Default Mode Network Modulation by Psychedelics: A Systematic Review.

Psychedelics are a unique class of drug that commonly produce vivid hallucinations as well as profound psychological and mystical experiences. A grouping of interconnected brain regions characterized by increased temporal coherence at rest have been termed the Default Mode Network (DMN). The DMN has been the focus of numerous studies assessing its role in self-referencing, mind wandering, and autobiographical memories. Altered connectivity in the DMN has been associated with a range of neuropsychiatric conditions such as depression, anxiety, post-traumatic stress disorder, attention deficit hyperactive disorder, schizophrenia, and obsessive-compulsive disorder. To date, several studies have investigated how psychedelics modulate this network, but no comprehensive review, to our knowledge, has critically evaluated how major classical psychedelic agents-lysergic acid diethylamide, psilocybin, and ayahuasca-modulate the DMN. Here we present a systematic review of the knowledge base. Across psychedelics there is consistent acute disruption in resting state connectivity within the DMN and increased functional connectivity between canonical resting-state networks. Various models have been proposed to explain the cognitive mechanisms of psychedelics, and in one model DMN modulation is a central axiom. Although the DMN is consistently implicated in psychedelic studies, it is unclear how central the DMN is to the therapeutic potential of classical psychedelic agents. This article aims to provide the field with a comprehensive overview that can propel future research in such a way as to elucidate the neurocognitive mechanisms of psychedelics.

Distinct and shared therapeutic neural mechanisms of mindfulness-based and social support stress reduction groups in adults with autism spectrum disorder.

BACKGROUND: Mindfulness-based stress reduction (MBSR) alleviates depression and anxiety in adults with autism spectrum disorder (ASD); however, underlying therapeutic neural mechanisms and mindfulness-specific effects have yet to be elucidated. METHODS: We randomly assigned adults with ASD to MBSR or social support/education (SE). They completed questionnaires that assessed depression, anxiety, mindfulness traits, autistic traits and executive functioning abilities as well as a self-reflection functional MRI task. We used repeated-measures analysis of covariance (ANCOVA) to evaluate behavioural changes. To identify task-specific connectivity changes, we performed a generalized psychophysiological interactions (gPPI) functional connectivity (FC) analysis on regions of interest (ROIs; insula, amygdala, cingulum and prefrontal cortex [PFC]). We used Pearson correlations to explore brain-behaviour relationships. RESULTS: Our final sample included 78 adults with ASD - 39 who received MBSR and 39 who received SE. Mindfulness-based stress reduction uniquely improved executive functioning abilities and increased mindfulness traits, whereas both MBSR and SE groups showed reductions in depression, anxiety and autistic traits. Decreases specific to MBSR in insula-thalamus FC were associated with anxiety reduction and increased mindfulness traits, including the trait "nonjudgment;" MBSR-specific decreases in PFC-posterior cingulate connectivity correlated with improved working memory. Both groups showed decreased amygdala-sensorimotor and medial-lateral PFC connectivity, which corresponded with reduced depression. LIMITATIONS: Larger sample sizes and neuropsychological evaluations are needed to replicate and extend these findings. CONCLUSION: Together, our findings suggest that MBSR and SE are similarly efficacious for depression, anxiety and autistic traits, whereas MBSR produced additional salutary effects related to executive functioning and mindfulness traits. Findings from gPPI identified shared and distinct therapeutic neural mechanisms, implicating the default mode and salience networks. Our results mark an early step toward the development of personalized medicine for psychiatric symptoms in ASD and offer novel neural targets for future neurostimulation research. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04017793.

Quality of life in adults with autism spectrum disorder: influence of age, sex, and a controlled, randomized mindfulness-based stress reduction pilot intervention.

