Brain substates induced by DMT relate to sympathetic output and meaningfulness of the experience.

N,N-Dimethyltryptamine (DMT) is a serotonergic psychedelic, known to rapidly induce short-lasting alterations in conscious experience, characterized by a profound and immersive sense of physical transcendence alongside rich and vivid auditory distortions and visual imagery. Multimodal neuroimaging data paired with dynamic analysis techniques offer a valuable approach for identifying unique signatures of brain activity - and linked autonomic physiology - naturally unfolding during the altered state of consciousness induced by DMT. We leveraged simultaneous fMRI and EKG data acquired in 14 healthy volunteers prior to, during, and after intravenous administration of DMT, and, separately, placebo. fMRI data was preprocessed to derive individual dynamic activity matrices, reflecting the similarity of brain activity in time, and community detection algorithms were applied on these matrices to identify brain activity substates; EKG data was used to derive continuous heart rate. We identified a brain substate occurring immediately after DMT injection, characterized by increased superior temporal lobe activity, and hippocampal and medial parietal deactivations under DMT. Results revealed that hippocampus and medial parietal cortex hypoactivity correlated with scores of meaningfulness of the experience. During this first post-injection substate, increased heart rate under DMT correlated negatively with the meaningfulness of the experience and positively with hippocampus/medial parietal deactivation. These results suggest a chain of influence linking sympathetic regulation to hippocampal and medial parietal deactivations under DMT, which combined, may contribute to positive mental health outcomes related to self-referential processing following psychedelic administration.

Digital rhythm training improves reading fluency in children.

Musical instrument training has been linked to improved academic and cognitive abilities in children, but it remains unclear why this occurs. Moreover, access to instrument training is not always feasible, thereby leaving less fortunate children without opportunity to benefit from such training. Although music-based video games may be more accessible to a broader population, research is lacking regarding their benefits on academic and cognitive performance. To address this gap, we assessed a custom-designed, digital rhythm training game as a proxy for instrument training to evaluate its ability to engender benefits in math and reading abilities. Furthermore, we tested for changes in core cognitive functions related to math and reading to inform how rhythm training may facilitate improved academic abilities. Classrooms of 8-9 year old children were randomized to receive either 6 weeks of rhythm training (N = 32) or classroom instruction as usual (control; N = 21). Compared to the control group, results showed that rhythm training improved reading, but not math, fluency. Assessments of cognition showed that rhythm training also led to improved rhythmic timing and language-based executive function (Stroop task), but not sustained attention, inhibitory control, or working memory. Interestingly, only the improvements in rhythmic timing correlated with improvements in reading ability. Together, these results provide novel evidence that a digital platform may serve as a proxy for musical instrument training to facilitate reading fluency in children, and that such reading improvements are related to enhanced rhythmic timing ability and not other cognitive functions associated with reading performance. RESEARCH HIGHLIGHTS: Digital rhythm training in the classroom can improve reading fluency in 8-9 year old children Improvements in reading fluency were positively correlated with enhanced rhythmic timing ability Alterations in reading fluency were not predicted by changes in other executive functions that support reading A digital platform may be a convenient and cost-effective means to provide musical rhythm training, which in turn, can facilitate academic skills.

Quantifying attention span across the lifespan.

Introduction: Studies examining sustained attention abilities typically utilize metrics that quantify performance on vigilance tasks, such as response time and response time variability. However, approaches that assess the duration that an individual can maintain their attention over time are lacking. Methods: Here we developed an objective attention span metric that quantified the maximum amount of time that a participant continuously maintained an optimal "in the zone" sustained attention state while performing a continuous performance task. Results: In a population of 262 individuals aged 7-85, we showed that attention span was longer in young adults than in children and older adults. Furthermore, declines in attention span over time during task engagement were related to clinical symptoms of inattention in children. Discussion: These results suggest that quantifying attention span is a unique and meaningful method of assessing sustained attention across the lifespan and in populations with inattention symptoms.

Gamma neuromodulation improves episodic memory and its associated network in amnestic mild cognitive impairment: a pilot study.

