Effects of Psychedelics in Older Adults: A Prospective Cohort Study.

OBJECTIVE: Affective symptoms such as anxiety, low mood, and loneliness are prevalent and highly debilitating symptoms among older adults (OA). Serotonergic psychedelics are currently investigated as novel interventions for affective disorders, yet little is known regarding their effects in OA. We investigated the mental health effects and psychological mechanisms of guided psychedelic group experiences in OA and a matched sample of younger adults (YA). METHODS: Using a prospective observational cohort design, we identified 62 OA (age ≥60 years) and 62 matched YA who completed surveys two weeks before, a day, two weeks, four weeks, and six months after a psychedelic group session. Mixed linear regression analyses were used to investigate longitudinal well-being changes, as well as baseline, acute, and post-acute predictors of change. RESULTS: OA showed post-psychedelic well-being improvements similar to matched YA. Among baseline predictors, presence of a lifetime psychiatric diagnosis was associated with greater well-being increases in OA (B = 6.72, p = .016 at the four-week key-endpoint). Compared to YA, acute subjective psychedelic effects were less intense in OA and did not significantly predict prospective well-being changes. However, relational experiences before and after psychedelic sessions emerged as predictors in OA (r(36) = .37,p = 0.025). CONCLUSIONS: Guided psychedelic group sessions enhance well-being in OA in line with prior naturalistic and controlled studies in YA. Interestingly, acute psychedelic effects in OA are attenuated and less predictive of well-being improvements, with relational experiences related to the group setting playing a more prominent role. Our present findings call for further research on the effects of psychedelics in OA.

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.

Improvements in well-being following naturalistic psychedelic use and underlying mechanisms of change in older adults: A prospective cohort study.

Affective symptoms such as anxiety, low mood, and loneliness are prevalent and highly debilitating symptoms among older adults (OA). Serotonergic psychedelics are novel experimental interventions for affective disorders, yet little is known regarding their effects in OA. Using a prospective cohort design, we identified 62 OA (age ≥ 60 years) and 62 matched younger adults (YA) who completed surveys two weeks before, and one day, two weeks, four weeks, and six months after a guided psychedelic group session in a retreat setting. Mixed linear regression analyses revealed significant well-being improvements in OA and YA, amplified in OA with a history of a psychiatric diagnosis. Compared to YA, acute subjective psychedelic effects were attenuated in OA and did not significantly predict well-being changes. However, a psychosocial measure of Communitas emerged as a predictor in OA, suggesting that the relational components in psychedelic group settings may hold particular value for OA.

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.

Effects of transcranial alternating current stimulation on cognitive function in people with multiple sclerosis: A randomized controlled trial.

BACKGROUND: Cognitive impairment is a core symptom that profoundly impacts the lives of people with multiple sclerosis (PwMS). Since the existing disease modifying therapies can only stabilize, but not actively treat, cognition in PwMS, there is an unmet need to expand approaches to treat these cognitive symptoms. Transcranial alternating current stimulation (tACS) permits frequency-specific entrainment of neural oscillations intrinsic to cognitive activity. However, the effects of the tACS on cognitive function in PwMS have not yet been assessed. We aimed to evaluate the potential efficacy of applying frontal theta-tACS to improve information processing speed in PwMS. METHODS: 60 PwMS with cognitive complaints were enrolled in a double-blinded, randomized, controlled trial with three stimulation groups: 2 mA, 1 mA, or sham control. A single session of theta-tACS was applied while participants were engaged in a cognitive program which has shown to improve processing speed in PwMS. tACS effects were examined by the Symbol Digit Modalities Test (SDMT). Tolerability, side effects and acceptability were measured. RESULTS: 1 mA groups had a significantly higher SDMT score after stimulation compared to their pre-stimulation score, 2 mA group showed a marginally significant improvement of their SDMT score, while the SDMT score in the sham group did not change. Overall, 49% of the stimulation group participants showed a clinically meaningful SDMT improvement (4+-point increase). CONCLUSION: tACS is a well-tolerated, non-pharmacological intervention. Based on the positive effects observed in the current study of a single session of tACS applied during cognitive engagement, the effects of repeated tACS on cognitive function in PwMS merit further research. TRIAL REGISTRATION: ClinicalTrials.gov NCT04466228.

Better together: novel methods for measuring and modeling development of executive function diversity while accounting for unity.

Introduction: Executive functions (EFs) are linked to positive outcomes across the lifespan. Yet, methodological challenges have prevented precise understanding of the developmental trajectory of their organization. Methods: We introduce novel methods to address challenges for both measuring and modeling EFs using an accelerated longitudinal design with a large, diverse sample of students in middle childhood (N = 1,286; ages 8 to 14). We used eight adaptive assessments hypothesized to measure three EFs, working memory, context monitoring, and interference resolution. We deployed adaptive assessments to equate EF challenge across ages and a data-driven, network analytic approach to reveal the evolving diversity of EFs while simultaneously accounting for their unity. Results and discussion: Using this methodological paradigm shift brought new precision and clarity to the development of these EFs, showing these eight tasks are organized into three stable components by age 10, but refinement of composition of these components continues through at least age 14.

