Of the classic psychedelics, lysergic acid diethylamide (LSD) is perhaps the best-known, but its complex chemical architecture has limited synthetic investigations aimed at generating analogues with improved safety and efficacy profiles. Here, we systematically deconstruct the tetracyclic ergoline core of LSD to create 9 simplified ergoline analogues (i.e., ergologs) and evaluate them in...
Natural hallucinogenic compounds have arisen independently across plants, fungi, and animals, evolving into a diverse chemical arsenal that includes phenethylamines, indolealkylamines, and terpenoid scaffolds. Beyond clinical and cultural frameworks, their ecological origins and evolutionary trajectories may help explain why such potent modulators of perception, emotion, and cognition persist...
Psychedelic drugs are poised to become mainstream treatments, yet we lack a circuit-level account of how they reshape brain activity. Emerging evidence suggests that multiple psychedelic compounds modulate activity in the brain's default mode network (DMN), often interpreted as either increased or decreased bottom-up hierarchical processing. Most imaging studies, however, quantify activity as...
Conscious thought is often treated as a special class of neural processing, distinct from the nonconscious computations that guide most behavior. Here I offer a different perspective, grounded in the neuroscience of decision-making. I argue that conscious thought arises not from a unique mechanism but from a distinctive use of neural representations already engaged in nonconscious thought....
Ketamine has been shown to reduce depression and suicidality in individuals resistant to treatment by other drugs. Exactly how ketamine works is not known. Here, I propose a new hypothesis that involves synaptic and circuit plasticity and may lead to enhanced efficacy in treating depression as well as other conditions.
Everyday cognition depends on the brain's capacity to shift between sensing the external world and constructing it from memory. To achieve this, large-scale cortical systems must flexibly integrate incoming sensory signals with internally generated representations. Here, we show that this flexibility is reflected in the macroscale architecture of the default mode network (DMN). Using convergent...
Significance Many college students experience introductory physics courses as psychologically threatening contexts. Yet, succeeding in these high-stakes gateway courses is necessary to declare majors in engineering and physical sciences. We tested whether mindfulness, which centers attention to subjective experiences, can help provide students with tools to navigate their physics-related...
In the first months postterm, human infants are traditionally viewed as passive to their environment, unable to focus or sustain attention on specific objects. Here, we asked whether 4-mo-old infants could engage their attention strongly enough in a visual task to block the perception of a subsequent interesting stimulus-a phenomenon known as attentional blink, which in adults reflects a serial...
Does being awake necessarily mean being conscious of something? This study investigates the phenomenon of mind blanking (MB), characterized by an "emptiness of mind," comparing it with mind wandering (MW) and on-task (ON) states. Using a sustained attention task and electroencephalogram monitoring, behavioral, and neurophysiological signatures of MB were examined in 62 participants. MB...
With approximately 4% of the world's population using cannabis, there is a need to better understand its physiological effects. Cannabis consumption acutely promotes food intake ("the munchies") via delta-9-tetrahydrocannabinol-mediated activation of cannabinoid 1 receptors (CB1R); however, these appetitive effects have not been well characterized. We examined effects of cannabis vapor...
Neurofluids, including cerebrospinal fluid (CSF) and interstitial fluid, circulate through regulated central nervous system pathways to clear cerebral waste and support brain health, with elevated CSF flow hyperdynamicity and regurgitation through the cerebral aqueduct associating with aging and neurodegeneration. Sleep exerts state-dependent effects on neurofluid circulation, yet similar...
Conscious awareness refers to the subjective experience of perceiving, thinking, and feeling and the ability to report these experiences. These perceptions and thoughts are experienced as bound to an individual self. A fundamental aspect of this self-consciousness is the sense of bodily self-the experience of one's physical presence distinct from the external world, serving as the spatial...
While current arousal level assessments in patients with disorders of consciousness discriminate altered states of consciousness, there are significant limitations in characterizing the transition from one state to another or quantifying the frequent arousal level fluctuations observed in a patient. Here, we identified a repeated, temporally discrete, dynamical pattern evident in the recovery...