Amnestic mild cognitive impairment (aMCI) is a predementia stage of Alzheimer's disease associated with dysfunctional episodic memory and limited treatment options. We aimed to characterize feasibility, clinical, and biomarker effects of noninvasive neurostimulation for aMCI. 13 individuals with aMCI received eight 60-minute sessions of 40-Hz (gamma) transcranial alternating current stimulation (tACS) targeting regions related to episodic memory processing. Feasibility, episodic memory, and plasma Alzheimer's disease biomarkers were assessed. Neuroplastic changes were characterized by resting-state functional connectivity (RSFC) and neuronal excitatory/inhibitory balance. Gamma tACS was feasible and aMCI participants demonstrated improvement in multiple metrics of episodic memory, but no changes in biomarkers. Improvements in episodic memory were most pronounced in participants who had the highest modeled tACS-induced electric fields and exhibited the greatest changes in RSFC. Increased RSFC was also associated with greater hippocampal excitability and higher baseline white matter integrity. This study highlights initial feasibility and the potential of gamma tACS to rescue episodic memory in an aMCI population by modulating connectivity and excitability within an episodic memory network.

Influence of game features on attention in adults.

Introduction: The incorporation of game features into cognitive tasks can inform us about the influence of reward and motivation on attention. Continuous performance tasks (CPTs), designed to assess attention abilities, are examples of cognitive tasks that have been targeted for the addition of game features. However, previous results have been mixed regarding how game elements affect attention abilities and task performance. Methods: Here, we studied if there were factors that predict which individuals exhibit changes in attention from game features added to a CPT. Participants (N = 94, aged 21-71) played a traditional CPT and a game CPT with identical mechanics, but featured engaging game elements (aesthetics, storyline, competition, feedback, and reward). Results: We first found corroborating evidence that game features have mixed effects on attention performance: most attention metrics of interest exhibited no overall difference between the traditional and game CPT, while game elements reduced performance for a few metrics. Importantly, we also found that specific behavioral and demographic profiles predicted individual differences in performance on the game CPT compared to the traditional CPT. Those with more attention difficulties (ADHD symptoms), more reward responsiveness, and younger adults performed better on the game CPT while, conversely, those with fewer ADHD symptoms, less reward responsiveness, and older adults performed better on the traditional CPT. Discussion: These findings provide insights into how game features can influence attention in different individuals and have important implications for the use of game elements in cognitive tasks and training interventions.

Influence of goals on modular brain network organization during working memory.

Introduction: Top-down control underlies our ability to attend relevant stimuli while ignoring irrelevant, distracting stimuli and is a critical process for prioritizing information in working memory (WM). Prior work has demonstrated that top-down biasing signals modulate sensory-selective cortical areas during WM, and that the large-scale organization of the brain reconfigures due to WM demands alone; however, it is not yet understood how brain networks reconfigure between the processing of relevant versus irrelevant information in the service of WM. Methods: Here, we investigated the effects of task goals on brain network organization while participants performed a WM task that required participants to detect repetitions (e.g., 0-back or 1-back) and had varying levels of visual interference (e.g., distracting, irrelevant stimuli). We quantified changes in network modularity-a measure of brain sub-network segregation-that occurred depending on overall WM task difficulty as well as trial-level task goals for each stimulus during the task conditions (e.g., relevant or irrelevant). Results: First, we replicated prior work and found that whole-brain modularity was lower during the more demanding WM task conditions compared to a baseline condition. Further, during the WM conditions with varying task goals, brain modularity was selectively lower during goal-directed processing of task-relevant stimuli to be remembered for WM performance compared to processing of distracting, irrelevant stimuli. Follow-up analyses indicated that this effect of task goals was most pronounced in default mode and visual sub-networks. Finally, we examined the behavioral relevance of these changes in modularity and found that individuals with lower modularity for relevant trials had faster WM task performance. Discussion: These results suggest that brain networks can dynamically reconfigure to adopt a more integrated organization with greater communication between sub-networks that supports the goal-directed processing of relevant information and guides WM.

A complex systems perspective on psychedelic brain action.

Recent findings suggesting the potential transdiagnostic efficacy of psychedelic-assisted therapy have fostered the need to deepen our understanding of psychedelic brain action. Functional neuroimaging investigations have found that psychedelics reduce the functional segregation of large-scale brain networks. However, beyond this general trend, findings have been largely inconsistent. We argue here that a perspective based on complexity science that foregrounds the distributed, interactional, and dynamic nature of brain function may render these inconsistencies intelligible. We propose that psychedelics induce a mode of brain function that is more dynamically flexible, diverse, integrated, and tuned for information sharing, consistent with greater criticality. This 'meta' perspective has the potential to unify past findings and guide intuitions toward compelling mechanistic models.

Contribution of sustained attention abilities to real-world academic skills in children.

