Explore the vast range of titles available.

Abstract The recent renaissance of psychedelic science has reignited interest in the similarity of drug-induced experiences to those more commonly observed in psychiatric contexts such as the schizophrenia-spectrum. This report from a multidisciplinary working group of the International Consortium on Hallucinations Research (ICHR) addresses this issue, putting special emphasis on hallucinatory experiences. We review evidence collected at different scales of understanding, from pharmacology to brain-imaging, phenomenology and anthropology, highlighting similarities and differences between hallucinations under psychedelics and in the schizophrenia-spectrum disorders. Finally, we attempt to integrate these findings using computational approaches and conclude with recommendations for future research.

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. Healthy adults were tracked before, during and after high doses of psilocybin and methylphenidate to assess how psychedelics can change human brain networks, and psilocybin was found to massively disrupt functional connectivity in cortex and subcortex with some changes persisting for weeks.

Psilocybin is a classic psychedelic compound that may have efficacy for the treatment of mood and substance use disorders. Acute psilocybin effects include reduced negative mood, increased positive mood, and reduced amygdala response to negative affective stimuli. However, no study has investigated the long-term, enduring impact of psilocybin on negative affect and associated brain function. Twelve healthy volunteers (7F/5M) completed an open-label pilot study including assessments 1-day before, 1-week after, and 1-month after receiving a 25 mg/70 kg dose of psilocybin to test the hypothesis that psilocybin administration leads to enduring changes in affect and neural correlates of affect. One-week post-psilocybin, negative affect and amygdala response to facial affect stimuli were reduced, whereas positive affect and dorsal lateral prefrontal and medial orbitofrontal cortex responses to emotionally-conflicting stimuli were increased. One-month post-psilocybin, negative affective and amygdala response to facial affect stimuli returned to baseline levels while positive affect remained elevated, and trait anxiety was reduced. Finally, the number of significant resting-state functional connections across the brain increased from baseline to 1-week and 1-month post-psilocybin. These preliminary findings suggest that psilocybin may increase emotional and brain plasticity, and the reported findings support the hypothesis that negative affect may be a therapeutic target for psilocybin.

Astrocytes differentially regulate excitatory and inhibitory synaptic transmission in the CeM, the major output nucleus of the amygdala. Astrocytes thereby reduce neuronal activity in the CeM and diminish fear expression in vivo . Therefore, astrocytes influence neural network activity and animal behavior through the regulation of specific synapses. The amygdala plays key roles in fear and anxiety. Studies of the amygdala have largely focused on neuronal function and connectivity. Astrocytes functionally interact with neurons, but their role in the amygdala remains largely unknown. We show that astrocytes in the medial subdivision of the central amygdala (CeM) determine the synaptic and behavioral outputs of amygdala circuits. To investigate the role of astrocytes in amygdala-related behavior and identify the underlying synaptic mechanisms, we used exogenous or endogenous signaling to selectively activate CeM astrocytes. Astrocytes depressed excitatory synapses from basolateral amygdala via A 1 adenosine receptor activation and enhanced inhibitory synapses from the lateral subdivision of the central amygdala via A 2A receptor activation. Furthermore, astrocytic activation decreased the firing rate of CeM neurons and reduced fear expression in a fear-conditioning paradigm. Therefore, we conclude that astrocyte activity determines fear responses by selectively regulating specific synapses, which indicates that animal behavior results from the coordinated activity of neurons and astrocytes.

A graphdiyne-based artificial synapse (GAS), exhibiting intrinsic short-term plasticity, has been proposed to mimic biological signal transmission behavior. The impulse response of the GAS has been reduced to several millivolts with competitive femtowatt-level consumption, exceeding the biological level by orders of magnitude. Most importantly, the GAS is capable of parallelly processing signals transmitted from multiple pre-neurons and therefore realizing dynamic logic and spatiotemporal rules. It is also found that the GAS is thermally stable (at 353 K) and environmentally stable (in a relative humidity up to 35%). Our artificial efferent nerve, connecting the GAS with artificial muscles, has been demonstrated to complete the information integration of pre-neurons and the information output of motor neurons, which is advantageous for coalescing multiple sensory feedbacks and reacting to events. Our synaptic element has potential applications in bioinspired peripheral nervous systems of soft electronics, neurorobotics, and biohybrid systems of brain–computer interfaces. Constructing artificial sensorimotor systems for robotic applications calls for development of synaptic connections for complicated information processing. Wei et al. propose a graphdiyne-based artificial synapse capable of parallel processing signals and utilize it in an artificial mechanoreceptor system.

