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OBJECTIVE: We investigated healthy controls (HCs), and patients with mild cognitive impairment (MCI) and early Alzheimer's disease (AD) to identify neuronal correlates of clock time representation and changes resulting from neurodegenerative processes using functional magnetic resonance imaging. METHODS: Two clock-specific tasks demanding conceptual knowledge of clock hands, i.e. a minute hand and an hour hand task, were compared with a semantic control task. RESULTS: We observed that the minute hand task provoked a stronger activation of areas in the parietal lobes known to be involved in spatial mental imagery, while the semantic task primarily activated regions of the superior temporal lobes associated with verbal conceptual knowledge. The performance of the MCI group did not differ from that of the HC group, but additional activation was found in several brain regions. Decreased activation was detected during the minute hand task in the right middle temporal gyrus. Patients with early AD showed deteriorated performance in both clock tasks along with reduced activation in the occipital lobes and the left fusiform gyrus. Additional activation was detected in the precuneus. CONCLUSIONS: The fusiform gyrus might be crucial for the visual-semantic retrieval of clock time representation. In patients with early AD, access to this visual-semantic knowledge appears to be reduced. [ABSTRACT FROM AUTHOR]

An abstract of the article "Cerebral Processing of Linguistic and Emotional Prosody: fMRI Studies," by D. Wildgruber and colleagues is presented.

Background: Acylcarnitine (AC) profiling in dried blood spots by means of electrospray ionisation tandem mass spectrometry (ESI-MS/MS) has proven to be a useful method in neonatal screening, able to detect inborn errors of fatty acid oxidation, amino acid, organic acid and carnitine metabolism. Furthermore, this method is becoming increasingly applied in selective screening and in prenatal and postmortal diagnostics of inborn metabolic disorders, where urine is commonly used as specimen of interest. We therefore developed and validated a butylation method of acylcarnitine profiling in urine by ESI-MS/MS without previous chromatographic separation. Methods: Random urine specimens were used for investigation of the analytical imprecision of the method. Recovery, precision and linearity were determined using methanolic standard solutions of free carnitine, octanoylcarnitine and palmitoylcarnitine at various concentrations. Results: The mean coefficients of variation of within-run and run-to-run analysis of these analytes were found between 10% and 20% and demonstrated that the method fulfills the analytical requirements within the relevant ranges of concentration. Creatinine-related and age-related reference values of free carnitine and the ACs (C2–C18) were established. The definite discrimination was possible between patients with fatty acid oxidation disorders, organic acidurias, and healthy controls. The AC profiles from patients with various specific disorders were diagnostically helpful during acute deterioration and even during conditions of well-compensated metabolic state. Conclusion: The method used in this study is suitable both for selective screening and for confirmation of diagnosis with the advantage of high-throughput quantitative measurement. [Copyright &y& Elsevier]