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.

Enhancing cognitive control in amnestic mild cognitive impairment via at-home non-invasive neuromodulation in a randomized trial.

Individuals with multi-domain amnestic mild cognitive impairment (md-aMCI) have an elevated risk of dementia and need interventions that may retain or remediate cognitive function. In a feasibility pilot study, 30 older adults aged 60-80 years with md-aMCI were randomized to 8 sessions of transcranial alternating current stimulation (tACS) with simultaneous cognitive control training (CCT). The intervention took place within the participant's home without direct researcher assistance. Half of the participants received prefrontal theta tACS during CCT and the other half received control tACS. We observed high tolerability and adherence for at-home tACS + CCT. Within 1-week, only those who received theta tACS exhibited improved attentional abilities. Neuromodulation is feasible for in-home settings, which can be conducted by the patient, thereby enabling treatment in difficult to reach populations. TACS with CCT may facilitate cognitive control abilities in md-aMCI, but research in a larger population is needed to validate efficacy.

A virtual reality program to assess cognitive function in multiple sclerosis: A pilot study.

Introduction: Cognitive impairment is a debilitating symptom in people with multiple sclerosis (MS). Most of the neuropsychological tasks have little resemblance to everyday life. There is a need for ecologically valid tools for assessing cognition in real-life functional contexts in MS. One potential solution would involve the use of virtual reality (VR) to exert finer control over the task presentation environment; however, VR studies in the MS population are scarce. Objectives: To explore the utility and feasibility of a VR program for cognitive assessment in MS. Methods: A VR classroom embedded with a continuous performance task (CPT) was assessed in 10 non-MS adults and 10 people with MS with low cognitive functioning. Participants performed the CPT with distractors (i.e., WD) and without distractors (i.e., ND). The Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-II (CVLT-II), and a feedback survey on the VR program was administered. Results: People with MS exhibited greater reaction time variability (RTV) compared to non-MS participants, and greater RTV in both WD and ND conditions was associated with lower SDMT. Conclusions: VR tools warrant further research to determine their value as an ecologically valid platform for assessing cognition and everyday functioning in people with MS.

Musical Training Facilitates Exogenous Temporal Attention via Delta Phase Entrainment within a Sensorimotor Network.

Temporal orienting of attention plays an important role in our day-to-day lives and can use timing information from exogenous or endogenous sources. Yet, it is unclear what neural mechanisms give rise to temporal attention, and it is debated whether both exogenous and endogenous forms of temporal attention share a common neural source. Here, older adult nonmusicians (N = 47, 24 female) were randomized to undergo 8 weeks of either rhythm training, which places demands on exogenous temporal attention, or word search training as a control. The goal was to assess (1) the neural basis of exogenous temporal attention and (2) whether training-induced improvements in exogenous temporal attention can transfer to enhanced endogenous temporal attention abilities, thereby providing support for a common neural mechanism of temporal attention. Before and after training, exogenous temporal attention was assessed using a rhythmic synchronization paradigm, whereas endogenous temporal attention was evaluated via a temporally cued visual discrimination task. Results showed that rhythm training improved performance on the exogenous temporal attention task, which was associated with increased intertrial coherence within the δ (1-4 Hz) band as assessed by EEG recordings. Source localization revealed increased δ-band intertrial coherence arose from a sensorimotor network, including premotor cortex, anterior cingulate cortex, postcentral gyrus, and the inferior parietal lobule. Despite these improvements in exogenous temporal attention, such benefits were not transferred to endogenous attentional ability. These results support the notion that exogenous and endogenous temporal attention uses independent neural sources, with exogenous temporal attention relying on the precise timing of δ band oscillations within a sensorimotor network.SIGNIFICANCE STATEMENT Allocating attention to specific points in time is known as temporal attention, and may arise from external (exogenous) or internal (endogenous) sources. Despite its importance to our daily lives, it is unclear how the brain gives rise to temporal attention and whether exogenous- or endogenous-based sources for temporal attention rely on shared brain regions. Here, we demonstrate that musical rhythm training improves exogenous temporal attention, which was associated with more consistent timing of neural activity in sensory and motor processing brain regions. However, these benefits did not extend to endogenous temporal attention, indicating that temporal attention relies on different brain regions depending on the source of timing information.

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.

Involuntary refreshing of mental representations.

