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Both psychedelics and meditation exert profound modulatory effects on consciousness, perception and cognition, but their combined, possibly synergistic effects on neurobiology are unknown. Accordingly, we conducted a randomized, double-blind, placebo-controlled study with 38 participants following a single administration of the psychedelic psilocybin (315 μg/kg p.o.) during a 5-day mindfulness retreat. Brain dynamics were quantified directly pre- and post-intervention by functional magnetic resonance imaging during the resting state and two meditation forms. The analysis of functional connectivity identified psilocybin-related and mental state–dependent alterations in self-referential processing regions of the default mode network (DMN). Notably, decoupling of medial prefrontal and posterior cingulate cortices, which is thought to mediate sense of self, was associated with the subjective ego dissolution effect during the psilocybin-assisted mindfulness session. The extent of ego dissolution and brain connectivity predicted positive changes in psycho-social functioning of participants 4 months later. Psilocybin, combined with meditation, facilitated neurodynamic modulations in self-referential networks, subserving the process of meditation by acting along the anterior–posterior DMN connection. The study highlights the link between altered self-experience and subsequent behavioral changes. Understanding how interventions facilitate transformative experiences may open novel therapeutic perspectives. Insights into the biology of discrete mental states foster our understanding of non-ordinary forms of human self-consciousness and their concomitant brain substrate. •Study investigates the psychedelic effects of psilocybin within a mindfulness retreat.•Drug-specific modulations in self-referential brain areas were found post-intervention.•Reduced antero-posterior DMN connectivity was linked to drug-induced ego dissolution.•Extent of altered self-experience and connectivity predicted lasting positive changes.

The mammalian nervous system encodes many different forms of pain, from those that arise as a result of short-term low-grade interactions with noxious thermal, chemical, or mechanical sources to more serious forms of pain induced by trauma and disease. In this Review, we highlight recent advances in our understanding of the neural circuits that encode these types of pain. Promising therapeutic strategies based on recent advances are also highlighted.

Most brain activity occurs in an ongoing manner not directly locked to external events or stimuli. Regional ongoing activity fluctuates in unison with some brain regions but not others, and the degree of long-range coupling is called functional connectivity, often measured with correlation. Strength and spatial distributions of functional connectivity dynamically change in an ongoing manner over seconds to minutes, even when the external environment is held constant. Direct evidence for any behavioral relevance of these continuous large-scale dynamics has been limited. Here, we investigated whether ongoing changes in baseline functional connectivity correlate with perception. In a continuous auditory detection task, participants perceived the target sound in roughly one-half of the trials. Very long (22–40 s) interstimulus intervals permitted investigation of baseline connectivity unaffected by preceding evoked responses. Using multivariate classification, we observed that functional connectivity before the target predicted whether it was heard or missed. Using graph theoretical measures, we characterized the difference in functional connectivity between states that lead to hits vs. misses. Before misses compared with hits and task-free rest, connectivity showed reduced modularity, a measure of integrity of modular network structure. This effect was strongest in the default mode and visual networks and caused by both reduced within-network connectivity and enhanced across-network connections before misses. The relation of behavior to prestimulus connectivity was dissociable from that of prestimulus activity amplitudes. In conclusion, moment to moment dynamic changes in baseline functional connectivity may shape subsequent behavioral performance. A highly modular network structure seems beneficial to perceptual efficiency.

Compassion is a key motivator of altruistic behavior, but little is known about individuals’ capacity to cultivate compassion through training. We examined whether compassion may be systematically trained by testing whether (a) short-term compassion training increases altruistic behavior and (b) individual differences in altruism are associated with training-induced changes in neural responses to suffering. In healthy adults, we found that compassion training increased altruistic redistribution of funds to a victim encountered outside of the training context. Furthermore, increased altruistic behavior after compassion training was associated with altered activation in brain regions implicated in social cognition and emotion regulation, including the inferior parietal cortex and dorsolateral prefrontal cortex (DLPFC), and in DLPFC connectivity with the nucleus accumbens. These results suggest that compassion can be cultivated with training and that greater altruistic behavior may emerge from increased engagement of neural systems implicated in understanding the suffering of other people, executive and emotional control, and reward processing.

Mindfulness practice is beneficial for emotion regulation; however, the neural mechanisms underlying this effect are poorly understood. The current study focuses on effects of attention-to-breath (ATB) as a basic mindfulness practice on aversive emotions at behavioral and brain levels. A key finding across different emotion regulation strategies is the modulation of amygdala and prefrontal activity. It is unclear how ATB relevant brain areas in the prefrontal cortex integrate with amygdala activation during emotional stimulation. We proposed that, during emotional stimulation, ATB down-regulates activation in the amygdala and increases its integration with prefrontal regions. To address this hypothesis, 26 healthy controls were trained in mindfulness-based attention-to-breath meditation for two weeks and then stimulated with aversive pictures during both attention-to-breath and passive viewing while undergoing fMRI. Data were controlled for breathing frequency. Results indicate that (1) ATB was effective in regulating aversive emotions. (2) Left dorso-medial prefrontal cortex was associated with ATB in general. (3) A fronto-parietal network was additionally recruited during emotional stimulation. (4) ATB down regulated amygdala activation and increased amygdala–prefrontal integration, with such increased integration being associated with mindfulness ability. Results suggest amygdala–dorsal prefrontal cortex integration as a potential neural pathway of emotion regulation by mindfulness practice. •Attention to breath (ATB) reduces emotional responses in the amygdala.•Amygdala–prefrontal cortex functional connectivity increases during ATB.•Connectivity increase is linked with individual differences in mindful disposition.