PURPOSE: Adults with autism spectrum disorder (ASD) consistently report worse functional health and well-being, compared to neurotypical (NT) peers. In a series of studies, we aimed to elucidated the effects of sex, age, and their interaction on health-related quality of life (HRQoL) and evaluated the effectiveness of mindfulness-based stress reduction (MBSR) for improving health-, disability-, and autism-related QoL, with possible sex and age outcome moderators, in adults with ASD. METHODS: Study 1 used the 36-Item Short Form Survey to compare mental and physical HRQoL composite scores in adults with ASD (n = 67) and matched NT adults (n = 66). Study 2 was a randomized pilot evaluation of the effect of MBSR, compared to an active control intervention with social support and relaxation education (support/education; n = 56), on the World Health Organization QoL BREF, Disability, and Autism-Specific scales in adults with ASD. RESULTS: In Study 1, we replicated findings that mental HRQoL is worse in both men and women with ASD, compared to NT counterparts, but physical HRQoL is only worse in women with ASD. We present novel findings that older age is associated with better mental HRQoL in women with ASD only. In Study 2, MBSR improved disability-related QoL in adults with ASD over and above the support/education intervention, but both interventions improved mental HRQoL. Lastly, both interventions were more effective for HRQoL improvements in women with ASD. CONCLUSION: Findings encourage precision medicine approaches tailored to age and sex groups for best HRQoL outcomes in adults with ASD. CLINICALTRIALS: gov Identifier: NCT04017793.

The neural correlates of mindfulness-induced depression reduction in adults with autism spectrum disorder: A pilot study.

Adults with autism spectrum disorder (ASD) experience high rates of depression and anxiety, and some evidence suggests mindfulness-based stress reduction (MBSR) is effective in reducing these symptoms. However, the neural mechanisms of symptom alleviation, and benefit of MBSR beyond education/support groups are unknown. Maladaptive forms of self-reflection are linked to ASD, depression, and anxiety. In this pilot study, we hypothesized (a) MBSR would reduce depression and anxiety in adults with ASD and (b) a mechanism of symptom alleviation would be increased blood oxygen level-dependent signal in neural self-reflection hubs. Twenty-eight adults were randomly assigned to an 8-week MBSR group (n = 15) or a support group (n = 13) that met for the same amount of time with relaxation education materials. Based on previous self-reflection literature in ASD, regions of interest (ROIs) were middle cingulate cortex (MCC) and ventromedial prefrontal cortex (vmPFC). Only the MBSR group demonstrated significant reductions in depression, and neither group significantly changed in anxiety. Only the MBSR group increased activity of right MCC during self-reflection, and the increase correlated with depression alleviation. There were no changes in vmPFC for the MBSR group or either ROI for the support/education group. Seed-to-voxel connectivity analysis revealed that only the MBSR group increased functional connectivity between right MCC and pre/postcentral gyrus, suggesting MBSR may increase primary sensorimotor input to higher order cognitive brain regions. Taken together, MBSR may be effective for reducing depression in adults with ASD, and the neural mechanism may be increasing frontal circuit involvement during self-directed thought.

Exploring the Potential Utility of Psychedelic Therapy for Patients With Amyotrophic Lateral Sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is an aggressive, terminal neurodegenerative disease that causes death of motor neurons and has an average survival time of 3-4 years. ALS is the most common motor neuron degenerative disease and is increasing in prevalence. There is a pressing need for more effective ALS treatments as available pharmacotherapies do not reverse disease progression or provide substantial clinical benefit. Furthermore, despite psychological distress being highly prevalent in ALS patients, psychological treatments remain understudied. Psychedelics (i.e., serotonergic psychedelics and related compounds like ketamine) have seen a resurgence of research into therapeutic applications for treating a multitude of neuropsychiatric conditions, including psychiatric and existential distress in life-threatening illnesses. Methods: We conducted a narrative review to examine the potential of psychedelic assisted-psychotherapy (PAP) to alleviate psychiatric and psychospiritual distress in ALS. We also discussed the safety of using psychedelics in this population and proposed putative neurobiological mechanisms that may therapeutically intervene on ALS neuropathology. Results: PAP has the potential to treat psychological dimensions and may also intervene on neuropathological dimensions of ALS. Robust improvements in psychiatric and psychospiritual distress from PAP in other populations provide a strong rationale for utilizing this therapy to treat ALS-related psychiatric and existential distress. Furthermore, relevant neuroprotective properties of psychedelics warrant future preclinical trials to investigate this area in ALS models. Conclusion: PAP has the potential to serve as an effective treatment in ALS. Given the lack of effective treatment options, researchers should rigorously explore this therapy for ALS in future trials.