Adults with attention-deficit/hyperactivity disorder (ADHD) experience impairing levels of inattention and/or hyperactivity-impulsivity, while individuals without ADHD experience these symptoms to a lesser extent. Yet, ADHD self-report scales so far hardly captured continuous distributions across the general population. In addition, they focused on weaknesses and ignored strengths. To address these shortcomings, we present here the Strengths and Weaknesses of ADHD and Normal-Behavior Scale Self-Report (SWAN-DE-SB) . The normal distribution of the data collected and the scale's internal consistency, and factorial and convergent validity were assessed using data from a general population sample. Its clinical utility was evaluated by comparing scores from a clinical sample and a sample of individuals without ADHD and by calculating optimal cut-off values for specificity and sensitivity. The SWAN-DE-SB demonstrated normal distribution of the data collected, high internal consistency, and factorial and convergent validity. It reliably discriminated individuals with and without ADHD, with high specificity and sensitivity. It should therefore be considered a psychometrically convincing measure to assess strengths and weaknesses of ADHD symptoms and normal behavior in clinical and general population samples., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: We aimed to investigate differences in episodic memory networks between patients with temporal lobe epilepsy (TLE) due to hippocampal sclerosis and healthy controls, especially with regards to the parietal memory network (PMN), as well as their relation to neuropsychological memory performance after mesial temporal resection., Methods: 28 healthy subjects as well as 21 patients with TLE (12 left, 9 right) were investigated using a spatial memory fMRI paradigm, which has been shown to activate the PMN. Regions of interest (ROI) were defined based on the results of the second-level analyses and activations within the predefined ROIs were compared across groups and correlated with postoperative verbal and nonverbal memory scores., Results: Healthy subjects showed activations within regions belonging to the dorsal visual stream and the PMN as well as the bilateral parahippocampal place area, the bilateral frontal eye field, and the bilateral middle frontal gyrus. Comparison between groups revealed that TLE patients activated significantly less in the left middle occipital gyrus and the right precuneus. The activation pattern in left TLE patients showed further reductions, mainly in areas belonging to the dorsal visual stream and the PMN within the left hemisphere. Activations within the left superior parietal lobulus, bilateral inferior parietal lobulus, bilateral middle temporal gyrus, left precuneus, left frontal eye field, and left middle frontal gyrus correlated significantly with postoperative verbal memory scores, and activations within the left superior parietal lobulus, left inferior parietal lobulus, left middle temporal gyrus, and left precuneus correlated significantly with higher performance in postoperative nonverbal memory scores., Significance: The PMN is involved in episodic memory encoding. Higher activations in areas belonging to the PMN and the dorsal visual stream, especially within the left hemisphere, before amygdalohippocampectomy may result in higher postoperative memory scores., Plain Language Summary: This study aims to investigate the effects of epilepsy due to hippocampal sclerosis, i.e. scarring in the temporal lobe, on memory networks in the brain. We discovered that especially patients with left-sided hippocampal sclerosis show reduced brain activations in visual areas and memory networks within the left hemisphere of the brain during orientation in space. Importantly, higher activations within these areas may result in better memory after epilepsy surgery., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation treatment used as an alternative or complementary treatment for various neuropsychiatric disorders, and could be an alternative or add-on therapy to psychostimulants in attention-deficit hyperactivity disorder (ADHD). Previous studies provided some evidence for improvements in cognition and clinical symptoms in pediatric and adult ADHD patients. However, data from multi-center randomized controlled trials (RCTs) for this condition are lacking. Thus, our aim is to evaluate short- and mid-term effects of tDCS in this multi-center, randomized, double blind, and sham-controlled, parallel group clinical trial with a 1:1 randomization ratio. Primary endpoint is the total score of DSM-IV scale of the internationally established Conners' Adult ADHD Rating Scales (German self-report screening version, CAARS-S-SR), at day 14 post-intervention (p.i.) to detect short-term lasting effects analyzed via analyses of covariance (ANCOVAs). In case of significant between-groups differences at day 14 p.i., hierarchically ordered hypotheses on mid-term lasting effects will be investigated by linear mixed models with visit (5 time points), treatment, treatment by visit interaction, and covariates as fixed categorical effects plus a patient-specific visit random effect, using an unstructured covariance structure to model the residual within-patient errors. Positive results of this clinical trial will expand the treatment options for adult ADHD patients with tDCS and provide an alternative or add-on therapy to psychostimulants with a low risk for side effects.Trial Registration The trial was registered on July 29, 2022 in the German Clinical Trials Register (DRKS00028148)., (© 2023. The Author(s).)

Introduction: The role of emotional dysregulation (ED) in attention-deficit/hyperactivity disorder (ADHD) has become an important issue. This study, in which we analyzed data from a predictive pharmaco-EEG-trial, aimed to examine whether symptoms of ED in adult ADHD affect ADHD symptom severity, brain arousal regulation as measured by resting EEG, and the response to stimulant medication., Methods: ED is defined as having a sex- and age-corrected T -score of >70 on the emotional lability subscale of the German version of Conners' Adult ADHD Rating Scale. A total of 115 participants were included in the study, 56 of whom had ED. Participants with ED were more impaired in terms of the severity of core ADHD symptoms, especially inattentive symptoms, comorbid depressive symptoms, interpersonal relationships, and quality of life. In addition, participants with ED were more likely to report a total score above 13 on the Beck Depression Inventory-II, which was considered to be the cutoff for mild depression., Results: No differences were found between the ED and non-ED groups in response to stimulant medication or in brain arousal regulation. In addition, there was no significant effect of ED with comorbid depressive symptoms on treatment response. There was a trend for subgroups that showed a change in brain arousal regulation associated with symptom improvement., Discussion: Our findings may support the assumption that ED may be an important feature of ADHD. The use of EEG-based brain arousal regulation as a diagnostic and predictive tool in ADHD in the presence of ED and comorbid depressive symptoms should be further investigated., Competing Interests: MS has received speaker’s fees from MEDICE Arzneimittel Pütter GmbH & Co. KG and Takeda and was an advisory board member for Takeda in the past 3 years. AR has received honoraria for advisory boards or talks from MEDICE Arzneimittel Pütter GmbH & Co. KG, Takeda, Janssen, Boehringer Ingelheim, SAGE/Biogen, cyclerion, COMPASS and LivaNova. JG has received research funding from the German Federal Ministry of Education and Research, German Science Foundation, and speaker fees from Lundbeck, Janssen-Cilag, Lilly, and Boehringer. SK-S. has received author’s and speaker’s honoraria from Takeda and Medice Arzneimittel Pütter GmbH &Co. KG in the past 3 years. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Huang, Mauche, Ahlers, Bogatsch, Böhme, Ethofer, Fallgatter, Gallinat, Hegerl, Heuser, Hoffmann, Kittel-Schneider, Reif, Schöttle, Unterecker and Strauß.)

