High-order brain interactions in ketamine during rest and task: A double-blinded cross-over design using portable EEG.

In a double-blinded cross-over design, 30 adults (mean age = 25.57, SD = 3.74; all male) were administered racemic ketamine and compared against saline infusion as a control. Both task-driven (auditory oddball paradigm) and resting-state EEG were recorded. HOI were computed using advanced multivariate information theory tools, allowing us to quantify nonlinear statistical dependencies between all possible electrode combinations. Results: Ketamine increased redundancy in brain dynamics, most significantly in the alpha frequency band. Redundancy was more evident during the resting state, associated with a shift in conscious states towards more dissociative tendencies. Furthermore, in the task-driven context (auditory oddball), the impact of ketamine on redundancy was more significant for predictable (standard stimuli) compared to deviant ones. Finally, associations were observed between ketamine's HOI and experiences of derealization. Conclusions: Ketamine appears to increase redundancy and genuine HOI across metrics, suggesting these effects correlate with consciousness alterations towards dissociation. HOI represents an innovative method to combine all signal spatial interactions obtained from low-density dry EEG in drug interventions, as it is the only approach that exploits all possible combinations from different electrodes. This research emphasizes the potential of complexity measures coupled with portable EEG devices in monitoring shifts in consciousness, especially when paired with low-density configurations, paving the way for better understanding and monitoring of pharmacological-induced changes.

Association among childhood adversity and susceptibility to interference during varying salience: two studies in healthy males.

Childhood adversity, a prevalent experience, is related to a higher risk for externalizing and internalizing psychopathology. Alterations in the development of cognitive processes, for example in the attention-interference domain may link childhood adversity and psychopathology. Interfering stimuli can vary in their salience, i.e. ability to capture attentional focus, and valence. However, it is not known if interference by salience or valence is associated with self-reported adversity. In two independent study samples of healthy men (Study 1: n = 44; mean age [standard deviation (SD)] = 25.9 [3.4] years; Study 2: n = 37; 43.5 [9.7] years) we used the attention modulation task (AMT) that probed interference by two attention-modulating conditions, salience and valence separately across repeated target stimuli. The AMT measures the effects of visual distractors (pictures) on the performance of auditory discrimination tasks (target stimuli). We hypothesized that participants reporting higher levels of childhood adversity, measured with the childhood trauma questionnaire, would show sustained interference in trials with lower salience. Due to conflicting reports on the valence-modulation, we tested the valence condition in an exploratory manner. Linear mixed models revealed an interaction between reported childhood adversity and the salience condition across tone presentations in both study samples (Sample 1: p = .03; Sample 2: p = .04), while there were no effects for the valence condition across both studies. Our study suggests that higher self-reported childhood adversity is related to faster processing of target cues during high salience, but slower during low salience conditions. These results hint to the mechanisms linking childhood adversity and psychopathological symptoms in the attentional domain.

Altered brain dynamic in major depressive disorder: state and trait features.

Temporal neural synchrony disruption can be linked to a variety of symptoms of major depressive disorder (MDD), including mood rigidity and the inability to break the cycle of negative emotion or attention biases. This might imply that altered dynamic neural synchrony may play a role in the persistence and exacerbation of MDD symptoms. Our study aimed to investigate the changes in whole-brain dynamic patterns of the brain functional connectivity and activity related to depression using the hidden Markov model (HMM) on resting-state functional magnetic resonance imaging (rs-fMRI) data. We compared the patterns of brain functional dynamics in a large sample of 314 patients with MDD (65.9% female; age (mean ± standard deviation): 35.9 ± 13.4) and 498 healthy controls (59.4% female; age: 34.0 ± 12.8). The HMM model was used to explain variations in rs-fMRI functional connectivity and averaged functional activity across the whole-brain by using a set of six unique recurring states. This study compared the proportion of time spent in each state and the average duration of visits to each state to assess stability between different groups. Compared to healthy controls, patients with MDD showed significantly higher proportional time spent and temporal stability in a state characterized by weak functional connectivity within and between all brain networks and relatively strong averaged functional activity of regions located in the somatosensory motor (SMN), salience (SN), and dorsal attention (DAN) networks. Both proportional time spent and temporal stability of this brain state was significantly associated with depression severity. Healthy controls, in contrast to the MDD group, showed proportional time spent and temporal stability in a state with relatively strong functional connectivity within and between all brain networks but weak averaged functional activity across the whole brain. These findings suggest that disrupted brain functional synchrony across time is present in MDD and associated with current depression severity.