Laboratory tasks have revealed that mental representations (e.g., mental imagery) can enter consciousness in a manner that is involuntary, reliable, and insuppressible. These effects illuminate the capacities of involuntary processes as well as the function of voluntary, conscious processing. The Reflexive Imagery Task was developed a decade ago to investigate these involuntary effects systematically. Can refreshing yield such involuntary effects? Refreshing is the reactivating in mind of a mental representation that was activated moments ago. It is associated with mental rehearsal and executive function. We investigated whether a mental representation (subvocalization of an object name) can arise in consciousness involuntarily after a delayed interval, when the relevant stimulus is no longer present, and in response to a cue. In Experiment 1, participants were instructed not to refresh a previously presented (6 s before) stimulus in response to a cue. Involuntary refreshing occurred on a substantive proportion (0.56) of the trials. Experiment 2 replicated and extended this finding (proportion of the trials = 0.53) with a refreshing task that was more challenging than that of Experiment 1. Our findings suggest that mental representations arising from processes such as refreshing can occur involuntarily. We discuss the theoretical implications of this conclusion.

How musical rhythm training improves short-term memory for faces.

Playing a musical instrument engages numerous cognitive abilities, including sensory perception, selective attention, and short-term memory. Mounting evidence indicates that engaging these cognitive functions during musical training will improve performance of these same functions. Yet, it remains unclear the extent these benefits may extend to nonmusical tasks, and what neural mechanisms may enable such transfer. Here, we conducted a preregistered randomized clinical trial where nonmusicians underwent 8 wk of either digital musical rhythm training or word search as control. Only musical rhythm training placed demands on short-term memory, as well as demands on visual perception and selective attention, which are known to facilitate short-term memory. As hypothesized, only the rhythm training group exhibited improved short-term memory on a face recognition task, thereby providing important evidence that musical rhythm training can benefit performance on a nonmusical task. Analysis of electroencephalography data showed that neural activity associated with sensory processing and selective attention were unchanged by training. Rather, rhythm training facilitated neural activity associated with short-term memory encoding, as indexed by an increased P3 of the event-related potential to face stimuli. Moreover, short-term memory maintenance was enhanced, as evidenced by increased two-class (face/scene) decoding accuracy. Activity from both the encoding and maintenance periods each highlight the right superior parietal lobule (SPL) as a source for training-related changes. Together, these results suggest musical rhythm training may improve memory for faces by facilitating activity within the SPL to promote how memories are encoded and maintained, which can be used in a domain-general manner to enhance performance on a nonmusical task.

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.

Structural and functional network mechanisms of rescuing cognitive control in aging.

Age-related declines in cognitive control, an ability critical in most daily tasks, threaten individual independence. We previously showed in both older and younger adults that transcranial alternating current stimulation (tACS) can improve cognitive control, with effects observed across neural regions distant from the stimulated site and frequencies outside the stimulated range. Here, we assess network-level changes in neural activity that extend beyond the stimulated site and evaluate anatomical pathways that subserve these effects. We investigated the potential to rescue cognitive control in aging using prefrontal (F3-F4) theta (6 Hz) or control (1 Hz) tACS while older adults engaged in a cognitive control video game intervention on three consecutive days. Functional connectivity was assessed with EEG by measuring daily changes in frontal-posterior phase-locking values (PLV) from the tACS-free baseline. Structural connectivity was measured using MRI diffusion tractography data collected at baseline. Theta tACS improved multitasking performance, and individual gains reflected a dissociation in daily PLV changes, where theta tACS strengthened PLV and control tACS reduced PLV. Strengthened alpha-beta PLV in the theta tACS group correlated positively with inferior longitudinal fasciculus and corpus callosum body integrity, and further explained multitasking gains. These results demonstrate that theta tACS can improve cognitive control in aging by strengthening functional connectivity, particularly in higher frequency bands. However, the extent of functional connectivity gains is limited by the integrity of structural white matter tracts. Given that advanced age is associated with decreased white matter integrity, results suggest that the deployment of tACS as a therapeutic is best prior to advanced age.

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.

Validation of At-Home Application of a Digital Cognitive Screener for Older Adults.

Standardized neuropsychological assessments of older adults are important for both clinical diagnosis and biobehavioral research. Over decades, in-person testing has been the basis for population normative values that rank cognitive performance by demographic status. Most recently, digital tools have enabled remote data collection for cognitive measures, which offers the significant promise to extend the basis for normative values to be more inclusive of a larger cross section of the older population. We developed a Remote Characterization Module (RCM), using a speech-to-text interface, as a novel digital tool to administer an at-home, 25-min cognitive screener that mimics eight standardized neuropsychological measures. Forty cognitively healthy participants were recruited from a longitudinal aging research cohort, and they performed the same measures of memory, attention, verbal fluency and set-shifting in both in-clinic paper-and-pencil (PAP) and at-home RCM versions. The results showed small differences, if any, for how participants performed on in-person and remote versions in five of eight tasks. Critically, robust correlations between their PAP and RCM scores across participants support the finding that remote, digital testing can provide a reliable assessment tool for rapid and remote screening of healthy older adults' cognitive performance in several key domains. The implications for digital cognitive screeners are discussed.