EEG Microstates Across At-Risk Mental States

Study Overview
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Brief Summary
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The goal of this observational study is to compare subjects with at-risk-mental-state, early psychosis, schizophrenia, depression, and autism spectrum disorders, with healthy controls (N = 21 x 6). The main questions it aims to answer are: are EEG microstate anomalies associated with diagnosis, clinical and functional prognosis, both in resting conditions and during sleep ? are EEG microstates anomalies associated with differences in sensorimotor integration, prosodic and conversational, interoceptive, and narrative self ? an ancillary study will be to see whether in healthy controls EEG microstate properties vary under light hypnosis conditions. Participants will: undergo deep phenotyping based on psychopathology and neuropsychological assessments undergo a high-resolution EEG (64 electrodes) with a resting period and a sensorimotor task; and healthy controls will have a light hypnosis period. undergo a recording of the characteristics of their voice (tone, prosody) undergo a one-night polysomnography undergo MRI and biological sampling for multi-omic analyses undergo a virtual reality experience

Detailed Description
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Aim of the study: EEG microstates translate the resting-state temporal dynamics of neuronal networks throughout the brain. Here, the investigators aim to see whether EEG microstate anomalies could constitute markers of psychiatric disorders. Methods: six groups of 21 participants each will be included. There will be five groups of participants with psychiatric disorders (at-risk-mental state - ARMS, first-episode psychosis - FEP, schizophrenia - SCZ, major depressive disorder - MDD, and autism spectrum disorders - ASD) and one group of healthy controls. Our main objective is to test differences in means between the groups, at rest and during sleep, for each of the variables characterizing each of the microstates (duration, frequency, occupation time) as well as, secondarily, EEG measures of connectivity (somatosensory evoked potentials), cortical excitability (alpha-band power), and prosodic and conversational linguistic measures. Regarding the microstates measures: a five minute eyes-closed resting-state EEG with 64 channels will be recorded (as part of the larger task including the sensorimotor task described below). A minimal preprocessing will be done with the MNE EEG software on Python, which includes a bandpass filter between 0.5 and 40 Hz, rereferencing to the mean, and visual and automatic correction for artifacts. Each recording will be visually reanalyzed by clinical neurophysiologists to ensure it is indeed an alpha-dominant, resting rhythm without any residual artifact. Microstate analysis will be done using the Pycrostates package. Global field power (GFP) will be determined for each participant. Only EEG topographies at GFP peaks will be retained to determine microstates' topographies, through a modified K-means clustering. For each subject the same number of GFP peaks will be extracted and concatenated into a single data set for clustering. A combined score will be used to compute the optimal number of clusters. The resulting clusters will be backfitted to each individual maps. Temporal smoothing will be used to ensure that periods of inter-peak noise, of low GFP, did not interrupt the sequences of quasi-stable segments. For each subject, three parameters will be computed for each microstate class: frequency of occurrence (occurrence), temporal coverage (coverage) and mean duration. Occurrence is the average number of times a given microstate occurs per second. Coverage (in %) is the percentage of total analysis time spent in a given microstate. Mean duration (in ms) is the average time during which a given microstate was present in an uninterrupted manner (after temporal smoothing). Regarding the linguistic measures: each participant undergoes a semi-structured interview with a trained experimenter. Both the participant and the interviewer wear head-set AKG-C544L condenser microphones, connected via AKG MPA VL phantom adaptors to a Zoom H4n Pro Handy recorder. Speech is digitally recorded at a sampling rating of 44000 Hz (16-bit). The distance between the mouth and the microphone is kept as constant as possible (2 cm) to assure consistent levels of vocal loudness. The interviews are done in a quiet room to limit environmental noise; the two interactants are placed as far as possible, to prevent crosstalk (i.e. speech of the interviewer caught by participant's microphone and vice versa). The .wav files obtained from the recordings are annotated using the Praat software and subsequently analysed with Praat and R. Prosodic features are extracted using the Prosogram tool (a set of Praat scripts, open-source) and a new modified version of scripts from the Prosogram tool. Turn-taking variables are extracted with new combined Praat and R scripts. Regarding the sensorimotor intergration measures: the sensorimotor integration is investigated using a visuo-haptic task. On each trial, the participant, seated in front of a screen, has a visual instruction (a point to the right or left of the screen). The task consists of pressing one of the two buttons positioned on each side of the body with the index finger of the corresponding hand according to the visual instruction. A vibrotactile stimulator (small speakers wired to an Arduino electronic card modulated by an amplifier) is applied to the first dorsal interosseous muscle of both hands. 