Lower affective empathy in oral contraceptive users: a cross-sectional fMRI study.

Evidence accumulates that oral contraceptive (OC) use modulates various socio-affective behaviors, including empathic abilities. Endogenous and synthetic sex hormones, such as estrogens and progestogens, bind to receptor sites in brain regions (i.e. frontal, limbic, and cerebellar) involved in socio-affective processing. Therefore, the aim of this study was to investigate the role of OC use in empathy. In a cross-sectional functional magnetic resonance imaging study, women in different hormonal states, including OC use (n = 46) or being naturally cycling in the early follicular (fNC: n = 37) or peri-ovulatory phase (oNC: n = 28), performed a visual, sentence-based empathy task. Behaviorally, OC users had lower empathy ratings than oNC women. Congruently, whole-brain analysis revealed significantly larger task-related activation of several brain regions, including the left dorsomedial prefrontal gyrus (dmPFG), left precentral gyrus, and left temporoparietal junction in oNC compared to OC women. In OC users, the activity of the left dmPFG and precentral gyrus was negatively associated with behavioral and self-reported affective empathy. Furthermore, empathy-related region-of-interest analysis indicated negative associations of brain activation with synthetic hormone levels in OC women. Overall, this multimodal, cross-sectional investigation of empathy suggests a role of OC intake in especially affective empathy and highlights the importance of including synthetic hormone levels in OC-related analyses.

Neuroscience from the comfort of your home: Repeated, self-administered wireless dry EEG measures brain function with high fidelity.

Recent advances have enabled the creation of wireless, "dry" electroencephalography (EEG) recording systems, and easy-to-use engaging tasks, that can be operated repeatedly by naïve users, unsupervised in the home. Here, we evaluated the validity of dry-EEG, cognitive task gamification, and unsupervised home-based recordings used in combination. Two separate cohorts of participants-older and younger adults-collected data at home over several weeks using a wireless dry EEG system interfaced with a tablet for task presentation. Older adults (n = 50; 25 females; mean age = 67.8 years) collected data over a 6-week period. Younger male adults (n = 30; mean age = 25.6 years) collected data over a 4-week period. All participants were asked to complete gamified versions of a visual Oddball task and Flanker task 5-7 days per week. Usability of the EEG system was evaluated via participant adherence, percentage of sessions successfully completed, and quantitative feedback using the System Usability Scale. In total, 1,449 EEG sessions from older adults (mean = 28.9; SD = 6.64) and 684 sessions from younger adults (mean = 22.87; SD = 1.92) were collected. Older adults successfully completed 93% of sessions requested and reported a mean usability score of 84.5. Younger adults successfully completed 96% of sessions and reported a mean usability score of 88.3. Characteristic event-related potential (ERP) components-the P300 and error-related negativity-were observed in the Oddball and Flanker tasks, respectively. Using a conservative threshold for inclusion of artifact-free data, 50% of trials were rejected per at-home session. Aggregation of ERPs across sessions (2-4, depending on task) resulted in grand average signal quality with similar Standard Measurement Error values to those of single-session wet EEG data collected by experts in a laboratory setting from a young adult sample. Our results indicate that easy-to-use task-driven EEG can enable large-scale investigations in cognitive neuroscience. In future, this approach may be useful in clinical applications such as screening and tracking of treatment response.

Corrigendum to "EEG revealed improved vigilance regulation after stress exposure under Nx4 - A randomized, placebo-controlled, double-blind, cross-over trial" [IBRO Neurosci. Rep. 11C (2021) 175-182].