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, EPI bipolar )., 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 EPI bipolar 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.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li + PGS ) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li + PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi + Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li + PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li + PGS was positively associated with lithium treatment response in the ConLi + Gen cohort, in both the categorical (P = 9.8 × 10 - 12 , R 2  = 1.9%) and continuous (P = 6.4 × 10 - 9 , R 2  = 2.6%) outcomes. Compared to bipolar patients in the 1 st decile of the risk distribution, individuals in the 10 th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10 - 4 , R 2  = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li + PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment., (© 2023. The Author(s).)

Background: In bipolar disorder (BD), the alternation of extreme mood states indicates deficits in emotion processing, accompanied by aberrant neural function of the emotion network. The present study investigated 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 patients with BD received one of two interventions over 6 months: an unstructured, emotion-focused intervention (FEST), where patients were guided to adequately perceive and label their emotions (n = 28), or a specific, structured, cognitive behavioral intervention (SEKT) (n = 31). Before and after interventions, functional magnetic resonance imaging was conducted while patients completed an emotional face-matching paradigm (final functional magnetic resonance imaging sample of patients completing both measurements: SEKT, n = 17; FEST, n = 17). Healthy control subjects (n = 32) were scanned twice after the same interval without receiving any intervention. Given the focus of FEST on emotion processing, we expected FEST to strengthen amygdala activation and connectivity., Results: Clinically, both interventions stabilized patients' euthymic states in terms of affective symptoms. At the neural level, FEST versus SEKT increased amygdala activation and amygdala-insula connectivity at postintervention relative to preintervention time point. In FEST, the increase in amygdala activation was associated with fewer depressive symptoms (r = 0.72) 6 months after intervention., Conclusions: Enhanced activation and functional connectivity of the amygdala after FEST versus SEKT may represent a neural marker of improved emotion processing, supporting the FEST intervention as an effective tool in relapse prevention in patients with BD., (Copyright © 2023. Published by Elsevier Inc.)

The pathophysiology of bipolar disorder (BD) remains mostly unclear. Yet, a valid biomarker is necessary to improve upon the early detection of this serious disorder. Patients with manifest BD display reduced volumes of the hippocampal subfields and amygdala nuclei. In this pre-registered analysis, we used structural MRI ( n = 271, 7 sites) to compare volumes of hippocampus, amygdala and their subfields/nuclei between help-seeking subjects divided into risk groups for BD as estimated by BPSS-P, BARS and EPI bipolar . We performed between-group comparisons using linear mixed effects models for all three risk assessment tools. Additionally, we aimed to differentiate the risk groups using a linear support vector machine. We found no significant volume differences between the risk groups for all limbic structures during the main analysis. However, the SVM could still classify subjects at risk according to BPSS-P criteria with a balanced accuracy of 66.90% (95% CI 59.2-74.6) for 10-fold cross-validation and 61.9% (95% CI 52.0-71.9) for leave-one-site-out. Structural alterations of the hippocampus and amygdala may not be as pronounced in young people at risk; nonetheless, machine learning can predict the estimated risk for BD above chance. This suggests that neural changes may not merely be a consequence of BD and may have prognostic clinical value.

Background: 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., Methods: 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., 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, bilateral temporoparietal junction, posterior cingulate cortex, and 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., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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, M age (SD) = 30.7 (10.0) years, n female  = 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., (© 2023. The Author(s).)

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., (© 2022. The Author(s).)

