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Depression is a highly prevalent and debilitating mental disorder that often begins in adolescence. However, it remains unclear whether adults and adolescents with depression exhibit common or distinct brain dysfunctions during reward processing. We aimed to identify common and separable neurofunctional alterations during receipt of rewards and brain structure in adolescents and adults with depression. A coordinate-based meta-analysis was employed using Seed-based d mapping with permutation of subject images (SDM-PSI). Compared with healthy controls, both age groups exhibited common activity decreases in the right striatum (putamen, caudate) and subgenual ACC. Adults with depression showed decreased reactivity in the right putamen and subgenual ACC, while adolescents with depression showed decreased activity in the left mid cingulate, right caudate but increased reactivity in the right postcentral gyrus. This meta-analysis revealed shared (caudate) and separable (putamen and mid cingulate cortex) reward-related alterations in adults and adolescents with depression. The findings suggest age-specific neurofunctional alterations and stress the importance of adolescent-specific interventions that target social functions., Competing Interests: Declaration of Competing Interest None reported., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Abnormal accumulation of misfolded and hyperphosphorylated tau protein in brain is the defining feature of several neurodegenerative diseases called tauopathies, including Alzheimer's disease (AD). In AD, this pathological change is reflected by highly specific cerebrospinal fluid (CSF) tau biomarkers, including both phosphorylated and non-phosphorylated variants. Interestingly, despite tau pathology being at the core of all tauopathies, CSF tau biomarkers remain unchanged in certain tauopathies, e.g., progressive supranuclear palsy (PSP), Pick's disease (PiD), and corticobasal neurodegeneration (CBD). To better understand commonalities and differences between tauopathies, we report a multiplex assay combining immunoprecipitation and high-resolution mass spectrometry capable of detecting and quantifying peptides from different tau protein isoforms as well as non-phosphorylated and phosphorylated peptides, including those carrying multiple phosphorylations. We investigated the tau proteoforms in soluble and insoluble fractions of brain tissue from subjects with autopsy-confirmed tauopathies, including sporadic AD (n = 10), PSP (n = 11), PiD (n = 10), and CBD (n = 10), and controls (n = 10). Our results demonstrate that non-phosphorylated tau profiles differ across tauopathies, generally showing high abundance of microtubule-binding region (MTBR)-containing peptides in insoluble protein fractions compared with controls; the AD group showed 12-72 times higher levels of MTBR-containing aggregates. Quantification of tau isoforms showed the 3R being more abundant in PiD and the 4R isoform being more abundant in CBD and PSP in the insoluble fraction. Twenty-three different phosphorylated peptides were quantified. Most phosphorylated peptides were measurable in all investigated tauopathies. All phosphorylated peptides were significantly increased in AD insoluble fraction. However, doubly and triply phosphorylated peptides were significantly increased in AD even in the soluble fraction. Results were replicated using a validation cohort comprising AD (n = 10), CBD (n = 10), and controls (n = 10). Our study demonstrates that abnormal levels of phosphorylation and aggregation do indeed occur in non-AD tauopathies, however, both appear pronouncedly increased in AD, becoming a distinctive characteristic of AD pathology., (© 2024. The Author(s).)

Background: Internalising disorders are highly prevalent emotional dysregulations during preadolescence but clinical decision-making is hampered by high heterogeneity. During this period impulsivity represents a major risk factor for psychopathological trajectories and may act on this heterogeneity given the controversial anxiety-impulsivity relationships. However, how impulsivity contributes to the heterogeneous symptomatology, neurobiology, neurocognition and clinical trajectories in preadolescent internalising disorders remains unclear., Aims: The aim was to determine impulsivity-dependent subtypes in preadolescent internalising disorders that demonstrate distinct anxiety-impulsivity relationships, neurobiological, genetic, cognitive and clinical trajectory signatures., Method: We applied a data-driven strategy to determine impulsivity-related subtypes in 2430 preadolescents with internalising disorders from the Adolescent Brain Cognitive Development study. Cross-sectional and longitudinal analyses were employed to examine subtype-specific signatures of the anxiety-impulsivity relationship, brain morphology, cognition and clinical trajectory from age 10 to 12 years., Results: We identified two distinct subtypes of patients who internalise with comparably high anxiety yet distinguishable levels of impulsivity, i.e. enhanced (subtype 1) or decreased (subtype 2) compared with control participants. The two subtypes exhibited opposing anxiety-impulsivity relationships: higher anxiety at baseline was associated with higher lack of perseverance in subtype 1 but lower sensation seeking in subtype 2 at baseline/follow-up. Subtype 1 demonstrated thicker prefrontal and temporal cortices, and genes enriched in immune-related diseases and glutamatergic and GABAergic neurons. Subtype 1 exhibited cognitive deficits and a detrimental trajectory characterised by increasing emotional/behavioural dysregulations and suicide risks during follow-up., Conclusions: Our results indicate impulsivity-dependent subtypes in preadolescent internalising disorders and unify past controversies about the anxiety-impulsivity interaction. Clinically, individuals with a high-impulsivity subtype exhibit a detrimental trajectory, thus early interventions are warranted.

