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Journal articleGirn M, Roseman L, Bernhardt B, et al., 2020,
Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex
<jats:title>Abstract</jats:title> <jats:p>LSD and psilocybin are serotonergic psychedelic compounds with potential in the treatment of mental health disorders. Past neuroimaging investigations have revealed that both compounds can elicit significant changes to whole-brain functional organization and dynamics. A recent proposal linked past findings into a unified model and hypothesized reduced whole-brain hierarchical organization as a key mechanism underlying the psychedelic state, but this has yet to be directly tested. We applied a non-linear dimensionality reduction technique previously used to map hierarchical connectivity gradients to pharmacological resting-state fMRI data to assess cortical organization in the LSD and psilocybin state. Results supported our primary hypothesis: The principal gradient of cortical connectivity, describing a hierarchy from unimodal to transmodal cortex, was significantly flattened under both drugs relative to their respective placebo conditions. Between-condition contrasts revealed that this was driven by a reduction of functional differentiation at both hierarchical extremes – default and frontoparietal networks at the upper end, and somatomotor at the lower. Gradient-based connectivity mapping confirmed that this was underpinned by increased unimodal-transmodal crosstalk. In addition, LSD-dependent principal gradient changes tracked changes in self-reported ego-dissolution. Results involving the second and third gradient, which respectively represent axes of sensory and executive differentiation, also showed significant alterations across both drugs. These findings provide support for a recent mechanistic model of the psychedelic state relevant to therapeutic applications of psychedelics. More fundamentally, we provide the first evidence that macroscale connectivity gradients are sensitive to a pharmacological manipulation, specifically highlighting an important relationship between cortic
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Journal articleKringelbach ML, Cruzat J, Cabral J, et al., 2020,
Dynamic coupling of whole-brain neuronal and neurotransmitter systems
, Proceedings of the National Academy of Sciences of USA, Vol: 117, Pages: 9566-9576, ISSN: 0027-8424Remarkable progress has come from whole-brain models linking anatomy and function. Paradoxically, it is not clear how a neuronal dynamical system running in the fixed human anatomical connectome can give rise to the rich changes in the functional repertoire associated with human brain function, which is impossible to explain through long-term plasticity. Neuromodulation evolved to allow for such flexibility by dynamically updating the effectivity of the fixed anatomical connectivity. Here, we introduce a theoretical framework modeling the dynamical mutual coupling between the neuronal and neurotransmitter systems. We demonstrate that this framework is crucial to advance our understanding of whole-brain dynamics by bidirectional coupling of the two systems through combining multimodal neuroimaging data (diffusion magnetic resonance imaging [dMRI], functional magnetic resonance imaging [fMRI], and positron electron tomography [PET]) to explain the functional effects of specific serotoninergic receptor (5-HT2AR) stimulation with psilocybin in healthy humans. This advance provides an understanding of why psilocybin is showing considerable promise as a therapeutic intervention for neuropsychiatric disorders including depression, anxiety, and addiction. Overall, these insights demonstrate that the whole-brain mutual coupling between the neuronal and the neurotransmission systems is essential for understanding the remarkable flexibility of human brain function despite having to rely on fixed anatomical connectivity.
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Journal articleMertens LJ, Wall MB, Roseman L, et al., 2020,
Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression
, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 34, Pages: 167-180, ISSN: 0269-8811- Cite
- Citations: 139
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Conference paperMertens LJ, Wall MB, Roseman L, et al., 2019,
Therapeutic mechanisms of psychedelic drugs: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression
, 32nd Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER, Pages: S416-S417, ISSN: 0924-977X -
Conference paperStenbaek D, Madsen MK, Ozenne B, et al., 2019,
Modelling the acute temporal dynamics of psilocybin psychoactive effects; relation to brain serotonin 2a receptor levels
, 32nd Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER, Pages: S558-S558, ISSN: 0924-977X -
Journal articleRuss SL, Carhart-Harris RL, Maruyama G, et al., 2019,
Replication and extension of a model predicting response to psilocybin
, PSYCHOPHARMACOLOGY, Vol: 236, Pages: 3221-3230, ISSN: 0033-3158- Author Web Link
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- Citations: 32
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Journal articleLord L-D, Expert P, Atasoy S, et al., 2019,
Dynamical exploration of the repertoire of brain networks at rest is modulated by psilocybin
, NeuroImage, Vol: 199, Pages: 127-142, ISSN: 1053-8119Growing 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.
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Journal articleJefsen O, Hojgaard K, Christiansen SL, et al., 2019,
Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat
, ACTA NEUROPSYCHIATRICA, Vol: 31, Pages: 213-219, ISSN: 1601-5215- Author Web Link
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- Citations: 27
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Journal articleMadsen MK, Fisher PM, Burmester D, et al., 2019,
Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels
, NEUROPSYCHOPHARMACOLOGY, Vol: 44, Pages: 1328-1334, ISSN: 0893-133X- Cite
- Citations: 170
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Journal articleMadsen MK, Fisher PM, Burmester D, et al., 2019,
Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels (vol 44, pg 1328, 2019)
, NEUROPSYCHOPHARMACOLOGY, Vol: 44, Pages: 1336-1337, ISSN: 0893-133X
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