-matching paradigm contrasting emotional faces versus shapes during functional magnetic resonance imaging (fMRI). Healthy controls (n = 32) were scanned twice after the same interval without receiving any intervention. Given the focus of FEST on emotion processing, we expected the FEST intervention to strengthen amygdala activation and connectivity. Results: Clinically, both interventions effectively stabilized patients’ euthymic states in terms of affective symptoms. At the neural level, FEST versus SEKT showed increased amygdala activation and connectivity with the insula at post relative to prae-intervention timepoint. In FEST, the increase in amygdala activation was further associated with fewer depressive symptoms (r = .72) six months post-intervention. Conclusion: Enhanced activation and functional connectivity of the amygdala during emotional face-matching for FEST versus SEKT may represent a neural marker of improved emotion processing and remediated depressive symptoms thus promoting the FEST intervention as effective tool in the relapse prevention treatment of BD.

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (dlPFC) is currently evolving as an effective and safe therapeutic tool in the treatment of major depressive disorder (MDD). However, already established rTMS treatment paradigms are rather time-consuming. With theta burst stimulation (TBS), a patterned form of rTMS, treatment time can be substantially reduced. Pilot studies and a randomized controlled trial (RCT) demonstrate non-inferiority of TBS to 10 Hz rTMS and support a wider use in MDD. Still, data from placebo-controlled multicenter RCTs are lacking. In this placebo-controlled multicenter study, 236 patients with MDD will be randomized to either intermittent TBS (iTBS) to the left and continuous TBS (cTBS) to the right dlPFC or bilateral sham stimulation (1:1 ratio). The treatment will be performed with 80% resting motor threshold intensity over six consecutive weeks (30 sessions). The primary outcome is the treatment response rate (Montgomery-Asberg Depression Rating Scale reduction ≥ 50%). The aim of the study is to confirm the superiority of active bilateral TBS compared to placebo treatment. In two satellite studies, we intend to identify possible MRI-based and (epi-)genetic predictors of responsiveness to TBS therapy. Positive results will support the clinical use of bilateral TBS as an advantageous, efficient, and well-tolerated treatment and pave the way for further individualization of MDD therapy.Trial registration: ClinicalTrials.gov (NCT04392947).

Background Deficits in emotion recognition have been repeatedly documented in patients diagnosed with attention-deficit/hyperactivity disorder (ADHD), but their neural basis is unknown so far. Methods In the current study, adult patients with ADHD (n = 44) and healthy control subjects (n = 43) underwent functional magnetic resonance imaging during explicit emotion recognition of stimuli expressing affective information in face, voice, or face–voice combinations. The employed experimental paradigm allowed us to delineate areas for processing audiovisual information based on their functional activation profile, including the bilateral posterior superior temporal gyrus/middle temporal gyrus, amygdala, medial prefrontal cortex, and precuneus, as well as the right posterior thalamus. Results As expected, unbiased hit rates for correct classification of the expressed emotions were lower in patients with ADHD than in healthy control subjects irrespective of the presented sensory modality. This deficit at a behavioral level was accompanied by lower activation in patients with ADHD versus healthy control subjects in the cortex adjacent to the right superior temporal gyrus/middle temporal gyrus and the right posterior thalamus, which represent key areas for processing socially relevant signals and their integration across modalities. A cortical region adjacent to the right posterior superior temporal gyrus was the only brain region that showed a significant correlation between brain activation and emotion identification performance. Conclusions Altogether, these results provide the first evidence for a potential neural substrate of the observed impairments in emotion recognition in adults with ADHD.

EEG studies have shown that adult ADHD patients have less stable brain arousal regulation than age and gender matched controls. Psychostimulants have brain arousal stabilising properties evident in EEG patterns. The aim of this study was to investigate whether the stability of brain arousal regulation has prognostic value in predicting response to methylphenidate therapy in adult ADHD patients. In an open-label, single-arm, multi-centre, confirmatory trial, 121 adult ADHD patients were recruited and 112 qualified for the full analysis set. All participants received an initial dose of 20 mg extended release methylphenidate at baseline. After a titration phase of up to 4 weeks, patients remained on a weight-based target dose of extended release methylphenidate for 4 weeks. Using the Vigilance Algorithm Leipzig (VIGALL 2.1), we assessed brain arousal regulation before the treatment with methylphenidate, based on a 15-min EEG at quiet rest recorded at baseline. Using automatic stage-classification of 1 s segments, we computed the mean EEG-vigilance (indexing arousal level) and an arousal stability score (indexing arousal regulation). The primary endpoint was the association between successful therapy, defined by a 30% reduction in CAARS, and stable/unstable brain arousal. 52 patients (46%) showed an unstable brain arousal regulation of which 23% had therapy success. In the stable group, 35% had therapy success, implying an absolute difference of 12 percentage points (95% CI −5 to 29, p = 0.17) in the direction opposite to the hypothesized one. There were no new findings regarding the tolerability and safety of extended release methylphenidate therapy.