Age-associated changes in brain function play an important role in the development of neurodegenerative diseases. Although previous work has examined age-related changes in static functional connectivity, accumulating evidence suggests that advancing age is especially associated with alterations in the dynamic interactions and transitions between different brain states, which hitherto have received less attention. Conclusions of previous studies in this domain are moreover limited by suboptimal replicability of resting-state functional magnetic resonance imaging (fMRI) and culturally homogenous cohorts. Here, we investigate the robustness of age-associated changes in dynamic functional connectivity (dFC) by capitalizing on the availability of fMRI cohorts from two cultures (Western European and Chinese). In both the LEMON (Western European) and SALD (Chinese) cohorts, we consistently identify two distinct states: a more frequent segregated within-network connectivity state (state I) and a less frequent integrated between-network connectivity state (state II). Moreover, in both these cohorts, older (55-80 years) compared to younger participants (20-35 years) exhibited lower occurrence of and spent less time in state I. Older participants also tended to exhibit more transitions between networks and greater variance in global efficiency. Overall, our cross-cultural replication of age-associated changes in dFC metrics implies that advancing age is robustly associated with a reorganization of dynamic brain activation that favors the use of less functionally specific networks., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Determining and decoding emotional brain processes under ecologically valid conditions remains a key challenge in affective neuroscience. The current functional Magnetic Resonance Imaging (fMRI) based emotion decoding studies are mainly based on brief and isolated episodes of emotion induction, while sustained emotional experience in naturalistic environments that mirror daily life experiences are scarce. Here we used 12 different 10-minute movie clips as ecologically valid emotion-evoking procedures in n = 52 individuals to explore emotion-specific fMRI functional connectivity (FC) profiles on the whole-brain level at high spatial resolution (432 parcellations including cortical and subcortical structures). Employing machine-learning based decoding and cross validation procedures allowed to investigate FC profiles contributing to classification that can accurately distinguish sustained happiness and sadness and that generalize across subjects, movie clips, and parcellations. Both functional brain network-based and subnetwork-based emotion classification results suggested that emotion manifests as distributed representation of multiple networks, rather than a single functional network or subnetwork. Further, the results showed that the Visual Network (VN) and Default Mode Network (DMN) associated functional networks, especially VN-DMN, exhibited a strong contribution to emotion classification. To further estimate the temporal accumulative effect of naturalistic long-term movie-based video-evoking emotions, we divided the 10-min episode into three stages: early stimulation (1∼200 s), middle stimulation (201∼400 s), and late stimulation (401∼600 s) and examined the emotion classification performance at different stimulation stages. We found that the late stimulation contributes most to the classification (accuracy=85.32%, F1-score=85.62%) compared to early and middle stimulation stages, implying that continuous exposure to emotional stimulation can lead to more intense emotions and further enhance emotion-specific distinguishable representations. The present work demonstrated that sustained happiness and sadness under naturalistic conditions are presented in emotion-specific network profiles and these expressions may play different roles in the generation and modulation of emotions. These findings elucidated the importance of network level adaptations for sustained emotional experiences during naturalistic contexts and open new venues for imaging network level contributions under naturalistic conditions., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The autonomic nervous system regulates dynamic body adaptations to internal and external environment changes. Capitalizing on two different algorithms (that differ in empirical assumptions), we scrutinized the meta-analytic convergence of human neuroimaging studies investigating the neural basis of peripheral autonomic signal processing. Among the selected studies, we identified 42 records reporting 44 different experiments and testing 758 healthy individuals. The results of the two different algorithms converge in identifying the bilateral dorsal anterior insula and midcingulate cortex as the critical areas of the central autonomic system (CAN). Applying an unbiased approach, we were able to identify a single condition-independent functional circuit that supports CAN activity. Partially overlapping with the salience network this functional circuit includes the bilateral insular cortex and midcingulate cortex as well as the bilateral inferior parietal lobules. Remarkably, the critical regions of the CAN observed in this meta-analysis overlapped with the salience network as well as regions commonly reported across different cognitive and affective neuroimaging paradigms and regions being dysregulated across different mental and neurological disorders., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Fundamental and clinical neuroscience has benefited tremendously from the development of automated computational analyses. In excess of 600 human neuroimaging papers using Voxel-based Morphometry (VBM) are now published every year and a number of different automated processing pipelines are used, although it remains to be systematically assessed whether they come up with the same answers. Here we examined variability between four commonly used VBM pipelines in two large brain structural datasets. Spatial similarity and between-pipeline reproducibility of the processed gray matter brain maps were generally low between pipelines. Examination of sex-differences and age-related changes revealed considerable differences between the pipelines in terms of the specific regions identified. Machine learning-based multivariate analyses allowed accurate predictions of sex and age, however accuracy differed between pipelines. Our findings suggest that the choice of pipeline alone leads to considerable variability in brain structural markers which poses a serious challenge for reproducibility and interpretation., (© 2022. The Author(s).)

The novel coronavirus (COVID-19) pandemic has led to a surge in mental distress and fear-related disorders, including posttraumatic stress disorder (PTSD). Fear-related disorders are characterized by dysregulations in fear and the associated neural pathways. In the present study, we examined whether individual variations in the fear neural connectome can predict fear-related symptoms during the COVID-19 pandemic. Using machine learning algorithms and back-propagation artificial neural network (BP-ANN) deep learning algorithms, we demonstrated that the intrinsic neural connectome before the COVID-19 pandemic could predict who would develop high fear-related symptoms at the peak of the COVID-19 pandemic in China (Accuracy rate = 75.00%, Sensitivity rate = 65.83%, Specificity rate = 84.17%). More importantly, prediction models could accurately predict the level of fear-related symptoms during the COVID-19 pandemic by using the prepandemic connectome state, in which the functional connectivity of lvmPFC (left ventromedial prefrontal cortex)-rdlPFC (right dorsolateral), rdACC (right dorsal anterior cingulate cortex)-left insula, lAMY (left amygdala)-lHip (left hippocampus) and lAMY-lsgACC (left subgenual cingulate cortex) was contributed to the robust prediction. The current study capitalized on prepandemic data of the neural connectome of fear to predict participants who would develop high fear-related symptoms in COVID-19 pandemic, suggesting that individual variations in the intrinsic organization of the fear circuits represent a neurofunctional marker that renders subjects vulnerable to experience high levels of fear during the COVID-19 pandemic., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Early life stress has been associated with emotional dysregulations and altered architecture of limbic-prefrontal brain systems engaged in emotional processing. Serotonin regulates both, developmental and experience-dependent neuroplasticity in these circuits. Central serotonergic biosynthesis rates are regulated by Tryptophan hydroxylase 2 (TPH2) and transgenic animal models suggest that TPH2-gene associated differences in serotonergic signaling mediate the impact of aversive early life experiences on a phenotype characterized by anxious avoidance., Methods: The present study employed an imaging genetics approach that capitalized on individual differences in a TPH2 polymorphism (703G/T; rs4570625) to determine whether differences in serotonergic signaling modulate the effects of early life stress on brain structure and function and punishment sensitivity in humans (n = 252)., Results: Higher maltreatment exposure before the age of 16 was associated with increased gray matter volumes in a circuitry spanning thalamic-limbic-prefrontal regions and decreased intrinsic communication in limbic-prefrontal circuits selectively in TT carriers. In an independent replication sample, associations between higher early life stress and increased frontal volumes in TT carriers were confirmed. On the phenotype level, the genotype moderated the association between higher early life stress exposure and higher punishment sensitivity. In TT carriers, the association between higher early life stress exposure and punishment sensitivity was critically mediated by increased thalamic-limbic-prefrontal volumes., Conclusions: The present findings suggest that early life stress shapes the neural organization of the limbic-prefrontal circuits in interaction with individual variations in the TPH2 gene to promote a phenotype characterized by facilitated threat avoidance, thus promoting early adaptation to an adverse environment.