App-based meditation habits maintain reductions in depression symptoms among autistic adults.

LAY ABSTRACT: Existing research has identified an increased risk of depression among autistic adults, which can negatively impact their adaptive functioning abilities and socioeconomic outcomes. Mobile app-based meditation is a feasible, accessible, and effective self-care solution for depression among neurotypical adults, but there is limited evidence for the long-term benefits of app-based meditation among autistic adults. Habits are a key behavioral strategy for maintaining behavior change, and anchoring is one effective habit formation intervention that has yet to be tested among autistic adults. This study demonstrates that it is both feasible and effective to integrate the anchoring habit formation strategy into an app-based meditation intervention for establishing meditation habits among autistic adults. In addition, the study shows that app-based meditation habits were successful at maintaining reductions in depressive symptoms over 6 months. These results demonstrate the power of anchoring-based habit formation interventions for establishing healthy habits among autistic adults, which offers a promising behavioral intervention technique for establishing other healthy habits among autistic adults. The study also shows that app-based meditation habits are an effective long-term self-care solution for managing depressive symptoms among autistic adults that should be used by mental health providers and policymakers. Future research should test this combined anchoring and app-based meditation intervention technique among larger samples of autistic adults and over longer durations to better understand the mechanisms underlying the success of this intervention.

Co-use of MDMA with psilocybin/LSD may buffer against challenging experiences and enhance positive experiences.

Psilocybin and lysergic acid diethylamide (LSD) experiences can range from very positive to highly challenging (e.g., fear, grief, and paranoia). These challenging experiences contribute to hesitancy toward psychedelic-assisted psychotherapy among health care providers and patients. Co-use of 3,4-Methylenedioxy methamphetamine (MDMA) with psilocybin/LSD anecdotally reduces challenging experiences and enhances positive experiences associated with psilocybin/LSD. However, limited research has investigated the acute effects of co-use of MDMA and psilocybin/LSD. In a prospective convenience sample (N = 698) of individuals with plans to use psilocybin/LSD, we examined whether co-use of MDMA with psilocybin/LSD (n = 27) is associated with differences in challenging or positive experiences. Challenging experiences were measured using the Challenging Experiences Questionnaire and positive experiences were measured using the Mystical Experience Questionnaire and single-item measures of self-compassion, compassion, love, and gratitude. Potentially confounding variables were identified and included as covariates. Relative to psilocybin/LSD alone, co-use of psilocybin/LSD with a self-reported low (but not medium-high) dose of MDMA was associated with significantly less intense total challenging experiences, grief, and fear, as well as increased self-compassion, love and gratitude. Co-use of psilocybin/LSD and MDMA was not associated with differences in mystical-type experiences or compassion. Findings suggest co-use of MDMA with psilocybin/LSD may buffer against some aspects of challenging experiences and enhance certain positive experiences. Limitations include use of a convenience sample, small sample size, and non-experimental design. Additional studies (including controlled dose-response studies) that examine the effects and safety of co-administering MDMA with psilocybin/LSD (in healthy controls and clinical samples) are warranted and may assist the development of personalized treatments.

Preliminary findings of accelerated visual memory decline and baseline brain correlates in middle-age and older adults with autism: The case for hippocampal free-water.