Growing evidence from the dynamical analysis of functional neuroimaging data suggests that brain function can be understood as the exploration of a repertoire of metastable connectivity patterns (‘functional brain networks’), which potentially underlie different mental processes. The present study characterizes how the brain's dynamical exploration of resting-state networks is rapidly modulated by intravenous infusion of psilocybin, a tryptamine psychedelic found in “magic mushrooms”. We employed a data-driven approach to characterize recurrent functional connectivity patterns by focusing on the leading eigenvector of BOLD phase coherence at single-TR resolution. Recurrent BOLD phase-locking patterns (PL states) were assessed and statistically compared pre- and post-infusion of psilocybin in terms of their probability of occurrence and transition profiles. Results were validated using a placebo session. Recurrent BOLD PL states revealed high spatial overlap with canonical resting-state networks. Notably, a PL state forming a frontoparietal subsystem was strongly destabilized after psilocybin injection, with a concomitant increase in the probability of occurrence of another PL state characterized by global BOLD phase coherence. These findings provide evidence of network-specific neuromodulation by psilocybin and represent one of the first attempts at bridging molecular pharmacodynamics and whole-brain network dynamics. [Display omitted] •Recurrent BOLD phase-locking (PL) states reveal canonical resting-state networks.•Psilocybin changes occupancy of two BOLD PL states compared to placebo.•Frontoparietal network occupancy negatively relates to subjective psychedelic scores.•The occurrence of all BOLD PL states is consistent at baseline over >1 week.•Results bridge molecular pharmacodynamics and whole-brain network dynamics.

Learning causes a change in how information is processed by neuronal circuits. Whereas synaptic plasticity, an important cellular mechanism, has been studied in great detail, we know much less about how learning is implemented at the level of neuronal circuits and, in particular, how interactions between distinct types of neurons within local networks contribute to the process of learning. Here we show that acquisition of associative fear memories depends on the recruitment of a disinhibitory microcircuit in the mouse auditory cortex. Fear-conditioning-associated disinhibition in auditory cortex is driven by foot-shock-mediated cholinergic activation of layer 1 interneurons, in turn generating inhibition of layer 2/3 parvalbumin-positive interneurons. Importantly, pharmacological or optogenetic block of pyramidal neuron disinhibition abolishes fear learning. Together, these data demonstrate that stimulus convergence in the auditory cortex is necessary for associative fear learning to complex tones, define the circuit elements mediating this convergence and suggest that layer-1-mediated disinhibition is an important mechanism underlying learning and information processing in neocortical circuits. Stimulus convergence and concomitant auditory cortex disinhibition are essential for fear learning. Sounds like fear It is generally recognized that learned behavioural responses, such as those associated with sound, involve changes within specific neural circuits. However, we are only beginning to understand how those changes are implemented and what interactions between different types of neurons within the circuits contribute to the learning process. Using classical sound-based fear-conditioning in mice as a model system, Andreas Lüthi and colleagues identify a distinct disinhibition-based circuit that is critical to learning. The neural circuit involved is not specific to auditory cortex, and may represent a general mechanism through which cholinergic neuromodulation gates cortical activity.