[This corrects the article DOI: 10.1016/j.ibneur.2021.09.002.].

Pregnancy and brain architecture: Associations with hormones, cognition and affect.

Sex hormones such as estradiol (E2) have long-lasting influence on brain architecture. Recent studies indicate further structural changes during hormonal transition periods including pregnancy, when women experience the greatest increase in sex hormone levels across their life span. In the present study, three groups of women (n = 44) with different levels of E2 underwent structural magnetic resonance imaging: (1) first-time pregnant women (n = 13, 'extreme E2 group'); (2), nulliparous, naturally cycling women who received 12 mg of E2 valerate (n = 16, 'high E2 group'); and (3) nulliparous, naturally cycling women receiving a placebo and hence low E2 (n = 15, 'low E2 group'). Blood samples were taken to assess hormonal levels. Moreover, parameters for cognition, emotion regulation and affect were assessed. On the neuronal level, the extreme E2 compared to the high E2 group showed a reduced gray matter volume in the left putamen. However, no significant differences were found between the low vs. high E2 groups, nor between the low E2 and extreme E2 groups. Cognitive performance was reduced in the extreme E2 group, although a positive affect was increased compared to the high E2 and low E2 groups. Furthermore, regression analyses revealed several associations between cognition, subjective measures of affect, emotion regulation and gray matter volume. A volume reduction of the left putamen during pregnancy further supports the notion that the female brain is shaped by hormonal transition phases, possibly preparing women for their future roles (e.g., pregnant women for their role as mothers).

Nx4 Reduced Susceptibility to Distraction in an Attention Modulation Task.

Background: Stress adversely affects the attentional focus, the active concentration on stimuli, and increases susceptibility to distraction. To experimentally explore the susceptibility to distraction, the Attention Modulation by Salience Task (AMST) is a validated paradigm measuring reaction times (RT) for processing auditory information while presenting task-irrelevant visual distractors of high or low salience. We extended the AMST by an emotional dimension of distractors and an EEG-based evaluation. We then investigated the effect of the stress-relieving medication Neurexan (Nx4) on the participants' susceptibility to distraction. Methods: Data from a randomized, placebo-controlled, crossover trial (NEURIM study; ClinicalTrials.gov: NCT02602275) were exploratively reanalyzed post-hoc. In this trial, 39 participants received a single dose of placebo or Nx4 immediately before the AMST. Participants had to discriminate two different tone modulations (ascending or descending) while simultaneously perceiving task-irrelevant pictures of different salience (high or low) or valence (negative or positive) as distractors. Using EEG recordings, RT and the event-related potential (ERP) components N1, N2, and N3 were analyzed as markers for susceptibility to distraction. Results: In the placebo condition, we could replicate the previously reported task effects of salient distractors with longer RT for high salient distractors on the behavioral level. On the electrophysiological level, we observed significantly increased amplitudes of the N2 and N3 ERP components for positive emotional pictures. In terms of drug effect, we found evidence that Nx4 reduced distractibility by emotional distractors. The effect was shown by significantly reduced amplitudes of N2 and N3 ERP components and reduced RT for the positive valence domain under Nx4 compared to placebo. The Nx4 effects on RT and ERP components also showed a significant correlation. Conclusion: Emotional distractors in addition to the previously used salience distractors and the EEG based evaluation of ERPs valuably complement the AMST. Salient distractors were affecting attentional processes earlier, while valent distractors show modulatory effects later. Our results suggest that Nx4 has beneficial effects on attention by inhibiting the effect of task-irrelevant information and reducing susceptibility to emotionally distracting stimuli. The observation of a beneficial impact of Nx4 on attention regulation is supportive of Nx4's claim as a stress-relieving medication.

Progressive modulation of resting-state brain activity during neurofeedback of positive-social emotion regulation networks.