Research aimed at understanding cognitive and brain aging in adults with autism spectrum disorder (ASD) is growing, but critical longitudinal work is scant. Adults with ASD struggle with tasks involving visual memory compared with neurotypical adults (NT). This may be related to differences in size or integrity of the hippocampus and its' primary structural connectivity pathway, the fornix. The aim of this study was to describe preliminary findings of longitudinal aging trajectories in short- and long-term visual memory abilities in middle-age and older adults with ASD, compared with matched NT adults. We then evaluated baseline multi-modal imaging metrics of the hippocampal system, including the relatively novel metric of free-water, as potential correlates of longitudinal memory change in the ASD group. Middle-age and older adults with ASD (n = 25) and matched NT adults (n = 25) between the ages of 40 and 70 years were followed longitudinally at ~2-year intervals (range 2-5 years). Participants completed the Wechsler Memory Scale III Visual Reproduction task. Longitudinal mixed models were utilized to detect group differences in memory change with baseline age and sex as covariates. Hippocampal volume was measured via T1-weighted MRI images with FreeSurfer. Fornix fractional anisotropy and hippocampal and fornix free-water were measured from diffusion tensor imaging scans. Exploratory correlations were run between individual hippocampal system metrics and longitudinal slopes of visual memory change. There was a significant group by time interaction for long-term visual memory, such that middle-age and older adults with ASD declined faster than matched NT adults. There was no group by time interaction for short-term visual memory. Baseline hippocampal free-water was the only hippocampal system metric that correlated with long-term visual memory change in the ASD group. As one of the first longitudinal cognitive and brain aging studies in middle-age and older adults with ASD, our findings suggest vulnerabilities for accelerated long-term visual memory decline, compared to matched NT adults. Further, baseline hippocampal free-water may be a predictor of visual memory change in middle-age and older adults with ASD. These preliminary findings lay the groundwork for future prognostic applications of MRI for cognitive aging in middle-age and older adults with ASD.

Changes in mental health, wellbeing and personality following ayahuasca consumption: Results of a naturalistic longitudinal study.

Background: Naturalistic and placebo-controlled studies suggest ayahuasca, a potent psychedelic beverage originating from Indigenous Amazonian tradition, may improve mental health, alter personality structure, and reduce alcohol and drug intake. To better understand ayahuasca's therapeutic potential and to identify factors that influence therapeutic efficacy, we conducted a naturalistic, longitudinal study of facilitated ayahuasca consumption in naïve participants using a comprehensive battery of self-report questionnaires. Materials and Methods: Ayahuasca naive individuals registering for ayahuasca ceremonies were asked to complete a range of validated questionnaires assessing mental health, alcohol/cannabis use, relationships, personality, and connection to self and spirituality, prior to and 1 month after attending an ayahuasca ceremony. Data for two mental health measures (the DASS-21 and PANAS) and acute subjective effects via the MEQ-30 were also assessed 7 days post-ceremony. Repeated measures ANOVA were used to examine pre-to-post changes, and Pearson correlations explored predictors of improvement in outcomes. Results: Fifty-three attendees (32 women, 21 men) completed pre and post ayahuasca assessments with 55.6% of the sample reporting a complete mystical experience based on the MEQ-30. One-month post-ayahuasca, significant reductions were identified in depression, anxiety, stress, alcohol and cannabis use, body dissociation, accepting external influence, self-alienation, impulsivity, and negative affect/emotionality. Significant increases were identified in positive mood, self-efficacy, authentic living, extraversion, agreeableness, open-mindedness, spirituality, and satisfaction with relationships. While facets of the mystical experience held little predictive validity on outcome measures, baseline traits, particularly high negative emotionality and body dissociation, and low sense of self-efficacy, robustly predicted improvements in mental health and alcohol/cannabis use, and alterations in personality structure which are linked to better mental health. Discussion: This study suggests facilitated ayahuasca consumption in naïve participants may precipitate wide-ranging improvements in mental health, relationships, personality structure, and alcohol use. Associations between baseline traits and therapeutic improvements mark an important first step toward personalized, precision-based medicine and warrant randomized controlled trials to confirm and elaborate on these findings. Contribution Statement: Longitudinal, observational studies and randomized clinical control trials suggest ayahuasca may exert therapeutic effects on mental health and alcohol/cannabis use, and alter personality structure. However, it is unclear if improvements are diagnosis-specific and factors that predict therapeutic gains have yet to be extensively elucidated. This longitudinal, observational study examined the effects of facilitated ayahuasca consumption in naive participants on mental health, alcohol and substance use/abuse, personality traits, relationships, and connection to self and spirituality. We found wide-ranging improvements 1-month post-treatment across these domains, and identified baseline traits which predict pre-to-post changes on primary outcome measures. Improvements were not diagnostic-specific, suggesting ayahuasca may be generally efficacious. Personality traits, body dissociation, and self-efficacy were strong predictors of therapeutic improvements, marking an important first step toward personalized, precision-based medicine. Randomized controlled trials are warranted to confirm and elaborate on these findings.