In bipolar disorder, impaired affective theory of mind (aToM) performance and aberrant neural activation in the ToM brain network partly explain social functioning impairments. However, it is not yet known whether psychotherapy of bipolar disorder influences neuroimaging markers of aToM.In this study, conducted within the multicentric randomized controlled trial of the BipoLife consortium, patients with euthymic bipolar disorder underwent 2 group interventions over 6 months (mean = 28.45 weeks): 1) a specific, cognitive behavioral intervention (specific psychotherapeutic intervention [SEKT]) (n = 31) targeting impulse regulation, ToM, and social skills and 2) an emotion-focused intervention (FEST) (n = 28). To compare the effect of SEKT and FEST on neural correlates of aToM, patients performed an aToM task during functional magnetic resonance imaging before and after interventions (final functional magnetic resonance imaging sample of pre- and postcompleters, SEKT: n = 16; FEST: n = 17). Healthy control subjects (n = 32) were scanned twice with the same time interval. Because ToM was trained in SEKT, we expected an increased ToM network activation in SEKT relative to FEST postintervention.Both treatments effectively stabilized patients' euthymic state in terms of affective symptoms, life satisfaction, and global functioning. Confirming our expectations, SEKT patients showed increased neural activation within regions of the ToM network, bilateral temporoparietal junction, posterior cingulate cortex, and precuneus, whereas FEST patients did not.The stabilizing effect of SEKT on clinical outcomes went along with increased neural activation of the ToM network, while FEST possibly exerted its positive effect by other, yet unexplored routes.

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder, characterized by core symptoms of inattention, hyperactivity and impulsivity. Comorbid depression is commonly observed in ADHD-patients. Psychostimulants are recommended as first-line treatment for ADHD. Aberrant long-range temporal correlations (LRTCs) of neuronal activities in resting-state are known to be associated with disorganized thinking and concentrating difficulties (typical in ADHD) and with maladaptive thinking (typical in depression). It has yet to be examined whether (1) LRTC occur in ADHD-patients, and if so, (2) whether LRTC might be a competent biomarker in ADHD comorbid with current depression and (3) how depression affects psychostimulant therapy of ADHD symptoms. The present study registered and compared LRTCs in different EEG frequency bands in 85 adults with ADHD between groups with (n = 28) and without (n = 57) additional depressive symptoms at baseline. Treatment-related changes in ADHD, depressive symptoms and LRTC were investigated in the whole population and within each group. Our results revealed significant LRTCs existed in all investigated frequency bands. There were, however, no significant LRTC-differences between ADHD-patients with and without depressive symptoms at baseline and no LRTC-changes following treatment. However, depressed ADHD patients did seem to benefit more from the therapy with psychostimulant based on self-report.

Human nonverbal social signals are transmitted to a large extent by vocal and facial cues. The prominent importance of these cues is reflected in specialized cerebral regions which preferentially respond to these stimuli, e.g. the temporal voice area (TVA) for human voices and the fusiform face area (FFA) for human faces. But it remained up to date unknown whether there are respective specializations during resting state, i.e. in the absence of any cues, and if so, whether these representations share neural substrates across sensory modalities. In the present study, resting state functional connectivity (RSFC) as well as voice- and face-preferential activations were analysed from functional magnetic resonance imaging (fMRI) data sets of 60 healthy individuals. Data analysis comprised seed-based analyses using the TVA and FFA as regions of interest (ROIs) as well as multi voxel pattern analyses (MVPA). Using the face- and voice-preferential responses of the FFA and TVA as regressors, we identified several correlating clusters during resting state spread across frontal, temporal, parietal and occipital regions. Using these regions as seeds, characteristic and distinct network patterns were apparent with a predominantly convergent pattern for the bilateral TVAs whereas a largely divergent pattern was observed for the bilateral FFAs. One region in the anterior medial frontal cortex displayed a maximum of supramodal convergence of informative connectivity patterns reflecting voice- and face-preferential responses of both TVAs and the right FFA, pointing to shared neural resources in supramodal voice and face processing. The association of individual voice- and face-preferential neural activity with resting state connectivity patterns may support the perspective of a network function of the brain beyond an activation of specialized regions.

