Neural signatures of shared subjective affective engagement and disengagement during movie viewing.

When watching a negative emotional movie, we differ from person to person in the ease with which we engage and the difficulty with which we disengage throughout a temporally evolving narrative. We investigated neural responses of emotional processing, by considering inter-individual synchronization in subjective emotional engagement and disengagement. The neural underpinnings of these shared responses are ideally studied in naturalistic scenarios like movie viewing, wherein individuals emotionally engage and disengage at their own time and pace throughout the course of a narrative. Despite the rich data that naturalistic designs can bring to the study, there is a challenge in determining time-resolved behavioral markers of subjective engagement and disengagement and their underlying neural responses. We used a within-subject cross-over design instructing 22 subjects to watch clips of either neutral or sad content while undergoing functional magnetic resonance imaging (fMRI). Participants watched the same movies a second time while continuously annotating the perceived emotional intensity, thus enabling the mapping of brain activity and emotional experience. Our analyses revealed that between-participant similarity in waxing (engagement) and waning (disengagement) of emotional intensity was directly related to the between-participant similarity in spatiotemporal patterns of brain activation during the movie(s). Similar patterns of engagement reflected common activation in the bilateral ventromedial prefrontal cortex, regions often involved in self-referenced evaluation and generation of negative emotions. Similar patterns of disengagement reflected common activation in central executive and default mode network regions often involved in top-down emotion regulation. Together this work helps to better understand cognitive and neural mechanisms underpinning engagement and disengagement from emotionally evocative narratives.

Disturbances in fear extinction learning after mild traumatic brain injury in mice are accompanied by alterations in dendritic plasticity in the medial prefrontal cortex and basolateral nucleus of the amygdala.

Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) have emerged as the signature injuries of the U.S. veterans who served in Iraq and Afghanistan, and frequently co-occur in both military and civilian populations. To better understand how fear learning and underlying neural systems might be altered after mTBI, we examined the acquisition of cued fear conditioning and its extinction along with brain morphology and dendritic plasticity in a mouse model of mTBI. To induce mTBI in adult male C57BL/6J mice, a lateral fluid percussive injury (LFP 1.7) was produced using a fluid pulse of 1.7 atmosphere force to the right parietal lobe. Behavior in LFP 1.7 mice was compared to behavior in mice from two separate control groups: mice subjected to craniotomy without LFP injury (Sham) and mice that did not undergo surgery (Unoperated). Following behavioral testing, neural endpoints (dendritic structural plasticity and neuronal volume) were assessed in the basolateral nucleus of the amygdala (BLA), which plays a critical sensory role in fear learning, and medial prefrontal cortex (mPFC), responsible for executive functions and inhibition of fear behaviors. No gross motor abnormalities or increased anxiety-like behaviors were observed in LFP or Sham mice after surgery compared to Unoperated mice. We found that all mice acquired fear behavior, assessed as conditioned freezing to auditory cue in a single session of 6 trials, and acquisition was similar across treatment groups. Using a linear mixed effects analysis, we showed that fear behavior decreased overall over 6 days of extinction training with no effect of treatment group across extinction days. However, a significant interaction was demonstrated between the treatment groups during within-session freezing behavior (5 trials per day) during extinction training. Specifically, freezing behavior increased across within-session extinction trials in LFP 1.7 mice, whereas freezing behavior in control groups did not change on extinction test days, reflecting a dissociation between within-trial and between-trial fear extinction. Additionally, LFP mice demonstrated bilateral increases in dendritic spine density in the BLA and decreases in dendritic complexity in the PFC. The translational implications are that individuals with TBI undergoing fear extinction therapy may demonstrate within-session aberrant learning that could be targeted for more effective treatment interventions.

PTSD symptomatology is selectively associated with impaired sustained attention ability and dorsal attention network synchronization.

