Characterization of Altered Waking States of Consciousness in Healthy Humans

Altered waking states of consciousness and its underlying functional organization have gained increasing interest in recent years, i.e. in identifying the neural basis of consciousness. To overcome fundamental shortcomings of current methods to objectively assess the level of consciousness, the investigators propose here to apply a novel and empirically validated measure called 'perturbational complexity index' (PCI) based on the integrated information theory (IIT). This involves a combination of transcranial magnetic stimulation (TMS) and highdensity electroencephalography (hd-EEG) to measure electrocortical responses as distributed cerebral interactions ('integration') and spatiotemporal pattern ('information'). Given the finding of subjectively expanded consciousness as induced here by psilocybin, the investigators hypothesize that the PCI may be higher in such states. This will be the first TMS/hd-EEG study to investigate quantitatively the level of consciousness in a pharmacologically altered waking state of consciousness.

In this study the investigators will apply navigated TMS/high-density(hd)-EEG to directly stimulate defined cortical areas and investigate quantitatively the level of consciousness in psilocybin-induced altered brain states. For this purpose, PCI is the primary outcome in psilocybin versus placebo condition. Given the findings and the subjective feeling of an 'expanded' consciousness in such states, the investigators primarily hypothesize that psilocybin will induce a higher PCI as compared to placebo in TMS/hd-EEG measurements over all targeted cortical areas in the acute phase of treatment (80 minutes after substance intake). Measurements will be done over the premotor cortex (Brodmann-Areal BA06), the midline sensorimotor cortex (BA04) and the superior occipital gyrus/cuneus (BA19) and may be related to the experience of an altered sense of self, e.g. measures of selflessness and egodissolution.

This study further seeks to characterize the effects of psilocybin compared to placebo on resting state EEG. To this aim, the current source density and the lagged phase synchronization of neuronal oscillations across distributed brain regions will be computed and correlated to reproduce interesting results in a recent work of Kometer and colleagues. More specifically, psilocybin decreased the current source density of neuronal oscillations within a neural network comprising the anterior and posterior cingulate cortices and parahippocampal regions. Even more, psilocybin-induced insightfulness and spiritual experience correlated with the lagged phase synchronization of delta oscillations between the retrosplenial cortex, the parahippocampus and the lateral orbitofrontal area, showing evidence for a direct association of spatiotemporal neuronal mechanism with enhanced insight into life and existence. The investigators therefore hypothesize that current source density of neuronal oscillations within the cingulate cortices and the parahippocampal regions (1.5-20 Hz) will be decreased and the lagged-phase synchronization of delta oscillations (1.5-4 Hz) between the retrosplenial cortex, the parahippocampus and the lateral orbitofrontal area will be correlated to insightfulness.

Additionally, psychometric assessment of the sense of self, of perceptual alterations and of mood will be conducted before and after each TMS session (Hood's Mysticism-Scale; 5-Dimensional Altered States of Consciousness Rating Scale; Positive and Negative Affect Schedule). the investigators expect to find a relationship between substance induced changes in perception and mood as indexed by these questionnaires.

Furthermore, the investigators will be conducting a probabilistic learning task (emotLearn) to examine the computational processes behind the interaction between reward learning and subconscious versus conscious emotional processing to estimate how emotional stimuli affect the learning rate in psilocybin compared to placebo condition. The investigators hypothesize that psilocybin decreases the conscious and subconscious learning rate by attenuating the processing of emotional cues.

The study design will be randomized, double-blind, placebo-controlled with one-time application of a single dose for each substance (moderate psilocybin dose of 20mg versus mannitol), within-subject and single center at the Psychiatrische Universitätsklinik Zurich. The number of participants is 25 healthy subjects as determined by power analysis. Inclusion criteria are healthy male or female volunteers aged 18-40 years. Exclusion criteria are personal and family history of major psychiatric disease (e.g. major depression, bipolar disorder, psychotic disorder) as defined in the DSM-V, any major medical condition (e.g. neurologic, cardiovascular, metabolic disease), family history of seizure disorder, current psychopharmacological treatment or pregnant respectively breastfeeding women. The study comprises a total of 3 visits in 3 weeks - 1 screening visit and 2 investigational visits and a written follow-up 12 weeks after the last investigational visit per participant. On the investigational visits participants will receive placebo or psilocybin in a randomized and counterbalanced order. The screening visit consists of a psychiatric assessment, physical examination, routine lab/toxicology, electrocardiogram (ECG), EEG and cranial T1 weighted magnetic resonance tomography (MRT). Study duration will be 2-3 years.

The research project was approved by the local ethics committee (KEK Zurich) in December 2018 as "Other clinical trial" as specified in the "Ordinance on Clinical Trials in Human Research" (KlinV, Chapter 2) without health-related intervention or investigational Medical Product (IMP) \[25\], Category B.

Eligibility Criteria:
Inclusion Criteria:

* Healthy male or female volunteers aged 18-40 years

Exclusion Criteria:

* Personal and family history of major psychiatric disease (e.g. major depression, bipolar disorder, psychotic disorder) as defined in the DSM-V
* Any major medical condition (e.g. neurologic, cardiovascular, metabolic disease), family history of seizure disorder
* Current psychopharmacological treatment / use of medication
* Pregnant or breastfeeding women