Objectives: In BD, impaired affective theory of mind (aToM) performance and aberrant neural activation in the ToM brain network partly explain social functioning impairments. However, it is not yet known whether psychotherapy of BD influences neuroimaging markers of aToM.Methods: In the present study conducted within the multicentric randomized controlled trial of the BipoLife consortium, euthymic BD patients underwent two group interventions over 6 months (M = 28.45 weeks): a specific, cognitive-behavioral intervention (SEKT, n = 31) targeting impulse regulation, ToM, and social skills versus an emotion-focused intervention (FEST, n = 28). To compare the effect of SEKT and FEST on neural correlates of aToM, patients performed an aToM task during functional magnetic resonance imaging before and after interventions (final fMRI sample of pre- and post-completers, SEKT: n = 16; FEST: n = 17). Healthy controls (n = 32) were scanned twice with the same time interval. Since ToM was trained in SEKT, we expected an increased ToM network activation in SEKT relative to FEST post-intervention. Results: Both treatments effectively stabilized patients’ euthymic state in terms of affective symptoms, life satisfaction, and global functioning. Confirming our expectations, SEKT patients showed increased neural activation within regions of the ToM network, the bilateral temporoparietal junction (TPJ), the posterior cingulate cortex (PCC), and the precuneus, whereas FEST patients did not. Conclusions: The stabilizing effect of SEKT on clinical outcomes went along with increased neural activation of the ToM network, while FEST possibly exerted its positive effect by other, yet unexplored routes.

Objective Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. Methods We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. Results There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen’s d from −0.18 to 0.18) and would not survive study-wide correction for multiple testing. Conclusion Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait., Journal of Child Psychology and Psychiatry, 62 (10), ISSN:0021-9630, ISSN:1469-7610

Laughter is a multifaceted signal, which can convey social acceptance facilitating social bonding as well as social rejection inflicting social pain. In the current study, we addressed the neural correlates of social intent attribution to auditory or visual laughter within an fMRI study to identify brain areas showing linear increases of activation with social intent ratings. Negative social intent attributions were associated with activation increases within the medial prefrontal cortex/anterior cingulate cortex (mPFC/ACC). Interestingly, negative social intent attributions of auditory laughter were represented more rostral than visual laughter within this area. Our findings corroborate the role of the mPFC/ACC as key node for processing “social pain” with distinct modality‐specific subregions. Other brain areas that showed an increase of activation included bilateral inferior frontal gyrus and right superior/middle temporal gyrus (STG/MTG) for visually presented laughter and bilateral STG for auditory presented laughter with no overlap across modalities. Similarly, positive social intent attributions were linked to hemodynamic responses within the right inferior parietal lobe and right middle frontal gyrus, but there was no overlap of activity for visual and auditory laughter. Our findings demonstrate that social intent attribution to auditory and visual laughter is located in neighboring, but spatially distinct neural structures.

Voices and faces are the most common sources of threat in social anxiety (SA) where the fear of negative evaluation and social exclusion is the central element. SA itself is spectrally distributed among the general population and its clinical manifestation, termed social anxiety disorder, is one of the most common anxiety disorders. While heightened cerebral responses to angry or contemptuous facial or vocal expressions are well documented, it remains unclear if the brain of socially anxious individuals is generally more sensitive to voices and faces. Using functional magnetic resonance imaging, we investigated how SA affects the cerebral processing of voices and faces as compared to various other stimulus types in a study population with greatly varying SA (N = 50, 26 female). While cerebral voice-sensitivity correlated positively with SA in the left temporal voice area (TVA) and the left amygdala, an association of face-sensitivity and SA was observed in the right fusiform face area (FFA) and the face processing area of the right posterior superior temporal sulcus (pSTSFA). These results demonstrate that the increase of cerebral responses associated with social anxiety is not limited to facial or vocal expressions of social threat but that the respective sensory and emotion processing structures are also generally tuned to voices and faces.

