Characterization of Altered Waking States of Consciousness in Healthy Humans
Condition: Altered Waking States of Consciousness in Healthy Humans
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): TMS/EEG
Intervention type(s): Other
Intervention description(s): 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
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science