Functional brain networks have been shown to undergo fundamental changes associated with aging or schizophrenia. However, the mechanism of how these factors exert influences jointly or interactively on brain networks remains elusive. A unified recognition of connectomic alteration patterns was also hampered by heterogeneities in network construction and thresholding methods. Recently, an unbiased network representation method regardless of network thresholding, so called minimal spanning tree algorithm, has been applied to study the critical skeleton of the brain network. In this study, we aimed to use minimum spanning tree (MST) as an unbiased network reconstruction and employed structural equation modeling (SEM) to unravel intertwined relationships among multiple phenotypic and connectomic variables in schizophrenia. First, we examined global and local brain network properties in 40 healthy subjects and 40 schizophrenic patients aged 21-55 using resting-state functional magnetic resonance imaging (rs-fMRI). Global network alterations are measured by graph theoretical metrics of MSTs and a connectivity-transitivity two-dimensional approach was proposed to characterize nodal roles. We found that networks of schizophrenic patients exhibited a more star-like global structure compared to controls, indicating excessive integration, and a loss of regional transitivity in the dorsal frontal cortex (corrected p <.05). Regional analysis of MST network topology revealed that schizophrenia patients had more network hubs in frontal regions, which may be linked to the "overloading" hypothesis. Furthermore, using SEM, we found that the level of MST integration mediated the influence of age on negative symptom severity (indirect effect 95% CI [0.026, 0.449]). These findings highlighted an altered network skeleton in schizophrenia and suggested that aging-related enhancement of network integration may undermine functional specialization of distinct neural systems and result in aggravated schizophrenic symptoms., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Exaggerated reactivity to drug-cues and emotional dysregulations represent key symptoms of early stages of substance use disorders. The diagnostic criteria for (Internet) gaming disorder strongly resemble symptoms for substance-related addictions. However, previous cross-sections studies revealed inconsistent results with respect to neural cue reactivity and emotional dysregulations in these populations. To this end, the present fMRI study applied a combined cross-sectional and longitudinal design in regular online gamers (n = 37) and gaming-naïve controls (n = 67). To separate gaming-associated changes from predisposing factors, gaming-naive subjects were randomly assigned to 6 weeks of daily Internet gaming or a non-gaming condition. At baseline and after the training, subjects underwent an fMRI paradigm presenting gaming-related cues and non-gaming-related emotional stimuli. Cross-sectional comparisons revealed gaming-cue specific enhanced valence attribution and neural reactivity in a parietal network, including the posterior cingulate in regular gamers as compared to gaming naïve-controls. Longitudinal analysis revealed that 6 weeks of gaming elevated valence ratings as well as neural cue-reactivity in a similar parietal network, specifically the posterior cingulate in previously gaming-naïve controls. Together, the longitudinal design did not reveal supporting evidence for altered emotional processing of non-gaming associated stimuli in regular gamers whereas convergent evidence for increased emotional and neural reactivity to gaming-associated stimuli was observed. Findings suggest that exaggerated neural reactivity in posterior parietal regions engaged in default mode and automated information processing already occur during early stages of regular gaming and probably promote continued engagement in gaming behavior., (© 2020 Society for the Study of Addiction.)

Despite a growing number of functional MRI studies reporting exercise-induced changes during cognitive processing, a systematic determination of the underlying neurobiological pathways is currently lacking. To this end, our neuroimaging meta-analysis included 20 studies and investigated the influence of physical exercise on cognition-related functional brain activation. The overall meta-analysis encompassing all experiments revealed physical exercise-induced changes in the left parietal lobe during cognitive processing. Subgroup analysis further revealed that in the younger-age group (< 35 years old) physical exercise induced more widespread changes in the right hemisphere, whereas in the older-age group (≥ 35 years old) exercise-induced changes were restricted to the left parietal lobe. Subgroup analysis for intervention duration showed that shorter exercise interventions induced changes in regions connected with frontoparietal and default mode networks, whereas regions exhibiting effects of longer interventions connected with frontoparietal and dorsal attention networks. Our findings suggest that physical exercise interventions lead to changes in functional activation patterns primarily located in precuneus and associated with frontoparietal, dorsal attention and default mode networks.