Posttraumatic Stress Disorder (PTSD) symptomatology is associated with dysregulated sustained attention, which produces functional impairments. Performance on sustained attention paradigms such as continuous performance tasks are influenced by both the ability to sustain attention and response strategy. However, previous studies have not dissociated PTSD-related associations with sustained attention ability and strategy, which limits characterization of neural circuitry underlying PTSD-related attentional impairments. Therefore, we characterized and replicated PTSD-related associations with sustained attention ability and response strategy in trauma-exposed Veterans, which guided characterization of PTSD-related differences in neural circuit function. In Study 1, PTSD symptoms were selectively associated with reduced sustained attention ability, but not more impulsive response strategies. In Study 2, we utilized task and resting-state fMRI to characterize neural circuitry underlying PTSD-related differences in sustained attention ability. Both PTSD symptomatology and sustained attention ability exhibited converging associations with reduced dorsal attention network (DAN) synchronization to endogeneous attentional fluctuations. Post-hoc time course analyses demonstrated that PTSD symptoms were most accurately characterized by delayed, rather than globally reduced, DAN synchronization to endogenous attentional fluctuations. Together, these findings suggest that PTSD symptomatology may selectively impair sustained attention ability by disrupting proactive engagement of attentional control circuitry.

Neural Basis of Impaired Emotion Recognition in Adult Attention-Deficit/Hyperactivity Disorder.

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

Impaired executive function exacerbates neural markers of posttraumatic stress disorder.

BACKGROUND: A major obstacle in understanding and treating posttraumatic stress disorder (PTSD) is its clinical and neurobiological heterogeneity. To address this barrier, the field has become increasingly interested in identifying subtypes of PTSD based on dysfunction in neural networks alongside cognitive impairments that may underlie the development and maintenance of symptoms. The current study aimed to determine if subtypes of PTSD, based on normative-based cognitive dysfunction across multiple domains, have unique neural network signatures. METHODS: In a sample of 271 veterans (90% male) that completed both neuropsychological testing and resting-state fMRI, two complementary, whole-brain functional connectivity analyses explored the link between brain functioning, PTSD symptoms, and cognition. RESULTS: At the network level, PTSD symptom severity was associated with reduced negative coupling between the limbic network (LN) and frontal-parietal control network (FPCN), driven specifically by the dorsolateral prefrontal cortex and amygdala Hubs of Dysfunction. Further, this relationship was uniquely moderated by executive function (EF). Specifically, those with PTSD and impaired EF had the strongest marker of LN-FPCN dysregulation, while those with above-average EF did not exhibit PTSD-related dysregulation of these networks. CONCLUSION: These results suggest that poor executive functioning, alongside LN-FPCN dysregulation, may represent a neurocognitive subtype of PTSD.

The missing role of gray matter in studying brain controllability.

Brain controllability properties are normally derived from the white matter fiber tracts in which the neural substrate of the actual energy consumption, namely the gray matter, has been widely ignored. Here, we study the relationship between gray matter volume of regions across the whole cortex and their respective control properties derived from the structural architecture of the white matter fiber tracts. The data suggests that the ability of white fiber tracts to exhibit control at specific nodes not only depends on the connection strength of the structural connectome but additionally depends on gray matter volume at the host nodes. Our data indicate that connectivity strength and gray matter volume interact with respect to the brain's control properties. Disentangling effects of the regional gray matter volume and connectivity strength, we found that frontal and sensory areas play crucial roles in controllability. Together these results suggest that structural and regional properties of the white matter and gray matter provide complementary information in studying the control properties of the intrinsic structural and functional architecture of the brain.

Integration and segregation across large-scale intrinsic brain networks as a marker of sustained attention and task-unrelated thought.

