Psilocybin desynchronizes the human brain.

A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1-4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5-8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6-12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.

Association between retinal microvascular abnormalities and late-life brain amyloid-ß deposition: the ARIC-PET study.

BACKGROUND: Retinal microvascular signs are accessible measures of early alterations in microvascular dysregulation and have been associated with dementia; it is unclear if they are associated with AD (Alzheimer's disease) pathogenesis as a potential mechanistic link. This study aimed to test the association of retinal microvascular abnormalities in mid and late life and late life cerebral amyloid. METHODS: Participants from the ARIC-PET (Atherosclerosis Risk in Communities-Positron Emission Tomography) study with a valid retinal measure (N = 285) were included. The associations of mid- and late-life retinal signs with late-life amyloid-ß (Aß) by florbetapir PET were tested. Two different measures of Aß burden were included: (1) elevated amyloid (SUVR > 1.2) and (2) continuous amyloid SUVR. The retinal measures' association with Aß burden was assessed using logistic and robust linear regression models. A newly created retinal score, incorporating multiple markers of retinal abnormalities, was also evaluated in association with greater Aß burden. RESULTS: Retinopathy in midlife (OR (95% CI) = 0.36 (0.08, 1.40)) was not significantly associated with elevated amyloid burden. In late life, retinopathy was associated with increased continuous amyloid standardized value uptake ratio (SUVR) (ß (95%CI) = 0.16 (0.02, 0.32)) but not elevated amyloid burden (OR (95%CI) = 2.37 (0.66, 9.88)) when accounting for demographic, genetic and clinical risk factors. A high retinal score in late life, indicating a higher burden of retinal abnormalities, was also significantly associated with increased continuous amyloid SUVR (ß (95% CI) = 0.16 (0.04, 0.32)) independent of vascular risk factors. CONCLUSIONS: Retinopathy in late life may be an easily obtainable marker to help evaluate the mechanistic vascular pathway between retinal measures and dementia, perhaps acting via AD pathogenesis. Well-powered future studies with a greater number of retinal features and other microvascular signs are needed to test these findings.

Social relationships, amyloid burden, and dementia: The ARIC-PET study.

INTRODUCTION: This study aimed to assess whether social relationships in mid-life reduce the risk of dementia related to amyloid burden. METHODS: Participants in the Atherosclerosis Risk in Communities (ARIC) study were assessed for social support and isolation (visit 2; 1990-1992). A composite measure, "social relationships," was generated. Brain amyloid was evaluated with florbetapir positron emission tomography (PET); (visit 5; 2012-2014). Incident dementia cases were identified following visit 5 through 2019 using ongoing surveillance. Relative contributions of mid-life social relationships and elevated brain amyloid to incident dementia were evaluated with Cox regression models. RESULTS: Among 310 participants without dementia, strong mid-life social relationships were associated independently with lower dementia risk. Elevated late-life brain amyloid was associated with greater dementia risk. DISCUSSION: Although mid-life social relationships did not moderate the relationship between amyloid burden and dementia, these findings affirm the importance of strong social relationships as a potentially protective factor against dementia.

Associations Between Mid-Life Psychosocial Measures and Estimated Late Life Amyloid Burden: The Atherosclerosis Risk in Communities (ARIC)-PET Study.

Background: Psychosocial factors are modifiable risk factors for Alzheimer's disease (AD). One mechanism linking psychosocial factors to AD risk may be through biological measures of brain amyloid; however, this association has not been widely studied. Objective: To determine if mid-life measures of social support and social isolation in the Atherosclerosis Risk in Communities (ARIC) Study cohort are associated with late life brain amyloid burden, measured using florbetapir positron emission tomography (PET). Methods: Measures of social support and social isolation were assessed in ARIC participants (visit 2: 1990-1992). Brain amyloid was evaluated with florbetapir PET standardized uptake value ratios (SUVRs; visit 5: 2012-2014). Results: Among 316 participants without dementia, participants with intermediate (odds ratio (OR), 0.47; 95% CI, 0.25-0.88), or low social support (OR, 0.43; 95% CI, 0.22-0.83) in mid-life were less likely to have elevated amyloid SUVRs, relative to participants with high social support. Participants with moderate risk for social isolation in mid-life (OR, 0.32; 95% CI, 0.14-0.74) were less likely to have elevated amyloid burden than participants at low risk for social isolation. These associations were not significantly modified by sex or race. Conclusions: Lower social support and moderate risk of social isolation in mid-life were associated with lower odds of elevated amyloid SUVR in late life, compared to participants with greater mid-life psychosocial measures. Future longitudinal studies evaluating mid-life psychosocial factors, in relation to brain amyloid as well as other health outcomes, will strengthen our understanding of the role of these factors throughout the lifetime.

Dysregulated Salience Network Control over Default-Mode and Central-Executive Networks in Schizophrenia Revealed Using Stochastic Dynamical Causal Modeling.

Introduction: Neuroimaging studies suggest that the human brain consists of intrinsically organized, large-scale neural networks. Among these networks, the interplay among the default-mode network (DMN), salience network (SN), and central-executive network (CEN) has been widely used to understand the functional interaction patterns in health and disease. This triple network model suggests that the SN causally controls over the DMN and CEN in healthy individuals. This interaction is often referred to as SN's dynamic regulating mechanism. However, such interactions are not well understood in individuals with schizophrenia. Methods: In this study, we leveraged resting-state functional magnetic resonance imaging data from schizophrenia (n = 67) and healthy controls (n = 81) and evaluated the directional functional interactions among DMN, SN, and CEN using stochastic dynamical causal modeling methodology. Results: In healthy controls, our analyses replicated previous findings that SN regulates DMN and CEN activities (Mann-Whitney U test; p < 10-8). In schizophrenia, however, our analyses revealed a disrupted SN-based controlling mechanism over the DMN and CEN (Mann-Whitney U test; p < 10-16). Conclusions: These results indicate that the disrupted controlling mechanism of SN over the other two neural networks may be a candidate neuroimaging phenotype in schizophrenia.

Human Cortical Serotonin 2A Receptor Occupancy by Psilocybin Measured Using [11C]MDL 100,907 Dynamic PET and a Resting-State fMRI-Based Brain Parcellation.

Psilocybin (a serotonin 2A, or 5-HT2A, receptor agonist) has shown preliminary efficacy as a treatment for mood and substance use disorders. The current report utilized positron emission tomography (PET) with the selective 5-HT2A receptor inverse agonist radioligand [11C]MDL 100,907 (a.k.a. M100,907) and cortical regions of interest (ROIs) derived from resting-state functional connectivity-based brain parcellations in 4 healthy volunteers (2 females) to determine regional occupancy/target engagement of 5-HT2A receptors after oral administration of a psychoactive dose of psilocybin (10 mg/70 kg). Average 5-HT2A receptor occupancy across all ROIs was 39.5% (± 10.9% SD). Three of the ROIs with greatest occupancy (between 63.12 and 74.72% occupancy) were within the default mode network (subgenual anterior cingulate and bilateral angular gyri). However, marked individual variability in regional occupancy was observed across individuals. These data support further investigation of the relationship between individual differences in the acute and enduring effects of psilocybin and the degree of regional 5-HT2A receptor occupancy.