Loss of white matter integrity (WMI) is associated with gait deficits in middle-aged and older adults. However, these deficits are often only apparent under cognitively demanding situations, such as walking and simultaneously performing a secondary cognitive task. Moreover, evidence suggests that declining executive functions (EF) are linked to gait decline, and their co-occurrence may point to a common underlying pathology, i.e., degeneration of shared brain regions. In this study, we applied diffusion tensor imaging (DTI) and a standardized gait assessment under single- and dual-tasking (DT) conditions (walking and subtracting) in 74 middle-aged and older adults without any significant gait or cognitive impairments to detect subtle WM alterations associated with gait decline under DT conditions. Additionally, the Trail Making Test (TMT) was used to assess EF, classify participants into three groups based on their performance, and examine a possible interaction between gait, EF, and WMI. Gait speed and subtracting speed while dual-tasking correlated significantly with the fractional anisotropy (FA) in the bilateral anterior corona radiata (highest r = 0.51/ p < 0.0125 FWE-corrected). Dual-task costs (DTC) of gait speed correlated significantly with FA in widespread pathways, including the corpus callosum, bilateral anterior and superior corona radiata, as well as the left superior longitudinal fasciculus (highest r = -0.47/ p < 0.0125 FWE-corrected). EF performance was associated with FA in the left anterior corona radiata ( p < 0.05); however, EF did not significantly mediate the effects of WMI on DTC of gait speed. There were no significant correlations between TMT and DTC of gait and subtracting speed, respectively. Our findings indicate that gait decline under DT conditions is associated with widespread WM deterioration even in middle-aged and older adults without any significant gait or cognitive impairments. However, this relationship was not mediated by EF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alzaid, Ethofer, Kardatzki, Erb, Scheffler, Berg, Maetzler and Hobert.)

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., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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., (© 2022. The Author(s).)

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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)., (© 2021. The Author(s).)

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., (© 2021 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

In psychiatry, there has been a growing focus on identifying at-risk populations. For schizophrenia, these efforts have led to the development of early recognition and intervention measures. Despite a similar disease burden, the populations at risk of bipolar disorder have not been sufficiently characterized. Within the BipoLife consortium, we used magnetic resonance imaging (MRI) data from a multicenter study to assess structural gray matter alterations in N = 263 help-seeking individuals from seven study sites. We defined the risk using the EPIbipolar assessment tool as no-risk, low-risk, and high-risk and used a region-of-interest approach (ROI) based on the results of two large-scale multicenter studies of bipolar disorder by the ENIGMA working group. We detected significant differences in the thickness of the left pars opercularis (Cohen's d = 0.47, p = 0.024) between groups. The cortex was significantly thinner in high-risk individuals compared to those in the no-risk group (p = 0.011). We detected no differences in the hippocampal volume. Exploratory analyses revealed no significant differences in other cortical or subcortical regions. The thinner cortex in help-seeking individuals at risk of bipolar disorder is in line with previous findings in patients with the established disorder and corresponds to the region of the highest effect size in the ENIGMA study of cortical alterations. Structural alterations in prefrontal cortex might be a trait marker of bipolar risk. This is the largest structural MRI study of help-seeking individuals at increased risk of bipolar disorder., (© 2021. The Author(s).)

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 (n total = 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.

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., Competing Interests: Declaration of Competing Interest MS has received speaker fees from Lilly, Medice Arzneimitte Pütter GmbH & Co. KG and Servier and was an advisory board member for Shire/Takeda. AR has received speaker's honoraria and/or served on advisory boards for Medice, Shire/Takeda, Janssen, neuraxpharm, Sevier and SAGE. SKS received author's, speaker's and consultant's honoraria from Medice MEDICE Arzneimittel Pütter GmbH & Co. KG and Shire/Takeda. EA was an advisory board member for Shire/Takeda. JG has received research funding from the German Federal Ministry of Education and Research, German Science Foundation, and speaker fees from Sanofi, Lundbeck, Janssen-Cilag, Lilly and Otsuka. UH has received funding from Medice Arzneimittel Pütter GmbH & Co. KG and was a consultant for Medice Arzneimittel Pütter GmbH & Co. KG and an advisory board member for Janssen-Cilag. The other authors do not report any possible conflicts of interest., (Copyright © 2020 Elsevier B.V. and ECNP. All rights reserved.)

Importance: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood., Objective: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia., Design, Setting, and Participants: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244., Main Outcomes and Measures: Interregional profiles of group difference in cortical thickness between cases and controls., Results: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders., Conclusions and Relevance: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.