The neuropeptide oxytocin is a key modulator of social-emotional behavior and its intranasal administration can influence the functional connectivity of brain networks involved in the control of attention, emotion and reward reported in humans. However, no studies have systematically investigated the effects of oxytocin on dynamic or directional aspects of functional connectivity. The present study employed a novel computational framework to investigate these latter aspects in 15 oxytocin-sensitive regions using data from randomized placebo-controlled between-subject resting state functional MRI studies incorporating 200 healthy subjects. In order to characterize the temporal dynamics, the 'temporal state' was defined as a temporal segment of the whole functional MRI signal which exhibited a similar functional interaction pattern among brain regions of interest. Results showed that while no significant effects of oxytocin were found on brain temporal state related characteristics (including temporal state switching frequency, probability of transitions between neighboring states, and averaged dwell time on each state) oxytocin extensively (n = 54 links) modulated effective connectivity among the 15 regions. The effects of oxytocin were primarily characterized by increased effective connectivity both between and within emotion, reward, salience, attention and social cognition processing networks and their interactions with the default mode network. Top-down control over emotional processing regions such as the amygdala was particularly affected. Oxytocin also increased effective homotopic interhemispheric connectivity in almost all these regions. Additionally, the effects of oxytocin on effective connectivity were sex-dependent, being more extensive in males. Overall, these findings suggest that modulatory effects of oxytocin on both within- and between-network interactions may underlie its functional influence on social-emotional behaviors, although in a sex-dependent manner. These findings may be of particular relevance to potential therapeutic use of oxytocin in psychiatric disorders associated with social dysfunction, such as autism spectrum disorder and schizophrenia, where directionality of treatment effects on causal interactions between networks may be of key importance ., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Attention and salience processing have been linked to the intrinsic between- and within-network dynamics of large-scale networks engaged in internal (default network [DN]) and external attention allocation (dorsal attention network [DAN] and salience network [SN]). The central oxytocin (OXT) system appears ideally organized to modulate widely distributed neural systems and to regulate the switch between internal attention and salient stimuli in the environment. The current randomized placebo (PLC)-controlled between-subject pharmacological resting-state fMRI study in N = 187 (OXT, n = 94; PLC, n = 93; single-dose intranasal administration) healthy male and female participants employed an independent component analysis approach to determine the modulatory effects of OXT on the within- and between-network dynamics of the DAN-SN-DN triple network system. OXT increased the functional integration between subsystems within SN and DN and increased functional segregation of the DN with both attentional control networks (SN and DAN). Whereas no sex differences were observed, OXT effects on the DN-SN interaction were modulated by autistic traits. Together, the findings suggest that OXT may facilitate efficient attention allocation by modulating the intrinsic functional dynamics between DN components and large-scale networks involved in external attentional demands (SN and DAN)., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Synaptic pathology is a central event in Alzheimer's disease (AD) and other neurodegenerative conditions, and investigation of synaptic proteins can provide valuable tools to follow synaptic dysfunction and loss in these diseases. Neuroligin-1 (Nlgn1) is a postsynaptic cell adhesion protein, important for synapse stabilization and formation. Nlgn1 has been connected to cognitive disorders, and specifically to AD, as target of the synaptotoxic effect of amyloid-β (Aβ) oligomers and Aβ fibrils. To address changes in Nlgn1 expression in human brain, brain regions in different neurological disorders were examined by Western blot and mass spectrometry. Brain specimens from AD (n = 23), progressive supranuclear palsy (PSP, n = 11), corticobasal degeneration (CBD, n = 10), and Pick's disease (PiD, n = 9) were included. Additionally, cerebrospinal fluid (CSF) samples of AD patients (n = 43) and non-demented controls (n = 42) were analysed. We found decreased levels of Nlgn1 in temporal and parietal cortex (~ 50-60% reductions) in AD brains compared with controls. In frontal grey matter the reduction was not seen for AD patients; however, in the same region, marked reduction was found for PiD (~ 77%), CBD (~ 66%) and to a lesser extent for PSP (~ 43%), which could clearly separate these tauopathies from controls. The Nlgn1 level was reduced in CSF from AD patients compared to controls, but with considerable overlap. The dramatic reduction of Nlgn1 seen in the brain extracts of tauopathies warrants further investigation regarding the potential use of Nlgn1 as a biomarker for these neurodegenerative diseases.

Neurofeedback training has been shown to influence behavior in healthy participants as well as to alleviate clinical symptoms in neurological, psychosomatic, and psychiatric patient populations. However, many real-time fMRI neurofeedback studies report large inter-individual differences in learning success. The factors that cause this vast variability between participants remain unknown and their identification could enhance treatment success. Thus, here we employed a meta-analytic approach including data from 24 different neurofeedback studies with a total of 401 participants, including 140 patients, to determine whether levels of activity in target brain regions during pretraining functional localizer or no-feedback runs (i.e., self-regulation in the absence of neurofeedback) could predict neurofeedback learning success. We observed a slightly positive correlation between pretraining activity levels during a functional localizer run and neurofeedback learning success, but we were not able to identify common brain-based success predictors across our diverse cohort of studies. Therefore, advances need to be made in finding robust models and measures of general neurofeedback learning, and in increasing the current study database to allow for investigating further factors that might influence neurofeedback learning., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Pain empathy can be evoked by multiple cues, particularly observation of acute pain inflictions or facial expressions of pain. Previous studies suggest that these cues commonly activate the insula and anterior cingulate, yet vicarious pain encompasses pain-specific responses as well as unspecific processes (e.g. arousal) and overlapping activations are not sufficient to determine process-specific shared neural representations. We employed multivariate pattern analyses to fMRI data acquired during observation of noxious stimulation of body limbs (NS) and painful facial expressions (FE) and found spatially and functionally similar cross-modality (NS versus FE) whole-brain vicarious pain-predictive patterns. Further analyses consistently identified shared neural representations in the bilateral mid-insula. The vicarious pain patterns were not sensitive to respond to non-painful high-arousal negative stimuli but predicted self-experienced thermal pain. Finally, a domain-general vicarious pain pattern predictive of self-experienced pain but not arousal was developed. Our findings demonstrate shared pain-associated neural representations of vicarious pain., Competing Interests: FZ, JL, WZ, LX, XZ, MF, SY, KK, TW, BB No competing interests declared, (© 2020, Zhou et al.)

Recent approaches for understanding the neural basis of pain empathy emphasize the dynamic construction of networks underlying this multifaceted social cognitive process. Inter-subject phase synchronization (ISPS) is an approach for exploratory analysis of task-fMRI data that reveals brain networks dynamically synchronized to task-features across participants. We applied ISPS to task-fMRI data assessing vicarious pain empathy in healthy participants (n = 238). The task employed physical (limb) and affective (face) painful and corresponding non-painful visual stimuli. ISPS revealed two distinct networks synchronized during physical pain observation, one encompassing anterior insula and midcingulate regions strongly engaged in (vicarious) pain and another encompassing parietal and inferior frontal regions associated with social cognitive processes which may modulate and support the physical pain empathic response. No robust network synchronization was observed for affective pain, possibly reflecting high inter-individual variation in response to socially transmitted pain experiences. ISPS also revealed networks related to task onset or general processing of physical (limb) or affective (face) stimuli which encompassed networks engaged in object manipulation or face processing, respectively. Together, the ISPS approach permits segregation of networks engaged in different psychological processes, providing additional insight into shared neural mechanisms of empathy for physical pain, but not affective pain, across individuals., (© The Author(s) 2020. Published by Oxford University Press.)