400 msec before the visual instruction, one of the two hands receives a tactile cue (vibration) on one hand for 100 msec. This cue is more or less reliable depending on the block. In some blocks, it is quite reliable, since 90% of the trials present the vibration and visual instruction congruently (indicating the same hand). Another condition is composed of only 50% of the congruent trials, and in this case, the tactile cue is not reliable. Two blocks with 70% congruent cases are carried out intermediately. Finally, a baseline block which does not contain any tactile cues is presented at the beginning and the end of the task. The order of the 90% and 50% blocks is randomized. The tactile and visual stimuli are generated with a MATLAB script. Each block consists of 100 trials, in total 500 trials. Electroencephalographic (EEG) data is recorded throughout the task, using a 64-channel EEG cap (from Biosemi) in order to record the electrical brain activity. The setup is coupled to an eyetracker, to control that the participant is fixating the cross at the center of the screen during each block. Regarding the multidimensional self and episodic memory task (task design: Laboratoire Mémoire, Cerveau et Cognition): at baseline, participants will be submitted to self-reported questionnaires assessing their sense of minimal Self on 8 domains (Multidimensional Assessment of Interoceptive Awareness - Version 2) and sense of narrative Self on 5 domains (Tennessee Self Concept Scale - Short Form, Present). They will undergo a neuropsychological test assessing their visual episodic memory performance (Family Pictures from Wechsler Memory Scale-III). They will rate their current emotional state on a visual analogue scale on 4 domains (Mood Visual Analogue Scale). Following each of the two navigation sessions in virtual reality, which consist in a walk through a virtual city where participants encounter daily life events that aim to be incidentally encoded in episodic memory, associated with different levels of self-reference, participants will be submitted to self-reported questionnaires assessing their sense of embodiment on 4 domains (Embodiment Questionnaire), their sense of presence on 4 domains (Igroup Presence Questionnaire), and their cybersickness on 2 domains (Simulator Sickness Questionnaire). They will rate again their current emotional state on a visual analogue scale (Mood Visual Analogue Scale). Finally, participants will undergo two episodic memory tests: a free recall task and a recognition task. The free recall will be based on a verbal interview of 20 minutes, during which participants will be asked to recall all the events that they remember encountering in the virtual city. For each event, they will be asked to recall systematically and the most precisely possible: what was the event, where and when it happened during the navigation, in which of the two navigation it happened (source), who was the referent according to which the personal significance of the event was assessed, objective (perceptive) and subjective (phenomenological) details of the event, and if the event was vividly relived or felt merely familiar (Remember/Know procedure). The recognition test will be performed on a computer and programmed using the Python module Neuropsydia. All 32 encountered events mixed with 16 lures which were not encountered will be displayed successfully in a random order on a computer screen. For each event, several questions will be asked successfully and participants will click on what they consider the correct answer among several propositions: did they encounter the event (Yes/No), and if yes where it happened (among several possible localisations on a picture of the zone where the event occurred), when it happened (replacing the event in the chronological order with two other events), in which navigation (first or second navigation), and who was the referent (Me/Other). For each event, participants will also rate on scales ranging from 0 to 100: the degree of reliving or familiarity of the event (100 = Remember, 0 = Know), the perspective of the memory (100 = first-person perspective, 0 = third-person perspective), its vivacity, fidelity, emotional intensity, strength of associated bodily sensations, episodic self-reference, and semantic self-reference. For all variables, the investigators will apply a repeated measures ANOVA, and use the following contrasts: ARMS, FEP, SCZ, ASD, MDD vs. Healthy subjects (microstates are tested as markers of general psychopathology); ARMS, FEP, SCZ vs ASD, MDD (microstates are tested as specific markers of psychosis; equivalently, the specificity of this signature for depression and ASD will be tested) ARMS vs. FEP vs. SCZ (microstates are tested as evolutionary markers); Finally, depending on the rate of transition to psychosis among UHRs, a comparison of UHR-T vs UHR-NT can be made (microstates are tested as predictive markers of psychosis All subjects will undergo a deep phenotyping including neuropsychology, psychopathology, neurological soft signs scales, as well as structural MRI, and genetic and epigenetic measures. Hypothesis: imbalances in EEG microstates C and D are expected to be more pronounced across the spectrum of psychosis and in ASD compared to controls, MDD, and ARMS, and be associated with anomalies in somatosensory, interoceptive, and language characteristics.