Large-scale biophysical circuit models provide mechanistic insights into the micro-scale and macro-scale properties of brain organization that shape complex patterns of spontaneous brain activity. We developed a spatially heterogeneous large-scale dynamical circuit model that allowed for variation in local synaptic properties across the human cortex. Here we show that parameterizing local circuit properties with both anatomical and functional gradients generates more realistic static and dynamic resting-state functional connectivity (FC). Furthermore, empirical and simulated FC dynamics demonstrates remarkably similar sharp transitions in FC patterns, suggesting the existence of multiple attractors. Time-varying regional fMRI amplitude may track multi-stability in FC dynamics. Causal manipulation of the large-scale circuit model suggests that sensory-motor regions are a driver of FC dynamics. Finally, the spatial distribution of sensory-motor drivers matches the principal gradient of gene expression that encompasses certain interneuron classes, suggesting that heterogeneity in excitation-inhibition balance might shape multi-stability in FC dynamics. Spontaneous fluctuations in brain activity exhibit complex spatiotemporal patterns across animal species. Here the authors show that sensory-motor regions and spatial heterogeneity in excitation-inhibition balance might shape multi-stability in brain dynamics.

Internal representations of relationships between events in the external world can be utilized to infer outcomes when direct experience is lacking. This process is thought to involve the orbitofrontal cortex (OFC) and hippocampus (HPC), but there is little evidence regarding the relative role of these areas and their interactions in inference. Here, we used a sensory preconditioning task and pattern-based neuroimaging to study this question. We found that associations among value-neutral cues were acquired in both regions during preconditioning but that value-related information was only represented in the OFC at the time of the probe test. Importantly, inference was accompanied by representations of associated cues and inferred outcomes in the OFC, as well as by increased HPC-OFC connectivity. These findings suggest that the OFC and HPC represent only partially overlapping information and that interactions between the two regions support model-based inference.

Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate-modulating NMDA receptor antagonist ketamine. Targeting the glutamatergic system might thus provide a novel molecular strategy for antidepressant treatment. Since glutamate is the most abundant and major excitatory neurotransmitter in the brain, pathophysiological changes in glutamatergic signaling are likely to affect neurobehavioral plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder. Using resting state functional magnetic resonance imaging (rsfMRI), the \"dorsal nexus \"(DN) was recently identified as a bilateral dorsal medial prefrontal cortex region showing dramatically increased depression-associated functional connectivity with large portions of a cognitive control network (CCN), the default mode network (DMN), and a rostral affective network (AN). Hence, Sheline and colleagues (2010) proposed that reducing increased connectivity of the DN might play a critical role in reducing depression symptomatology and thus represent a potential therapy target for affective disorders. Here, using a randomized, placebo-controlled, double-blind, crossover rsfMRI challenge in healthy subjects we demonstrate that ketamine decreases functional connectivity of the DMN to the DN and to the pregenual anterior cingulate (PACC) and medioprefrontal cortex (MPFC) via its representative hub, the posterior cingulate cortex (PCC). These findings in healthy subjects may serve as a model to elucidate potential biomechanisms that are addressed by successful treatment of major depression. This notion is further supported by the temporal overlap of our observation of subacute functional network modulation after 24 hours with the peak of efficacy following an intravenous ketamine administration in treatment-resistant depression.

Heart rate variability is a robust biomarker of emotional well-being, consistent with the shared brain networks regulating emotion regulation and heart rate. While high heart rate oscillatory activity clearly indicates healthy regulatory brain systems, can increasing this oscillatory activity also enhance brain function? To test this possibility, we randomly assigned 106 young adult participants to one of two 5-week interventions involving daily biofeedback that either increased heart rate oscillations (Osc+ condition) or had little effect on heart rate oscillations (Osc− condition) and examined effects on brain activity during rest and during regulating emotion. While there were no significant changes in the right amygdala-medial prefrontal cortex (MPFC) functional connectivity (our primary outcome), the Osc+ intervention increased left amygdala-MPFC functional connectivity and functional connectivity in emotion-related resting-state networks during rest. It also increased down-regulation of activity in somatosensory brain regions during an emotion regulation task. The Osc− intervention did not have these effects. In this healthy cohort, the two conditions did not differentially affect anxiety, depression, or mood. These findings indicate that modulating heart rate oscillatory activity changes emotion network coordination in the brain.

A small population of brainstem noradrenaline neurons powerfully modulates global brain function, but how they regulate diverse—and at times opposing—functions is not clear. The authors report that a modular organization in this neuromodulatory system, coupled with context-dependent activation modes, controls the balance between opposing emotional and flexible learning states. Noradrenaline modulates global brain states and diverse behaviors through what is traditionally believed to be a homogeneous cell population in the brainstem locus coeruleus (LC). However, it is unclear how LC coordinates disparate behavioral functions. We report a modular LC organization in rats, endowed with distinct neural projection patterns and coding properties for flexible specification of opposing behavioral learning states. LC projection mapping revealed functionally distinct cell modules with specific anatomical connectivity. An amygdala-projecting ensemble promoted aversive learning, while an independent medial prefrontal cortex-projecting ensemble extinguished aversive responses to enable flexible behavior. LC neurons displayed context-dependent inter-relationships, with moderate, discrete activation of distinct cell populations by fear or safety cues and robust, global recruitment of most cells by strong aversive stimuli. These results demonstrate a modular organization in LC in which combinatorial activation modes are coordinated with projection- and behavior-specific cell populations, enabling adaptive tuning of emotional responding and behavioral flexibility.