Sustained attention is a fundamental cognitive process that can be decoupled from distinct external events, and instead emerges from ongoing intrinsic large-scale network interdependencies fluctuating over seconds to minutes. Lapses of sustained attention are commonly associated with the subjective experience of mind wandering and task-unrelated thoughts. Little is known about how fluctuations in information processing underpin sustained attention, nor how mind wandering undermines this information processing. To overcome this, we used fMRI to investigate brain activity during subjects' performance (n=29) of a cognitive task that was optimized to detect and isolate continuous fluctuations in both sustained attention (via motor responses) and task-unrelated thought (via subjective reports). We then investigated sustained attention with respect to global attributes of communication throughout the functional architecture, i.e., by the segregation and integration of information processing across large scale-networks. Further, we determined how task-unrelated thoughts related to these global information processing markers of sustained attention. The results show that optimal states of sustained attention favor both enhanced segregation and reduced integration of information processing in several task-related large-scale cortical systems with concurrent reduced segregation and enhanced integration in the auditory and sensorimotor systems. Higher degree of mind wandering was associated with losses of the favored segregation and integration of specific subsystems in our sustained attention model. Taken together, we demonstrate that intrinsic ongoing neural fluctuations are characterized by two converging communication modes throughout the global functional architecture, which give rise to optimal and suboptimal attention states. We discuss how these results might potentially serve as neural markers for clinically abnormal attention. SIGNIFICANCE STATEMENT: Most of our brain activity unfolds in an intrinsic manner, i.e., is unrelated to immediate external stimuli or tasks. Here we use a gradual continuous performance task to map this intrinsic brain activity to both fluctuations of sustained attention and mind wandering. We show that optimal sustained attention is associated with concurrent segregation and integration of information processing within many large-scale brain networks, while task-unrelated thought is related to sub-optimal information processing in specific subsystems of this sustained attention network model. These findings provide a novel information processing framework for investigating the neural basis of sustained attention, by mapping attentional fluctuations to genuinely global features of intra-brain communication.

Specific Effects of Individualized Cognitive Training in Children with Attention-Deficit/Hyperactivity Disorder (ADHD): The Role of Pre-Training Cognitive Impairment and Individual Training Performance.

Objective: We investigated the impact of the pre-training neuropsychological (NP) impairment and of the training progress on the NP and behavioural outcome after computerized cognitive training (CogT) in children with ADHD. Method: Thirty-one participants underwent individualized CogT (focussing on one or two cognitive domains: working memory, inhibition, attention) over 12 weeks. NP tests and behaviour ratings served as outcome measures. Results: After CogT, significant improvements emerged according to parents' ratings, but only on very few NP test measures. Children with milder/no pre-training NP impairment showed larger improvements on behavioural ratings than more impaired children. A steeper training performance slope was related to better behavioural outcomes. Conclusion: We find partial support for specific effects of CogT, but the assumption that an individually tailored selection of training tasks would be particularly beneficial for children with ADHD with NP deficits was not confirmed. Trial registration number: NCT02358941.

Mixed-Effects Modeling of Neurofeedback Self-Regulation Performance: Moderators for Learning in Children with ADHD.

Introduction: Neurofeedback (NF) has gained increasing popularity as a training method for children and adults with attention deficit hyperactivity disorder (ADHD). However, it is unclear to what extent children learn to regulate their brain activity and in what way NF learning may be affected by subject- and treatment-related factors. Methods: In total, 48 subjects with ADHD (age 8.5-16.5 years; 16 subjects on methylphenidate (MPH)) underwent 15 double training sessions of NF in either a clinical or a school setting. Four mixed-effects models were employed to analyze learning: training within-sessions, across-sessions, with continuous feedback, and with transfer in which performance feedback is delayed. Results: Age and MPH affected the NF performance in all models. Cross-session learning in the feedback condition was mainly moderated by age and MPH, whereas NF learning in the transfer condition was mainly boosted by MPH. Apart from IQ and task types, other subject-related or treatment-related effects were unrelated to NF learning. Conclusion: This first study analyzing moderators of NF learning in ADHD with a mixed-effects modeling approach shows that NF performance is moderated differentially by effects of age and MPH depending on the training task and time window. Future studies may benefit from using this approach to analyze NF learning and NF specificity. The trial name Neurofeedback and Computerized Cognitive Training in Different Settings for Children and Adolescents With ADHD is registered with NCT02358941.