Official Title
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Determination of EEG Microstates Associated With Mental Disorders in At-Risk States (Détermination Des Microétats EEG associés Aux Troubles Psychiques Dans Les États à Risque - DEMETER)

Conditions
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Psychotic Disorders, Autism Spectrum Disorder, Major Depressive Disorder, Schizophrenia

Intervention / Treatment
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* Device: EEG 64 channels
* Device: Polysomnography 19 electrodes
* Behavioral: Light hypnosis
* Biological: Biological sampling
* Behavioral: Virtual reality
* Device: Voice recording


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age between 15 and 30 years subjects meeting CAARMS criteria for stage Ia or Ib mental states at risk (for stage Ia, mild or nonspecific symptoms of psychosis or severe mood disorder, and mild functional impairment; for stage Ib, moderate symptoms below intervention threshold and moderate functional impairment) subjects meeting any DSM-5 criteria associated with a first onset of psychotic symptoms (first episode psychosis) subjects satisfying DSM-5 criteria for depressive disorder subjects meeting DSM-5 criteria for autism spectrum disorder healthy control subjects recruited from the general population Exclusion Criteria: suicidal risk severe or non-stabilized somatic and neurological disorders epilepsy head trauma IQ below 70 for healthy control subjects, a family history of psychosis is an exclusion criterion bipolar disorder obsessive-compulsive disorder substance use disorder, except for cannabis, tolerated up to 5 joints/day.