Neurofeedback allows for the self-regulation of brain circuits implicated in specific maladaptive behaviors, leading to persistent changes in brain activity and connectivity. Positive-social emotion regulation neurofeedback enhances emotion regulation capabilities, which is critical for reducing the severity of various psychiatric disorders. Training dorsomedial prefrontal cortex (dmPFC) to exert a top-down influence on bilateral amygdala during positive-social emotion regulation progressively (linearly) modulates connectivity within the trained network and induces positive mood. However, the processes during rest that interleave the neurofeedback training remain poorly understood. We hypothesized that short resting periods at the end of training sessions of positive-social emotion regulation neurofeedback would show alterations within emotion regulation and neurofeedback learning networks. We used complementary model-based and data-driven approaches to assess how resting-state connectivity relates to neurofeedback changes at the end of training sessions. In the experimental group, we found lower progressive dmPFC self-inhibition and an increase of connectivity in networks engaged in emotion regulation, neurofeedback learning, visuospatial processing, and memory. Our findings highlight a large-scale synergy between neurofeedback and resting-state brain activity and connectivity changes within the target network and beyond. This work contributes to our understanding of concomitant learning mechanisms post training and facilitates development of efficient neurofeedback training.

EEG-Microstates Reflect Auditory Distraction After Attentive Audiovisual Perception Recruitment of Cognitive Control Networks.

Processing of sensory information is embedded into ongoing neural processes which contribute to brain states. Electroencephalographic microstates are semi-stable short-lived power distributions which have been associated with subsystem activity such as auditory, visual and attention networks. Here we explore changes in electrical brain states in response to an audiovisual perception and memorization task under conditions of auditory distraction. We discovered changes in brain microstates reflecting a weakening of states representing activity of the auditory system and strengthening of salience networks, supporting the idea that salience networks are active after audiovisual encoding and during memorization to protect memories and concentrate on upcoming behavioural response.

EEG revealed improved vigilance regulation after stress exposure under Nx4 - A randomized, placebo-controlled, double-blind, cross-over trial.

OBJECTIVES: Vigilance is characterized by alertness and sustained attention. The hyper-vigilance states are indicators of stress experience in the resting brain. Neurexan (Nx4) has been shown to modulate the neuroendocrine stress response. Here, we hypothesized that the intake of Nx4 would alter brain vigilance states at rest. METHOD: In this post-hoc analysis of the NEURIM study, EEG recordings of three, 12 min resting-state conditions in 39 healthy male volunteers were examined in a randomized, placebo-controlled, double-blind, cross-over clinical trial. EEG was recorded at three resting-state sessions: at baseline (RS0), after single-dose treatment with Nx4 or placebo (RS1), and subsequently after a psychosocial stress task (RS2). During each resting-state session, each 2-s segment of the consecutive EEG epochs was classified into one of seven different brain states along a wake-sleep continuum using the VIGALL 2.1 algorithm. RESULTS: In the post-stress resting-state, subjects exhibited a hyper-stable vigilance regulation characterized by an increase in the mean vigilance level and by more rigidity in the higher vigilance states for a longer period of time. Importantly, Nx4-treated participants exhibited significantly lower mean vigilance level compared to placebo-treated ones. Also, Nx4- compared to placebo-treated participants spent comparably less time in higher vigilance states and more time in lower vigilance states in the post-stress resting-state. CONCLUSION: Study participants showed a significantly lower mean vigilance level in the post-stress resting-state condition and tended to stay longer in lower vigilance states after treatment with Nx4. These findings support the known stress attenuation effect of Nx4.

Estradiol administration modulates neural emotion regulation.