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., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. The authors sought to directly compare these disorders using structural brain imaging data from ENIGMA consortium data., Methods: Structural T 1 -weighted whole-brain MRI data from healthy control subjects (N=5,827) and from 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. The authors examined subcortical volume, cortical thickness, and cortical 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 intracranial volume for subcortical and surface area measures)., Results: No shared differences were found among all three disorders, and shared differences between any two disorders did not survive correction for multiple comparisons. Children with ADHD compared with those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller intracranial volume than control subjects and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared with adult control subjects and other clinical groups. No OCD-specific differences were observed across different age groups and surface area differences among all disorders in childhood and adulthood., Conclusions: The study findings suggest robust but subtle differences across different age groups among ADHD, ASD, and OCD. ADHD-specific intracranial volume and hippocampal differences in children and adolescents, and ASD-specific cortical thickness differences in the frontal cortex in adults, support previous work emphasizing structural brain differences in these disorders.

Background and Objective: Executive dysfunction is the most common cognitive impairment in Parkinson's disease (PD), occurring even in its early stages. In our study, we applied diffusion tensor imaging (DTI) to investigate white matter integrity and its association with a specific executive function such as cognitive flexibility in individuals with risk factors for PD., Methods: We examined 50 individuals with risk factors for developing PD and 24 healthy controls from the TREND (Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration) study including neuropsychological evaluation and DTI. Cognitive flexibility was assessed using the trail making test (TMT). Tract based spatial statistics (TBSS) were employed to assess white matter abnormalities and their correlation with cognitive flexibility., Results: TMT performance correlated with mean and axial diffusivity in several white matter regions, predominantly in the frontoparietal white matter. These effects were stronger in PD risk persons (PD-RP) than in controls as evidenced by a significant group interaction. White matter integrity and TMT performance did not significantly differ across groups., Conclusion: Based on our results, PD-RP do no exhibit white matter changes or impaired cognitive flexibility. However, specific executive functions in PD-RP are more related to white matter alterations than in healthy older adults., (Copyright © 2020 Alzaid, Ethofer, Hobert, Kardatzki, Erb, Maetzler and Berg.)

Faces and voices are very important sources of threat in social anxiety disorder (SAD), a common psychiatric disorder where core elements are fears of social exclusion and negative evaluation. Previous research in social anxiety evidenced increased cerebral responses to negative facial or vocal expressions and also generally increased hemodynamic responses to voices and faces. But it is unclear if also the cerebral process of face-voice-integration is altered in SAD. Applying functional magnetic resonance imaging, we investigated the correlates of the audiovisual integration of dynamic faces and voices in SAD as compared to healthy individuals. In the bilateral midsections of the superior temporal sulcus (STS) increased integration effects in SAD were observed driven by greater activation increases during audiovisual stimulation as compared to auditory stimulation. This effect was accompanied by increased functional connectivity with the visual association cortex and a more anterior position of the individual integration maxima along the STS in SAD. These findings demonstrate that the audiovisual integration of facial and vocal cues in SAD is not only systematically altered with regard to intensity and connectivity but also the individual location of the integration areas within the STS. These combined findings offer a novel perspective on the neuronal representation of social signal processing in individuals suffering from SAD., (Copyright © 2020 Kreifelts, Ethofer, Wiegand, Brück, Wächter, Erb, Lotze and Wildgruber.)

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., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Functional localizers are particularly prevalent in functional magnetic resonance imaging (fMRI) studies concerning face processing. In this study, we extend the knowledge on face localizers regarding four important aspects: First, activation differences in occipital and fusiform face areas (OFA/FFA) and amygdala are characterized by increased activation while precuneus and medial prefrontal cortex show decreased deactivation to faces versus control stimuli. The face-selective posterior superior temporal sulcus is a hybrid area exhibiting increased activation within its inferior and decreased deactivation within its superior part. Second, the employed control stimuli can impact on whether a region is classified in group analyses as face-selective or not. We specifically investigated this for recently described cytoarchitectonic subregions of the fusiform cortex (FG-2/FG-4). Averaged activity across voxels in FG-4 was stronger for faces than objects, houses, or landscapes. In FG-2, averaged activity was only significantly stronger in comparison with landscapes, but small peaks within this area were detected for comparison versus objects and houses. Third, reproducibility of individual peak activations is excellent for right FFA and quite good for right OFA, whereas within all other areas it was too low to provide valid information on time-invariant individual peaks. Finally, the fine-grained spatial activation patterns in right OFA and FFA are both time-invariant within each individual and sufficiently different between individuals to enable identification of individual participants with near-perfect precision (fMRI fingerprinting)., Competing Interests: The authors have declared that no competing interests exist.