Jealousy is a complex social emotion combining the different primary emotions of anger, fear and sadness. Previous evidence has suggested the involvement of fronto-striatal dopaminergic circuitry in pathological jealousy, although little is known about overlaps with the neural representation of primary emotions involved in non-morbid jealousy and the utility of a dimensional neuroimaging approach. In the current study, 85 healthy subjects underwent fMRI during an emotional face recognition paradigm and resting state. A total of 150 faces (happy, angry, fearful, sad, neutral) were presented and subjects required to identify the expression and rate its intensity. Trait jealousy was assessed using the Multidimensional Jealousy Scale. Behavioral results showed that only intensity ratings of angry faces were positively associated with subjects' jealousy scores. During processing of angry versus neutral expression faces, subjects with elevated jealousy exhibited increased activation in the right thalamus, insula, fusiform gyrus and hippocampus, left dorsal striatum, superior parietal lobule and bilateral cerebellum and inferior frontal gyrus after controlling for trait aggression and sex. Functional connectivity between the inferior frontal gyrus and dorsal striatum was also increased. No associations with resting-state functional connectivity were found. Overall, the present study demonstrates an association between exaggerated jealousy and increased intensity ratings of angry faces as well as activity and functional connectivity of the dorsal striatal-inferior frontal circuitry. Thus, increased emotional responsivity to social threat and enhanced activity in limbic regions and dopaminergic fronto-striatal circuitry may be features of both non-morbid and pathological jealousy confirming the utility of a dimensional approach.

The inability to control or inhibit emotional distractors characterizes a range of psychiatric disorders. Despite the use of a variety of task paradigms to determine the mechanisms underlying the control of emotional interference, a precise characterization of the brain regions and networks that support emotional interference processing remains elusive. Here, we performed coordinate-based and functional connectivity meta-analyses to determine the brain networks underlying emotional interference. Paradigms addressing interference processing in the cognitive or emotional domain were included in the meta-analyses, particularly the Stroop, Flanker, and Simon tasks. Our results revealed a consistent involvement of the bilateral dorsal anterior cingulate cortex, anterior insula, left inferior frontal gyrus, and superior parietal lobule during emotional interference. Follow-up conjunction analyses identified correspondence in these regions between emotional and cognitive interference processing. Finally, the patterns of functional connectivity of these regions were examined using resting-state functional connectivity and meta-analytic connectivity modeling. These regions were strongly connected as a distributed system, primarily mapping onto fronto-parietal control, ventral attention, and dorsal attention networks. Together, the present findings indicate that a domain-general neural system is engaged across multiple types of interference processing and that regulating emotional and cognitive interference depends on interactions between large-scale distributed brain networks.

Phonological processing has been postulated as a core area of deficit among children with dyslexia. Reduced brain activation during phonological processing in children with dyslexia has been observed in left-hemispheric temporoparietal regions. Musical training has shown positive associations with phonological processing abilities, but the neural mechanisms underlying this relationship remain unspecified. The present research aims to distinguish neural correlates of phonological processing in school-age typically developing musically trained children, musically untrained children, and musically untrained children with dyslexia utilizing fMRI. A whole-brain ANCOVA, accounting for gender and nonverbal cognitive abilities, identified a main effect of group in bilateral temporoparietal regions. Subsequent region-of-interest analyses replicated temporoparietal hypoactivation in children with dyslexia relative to typically developing children. By contrast, musically trained children showed greater bilateral activation in temporoparietal regions when compared to each musically untrained group. Therefore, musical training shows associations with enhanced bilateral activation of left-hemispheric regions known to be important for reading. Findings suggest that engagement of these regions through musical training may underlie the putative positive effects of music on reading development. This supports the hypothesis that musical training may facilitate the development of a bilateral compensatory neural network, which aids children with atypical function in left-hemispheric temporoparietal regions., (Copyright © 2018. Published by Elsevier Ltd.)

Multivariate regression models for age estimation are a powerful tool for assessing abnormal brain morphology associated to neuropathology. Age prediction models are built on cohorts of healthy subjects and are built to reflect normal aging patterns. The application of these multivariate models to diseased subjects usually results in high prediction errors, under the hypothesis that neuropathology presents a similar degenerative pattern as that of accelerated aging. In this work, we propose an alternative to the idea that pathology follows a similar trajectory than normal aging. Instead, we propose the use of metrics which measure deviations from the mean aging trajectory. We propose to measure these deviations using two different metrics: uncertainty in a Gaussian process regression model and a newly proposed age weighted uncertainty measure. Consequently, our approach assumes that pathologic brain patterns are different to those of normal aging. We present results for subjects with autism, mild cognitive impairment and Alzheimer's disease to highlight the versatility of the approach to different diseases and age ranges. We evaluate volume, thickness, and VBM features for quantifying brain morphology. Our evaluations are performed on a large number of images obtained from a variety of publicly available neuroimaging databases. Across all features, our uncertainty based measurements yield a better separation between diseased subjects and healthy individuals than the prediction error. Finally, we illustrate differences in the disease pattern to normal aging, supporting the application of uncertainty as a measure of neuropathology., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The emotional Stroop task (EST) is among the most influential paradigms used to probe attention-related or cognitive control-related emotional processing in healthy subjects and clinical populations. The neuropsychological mechanism underlying the emotional Stroop effect has attracted extensive and long-lasting attention in both cognitive and clinical psychology and neuroscience; however, a precise characterization of the neural substrates underlying the EST in healthy and clinical populations remains elusive. Here, we implemented a coordinate-based meta-analysis covering functional imaging studies that employed the emotion-word or emotional counting Stroop paradigms to determine the underlying neural networks in healthy subjects and the trans-diagnostic alterations across clinical populations. Forty-six publications were identified that reported relevant contrasts (negative > neutral; positive > neutral) for healthy or clinical populations as well as for hyper- or hypo-activation of patients compared to controls. We demonstrate consistent involvement of the vlPFC and dmPFC in healthy subjects and consistent involvement of the vlPFC in patients. We further identify a trans-diagnostic pattern of hyper-activation in the prefrontal and parietal regions. These findings underscore the critical roles of cognitive control processes in the EST and implicate trans-diagnostic cognitive control deficits. Unlike the current models that emphasize the roles of the amygdala and rACC, our findings implicate novel mechanisms underlying the EST for both healthy and clinical populations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