In recent years, the prediction of individual behaviour from the fMRI-based functional connectome has become a major focus of research. The motivation behind this research is to find generalizable neuromarkers of cognitive functions. However, insufficient prediction accuracies and long scan time requirements are still unsolved issues. Here we propose a new machine learning algorithm for predicting intelligence scores of healthy human subjects from resting state (rsfMRI) or task-based fMRI (tfMRI). In a cohort of 390 unrelated test subjects of the Human Connectome Project, we found correlations between the observed and the predicted general intelligence of more than 50 percent in tfMRI, and of around 59 percent when results from two tasks are combined. Surprisingly, we found that the tfMRI data were significantly more predictive of intelligence than rsfMRI even though they were acquired at much shorter scan times (approximately 10 minutes versus 1 hour). Existing methods that we investigated in a benchmark comparison underperformed on tfMRI data and produced prediction accuracies well below our results. Our proposed algorithm differs from existing methods in that it achieves dimensionality reduction via ensemble learning and partial least squares regression rather than via brain parcellations or ICA decompositions. In addition, it introduces Ricci-Forman curvature as a novel type of edge weight.

Background While the concept of prodromal Parkinson's disease (PD) is well established, reliable markers for the diagnosis of this disease stage are still lacking. We investigated the functional connectivity of the putamina in a resting-state functional MRI analysis in persons with at least two prodromal factors for PD, which is considered a high risk for PD (HRPD) group, in comparison to PD patients and controls. Methods We included 16 PD patients, 20 healthy controls and 20 HRPD subjects. Resting state echo planar images and anatomical T1-weighted images were acquired with a Siemens Prisma 3 T scanner. The computation of correlation maps of the left and the right putamen to the rest of the brain was done in a voxel-wise approach using the REST toolbox. Finally, group differences in the correlation maps were compared on voxel-level and summarized in cluster z-statistics. Results Compared to both PD patients and healthy controls, the HRPD group showed higher functional connectivity of both putamina to brain regions involved in execution of motion and coordination (cerebellum, vermis, pre- and postcentral gyrus, supplementary motor area) as well as the planning of movement (precuneus, cuneus, superior medial frontal lobe). Conclusions Higher functional connectivity of the putamina of HRPD subjects to other brain regions involved in motor execution and planning may indicate a compensatory mechanism. Follow-up evaluation and independent longitudinal studies should test whether our results reflect a dynamic process associated with a prodromal PD state.

ObjectiveAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders.MethodsStructural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures).ResultsWe found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed.ConclusionOur findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.

Adults diagnosed with attention-deficit/hyperactivity disorder (ADHD) experience impairing levels of inattention and/or hyperactivity-impulsivity (APA, 2013). However, symptoms are also prevalent in individuals without ADHD, following a continuum continuously distributed across the general population (e.g., Coghill & Sonuga-Barke, 2012). Yet, ADHD self-report scales so far hardly aimed to capture these continuous distributions. Additionally, they largely focused on individuals’ weaknesses and ignored strengths. To address these shortcomings, we here present the SWAN-DE-SB, a self-report version of the German version of the SWAN (Strengths and Weaknesses of ADHD-Symptoms and Normal-Behavior [SWAN] Scale; Schulz-Zhecheva et al., 2019; Swanson et al., 2012), for use with adults. The scale’s normality, internal consistency, and factorial and convergent validity were assessed using data from a general population sample of 398 adults (287 female, 109 male, 2 diverse), eleven of them with diagnosed ADHD (i.e., 2.5%; Song et al., 2021). Its clinical utility was evaluated by comparing scores of individuals without ADHD and a clinical sample of 49 adults diagnosed with ADHD (19 female, 28 male, 1 diverse, 1 unknown), and by computing optimal cut-off values for specificity and sensitivity. Information on the participants’ ethnicity was not obtained. The findings demonstrated the SWAN-DE-SB’s normality, high internal consistency, and factorial and convergent validity. It further reliably discriminated participants with and without ADHD, with high specificity and sensitivity. The SWAN-DE-SB should thus be considered to have excellent psychometric properties to assess strengths and weaknesses of ADHD symptoms and normal behavior in clinical and general population samples.