Sustained attention is a critical cognitive ability that improves over the course of development and predicts important real-world outcomes, such as academic achievement. However, the majority of work demonstrating links between sustained attention and academic skills has been conducted in lab-based settings that lack the ecological validity of a more naturalistic environment, like school. Further, most studies focus on targeted academic measures of specific sub-skills and have not fully examined whether this relationship generalizes to broad measures of academic achievement that are used for important, real-world, academic advancement decisions, such as standardized test scores. To address this gap, we examined the role of sustained attention in predicting targeted and broad assessments of academic abilities, where all skills were assessed in group-based environments in schools. In a sample of over 700 students aged 9-14, we showed that attention was positively related to performance on targeted assessments (math fluency and reading comprehension), as well as broad academic measures (statewide standardized test scores). Moreover, we found that attention was more predictive of targeted math sub-skills compared to assessments of broad math abilities, but was equally predictive of reading for both types of measures. Our findings add to our understanding of how sustained attention is linked to academic skills assessed in more 'real-world', naturalistic school environments and have important implications for designing tools to support student's academic success.

Integrated cognitive and physical fitness training enhances attention abilities in older adults.

Preserving attention abilities is of great concern to older adults who are motivated to maintain their quality of life. Both cognitive and physical fitness interventions have been utilized in intervention studies to assess maintenance and enhancement of attention abilities in seniors, and a coupling of these approaches is a compelling strategy to buttress both cognitive and physical health in a time- and resource-effective manner. With this perspective, we created a closed-loop, motion-capture video game (Body-Brain Trainer: BBT) that adapts a player's cognitive and physical demands in an integrated approach, thus creating a personalized and cohesive experience across both domains. Older adults who engaged in two months of BBT improved on both physical fitness (measures of blood pressure and balance) and attention (behavioral and neural metrics of attention on a continuous performance task) outcome measures beyond that of an expectancy matched, active, placebo control group, with maintenance of improved attention performance evidenced 1 year later. Following training, the BBT group's improvement on the attention outcome measure exceeded performance levels attained by an untrained group of 20-year olds, and showed age-equilibration of a neural signature of attention shown to decline with age: midline frontal theta power. These findings highlight the potential benefits of an integrated, cognitive-physical, closed-loop training platform as a powerful tool for both cognitive and physical enhancement in older adults.

Leveraging technology to personalize cognitive enhancement methods in aging.

As population aging advances at an increasing rate, efforts to help people maintain or improve cognitive function late in life are critical. Although some studies have shown promise, the question of whether cognitive training is an effective tool for improving general cognitive ability remains incompletely explored, and study results to date have been inconsistent. Most approaches to cognitive enhancement in older adults have taken a 'one size fits all' tack, as opposed to tailoring interventions to the specific needs of individuals. In this Perspective, we argue that modern technology has the potential to enable large-scale trials of public health interventions to enhance cognition in older adults in a personalized manner. Technology-based cognitive interventions that rely on closed-loop systems can be tailored to individuals in real time and have the potential for global testing, extending their reach to large and diverse populations of older adults. We propose that the future of cognitive enhancement in older adults will rely on harnessing new technologies in scientifically informed ways.

Enhancing neural markers of attention in children with ADHD using a digital therapeutic.

Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental condition characterized by diminished attentional control. Critically, these difficulties are related to negative consequences in real-life functioning both during development and into adulthood. There is now growing evidence that modulating the underlying neural circuits related to attention can improve behavior and brain function in children with ADHD. We have previously shown that game-based digital therapeutics targeting a key neural marker of attention-midline frontal theta (MFT)-yield positive effects on attentional control in several populations. However, the effects of such digital therapeutics in children with ADHD and no other comorbidities has not been yet examined. To address this gap, we assessed a sample of 25 children with ADHD (8-12 years old) on neural, behavioral, and clinical metrics of attention before and after a 4-week at-home intervention on an iPad targeting MFT circuitry. We found that children showed enhancements on a neural measure of attention (MFT power), as well as on objective behavioral measures of attention and parent reports of clinical ADHD symptoms. Importantly, we observed relationships between the neural and behavioral cognitive improvements, demonstrating that those children who showed the largest intervention-related neural gains were also those that improved the most on the behavioral tasks indexing attention. These findings provide support for using targeted, digital therapeutics to enhance multiple features of attentional control in children with ADHD. Study registration: ClinicalTrials.gov registry (NCT03844269) https://clinicaltrials.gov/ct2/show/NCT03844269.

Long-term maintenance of multitasking abilities following video game training in older adults.