Social anxiety (SA) comprises a multitude of persistent fears around the central element of dreaded negative evaluation and exclusion. This very common anxiety is spectrally distributed among the general population and associated with social perception biases deemed causal in its maintenance. Here, we investigated cerebral resting state markers linking SA and biased social perception. To this end, resting state functional connectivity (RSFC) was assessed as the neurobiological marker in a study population with greatly varying SA using fMRI in the first step of the experiment. One month later the impact of unattended laughter-exemplifying social threat-on a face rating task was evaluated as a measure of biased social perception. Applying a dimensional approach, SA-related cognitive biases tied to the valence, dominance and arousal of the threat signal and their underlying RSFC patterns among central nodes of the cerebral emotion, voice and face processing networks were identified. In particular, the connectivity patterns between the amygdalae and the right temporal voice area met all criteria for a cerebral mediation of the association between SA and the laughter valence-related interpretation bias. Thus, beyond this identification of non-state-dependent cerebral markers of biased perception in SA, this study highlights both a starting point and targets for future research on the causal relationships between cerebral connectivity patterns, SA and biased perception, potentially via neurofeedback methods.

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., (© 2018 The Authors. Bipolar Disorders Published by John Wiley & Sons Ltd.)

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., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

We explored anatomical details of the superior colliculus (SC) by in vivo magnetic resonance imaging (MRI) at 9.4T. The high signal-to-noise ratio allowed the acquisition of high resolution, multi-modal images with voxel sizes ranging between 176 × 132 × 600 μm and (800) 3 μm. Quantitative mapping of the longitudinal relaxation rate R1, the effective transverse relaxation rate R2*, and the magnetic susceptibility QSM was performed in 14 healthy volunteers. The images were analyzed in native space as well as after normalization to a common brain space (MNI). The coefficient-of-variation (CoV) across subjects was evaluated in prominent regions of the midbrain, reaching the best reproducibility (CoV of 5%) in the R2* maps of the SC in MNI space, while the CoV in the QSM maps remained high regardless of brain-space. To investigate whether more complex neurobiological architectural features could be detected, depth profiles through the SC layers towards the red nucleus (RN) were evaluated at different levels of the SC along the rostro-caudal axis. This analysis revealed alterations of the quantitative MRI parameters concordant with previous post mortem histology studies of the cyto- and myeloarchitecture of the SC. In general, the R1 maps were hyperintense in areas characterized by the presence of abundant myelinated fibers, and likely enabled detection of the deep white layer VII of the SC adjacent to the periaqueductal gray. While R1 maps failed to reveal finer details, possibly due to the relatively coarse spatial sampling used for this modality, these could be recovered in R2* maps and in QSM. In the central part of the SC along its rostro-caudal axis, increased R2* values and decreased susceptibility values were observed 2 mm below the SC surface, likely reflecting the myelinated fibers in the superficial optic layer (layer III). Towards the deeper layers, a second increase in R2* was paralleled by a paramagnetic shift in QSM suggesting the presence of an iron-rich layer about 3 mm below the surface of the SC, attributed to the intermediate gray layer (IV) composed of multipolar neurons. These results dovetail observations in histological specimens and animal studies and demonstrate that high-resolution multi-modal MRI at 9.4T can reveal several microstructural features of the SC in vivo., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Major depressive disorder (MDD) is characterized by a biased emotion perception. In the auditory domain, MDD patients have been shown to exhibit attenuated processing of positive emotions expressed by speech melody (prosody). So far, no neuroimaging studies examining the neural basis of altered processing of emotional prosody in MDD are available. In this study, we addressed this issue by examining the emotion bias in MDD during evaluation of happy, neutral, and angry prosodic stimuli on a five-point Likert scale during functional magnetic resonance imaging (fMRI). As expected, MDD patients rated happy prosody less intense than healthy controls (HC). At neural level, stronger activation in the middle superior temporal gyrus (STG) and the amygdala was found in all participants when processing emotional as compared to neutral prosody. MDD patients exhibited an increased activation of the amygdala during processing prosody irrespective of valence while no significant differences between groups were found for the STG, indicating that altered processing of prosodic emotions in MDD occurs rather within the amygdala than in auditory areas. Concurring with the valence-specific behavioral effect of attenuated evaluation of positive prosodic stimuli, activation within the left amygdala of MDD patients correlated with ratings of happy, but not neutral or angry prosody. Our study provides first insights in the neural basis of reduced experience of positive information and an abnormally increased amygdala activity during prosody processing., (© 2018 Wiley Periodicals, Inc.)