Key Points Vulnerability to relapse that persists even after prolonged abstinence is a major problem in treating cocaine addiction. Mechanisms underlying this persistent vulnerability can be studied using rodent models of cue-induced cocaine craving during abstinence from cocaine self-administration. Cue-induced cocaine craving in rodents progressively intensifies (incubates) over the first month of abstinence and remains high for months. Incubation of craving also occurs in human drug users. Incubation of cocaine craving depends on an evolving series of neuroadaptations in the reward circuitry. Early adaptations in the ventral tegmental area and perhaps also the amygdala lead to more persistent changes in the nucleus accumbens, medial prefrontal cortex and central nucleus of the amygdala that increase the reactivity of neurons in these regions to cocaine cues and are ultimately required for the expression of incubated craving. Increased reactivity of these regions of the rodent brain to cocaine cues presented during abstinence is important because neuroimaging studies in human cocaine users have found that heightened cue reactivity in related brain regions is associated with addiction severity and risk of relapse. The relationship between cocaine craving and synaptic transmission has been most thoroughly studied in the nucleus accumbens, where abstinence is associated with changes in AMPA receptor subunit composition and silent synapse-based remodelling. Strengthening of excitatory synapses on nucleus accumbens neurons is particularly important for the maintenance of incubated craving after prolonged abstinence. Dopamine transmission is altered during abstinence owing to plasticity within the ventral tegmental area and changes in dopamine receptor expression in dopaminergic projection areas, but many questions remain about the role of dopamine transmission in modulating synaptic plasticity and behaviour during abstinence. Potential therapeutic strategies to prolong abstinence, identified through rodent studies, include the use of agonists of metabotropic glutamate receptor 2 (mGluR2) and/or mGluR3, mGluR1 positive allosteric modulators, serotonin (5-HT) receptor ligands (including 5-HT 1B receptor agonists, 5-HT 2C receptor agonists and 5-HT 2A receptor antagonists), D3 dopamine receptor antagonists, environmental enrichment and interventions to normalize sleep patterns. One of the greatest challenges in treating addiction is preventing relapse during abstinence. In this Review, Marina Wolf discusses rodent models of cocaine craving that reveal the synaptic plasticity that occurs in reward-related brain regions during the abstinence phase. Although it is challenging for individuals with cocaine addiction to achieve abstinence, the greatest difficulty is avoiding relapse to drug taking, which is often triggered by cues associated with prior cocaine use. This vulnerability to relapse persists for long periods (months to years) after abstinence is achieved. Here, I discuss rodent studies of cue-induced cocaine craving during abstinence, with a focus on neuronal plasticity in the reward circuitry that maintains high levels of craving. Such work has the potential to identify new therapeutic targets and to further our understanding of experience-dependent plasticity in the adult brain under normal circumstances and in the context of addiction.

The brain is an endocrine organ, sensitive to the rhythmic changes in sex hormone production that occurs in most mammalian species. In rodents and nonhuman primates, estrogen and progesterone’s impact on the brain is evident across a range of spatiotemporal scales. Yet, the influence of sex hormones on the functional architecture of the human brain is largely unknown. In this dense-sampling, deep phenotyping study, we examine the extent to which endogenous fluctuations in sex hormones alter intrinsic brain networks at rest in a woman who underwent brain imaging and venipuncture for 30 consecutive days. Standardized regression analyses illustrate estrogen and progesterone’s widespread associations with functional connectivity. Time-lagged analyses examined the temporal directionality of these relationships and suggest that cortical network dynamics (particularly in the Default Mode and Dorsal Attention Networks, whose hubs are densely populated with estrogen receptors) are preceded—and perhaps driven—by hormonal fluctuations. A similar pattern of associations was observed in a follow-up study one year later. Together, these results reveal the rhythmic nature in which brain networks reorganize across the human menstrual cycle. Neuroimaging studies that densely sample the individual connectome have begun to transform our understanding of the brain’s functional organization. As these results indicate, taking endocrine factors into account is critical for fully understanding the intrinsic dynamics of the human brain. •Intrinsic fluctuations in sex hormones shape the brain’s functional architecture.•Estradiol facilitates tighter coherence within whole-brain functional networks.•Progesterone has the opposite, reductive effect.•Ovulation (via estradiol) modulates variation in topological network states.•Effects are pronounced in network hubs densely populated with estrogen receptors.

Βeta oscillatory activity (human: 13–35 Hz; primate: 8–24 Hz) is pervasive within the cortex and basal ganglia. Studies in Parkinson’s disease patients and animal models suggest that beta-power increases with dopamine depletion. However, the exact relationship between oscillatory power, frequency and dopamine tone remains unclear. We recorded neural activity in the cortex and basal ganglia of healthy non-human primates while acutely and chronically up- and down-modulating dopamine levels. We assessed changes in beta oscillations in patients with Parkinson’s following acute and chronic changes in dopamine tone. Here we show beta oscillation frequency is strongly coupled with dopamine tone in both monkeys and humans. Power, coherence between single-units and local field potentials (LFP), spike-LFP phase-locking, and phase-amplitude coupling are not systematically regulated by dopamine levels. These results demonstrate that beta frequency is a key property of pathological oscillations in cortical and basal ganglia networks. Dopamine tone modulation generates changes in beta oscillation physiology. Here the authors show beta frequency, and not power, coherence, phase-locking, or PAC is monotonically linked to dopamine tone and is likely the key property of pathological oscillations in cortical and basal ganglia networks.