Effects of age on the hippocampus and verbal memory in adults with autism spectrum disorder: Longitudinal versus cross-sectional findings.

Research studying aging in adults with autism spectrum disorder (ASD) is growing, but longitudinal work is needed. Autistic adults have increased risk of dementia, altered hippocampal volumes and fornix integrity, and verbal memory difficulties compared with neurotypical (NT) adults. This study examined longitudinal aging in middle-age adults with ASD versus a matched NT group, and compared findings with cross-sectional age effects across a broad adult age range. Participants were 194 adults with (n = 106; 74 male) and without (n = 88; 52 male) ASD, ages 18-71. Participants (n = 45; 40-70 age range) with two visits (2-3 years apart) were included in a longitudinal analysis. Hippocampal volume, fornix fractional anisotropy (FA), and verbal memory were measured via T1-weighted MRI, diffusion tensor imaging, and the Rey Auditory Verbal Learning Test, respectively. Longitudinal mixed models were used for hippocampal system variables and reliable change index categories were used for Auditory Verbal Learning Test analyses. Multivariate regression was used for cross-sectional analyses. Middle-age adults with ASD had greater longitudinal hippocampal volume loss and were more likely to show clinically meaningful decline in short-term memory, compared with NT. In contrast, cross-sectional associations between increasing age and worsening short-term memory were identified in NT, but not autistic adults. Reduced fornix FA and long-term memory in ASD were found across the broad cross-sectional age range. These preliminary longitudinal findings suggest accelerated hippocampal volume loss in ASD and slightly higher rates of clinically-meaningful decline in verbal short-term memory. Contradictory cross-sectional and longitudinal results underscore the importance of longitudinal aging research in autistic adults. LAY SUMMARY: Autistic adults have increased risk of dementia, differences in brain memory structures, and difficulty with memory compared with neurotypical (NT) adults. However, there are no publications that follow the same middle-age autistic adults over time to see how their brain and memory change. Our preliminary findings in a small middle-age autism sample suggest a key memory brain structure, the hippocampus, may shrink faster over 2-3 years compared with NT, and short-term memory may become more challenging for some. Across a broad adult range, autistic adults also had reduced integrity of connections to the hippocampus and greater challenges with long-term memory. In our larger sample across a broad age range, the results did not hint at this aforementioned pattern of accelerated aging. This underscores the importance of more aging research in autism, and especially research where people are followed over time.

Early Reflections on the Therapeutic Effects of Mindfulness-Based Therapies in Adults with Autism and Suggestions for Future Research.

Emerging research suggests mindfulness-based therapies positively impact adults with autism spectrum disorder (ASD). However, questions concerning intervention active ingredients, the breadth and duration of impact, and psychological and neural mechanisms of change remain. Here we discuss what is known about mindfulness-based therapies in adults with ASD and offer suggestions for future research.