Variations of sex hormones during the menstrual cycle can lead to changes in emotion processing. The ability to successfully regulate one's emotions is associated with better social abilities and mental health. While women show better performance in fear extinction learning under high estradiol (E2) compared to women under low E2 levels, little is known about the effect of E2 on emotion regulation. We explored whether E2 modulates emotion regulation in a functional magnetic resonance imaging paradigm and administered E2 valerate to 32 young naturally cycling women during their early follicular phase in a double-blind, placebo-controlled within-subject design. This standardized experimental control allowed us to explore the specific effect of E2 on emotion regulation while controlling for other hormones varying throughout the menstrual cycle. Behaviorally, no difference between conditions appeared. However, on the neural level, E2 administration was associated with lower activation in the right lingual- and left calcarine gyrus, right orbitofrontal cortex and left hippocampus relative to placebo. With respect to the main effect of down-regulation higher activation of the right superior frontal gyrus and left dorsomedial prefrontal cortex was seen; which is in accordance to previous literature. An interaction between drug condition and emotion regulation appeared for the left inferior frontal gyrus extending into the middle frontal gyrus indicating lower activation during down-regulation in the E2 condition than the placebo condition. On the behavioral level, women reported less negative affect in the E2 condition. The results fit well to a previously described psychoneuroendocrinological model in which E2 plays an important modulatory role on emotional processes and risk factors of mental health in women.

Evidence for modulation of EEG microstate sequence by vigilance level.

The momentary global functional state of the brain is reflected in its electric field configuration and cluster analytical approaches have consistently shown four configurations, referred to as EEG microstate classes A to D. Changes in microstate parameters are associated with a number of neuropsychiatric disorders, task performance, and mental state establishing their relevance for cognition. However, the common practice to use eye-closed resting state data to assess the temporal dynamics of microstate parameters might induce systematic confounds related to vigilance levels. Here, we studied the dynamics of microstate parameters in two independent data sets and showed that the parameters of microstates are strongly associated with vigilance level assessed both by EEG power analysis and fMRI global signal. We found that the duration and contribution of microstate class C, as well as transition probabilities towards microstate class C were positively associated with vigilance, whereas the sign was reversed for microstate classes A and B. Furthermore, in looking for the origins of the correspondence between microstates and vigilance level, we found Granger-causal effects of vigilance levels on microstate sequence parameters. Collectively, our findings suggest that duration and occurrence of microstates have a different origin and possibly reflect different physiological processes. Finally, our findings indicate the need for taking vigilance levels into consideration in resting-sate EEG investigations.

MEG reveals preference specific increases of sexual-image-evoked responses in paedophilic sexual offenders and healthy controls.

OBJECTIVES: Paedophilic disorder is characterised by sexual attraction towards children. Classification of a counterpart as sexually attractive likely occurs rapidly, and involves both conscious and unconscious attentional and cognitive processes. Magnetoencephalography (MEG) is an imaging method especially well-suited to examine visual and attentional processes triggered by sexual images within the range of milliseconds. METHODS: We investigated brain responses to sexual images depicting adults (frequent) and children (infrequent stimulus) in seventeen paedophilic patients with a history of child sexual offending (P + CSO) and twenty healthy controls (HC) during a passive visual oddball paradigm. Event-related fields (ERF) were measured to extract the magnetic visual mismatch negativity (vMMNm), and how it relates to the processing of different classes of sexual stimuli. RESULTS: P + CSO exhibited significantly longer vMMNm latencies (100-180 ms post-stimulus) than HC. Moreover, P + CSO showed widespread increased amplitudes in response to child images starting from P3a and P3b components and lasting up to 400 ms post-stimulus presentation localised in frontal and temporal brain regions. CONCLUSIONS: This study uncovers the first MEG differences in automatic change detection between P + CSO and HC during the presentation of subliminal sexual images of adults and children, contributing towards a better understanding of the neurobiological processes of P + CSO.

A Phase 1 Randomized Placebo-Controlled Study to Assess the Safety, Immunogenicity and Genetic Stability of a New Potential Pandemic H7N9 Live Attenuated Influenza Vaccine in Healthy Adults.

