Functional connectivity measures after psilocybin inform a novel hypothesis of early psychosis.

Psilocybin is a classic psychedelic and a candidate drug model of psychosis. This study measured the effects of psilocybin on resting-state network and thalamocortical functional connectivity (FC) using functional magnetic resonance imaging (fMRI). Fifteen healthy volunteers received intravenous infusions of psilocybin and placebo in 2 task-free resting-state scans. Primary analyses focused on changes in FC between the default-mode- (DMN) and task-positive network (TPN). Spontaneous activity in the DMN is orthogonal to spontaneous activity in the TPN, and it is well known that these networks support very different functions (ie, the DMN supports introspection, whereas the TPN supports externally focused attention). Here, independent components and seed-based FC analyses revealed increased DMN-TPN FC and so decreased DMN-TPN orthogonality after psilocybin. Increased DMN-TPN FC has been found in psychosis and meditatory states, which share some phenomenological similarities with the psychedelic state. Increased DMN-TPN FC has also been observed in sedation, as has decreased thalamocortical FC, but here we found preserved thalamocortical FC after psilocybin. Thus, we propose that thalamocortical FC may be related to arousal, whereas DMN-TPN FC is related to the separateness of internally and externally focused states. We suggest that this orthogonality is compromised in early psychosis, explaining similarities between its phenomenology and that of the psychedelic state and supporting the utility of psilocybin as a model of early psychosis.

[1]  C. Savage Variations in ego feeling induced by D-lysergic acid diethylamide (LSD-25). , 1955, Psychoanalytic review.

[2]  A. Hofmann,et al.  [Elucidation of the structure and the synthesis of psilocybin]. , 1958, Experientia.

[3]  N. Smart,et al.  Mysticism and Philosophy. , 1963 .

[4]  G. Klee Lysergic acid diethylamide (LSD-25) and ego functions. , 1963, Archives of general psychiatry.

[5]  J. Chapman The Early Symptoms of Schizophrenia , 1966, British Journal of Psychiatry.

[6]  M. Bowers,et al.  "Psychedelic" experiences in acute psychoses. , 1966, Archives of general psychiatry.

[7]  J. Bakalar,et al.  Psychedelic Drugs Reconsidered , 1979 .

[8]  A. Grinvald,et al.  Dynamics of Ongoing Activity: Explanation of the Large Variability in Evoked Cortical Responses , 1996, Science.

[9]  Stephen M. Smith,et al.  Investigations into resting-state connectivity using independent component analysis , 2005, Philosophical Transactions of the Royal Society B: Biological Sciences.

[10]  Maurizio Corbetta,et al.  The human brain is intrinsically organized into dynamic, anticorrelated functional networks. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[11]  R. Griffiths,et al.  Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance , 2006, Psychopharmacology.

[12]  Jeffrey M. Zacks,et al.  Coherent spontaneous activity accounts for trial-to-trial variability in human evoked brain responses , 2006, Nature Neuroscience.

[13]  D. V. Essen,et al.  Surface-Based and Probabilistic Atlases of Primate Cerebral Cortex , 2007, Neuron.

[14]  Abraham Z. Snyder,et al.  A default mode of brain function: A brief history of an evolving idea , 2007, NeuroImage.

[15]  R. Buckner,et al.  Self-projection and the brain , 2007, Trends in Cognitive Sciences.

[16]  Scott T. Grafton,et al.  Wandering Minds: The Default Network and Stimulus-Independent Thought , 2007, Science.

[17]  N. Farb,et al.  Attending to the present: mindfulness meditation reveals distinct neural modes of self-reference. , 2007, Social cognitive and affective neuroscience.

[18]  N. Franks General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal , 2008, Nature Reviews Neuroscience.

[19]  B. Harrison,et al.  Consistency and functional specialization in the default mode brain network , 2008, Proceedings of the National Academy of Sciences.

[20]  O. Sporns,et al.  Mapping the Structural Core of Human Cerebral Cortex , 2008, PLoS biology.

[21]  Bharat B. Biswal,et al.  Competition between functional brain networks mediates behavioral variability , 2008, NeuroImage.

[22]  Yihong Yang,et al.  Static and dynamic characteristics of cerebral blood flow during the resting state , 2009, NeuroImage.

[23]  R. Nathan Spreng,et al.  The Common Neural Basis of Autobiographical Memory, Prospection, Navigation, Theory of Mind, and the Default Mode: A Quantitative Meta-analysis , 2009, Journal of Cognitive Neuroscience.

[24]  Stephen M Smith,et al.  Correspondence of the brain's functional architecture during activation and rest , 2009, Proceedings of the National Academy of Sciences.

[25]  J. Gabrieli,et al.  Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia , 2009, Proceedings of the National Academy of Sciences.

[26]  Kevin Murphy,et al.  The impact of global signal regression on resting state correlations: Are anti-correlated networks introduced? , 2009, NeuroImage.

[27]  R. Buckner,et al.  Evidence for the Default Network's Role in Spontaneous Cognition , 2010 .

[28]  M. Boly,et al.  Breakdown of within- and between-network Resting State Functional Magnetic Resonance Imaging Connectivity during Propofol-induced Loss of Consciousness , 2010, Anesthesiology.

[29]  Jungsu S. Oh,et al.  Altered resting-state connectivity in subjects at ultra-high risk for psychosis: an fMRI study , 2010, Behavioral and Brain Functions.

[30]  Karl J. Friston,et al.  The default-mode, ego-functions and free-energy: a neurobiological account of Freudian ideas , 2010, Brain : a journal of neurology.

[31]  Paul M. Matthews,et al.  Nicotine replacement in abstinent smokers improves cognitive withdrawal symptoms with modulation of resting brain network dynamics , 2010, NeuroImage.

[32]  Edith Pomarol-Clotet,et al.  Overall brain connectivity maps show cortico‐subcortical abnormalities in schizophrenia , 2010, Human brain mapping.

[33]  D. Nutt,et al.  The administration of psilocybin to healthy, hallucinogen-experienced volunteers in a mock-functional magnetic resonance imaging environment: a preliminary investigation of tolerability , 2011, Journal of psychopharmacology.

[34]  Georg Northoff,et al.  How is our self related to midline regions and the default-mode network? , 2011, NeuroImage.

[35]  S. Heckers,et al.  Functional resting-state networks are differentially affected in schizophrenia , 2011, Schizophrenia Research.

[36]  J. Gray,et al.  Meditation experience is associated with differences in default mode network activity and connectivity , 2011, Proceedings of the National Academy of Sciences.

[37]  Ann K. Shinn,et al.  Abnormal Medial Prefrontal Cortex Resting-State Connectivity in Bipolar Disorder and Schizophrenia , 2011, Neuropsychopharmacology.

[38]  L. Barsalou,et al.  Effects of Meditation Experience on Functional Connectivity of Distributed Brain Networks , 2012, Front. Hum. Neurosci..

[39]  David J. Heeger,et al.  Influence of meditation on anti-correlated networks in the brain , 2012, Front. Hum. Neurosci..

[40]  Richard G. Wise,et al.  Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin , 2012, Proceedings of the National Academy of Sciences.