Brain oscillations in different behavioral states are essential for cognition, and oscillopathies contribute to cognitive dysfunction in neuropsychiatric diseases. Cannabis-1 receptor (CB1-R) activation was reported to suppress theta and fast gamma activities in rats during waking exploration, and here, we show that cannabis fundamentally alters network activity during sleep as well. Prominent...
Decreased dendritic spine density in the cortex is a key pathological feature of neuropsychiatric diseases including depression, addiction, and schizophrenia (SCZ). Psychedelics possess a remarkable ability to promote cortical neuron growth and increase spine density; however, these compounds are contraindicated for patients with SCZ or a family history of psychosis. Here, we report the...
Examination of the subjective qualitative aspects of an experience, or "qualia" in short, is a fundamental and core aspect of consciousness research. How can we characterize the particular quality of redness, i.e. a red quale? Based on a recent proposal of the structural characterization of qualia, which did not rely on verbal descriptions, we developed a task that obtained pairwise similarity...
Meditation is an accessible mental practice associated with emotional regulation and well-being. Loving-kindness meditation (LKM), a specific subtype of meditative practice, involves focusing one's attention on thoughts of well-being for oneself and others. Meditation has been proven to be beneficial in a variety of settings, including therapeutic applications, but the neural activity...
Predictive coding is a fundamental function of the cortex. The predictive routing model proposes a neurophysiological implementation for predictive coding. Predictions are fed back from the deep-layer cortex via alpha/beta (8 to 30 Hz) oscillations. They inhibit the gamma (40 to 100 Hz) and spiking that feed sensory inputs forward. Unpredicted inputs arrive in circuits unprepared by alpha/beta,...
Ketamine is an N-methyl-D-aspartate (NMDA)-receptor antagonist that produces sedation, analgesia, and dissociation at low doses and profound unconsciousness with antinociception at high doses. At high and low doses, ketamine can generate gamma oscillations (>25 Hz) in the electroencephalogram (EEG). The gamma oscillations are interrupted by slow-delta oscillations (0.1 to 4 Hz) at high doses....
Grid cells in the entorhinal cortex (EC) encode an individual's location in space, integrating both environmental and multisensory bodily cues. Notably, body-derived signals are also primary signals for the sense of self. While studies have demonstrated that continuous application of visuo-tactile bodily stimuli can induce perceptual shifts in self-location, it remains unexplored whether these...
Psychoactive mushrooms in the genus Psilocybe have immense cultural value and have been used for centuries in Mesoamerica. Despite the recent surge of interest in these mushrooms due to the psychotherapeutic potential of their natural alkaloid psilocybin, their phylogeny and taxonomy remain substantially incomplete. Moreover, the recent elucidation of the psilocybin biosynthetic gene cluster is...
Understanding the biological basis of social anxiety disorder (SAD), one of the most disabling of the anxiety disorders, will allow for novel treatment strategies to be developed. Here, we show that gut microbiota may be such a target. Mice ...Social anxiety disorder (SAD) is a crippling psychiatric disorder characterized by intense fear or anxiety in social situations and their avoidance....
Ketamine has emerged as a transformative and mechanistically novel pharmacotherapy for depression. Its rapid onset of action, efficacy for treatment-resistant symptoms, and protection against relapse distinguish it from prior antidepressants. Its discovery emerged from a reconceptualization of the neurobiology of depression and, in turn, insights from the elaboration of its mechanisms of action...
Understanding the neurobiological mechanisms underlying consciousness remains a significant challenge. Recent evidence suggests that the coupling between distal-apical and basal-somatic dendrites in thick-tufted layer 5 pyramidal neurons (L5PN), regulated by the nonspecific-projecting thalamus, is crucial for consciousness. Yet, it is uncertain whether this thalamocortical mechanism can support...
Psychedelics have attracted medical interest, but their effects on human brain function are incompletely understood. In a comprehensive, within-subjects, placebo-controlled design, we acquired multimodal neuroimaging [i.e., EEG-fMRI (electroencephalography-functional MRI)] data to assess the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT) on brain function in 20 healthy volunteers....