This study describes a double-blind randomized placebo-controlled phase I clinical trial in healthy adults of a new potential pandemic H7N9 live attenuated influenza vaccine (LAIV) based on the human influenza virus of Yangtze River Delta hemagglutinin lineage (ClinicalTrials.gov Identifier: NCT03739229). Two doses of H7N9 LAIV or placebo were administered intranasally to 30 and 10 subjects, respectively. The vaccine was well-tolerated and not associated with increased rates of adverse events or with any serious adverse events. Vaccine virus was detected in nasal swabs during the 6 days after vaccination or revaccination. A lower frequency of shedding was observed after the second vaccination. Twenty-five clinical viral isolates obtained after the first and second doses of vaccine retained the temperature-sensitive and cold-adapted phenotypic characteristics of LAIV. There was no confirmed transmission of the vaccine strain from vaccinees to placebo recipients. After the two H7N9 LAIV doses, an immune response was observed in 96.6% of subjects in at least one of the assays conducted.

Investigating the temporal dynamics of electroencephalogram (EEG) microstates using recurrent neural networks.

Electroencephalogram (EEG) microstates that represent quasi-stable, global neuronal activity are considered as the building blocks of brain dynamics. Therefore, the analysis of microstate sequences is a promising approach to understand fast brain dynamics that underlie various mental processes. Recent studies suggest that EEG microstate sequences are non-Markovian and nonstationary, highlighting the importance of the sequential flow of information between different brain states. These findings inspired us to model these sequences using Recurrent Neural Networks (RNNs) consisting of long-short-term-memory (LSTM) units to capture the complex temporal dependencies. Using an LSTM-based auto encoder framework and different encoding schemes, we modeled the microstate sequences at multiple time scales (200-2,000 ms) aiming to capture stably recurring microstate patterns within and across subjects. We show that RNNs can learn underlying microstate patterns with high accuracy and that the microstate trajectories are subject invariant at shorter time scales (≤400 ms) and reproducible across sessions. Significant drop in the reconstruction accuracy was observed for longer sequence lengths of 2,000 ms. These findings indirectly corroborate earlier studies which indicated that EEG microstate sequences exhibit long-range dependencies with finite memory content. Furthermore, we find that the latent representations learned by the RNNs are sensitive to external stimulation such as stress while the conventional univariate microstate measures (e.g., occurrence, mean duration, etc.) fail to capture such changes in brain dynamics. While RNNs cannot be configured to identify the specific discriminating patterns, they have the potential for learning the underlying temporal dynamics and are sensitive to sequence aberrations characterized by changes in metal processes. Empowered with the macroscopic understanding of the temporal dynamics that extends beyond short-term interactions, RNNs offer a reliable alternative for exploring system level brain dynamics using EEG microstate sequences.

An early post-traumatic reaction of lymph-heart striated muscle fibers in adult frog Rana temporaria during the first postoperative week: An electron microscopic and autoradiographic study.

According to the current opinion, lymph-heart striated muscle represents a specialized type of skeletal muscles in frogs. Here, we studied muscle fibers in mechanically damaged lymph hearts during the first postoperative week using electron-microscopic autoradiography. We present evidence that both, the satellite cells and pre-existing muscle fibers bordering the site of injury, contribute directly to the lymph-heart muscle regeneration. Several muscle fibers located in the vicinity of the damaged area displayed features of nuclear and sarcoplasmic activation. We also observed ultrastructural changes indicating activation of a few satellite cells, namely decondensation of chromatin, enlargement of nuclei and nucleoli, appearance of free ribosomes and rough endoplasmic reticulum tubules in the cytoplasm. Electron-microscopic autoradiography showed that 4 h after single (3)H-thymidine administration on the seventh day after injury not only the activated satellite cells, but also some nuclei of myofibers bordering the injured zone are labeled. We showed that both, the myonuclei of fibers displaying the signs of degenerative/reparative processes in the sarcoplasm and the myonuclei of the fibers enriched with highly organized myofibrils, can re-enter into the S-phase. Our results indicate that the nuclei of lymph-heart myofibers can reactivate DNA synthesis during regenerative myogenesis, unlike the situation in regenerating frog skeletal muscle where myogenic cells do not synthesize DNA at the onset of myofibrillogenesis.