Highlights • Best available evidence exists for neurophysiological baseline parameters. • No substantial effect of age and intelligence on training outcome in most cases. • Neurofeedback learning success predicts treatment outcome. • To date, a reliable selection of participants based on predictors is not possible., Neurofeedback (NF), a training tool aimed at enhancing neural self-regulation, has been suggested as a complementary treatment option for neuropsychiatric disorders. Despite its potential as a neurobiological intervention directly targeting neural alterations underlying clinical symptoms, the efficacy of NF for the treatment of mental disorders has been questioned recently by negative findings obtained in randomized controlled trials (e.g., Cortese et al., 2016). A possible reason for insufficient group effects of NF trainings vs. placebo could be related to the high rate of participants who fail to self-regulate brain activity by NF (“non-learners”). Another reason could be the application of standardized NF protocols not adjusted to individual differences in pathophysiology. Against this background, we have summarized information on factors determining training and treatment success to provide a basis for the development of individualized training protocols and/or clinical indications. The present systematic review included 25 reports investigating predictors for the outcome of NF trainings in healthy individuals as well as patients affected by mental disorders or epilepsy. We selected these studies based on searches in EBSCOhost using combinations of the keywords “neurofeedback” and “predictor/predictors”. As “NF training” we defined all NF applications with at least two sessions. The best available evidence exists for neurophysiological baseline parameters. Among them, the target parameters of the respective training seem to be of particular importance. However, particularities of the different experimental designs and outcome criteria restrict the interpretability of some of the information we extracted. Therefore, further research is needed to gain more profound knowledge about predictors of NF outcome.

Summary Objective Genetic generalized epilepsies (GGEs) are characterized by generalized spike‐wave discharges (GSWDs) in electroencephalography (EEG) recordings without underlying structural brain lesions. The origin of the epileptic activity remains unclear, although several studies have reported involvement of thalamus and default mode network (DMN). The aim of the current study was to investigate the networks involved in the generation and temporal evolution of GSWDs to elucidate the origin and propagation of the underlying generalized epileptic activity. Methods We examined 12 patients with GGE and GSWDs using EEG–functional magnetic resonance imaging (fMRI) and identified involved brain areas on the basis of a classical general linear model (GLM) analysis. The activation time courses of these areas were further investigated to reveal their temporal sequence of activations and deactivations. Dynamic causal modeling (DCM) was used to determine the generator of GSWDs in GGE. Results We observed activity changes in the thalamus, DMN, dorsal attention network (DAN), salience network (SN), basal ganglia, dorsolateral prefrontal cortex, and motor cortex with supplementary motor area, however, with a certain heterogeneity between patients. Investigation of the temporal sequence of activity changes showed deactivations in the DMN and DAN and activations in the SN and thalamus preceding the onset of GSWDs on EEG by several seconds. DCM analysis indicated that the DMN gates GSWDs in GGE. Significance The observed interplay between DMN, DAN, SN, and thalamus may indicate a downregulation of consciousness. The DMN seems to play a leading role as a driving force behind these changes. Overall, however, there were also clear differences in activation patterns between patients, reflecting a certain heterogeneity in this cohort of GGE patients.

OBJECTIVES: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients. METHODS: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models. RESULTS: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. CONCLUSIONS: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype. peerReviewed

Social anxiety disorder (SAD) is characterized by negatively biased perception of social cues and deficits in emotion regulation. While negatively biased perception is thought to maintain social anxiety, emotion regulation represents an ability necessary to overcome both biased perception and social anxiety. Here, we used laughter as a social threat in a functional magnetic resonance imaging (fMRI) study to identify cerebral mediators linking SAD with attention and interpretation biases and their modification through cognitive emotion regulation in the form of reappraisal. We found that reappraisal abolished the negative laughter interpretation bias in SAD and that this process was directly mediated through activation patterns of the left dorsolateral prefrontal cortex (DLPFC) serving as a cerebral pivot between biased social perception and its normalization through reappraisal. Connectivity analyses revealed reduced prefrontal control over threat-processing sensory cortices (here: the temporal voice area) during cognitive emotion regulation in SAD. Our results indicate a central role for the left DLPFC in SAD which might represent a valuable target for future research on interventions either aiming to directly modulate cognitive emotion regulation in SAD or to evaluate its potential as physiological marker for psychotherapeutic interventions relying on emotion regulation.