WeChat represents one of the most popular smartphone-based applications for communication. Although the application provides several useful features that simplify daily life, a growing number of users spend excessive amounts of time on the application. This may lead to interferences with everyday life and even to addictive patterns of use. In the context of the ongoing discussion on Internet Communication Disorder (ICD), the present study aimed to better characterize the addictive potential of communication applications, using WeChat as an example, by examining associations between individual variations in tendencies towards WeChat addiction and brain structural variations in fronto-striatal-limbic brain regions. To this end levels of addictive tendencies, frequency of use and structural MRI data were assessed in n = 61 healthy participants. Higher tendencies towards WeChat addiction were associated with smaller gray matter volumes of the subgenual anterior cingulate cortex, a key region for monitoring and regulatory control in neural networks underlying addictive behaviors. Moreover, a higher frequency of the paying function was associated with smaller nucleus accumbens volumes. Findings were robust after controlling for levels of anxiety and depression. The present results are in line with previous findings in substance and behavioral addictions, and suggest a similar neurobiological basis in ICD.

Major depression disorder (MDD) and anxiety disorder are both prevalent and debilitating. High rates of comorbidity between MDD and social anxiety disorder (SAD) suggest common pathological pathways, including aberrant neural processing of interpersonal signals. In patient populations, the determination of common and distinct neurofunctional markers of MDD and SAD is often hampered by confounding factors, such as generally elevated anxiety levels and disorder-specific brain structural alterations. This study employed a dimensional disorder approach to map neurofunctional markers associated with levels of depression and social anxiety symptoms in a cohort of 91 healthy subjects using an emotional face processing paradigm. Examining linear associations between levels of depression and social anxiety, while controlling for trait anxiety revealed that both were associated with exaggerated dorsal striatal reactivity to fearful and sad expression faces respectively. Exploratory analysis revealed that depression scores were positively correlated with dorsal striatal functional connectivity during processing of fearful faces, whereas those of social anxiety showed a negative association during processing of sad faces. No linear relationships between levels of depression and social anxiety were observed during a facial-identity matching task or with brain structure. Together, the present findings indicate that dorsal striatal neurofunctional alterations might underlie aberrant interpersonal processing associated with both increased levels of depression and social anxiety., (© 2017 Wiley Periodicals, Inc.)

Background: Brainshift is still a major issue in neuronavigation. Incorporating intra-operative ultrasound (iUS) with advanced registration algorithms within the surgical workflow is regarded as a promising approach for a better understanding and management of brainshift. This work is intended to (1) provide three-dimensional (3D) ultrasound reconstructions specifically for brain imaging in order to detect brainshift observed intra-operatively, (2) evaluate a novel iterative intra-operative ultrasound-based deformation correction framework, and (3) validate the performance of the proposed image-registration-based deformation estimation in a clinical environment., Methods: Eight patients with brain tumors undergoing surgical resection are enrolled in this study. For each patient, a 3D freehand iUS system is employed in combination with an intra-operative navigation (iNav) system, and intra-operative ultrasound data are acquired at three timepoints during surgery. On this foundation, we present a novel resolution-preserving 3D ultrasound reconstruction, as well as a framework to detect brainshift through iterative registration of iUS images. To validate the system, the target registration error (TRE) is evaluated for each patient, and both rigid and elastic registration algorithms are analyzed., Results: The mean TRE based on 3D-iUS improves significantly using the proposed brainshift compensation compared to neuronavigation (iNav) before (2.7 vs. 5.9 mm; [Formula: see text]) and after dural opening (4.2 vs. 6.2 mm, [Formula: see text]), but not after resection (6.7 vs. 7.5 mm; [Formula: see text]). iUS depicts a significant ([Formula: see text]) dynamic spatial brainshift throughout the three timepoints. Accuracy of registration can be improved through rigid and elastic registrations by 29.2 and 33.3%, respectively, after dural opening, and by 5.2 and 0.4%, after resection., Conclusion: 3D-iUS systems can improve the detection of brainshift and significantly increase the accuracy of the navigation in a real scenario. 3D-iUS can thus be regarded as a robust, reliable, and feasible technology to enhance neuronavigation.