The use of cognitive interventions to remediate deficient cognitive functions, or to enhance or preserve intact cognitive abilities, has been explored for some time, especially in older adults. However, few studies have investigated the long-term persistence of any positive benefits, with none examining whether changes in functional brain activity persist several years later. Here, we assessed whether enhanced cognitive abilities and potential underlying neural changes attained via the use of a custom-made video game (NeuroRacer) played by older adults (60-85 years old) continued to be elevated beyond control participants 6 years later. The NeuroRacer group continued to show reduced multitasking costs beyond control participants, with a neural signature of cognitive control, midline frontal theta power, also continuing to show heightened activity. However, previously evidenced performance benefits that had extended to untrained cognitive control abilities (i.e., enhanced sustained attention and working memory) did not persist, highlighting sustainability limitations. These findings continue to demonstrate the robust plasticity of the prefrontal cognitive control system in the aging brain, a potential neural mechanism underlying enhanced performance over time, and the possible long-term impact that digital therapeutics can have.

Closed-loop digital meditation improves sustained attention in young adults.

Attention is a fundamental cognitive process that is critical for essentially all aspects of higher-order cognition and real-world activities. Younger generations have deeply embraced information technology and multitasking in their personal lives, school and the workplace, creating myriad challenges to their attention. While improving sustained attention in healthy young adults would be beneficial, enhancing this ability has proven notoriously difficult in this age group. Here we show that 6 weeks of engagement with a meditation-inspired, closed-loop software program (MediTrain) delivered on mobile devices led to gains in both sustained attention and working memory in healthy young adults. These improvements were associated with positive changes in key neural signatures of attentional control (frontal theta inter-trial coherence and parietal P3b latency), as measured by electroencephalography. Our findings suggest the utility of delivering aspects of the ancient practice of focused-attention meditation in a modern, technology-based approach and its benefits on enhancing sustained attention.

Brain network modularity predicts cognitive training-related gains in young adults.

The brain operates via networked activity in separable groups of regions called modules. The quantification of modularity compares the number of connections within and between modules, with high modularity indicating greater segregation, or dense connections within sub-networks and sparse connections between sub-networks. Previous work has demonstrated that baseline brain network modularity predicts executive function outcomes in older adults and patients with traumatic brain injury after cognitive and exercise interventions. In healthy young adults, however, the functional significance of brain modularity in predicting training-related cognitive improvements is not fully understood. Here, we quantified brain network modularity in young adults who underwent cognitive training with casual video games that engaged working memory and reasoning processes. Network modularity assessed at baseline was positively correlated with training-related improvements on untrained tasks. The relationship between baseline modularity and training gain was especially evident in initially lower performing individuals and was not present in a group of control participants that did not show training-related gains. These results suggest that a more modular brain network organization may allow for greater training responsiveness. On a broader scale, these findings suggest that, particularly in low-performing individuals, global network properties can capture aspects of brain function that are important in understanding individual differences in learning.

Disentangling expectation from selective attention during perceptual decision making.

A large body of work has investigated the effects of attention and expectation on early sensory processing to support decision making. In a recent paper published in The Journal of Neuroscience, Rungratsameetaweemana et al. (Rungratsameetaweemana N, Itthipuripat S, Salazar A, Serences JT. J Neurosci 38: 5632-5648, 2018) found that expectations driven by implicitly learned task regularities do not modulate neural markers of early visual processing. Here, we discuss these findings and propose several lines of follow-up analyses and experiments that could expand on these findings in the broader perceptual decision making literature.

Brain Modularity: A Biomarker of Intervention-related Plasticity.

Interventions using methods such as cognitive training and aerobic exercise have shown potential to enhance cognitive abilities. However, there is often pronounced individual variability in the magnitude of these gains. Here, we propose that brain network modularity, a measure of brain subnetwork segregation, is a unifying biomarker of intervention-related plasticity. We present work from multiple independent studies demonstrating that individual differences in baseline brain modularity predict gains in cognitive control functions across several populations and interventions, spanning healthy adults to patients with clinical deficits and cognitive training to aerobic exercise. We believe that this predictive framework provides a foundation for developing targeted, personalized interventions to improve cognition.

Whole-Brain Calcium Imaging Reveals an Intrinsic Functional Network in Drosophila.