Current theories in cognitive neuroscience assume that internal simulation, i.e., the reproduction of brain activity underlying another person's inner state and behaviour in the perceiver's brain, plays an important role in understanding others. Here we test the prediction that common neural activity during facial communication of affect leads to interpersonal understanding. Six female senders and 30 male observers (six of which were the senders romantic partners and 24 unknown others) underwent pseudo-hyperscanning fMRI (functional magnetic resonance imaging). Senders were asked to submerge themselves into emotional situations and to facially express their emotional feelings as they arose to the observer. Observers were uninformed about the sender's task and were asked to watch and feel with the sender. Using between-brain spatial correlation analysis we found that mere emotion recognition was not closely related to the degree to which an observer reproduced the sender's spatial pattern of neural activity in his own brain. However, in runs in which the observer had correctly identified the communicated emotion, between-brain similarity of spatial patterns of neural activity predicted the degree to which the observer experienced a similar emotional feeling as the sender. This effect remained significant when differences between romantic partners and unknown others and sender effects were removed. These findings are in line with previous studies that suggest that facial emotion recognition, at least at a coarse level, might be supported by neural processes that do not rely on internal simulation. Shared affective experiences, on the other hand, might arise from common neural activity between the sender's and the observer's brain, leading to a "shared space of affect" which might be critical for the flow of more subtle affective information between brains.

Contains fulltext : 204879pub.pdf (Publisher’s version ) (Open Access) Contains fulltext : 204879pos.pdf (Author’s version postprint ) (Open Access) OBJECTIVE: Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies. METHODS: Cortical thickness and surface area (based on the Desikan-Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707). RESULTS: In the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen's d=-0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample. CONCLUSIONS: Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis.

Deficits in perception of emotional prosody have been described in patients with affective disorders at behavioral and neural level. In the current study, we use an imaging genetics approach to examine the impact of CACNA1C, one of the most promising genetic risk factors for psychiatric disorders, on prosody processing on a behavioral, functional and microstructural level. Using functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) we examined key areas involved in prosody processing, i.e. the amygdala and voice areas, in a healthy population. We found stronger activation to emotional than neutral prosody in the voice areas and the amygdala, but CACNA1C rs1006737 genotype had no influence on fMRI activity. However, significant microstructural differences (i.e. mean diffusivity) between CACNA1C rs1006737 risk allele carriers and non carriers were found in the amygdala, but not the voice areas. These modifications in brain architecture associated with CACNA1C might reflect a neurobiological marker predisposing to affective disorders and concomitant alterations in emotion perception., Highlights • Emotional prosody increases activation irrespective of genotype. • CACNA1C rs1006737 influences mean diffusivity in amygdala, not voice areas • CACNA1C rs1006737 results in changes of brain microstructure rather than function.

More often than not, emotion perception is a process guided by several sensory channels, accompanied by multimodal integration of emotional information. This process appears vital for effective social communication. This chapter provides an overview of recent studies describing the crossmodal integration of non-verbal emotional cues communicated via voices, faces, and bodies. The first parts of the chapter deal with the behavioural and neural correlates of multimodal integration in the healthy population using psychophysiological, electrophysiological, and neuroimaging measures, highlighting a network of brain areas involved in this process and discussing different methodological approaches. The final parts of the chapter, in contrast, are dedicated to the alterations of the multisensory integration of non-verbal emotional signals in states of psychiatric disease, with the main focus on schizophrenia and autism spectrum disorders.