Effective regulation of negative affective states has been associated with mental health. Impaired regulation of negative affect represents a risk factor for dysfunctional coping mechanisms such as drug use and thus could contribute to the initiation and development of problematic substance use. This study investigated behavioral and neural indices of emotion regulation in regular marijuana users (n = 23) and demographically matched nonusing controls (n = 20) by means of an fMRI cognitive emotion regulation (reappraisal) paradigm. Relative to nonusing controls, marijuana users demonstrated increased neural activity in a bilateral frontal network comprising precentral, middle cingulate, and supplementary motor regions during reappraisal of negative affect (P < 0.05, FWE) and impaired emotion regulation success on the behavioral level (P < 0.05). Amygdala-focused analyses further revealed impaired amygdala downregulation in the context of decreased amygdala-dorsolateral prefrontal cortex functional connectivity (P < 0.05, FWE) during reappraisal in marijuana users relative to controls. Together, the present findings could reflect an unsuccessful attempt of compensatory recruitment of additional neural resources in the context of disrupted amygdala-prefrontal interaction during volitional emotion regulation in marijuana users. As such, impaired volitional regulation of negative affect might represent a consequence of, or risk factor for, regular marijuana use. Hum Brain Mapp 38:4270-4279, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Animal studies suggest that N-methyl-D-aspartate receptor (NMDAR) dependent signalling in limbic and prefrontal regions is critically involved in both cognitive and emotional functions. In humans, ketamine-induced transient, and disorder associated chronic NMDAR hypofunction (i.e. in schizophrenia) has been associated with deficient performance in the domains of memory and higher-order emotional functioning, as well as altered neural activity in the underlying limbic-prefrontal circuits. To model the effects of NMDAR hypofunction on the integration of emotion and cognition the present pharmacological fMRI study applied the NMDAR antagonist ketamine (target plasma level=100ng/ml) to 21 healthy volunteers in a within-subject placebo-controlled crossover design during encoding of neutral, positive and negative pictures. Our results show that irrespective of emotion, ketamine suppressed parahippocampal and medial prefrontal activity. In contrast, ketamine selectively increased amygdala and orbitofrontal activity during successful encoding of negative stimuli. On the network level ketamine generally increased medial prefrontal-parahippocampal coupling while specifically decreasing amygdala-orbitofrontal interplay during encoding of negative stimuli. On the behavioural level, ketamine produced generally decreased memory performance and abolished the emotional enhancement of memory after a wash-out period of 5 days. The present findings suggest that ketamine produces general as well as valence-specific effects during emotional memory formation. The pattern partly overlaps with alterations previously observed in patients with schizophrenia., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The uncompetitive NMDA receptor antagonist ketamine has been proposed to model symptoms of psychosis. Smooth pursuit eye movements (SPEM) are an established biomarker of schizophrenia. SPEM performance has been shown to be impaired in the schizophrenia spectrum and during ketamine administration in healthy volunteers. However, the neural mechanisms mediating SPEM impairments during ketamine administration are unknown. In a counter-balanced, placebo-controlled, double-blind, within-subjects design, 27 healthy participants received intravenous racemic ketamine (100 ng/mL target plasma concentration) on one of two assessment days and placebo (intravenous saline) on the other. Participants performed a block-design SPEM task during functional magnetic resonance imaging (fMRI) at 3 Tesla field strength. Self-ratings of psychosis-like experiences were obtained using the Psychotomimetic States Inventory (PSI). Ketamine administration induced psychosis-like symptoms, during ketamine infusion, participants showed increased ratings on the PSI dimensions cognitive disorganization, delusional thinking, perceptual distortion and mania. Ketamine led to robust deficits in SPEM performance, which were accompanied by reduced blood oxygen level dependent (BOLD) signal in the SPEM network including primary visual cortex, area V5 and the right frontal eye field (FEF), compared to placebo. A measure of connectivity with V5 and FEF as seed regions, however, was not significantly affected by ketamine. These results are similar to the deviations found in schizophrenia patients. Our findings support the role of glutamate dysfunction in impaired smooth pursuit performance and the use of ketamine as a pharmacological model of psychosis, especially when combined with oculomotor biomarkers. Hum Brain Mapp 37:4047-4060, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Humans display an intriguing propensity to help the victim of social norm violations or punish the violators which require theory-of-mind (ToM)/mentalizing abilities. The hypothalamic peptide oxytocin (OXT) has been implicated in modulating various pro-social behaviors/perception including trust, cooperation, and empathy. However, it is still elusive whether OXT also influences neural responses during third-party altruistic decisions, especially in ToM-related brain regions such as the temporo-parietal junction (TPJ). To address this question, we conducted a pharmacological functional magnetic resonance imaging experiment with healthy male participants in a randomized, double-blind, cross-over design. After the intranasal administration synthetic OXT (OXT(IN)) or placebo (PLC), participants could transfer money from their own endowment to either punish a norm violator or help the victim. In some trials, participants observed the decisions made by a computer. Behaviorally, participants under OXT(IN) showed a trend to accelerate altruistic decisions. At the neural level, we observed a strong three-way interaction between drug treatment (OXT/PLC), agency (self/computer), and decision (help/punish), such that OXT(IN) selectively enhanced activity in the left TPJ during observations of others being helped by the computer. Collectively, our findings indicate that OXT enhances prosocial-relevant perception by increasing ToM-related neural activations.

In male Caucasian subjects, learning is facilitated by receipt of social compared with non-social feedback, and the neuropeptide oxytocin (OXT) facilitates this effect. In this study, we have first shown a cultural difference in that male Chinese subjects actually perform significantly worse in the same reinforcement associated learning task with social (emotional faces) compared with non-social feedback. Nevertheless, in two independent double-blind placebo (PLC) controlled between-subject design experiments we found OXT still selectively facilitated learning with social feedback. Similar to Caucasian subjects this OXT effect was strongest with feedback using female rather than male faces. One experiment performed in conjunction with functional magnetic resonance imaging showed that during the response, but not feedback phase of the task, OXT selectively increased activity in the amygdala, hippocampus, parahippocampal gyrus and putamen during the social feedback condition, and functional connectivity between the amygdala and insula and caudate. Therefore, OXT may be increasing the salience and reward value of anticipated social feedback. In the PLC group, response times and state anxiety scores during social feedback were associated with signal changes in these same regions but not in the OXT group. OXT may therefore have also facilitated learning by reducing anxiety in the social feedback condition. Overall our results provide the first evidence for cultural differences in social facilitation of learning per se, but a similar selective enhancement of learning with social feedback under OXT. This effect of OXT may be associated with enhanced responses and functional connectivity in emotional memory and reward processing regions., (© 2015 Wiley Periodicals, Inc.)

Qualitative poor decision-making and associated altered neuronal activation patterns have been described for the users of several drugs, amongst others for stimulants like amphetamine and MDMA. Deficits in decision-making might be caused by an augmented attraction to short-term rewarding properties despite negative long-term consequences, leading to rigid stimulus-response patterns. In the present imaging study, we investigated decision-making and associated neuronal activation in three groups differing in their exposure to amphetamine and MDMA. An established paradigm on risky choices was used to evaluate decision-making performance and corresponding functional magnet resonance imaging (fMRI) activation. Subjects could choose between a low-risk control gamble and an experimental gamble, which always differed in the probability of winning or losing, as well as the magnitudes of monetary gain or loss. Experienced users (EU), users with low exposure to stimulants and drug-naive controls, did not differ from each other in behavioral performance. In accordance with our hypotheses, the anticipation of reward led to an activation of primarily the frontal cortex and the striatum in low-exposure users and drug-naive controls. In contrast, frontal and parietal activation was observed in all groups when the actual outcome of an experimental gamble was presented. EU displayed more activation compared to both control groups when there was a high probability of winning. The study at hand supports the hypothesis that neuronal activation patterns might even differ between drug users and healthy controls when no behavioral deficits are apparent. In EU, the probability of the occurrence of an event has more influence on neuronal activation than on the actual magnitude of reinforcing properties of this event.

