Travis R. Reneau

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 trials^1–4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus^5–8. 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.

Awaiting news of uncertain outcomes is distressing because the news might be disappointing. To prevent such disappointments, people often “brace for the worst,” pessimistically lowering expectations before news arrives to decrease the possibility of surprising disappointment (a negative prediction error, or PE). Computational decision-making research commonly assumes that expectations do not drift within trials, yet it is unclear whether expectations pessimistically drift in real-world, high-stakes settings, what factors influence expectation drift, and whether it effectively buffers emotional responses to goal-relevant outcomes. Moreover, individuals learn from PEs to accurately anticipate future outcomes, but it is unknown whether expectation drift also impedes PE-based learning. In a sample of students awaiting exam grades ( N = 625), we found that expectations often drift and tend to drift pessimistically. We demonstrate that bracing is preferentially modulated by uncertainty; it transiently buffers the initial emotional impact of negative PEs but impairs PE-based learning, counterintuitively sustaining uncertainty into the future.

Increasing daily exploration is linked to improvements in affective well-being. However, COVID-19 elevated uncertainty when leaving the home, altering the risk-reward of balance of geospatial novelty. To this end, we simultaneously collected real-world geospatial tracking and experience sampling of emotion, prior to and during the first year of the pandemic in 630 individuals. COVID-19 reduced exploration and subjective well-being. Yet, despite the health risks of exploring during the pandemic, the days of highest affective well-being were those when individuals explored the most. However, this was not true for everyone: during the first months of the pandemic, at the height of the uncertainty surrounding the transmissibility and prognosis of a COVID-19 infection, more anxious individuals experienced no affective benefit to leaving home. Taken together, real-world exploration improved well-being regardless of the presence of real-world threat, but anxiety mitigated these benefits. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Organisms learn from prediction errors (PEs) to predict the future. Laboratory studies using small financial outcomes find that humans use PEs to update expectations and link individual differences in PE-based learning to internalizing disorders. Because of the low-stakes outcomes in most tasks, it is unclear whether PE learning emerges in naturalistic, high-stakes contexts and whether individual differences in PE learning predict psychopathology risk. Using experience sampling to assess 625 college students’ expected exam grades, we found evidence of PE-based learning and a general tendency to discount negative PEs, an “optimism bias.” However, individuals with elevated negative emotionality, a personality trait linked to the development of anxiety disorders, displayed a global pessimism and learning differences that impeded accurate expectations and predicted future anxiety symptoms. A sensitivity to PEs combined with an aversion to negative PEs may result in a pessimistic and inaccurate model of the world, leading to anxiety.

Experiential diversity promotes well-being in animal models. Here, using geolocation tracking, experience sampling and neuroimaging, we found that daily variability in physical location was associated with increased positive affect in humans. This effect was stronger for individuals who exhibited greater functional coupling of the hippocampus and striatum. These results link diversity in real-world daily experiences to fluctuations in positive affect and identify a hippocampal–striatal circuit associated with this bidirectional relationship.