Electroencephalography (EEG) represents a widely established method for assessing altered and typically developing brain function. However, systematic studies on EEG data quality, its correlates, and consequences are scarce. To address this research gap, the current study focused on the percentage of artifact-free segments after standard EEG pre-processing as a data quality index. We analyzed participant-related and methodological influences, and validity by replicating landmark EEG effects. Further, effects of data quality on spectral power analyses beyond participant-related characteristics were explored. EEG data from a multicenter ADHD-cohort (age range 6 to 45 years), and a non-ADHD school-age control group were analyzed (ntotal = 305). Resting-state data during eyes open, and eyes closed conditions, and task-related data during a cued Continuous Performance Task (CPT) were collected. After pre-processing, general linear models, and stepwise regression models were fitted to the data. We found that EEG data quality was strongly related to demographic characteristics, but not to methodological factors. We were able to replicate maturational, task, and ADHD effects reported in the EEG literature, establishing a link with EEG-landmark effects. Furthermore, we showed that poor data quality significantly increases spectral power beyond effects of maturation and symptom severity. Taken together, the current results indicate that with a careful design and systematic quality control, informative large-scale multicenter trials characterizing neurophysiological mechanisms in neurodevelopmental disorders across the lifespan are feasible. Nevertheless, results are restricted to the limitations reported. Future work will clarify predictive value.

Purpose To examine in vivo metabolic alterations in the isocitrate dehydrogenase (IDH) mutated gliomas using magnetic resonance spectroscopy (MRS) at magnetic field 9.4T. Materials and Methods Spectra were acquired with a 9.4T whole-body scanner with the use of a custom-built head coil (16 channel transmit and 31 channel receive). A modified stimulated echo acquisition mode (STEAM) sequence was used for localization. Eighteen patients with brain tumors of probable glial origin participated in this study. The study was performed in accordance with the guidelines of the local Ethics Committee. Results The increased spectral resolution allowed us to directly address metabolic alterations caused by the specific pathophysiology of IDH mutations including the presence of the oncometabolite 2-hydroxglutarate (2HG) and a significant decrease of the pooled glutamate and glutamine (20%, P = 0.024), which probably reflects an attempt to replenish α-ketoglutarate lost by conversion to 2HG. We also observed significantly reduced glutathione (GSH) levels (39%, P = 0.019), which could be similarly caused by depletion of dihydronicotinamide-adenine dinucleotide phosphate (NADPH) during this conversion in IDH mutant gliomas. Conclusion We demonstrate that MRS at 9.4T provides a noninvasive measure of 2HG in vivo, which may be used for therapy planning and prognostication, and may provide insights into related pathophysiologic metabolic alterations associated with IDH mutations. J. MAGN. RESON. IMAGING 2016;44:823–833.

PURPOSE To assess the impact of colored noise on statistics in event-related functional MRI (fMRI) (visual stimulation using checkerboards) acquired by simultaneous multislice imaging enabling repetition times (TRs) between 2.64 to 0.26 s. METHODS T-values within the visual cortex obtained with analysis tools that assume a first-order autoregressive plus white noise process (AR(1)+w) with a fixed AR coefficient versus higher-order AR models with spatially varying AR coefficients were compared. In addition, dependency of T-values on correction of physiological noise (respiration, heart rate) was evaluated. RESULTS Optimal statistical power was obtained for a TR of 0.33 s, but T-values as obtained by AR(1)+w models were strongly dependent on the predefined AR coefficients in fMRI with short TRs which required higher-order AR models to achieve stable statistics. Direct estimation of AR coefficients revealed the highest values within the default mode network while physiological noise had little influence on statistics in cortical structures. CONCLUSION Colored noise in event-related fMRI obtained at short TRs originates mainly from neural sources and calls for more sophisticated correction of serial autocorrelations which cannot be achieved with standard methods relying on AR(1)+w models with globally fixed AR coefficients. Magn Reson Med 76:1805-1813, 2016. © 2016 International Society for Magnetic Resonance in Medicine.

Attention-deficit/hyperactivity disorder (ADHD) is a neuropsychiatric disorder normally diagnosed in childhood and persisting into adulthood in up to two-thirds of the patients. Its core symptoms comprise inattention and hyperactive–impulsive behaviours. Several studies suggest that patients with ADHD show alterations in self-regulation and self-monitoring. So far, it has not been described whether these deficits also affect the awareness of one’s own bodily signals, that is, interoceptive awareness. To investigate possible alterations in interoceptive awareness, 14 adult patients with ADHD and 16 healthy controls performed a heartbeat detection task, in which they had to count their heartbeat without any external help (e.g. visualization on a screen). As an indicator of the individual interoceptive awareness ability, a score based on the comparison between recorded and counted heart beats was calculated. Our results showed that patients with ADHD performed significantly worse on this task than controls, which indicates that they were less aware of internal bodily signals while additionally experiencing deficits in regulating and monitoring their own (overt) behaviours.