Background: The human amygdala plays a crucial role in processing social signals, such as face expressions, particularly fearful ones, and facilitates responses to them in face-sensitive cortical regions. This contributes to social competence and individual amygdala size correlates with that of social networks. While rare patients with focal bilateral amygdala lesion typically show impaired recognition of fearful faces, this deficit is variable, and an intriguing possibility is that other brain regions can compensate to support fear and social signal processing., Methods: To investigate the brain's functional compensation of selective bilateral amygdala damage, we performed a series of behavioral, psychophysiological, and functional magnetic resonance imaging experiments in two adult female monozygotic twins (patient 1 and patient 2) with equivalent, extensive bilateral amygdala pathology as a sequela of lipoid proteinosis due to Urbach-Wiethe disease., Results: Patient 1, but not patient 2, showed preserved recognition of fearful faces, intact modulation of acoustic startle responses by fear-eliciting scenes, and a normal-sized social network. Functional magnetic resonance imaging revealed that patient 1 showed potentiated responses to fearful faces in her left premotor cortex face area and bilaterally in the inferior parietal lobule., Conclusions: The premotor cortex face area and inferior parietal lobule are both implicated in the cortical mirror-neuron system, which mediates learning of observed actions and may thereby promote both imitation and empathy. Taken together, our findings suggest that despite the pre-eminent role of the amygdala in processing social information, the cortical mirror-neuron system may sometimes adaptively compensate for its pathology., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To study reactive nitrogen species-mediated oxidative brain damage and antioxidant defenses in patients with acute bacterial meningitis., Methods: Nitrotyrosine (a widely used marker for the formation of reactive nitrogen species, such as peroxynitrite) and the lipid peroxidation product 4-hydroxynonenal were detected by immunohistochemistry in brain specimens obtained at autopsy. CSF concentrations of nitrotyrosine were quantified by ELISA. CSF and serum concentrations of ascorbic acid, uric acid, and its oxidation product allantoin were determined by high-pressure liquid chromatography., Results: Tyrosine nitration was strongly increased during meningitis. It was most evident in inflammatory cells and blood vessels in the subarachnoid space. The same cell types stained positive for the lipid peroxidation marker 4-hydroxynonenal, suggesting that reactive nitrogen species contribute to oxidative brain damage during meningitis. High CSF nitrotyrosine concentrations were associated with an unfavorable outcome according to the Glasgow Outcome Score. In the CSF, the increase of nitrotyrosine was accompanied by a depletion of the antioxidant ascorbic acid and an increased oxidation of the natural peroxynitrite scavenger uric acid to allantoin., Conclusion: These findings indicate that oxidative stress due to reactive nitrogen species and altered antioxidant defenses are involved in the pathophysiology of bacterial meningitis in humans.

The expression of the immunoglobulin superfamily member myelin-associated glycoprotein (MAG) and the extracellular matrix glycoprotein tenascin-R (TN-R) by oligodendrocytes overlaps in time and space. The two molecules can be neurite outgrowth-inhibitory or -promoting depending on the neuronal cell type and the environment in which they are presented. Here we show that the two molecules directly bind to each other in vitro and that binding sites on TN-R localize to two domains, the fibrinogen domain and the epidermal growth factor-like repeat domain with the N-terminal cysteine-rich stretch. We further show by a functional assay, namely the repulsion of MAG-transfected Chinese hamster ovary cells (CHO) cells from a TN-R substrate, that MAG is part of the signalling pathway of TN-R for cell repulsion. When coated as a uniform substrate, MAG was inhibitory for neurite outgrowth of hippocampal and cerebellar neurons in vitro, when compared to poly-L-lysine, while TN-R enhanced neurite outgrowth. When added to MAG, TN-R neutralized the neurite outgrowth-inhibitory effects of MAG, presumably by blocking the neurite outgrowth-inhibitory domain of MAG.

To determine the subsequent evolution of neurologic, neuropsychologic, and intracranial anatomic findings in long-term survivors of small-cell cancer, we repeated an evaluation done 4 years previously in patients 6 to 13 years after treatment. Fifteen patients were reevaluated with a history and physical examination, mental status examination, neuropsychologic testing, computed cranial tomographic (CCT) scans, and magnetic resonance imaging (MRI). All but one was ambulatory and none were institutionalized. Thirteen of 15 had neurologic complaints, 10 of 15 had an abnormal neurologic examination, seven of 14 had an abnormal mental status examination, 12 of 14 had abnormal neuropsychologic testing, 12 of 15 had abnormal CCT scans, and seven of 15 had white-matter abnormalities on MRI scans. No dramatic decline in performance status, functional status, neurologic symptoms, or neurologic examination occurred in these patients with 4 years of additional follow-up. More patients showed a decline in mental status examinations and neuropsychologic testing than demonstrated improvement. Anatomic studies showed no dramatic changes in the CCT scans and MRI confirmed these findings. From these data we conclude that there is a slow decline in neuropsychologic function in some of the patients surviving more than 6 years from a diagnosis of small-cell lung cancer. The anatomic abnormalities documented by CCT scans and MRI are more frequent in patients with abnormal neuropsychologic function.

We assessed the outcome in 252 patients with small-cell lung cancer 5 to 11 years after treatment with combination chemotherapy, with or without chest and cranial irradiation, in National Cancer Institute therapeutic trials from 1973 through 1978. Twenty-eight patients (11%) survived free of cancer for 30 months or more. Fourteen patients remain alive without evidence of cancer beyond 5 years (range, 6.4 to 11.3 years), and 7 patients have returned to a lifestyle similar to that before diagnosis. The other 14 patients who were cancer-free at 30 months have developed cancer or died; 6 patients had a relapse, 4 developed or died from non-small-cell lung cancer, and 4 died of unrelated causes. A few patients with small-cell lung cancer (5.6%) may be cured. Thirty-month, cancer-free survival is insufficient to show a cure. Although late toxicities are troublesome, they do not outweigh the benefits of prolonged survival and potential for cure with modern aggressive therapy in small-cell lung cancer. [ABSTRACT FROM AUTHOR]