A long-standing goal of neuroscience has been to understand how computations are implemented across large-scale brain networks. By correlating spontaneous activity during "resting states" [1], studies of intrinsic brain networks in humans have demonstrated a correspondence with task-related activation patterns [2], relationships to behavior [3], and alterations in processes such as aging [4] and brain disorders [5], highlighting the importance of resting-state measurements for understanding brain function. Here, we develop methods to measure intrinsic functional connectivity in Drosophila, a powerful model for the study of neural computation. Recent studies using calcium imaging have measured neural activity at high spatial and temporal resolution in zebrafish, Drosophila larvae, and worms [6-10]. For example, calcium imaging in the zebrafish brain recently revealed correlations between the midbrain and hindbrain, demonstrating the utility of measuring intrinsic functional connections in model organisms [8]. An important component of human connectivity research is the use of brain atlases to compare findings across individuals and studies [11]. An anatomical atlas of the central adult fly brain was recently described [12]; however, combining an atlas with whole-brain calcium imaging has yet to be performed in vivo in adult Drosophila. Here, we measure intrinsic functional connectivity in Drosophila by acquiring calcium signals from the central brain. We develop an alignment procedure to assign functional data to atlas regions and correlate activity between regions to generate brain networks. This work reveals a large-scale architecture for neural communication and provides a framework for using Drosophila to study functional brain networks.

Brain Network Modularity Predicts Exercise-Related Executive Function Gains in Older Adults.

Recent work suggests that the brain can be conceptualized as a network comprised of groups of sub-networks or modules. The extent of segregation between modules can be quantified with a modularity metric, where networks with high modularity have dense connections within modules and sparser connections between modules. Previous work has shown that higher modularity predicts greater improvements after cognitive training in patients with traumatic brain injury and in healthy older and young adults. It is not known, however, whether modularity can also predict cognitive gains after a physical exercise intervention. Here, we quantified modularity in older adults (N = 128, mean age = 64.74) who underwent one of the following interventions for 6 months (NCT01472744 on ClinicalTrials.gov): (1) aerobic exercise in the form of brisk walking (Walk), (2) aerobic exercise in the form of brisk walking plus nutritional supplement (Walk+), (3) stretching, strengthening and stability (SSS), or (4) dance instruction. After the intervention, the Walk, Walk+ and SSS groups showed gains in cardiorespiratory fitness (CRF), with larger effects in both walking groups compared to the SSS and Dance groups. The Walk, Walk+ and SSS groups also improved in executive function (EF) as measured by reasoning, working memory, and task-switching tests. In the Walk, Walk+, and SSS groups that improved in EF, higher baseline modularity was positively related to EF gains, even after controlling for age, in-scanner motion and baseline EF. No relationship between modularity and EF gains was observed in the Dance group, which did not show training-related gains in CRF or EF control. These results are consistent with previous studies demonstrating that individuals with a more modular brain network organization are more responsive to cognitive training. These findings suggest that the predictive power of modularity may be generalizable across interventions aimed to enhance aspects of cognition and that, especially in low-performing individuals, global network properties can capture individual differences in neuroplasticity.

Modular Brain Network Organization Predicts Response to Cognitive Training in Older Adults.

Cognitive training interventions are a promising approach to mitigate cognitive deficits common in aging and, ultimately, to improve functioning in older adults. Baseline neural factors, such as properties of brain networks, may predict training outcomes and can be used to improve the effectiveness of interventions. Here, we investigated the relationship between baseline brain network modularity, a measure of the segregation of brain sub-networks, and training-related gains in cognition in older adults. We found that older adults with more segregated brain sub-networks (i.e., more modular networks) at baseline exhibited greater training improvements in the ability to synthesize complex information. Further, the relationship between modularity and training-related gains was more pronounced in sub-networks mediating "associative" functions compared with those involved in sensory-motor processing. These results suggest that assessments of brain networks can be used as a biomarker to guide the implementation of cognitive interventions and improve outcomes across individuals. More broadly, these findings also suggest that properties of brain networks may capture individual differences in learning and neuroplasticity. Trail Registration: ClinicalTrials.gov, NCT#00977418.

Reconfiguration of brain network architecture to support executive control in aging.

Aging is accompanied by declines in executive control abilities and changes in underlying brain network architecture. Here, we examined brain networks in young and older adults during a task-free resting state and an N-back task and investigated age-related changes in the modular network organization of the brain. Compared with young adults, older adults showed larger changes in network organization between resting state and task. Although young adults exhibited increased connectivity between lateral frontal regions and other network modules during the most difficult task condition, older adults also exhibited this pattern of increased connectivity during less-demanding task conditions. Moreover, the increase in between-module connectivity in older adults was related to faster task performance and greater fractional anisotropy of the superior longitudinal fasciculus. These results demonstrate that older adults who exhibit more pronounced network changes between a resting state and task have better executive control performance and greater structural connectivity of a core frontal-posterior white matter pathway.