Social Cognition in Autism Spectrum Disorder Across the Adult Lifespan: Influence of Age and Sex on Reading the Mind in the Eyes Task in a Cross-sectional Sample.

Background: Approximately 50,000 U.S. teens with autism spectrum disorder (ASD) become adults every year, however little is known regarding how age influences social cognition and if men and women with ASD are differentially impacted across the adult lifespan. Social cognition declines non-linearly with age in neurotypical (NT) adults. Moreover, sex differences have been observed on RME tasks in NT adults but not adults with ASD, although aging effects have been largely ignored. Objective: This cross-sectional study examined the influence of age and sex on social cognition in adults with ASD compared to NT adults. Methods: The Reading the Mind in the Eyes (RME) task was administered to evaluate the theory of mind abilities in 95 adults with ASD and 82 NT adults ages 18-71 years. The main effects of diagnosis, age, and sex, as well as two-way and three-way interaction were modeled using linear and quadratic aging terms in a multiple regression analysis. Results: A main effect of diagnosis was observed, indicating poorer performance in adults with ASD relative to NT adults. Age and sex interactions were nonsignificant. Discussion: We replicated previous findings of reduced theory of mind (ToM) abilities in adults with ASD, compared to NT adults. While interactions were nonsignificant, visual inspection of quadratic age curves indicated the possibility of unique ToM trajectories in men and women with and without ASD that should be investigated in larger longitudinal studies.

Animal Models of the Impact of Social Stress on Cocaine Use Disorders.

Cocaine use disorders are strongly influenced by the social conditions prior, during, and after exposure to cocaine. In this chapter, we discuss how social factors such as early life stress, social rank stress, and environmental stress impact vulnerability and resilience to cocaine. The discussion of each animal model begins with a brief review of examples from the human literature, which provide the psychosocial background these models attempt to capture. We then discuss preclinical findings from use of each model, with emphasis on how social factors influence cocaine-related behaviors and how sex and age influence the behaviors and neurobiology. Models discussed include (1) early life social stress, such as maternal separation and neonatal isolation, (2) social defeat stress, (3) social hierarchies, and (4) social isolation and environmental enrichment. The cocaine-related behaviors reviewed for each of these animal models include cocaine-induced conditioned place preference, behavioral sensitization, and self-administration. Together, our review suggests that the degree of psychosocial stress experienced yields robust effects on cocaine-related behaviors and neurobiology, and these preclinical findings have translational impact for the future of cocaine use disorder treatment.

Interactions between Early Life Stress, Nucleus Accumbens MeCP2 Expression, and Methamphetamine Self-Administration in Male Rats.

Early life stress (ELS) is highly related to the development of psychiatric illnesses in adulthood, including substance use disorders. A recent body of literature suggests that long-lasting changes in the epigenome may be a mechanism by which experiences early in life can alter neurobiological and behavioral phenotypes in adulthood. In this study, we replicate our previous findings that ELS, in the form of prolonged maternal separation, increases adult methamphetamine self-administration (SA) in male rats as compared with handled controls. In addition, we show new evidence that both ELS and methamphetamine SA alter the expression of the epigenetic regulator methyl CpG-binding protein 2 (MeCP2) in key brain reward regions, particularly in the nucleus accumbens (NAc) core. In turn, viral-mediated knockdown of MeCP2 expression in the NAc core reduces methamphetamine SA, as well as saccharin intake. Furthermore, NAc core MeCP2 knockdown reduces methamphetamine, but not saccharin, SA on a progressive ratio schedule of reinforcement. These data suggest that NAc core MeCP2 may be recruited by both ELS and methamphetamine SA and promote the development of certain aspects of drug abuse-related behavior. Taken together, functional interactions between ELS, methamphetamine SA, and the expression of MeCP2 in the NAc may represent novel mechanisms that can ultimately be targeted for intervention in individuals with adverse early life experiences who are at risk for developing substance use disorders.