Informant-related effects of neurofeedback and cognitive training in children with ADHD including a waiting control phase: a randomized-controlled trial.

There is controversy regarding the clinical efficacy of neurofeedback (NF) and computerized cognitive training (CogT) as treatments for ADHD. Meta-analyses claim that probably blinded teachers observe smaller effects than parents, because they are less biased. We investigated informant-specific effects by manipulating the involvement of informants, by controlling for waiting time effects, and by adding a blinded outcome measure. Seventy-seven children with ADHD were randomly allocated to slow cortical potential NF or to individualized CogT (of attention, working memory or inhibition). The training was conducted in schools (NF: n = 19, CogT: n = 19) or in outpatient clinics (NF: n = 19, CogT: n = 20). Three assessments were scheduled: baseline, followed by a waiting period, pre-training, and post-training. Multivariate Analyses of Variance were conducted to assess parent- and teacher-rated changes in ADHD symptoms and executive functions (EF), and changes according to standardized classroom observations. Both treatments resulted in significant improvements according to informants, with larger effects for parents (ADHD symptoms: parent η p2  = .32; teacher η p2  = .10), and according to observations (η p2  = .19). The setting had no effect on outcome. Considerable waiting time effects were revealed for ADHD symptom ratings by both informants, for EF ratings only by teachers. Changed classroom behavior was uncorrelated with teacher-rated changes. Overall, the results do not support the notion that teachers are more objective while being as sensitive to change as parents. The three sources seem to contribute differential and mostly unrelated pieces of information to the evaluation of treatments.

A Review of the Clinical Utility of Systematic Behavioral Observations in Attention Deficit Hyperactivity Disorder (ADHD).

This review evaluates the clinical utility of tools for systematic behavioral observation in different settings for children and adolescents with ADHD. A comprehensive search yielded 135 relevant results since 1990. Observations from naturalistic settings were grouped into observations of classroom behavior (n = 58) and of social interactions (n = 25). Laboratory observations were subdivided into four contexts: independent play (n = 9), test session (n = 27), parent interaction (n = 11), and peer interaction (n = 5). Clinically relevant aspects of reliability and validity of employed instruments are reviewed. The results confirm the usefulness of systematic observations. However, no procedure can be recommended as a stand-alone diagnostic method. Psychometric properties are often unsatisfactory, which reduces the validity of observational methods, particularly for measuring treatment outcome. Further efforts are needed to improve the specificity of observational methods with regard to the discrimination of comorbidities and other disorders.

Are treatment effects of neurofeedback training in children with ADHD related to the successful regulation of brain activity? A review on the learning of regulation of brain activity and a contribution to the discussion on specificity.

While issues of efficacy and specificity are crucial for the future of neurofeedback training, there may be alternative designs and control analyses to circumvent the methodological and ethical problems associated with double-blind placebo studies. Surprisingly, most NF studies do not report the most immediate result of their NF training, i.e., whether or not children with ADHD gain control over their brain activity during the training sessions. For the investigation of specificity, however, it seems essential to analyze the learning and adaptation processes that take place in the course of the training and to relate improvements in self-regulated brain activity across training sessions to behavioral, neuropsychological and electrophysiological outcomes. To this aim, a review of studies on neurofeedback training with ADHD patients which include the analysis of learning across training sessions or relate training performance to outcome is presented. Methods on how to evaluate and quantify learning of EEG regulation over time are discussed. "Non-learning" has been reported in a small number of ADHD-studies, but has not been a focus of general methodological discussion so far. For this reason, selected results from the brain-computer interface (BCI) research on the so-called "brain-computer illiteracy", the inability to gain control over one's brain activity, are also included. It is concluded that in the discussion on specificity, more attention should be devoted to the analysis of EEG regulation performance in the course of the training and its impact on clinical outcome. It is necessary to improve the knowledge on characteristic cross-session and within-session learning trajectories in ADHD and to provide the best conditions for learning.