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Major depressive disorder<br>Major depressive disorder as defined by DSM-5 classification | Device: EEG 64 channels<br>* 64-channel EEG in wake and resting conditions for 1h30, with oculogram, electromyogram and electromyogram and electrocardiogram. Five minutes of eyes closed will be used for microstate analysis. 1h30 will be used for the sensorimotor task.<br>Device: Polysomnography 19 electrodes<br>* Overnight polysomnography with 19 EEG channels and ventilatory polygraphy.<br>Biological: Biological sampling<br>* Blood samples will be taken for genetic, epigenetic, proteomic, and metabolomic studies.<br>Device: Voice recording<br>* A double channel audio recorder will be used during 30 min to assess voice characteristics of all subjects.<br>|
| Experimental: Autism spectrum disorder<br>Autism spectrum disorder as defined by DSM-5 classification | Device: EEG 64 channels<br>* 64-channel EEG in wake and resting conditions for 1h30, with oculogram, electromyogram and electromyogram and electrocardiogram. Five minutes of eyes closed will be used for microstate analysis. 1h30 will be used for the sensorimotor task.<br>Device: Polysomnography 19 electrodes<br>* Overnight polysomnography with 19 EEG channels and ventilatory polygraphy.<br>Biological: Biological sampling<br>* Blood samples will be taken for genetic, epigenetic, proteomic, and metabolomic studies.<br>Device: Voice recording<br>* A double channel audio recorder will be used during 30 min to assess voice characteristics of all subjects.<br>|
| Experimental: At risk mental state<br>At risk mental state as defined in the CAARMS | Device: EEG 64 channels<br>* 64-channel EEG in wake and resting conditions for 1h30, with oculogram, electromyogram and electromyogram and electrocardiogram. Five minutes of eyes closed will be used for microstate analysis. 1h30 will be used for the sensorimotor task.<br>Device: Polysomnography 19 electrodes<br>* Overnight polysomnography with 19 EEG channels and ventilatory polygraphy.<br>Biological: Biological sampling<br>* Blood samples will be taken for genetic, epigenetic, proteomic, and metabolomic studies.<br>Behavioral: Virtual reality<br>* Participants will undergo a virtual reality task using a head-mounted display, and their multidimensional self will be assessed prior to and after the task via the self-reference effect on episodic memory.<br>Device: Voice recording<br>* A double channel audio recorder will be used during 30 min to assess voice characteristics of all subjects.<br>|
| Experimental: First episode psychosis<br>Any DSM-5 category associated with psychotic symptoms | Device: EEG 64 channels<br>* 64-channel EEG in wake and resting conditions for 1h30, with oculogram, electromyogram and electromyogram and electrocardiogram. Five minutes of eyes closed will be used for microstate analysis. 1h30 will be used for the sensorimotor task.<br>Device: Polysomnography 19 electrodes<br>* Overnight polysomnography with 19 EEG channels and ventilatory polygraphy.<br>Biological: Biological sampling<br>* Blood samples will be taken for genetic, epigenetic, proteomic, and metabolomic studies.<br>Behavioral: Virtual reality<br>* Participants will undergo a virtual reality task using a head-mounted display, and their multidimensional self will be assessed prior to and after the task via the self-reference effect on episodic memory.<br>Device: Voice recording<br>* A double channel audio recorder will be used during 30 min to assess voice characteristics of all subjects.<br>|
| Experimental: Schizophrenia<br>Schizophrenia as defined by DSM-5 classification | Device: EEG 64 channels<br>* 64-channel EEG in wake and resting conditions for 1h30, with oculogram, electromyogram and electromyogram and electrocardiogram. Five minutes of eyes closed will be used for microstate analysis. 1h30 will be used for the sensorimotor task.<br>Device: Polysomnography 19 electrodes<br>* Overnight polysomnography with 19 EEG channels and ventilatory polygraphy.<br>Biological: Biological sampling<br>* Blood samples will be taken for genetic, epigenetic, proteomic, and metabolomic studies.<br>Device: Voice recording<br>* A double channel audio recorder will be used during 30 min to assess voice characteristics of all subjects.<br>|
| Experimental: Healthy controls<br>Healthy controls with no history of neurodevelopmental disorder or psychotic disorder in a first degree relative | Device: EEG 64 channels<br>* 64-channel EEG in wake and resting conditions for 1h30, with oculogram, electromyogram and electromyogram and electrocardiogram. Five minutes of eyes closed will be used for microstate analysis. 1h30 will be used for the sensorimotor task.<br>Device: Polysomnography 19 electrodes<br>* Overnight polysomnography with 19 EEG channels and ventilatory polygraphy.<br>Behavioral: Light hypnosis<br>* Healthy controls will undergo a 5 min light hypnosis exercise that will be focused on proprioception.<br>Biological: Biological sampling<br>* Blood samples will be taken for genetic, epigenetic, proteomic, and metabolomic studies.<br>Behavioral: Virtual reality<br>* Participants will undergo a virtual reality task using a head-mounted display, and their multidimensional self will be assessed prior to and after the task via the self-reference effect on episodic memory.<br>Device: Voice recording<br>* A double channel audio recorder will be used during 30 min to assess voice characteristics of all subjects.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of EEG microstates | Average number of times a given microstate occurs per second. | Three years | 
| Coverage of EEG microstates | Percentage of total analysis time spent in a given microstate. | Three years | 
| Mean duration of EEG microstates | Average time during which a given microstate was present in an uninterrupted manner (after temporal smoothing). | Three years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Attention modulation | Measurement of alpha band power (in Hz) | Three years | 
| Cortical excitability and inhibition | Measurement of mu and theta bands (in Hz) | Three years | 
| Integration of sensory information: amplitudes | Measurement of amplitudes (in µV) of somatosensory evoked potentials | Three years | 
| Integration of sensory information: latencies | Measurement of latencies (in msec) of somatosensory evoked potentials | Three years | 
| Reaction time | The adaptation of the reaction time (in msec) to the button press according to the probabilistic context of congruency is examined. | Three years | 
| Speech rate | Measurement of number of syllables/sec in the recording of the subjects | Three years | 
| Fundamental frequency | Measurement of the fundamental frequency (in Hz) | Three years | 
| Pitch mean | Measurement of the pitch mean (in semi-tones) | Three years | 
| Pitch range | Measurement of the pitch range (in semi-tones) | Three years | 
| Pitch gliss | Measurement of the proportion of syllables with large pitch movement (in percents) | Three years | 
| Pitch rises | Measurement of the proportion of syllables with pitch rise (in percents) | Three years | 
| Pitch falls | Measurement of the proportion of syllables with pitch fall (in percents) | Three years | 
| Nuclei duration | Sum of durations for syllable nuclei for the speaker (in seconds) | Three years | 
| Internuclei Duration | Sum of durations between successive nuclei for the speaker (in seconds) | Three years | 
| Intrasyllabic Trajectory | Pitch trajectory (sum of absolute intervals) within syllabic nuclei, divided by duration (in semitones per second) | Three years | 
| Intersyllabic Trajectory | Pitch trajectory (sum of absolute intervals) between syllabic nuclei (except pauses or speaker turns), divided by duration (in semitones per second) | Three years | 
| Percentage of turns interviewer | Interviewer's total number of turns divided by the total number of turns of the dialogue (in percents) | Three years | 
| Percentage of turns participant | Participant's total number of turns divided by the total number of turns of the dialogue (in percents) | Three years | 
| Interviewer's Floor Occupation | Portion of time where only the interviewer is speaking (in percents) | Three years | 
| Participant's Floor Occupation | Portion of time where only the participant is speaking (in percents) | Three years | 
| Overlap | Portion of time where both interactants are speaking (in percents) | Three years | 
| Mutual silence | Portion of time where both interactants are silent (in percents) | Three years | 
| Between-Overlap | Turn transition composed of overlapping speech from both interlocutors (in percents) | Three years | 
| Gap | Silent interval between turn transitions (in percents) | Three years | 
| Within-Overlap | Passages of overlapping speech not followed by a change of speaker (in percents) | Three years | 
| Floor Transfer Offset | Measures of gaps (positive values) and overlaps (negative values) in milliseconds | Three years | 
| Interviewer's Speaking Turn Duration | Average duration of interviewer's speaking turns in milliseconds | Three years | 
| Interviewer's Silent Turn Duration | Average duration of interviewer's pauses in milliseconds | Three years | 
| Participant's Speaking Turn Duration | Average duration of the participant's speaking turns in milliseconds | Three years | 
| Participant's Silent Turn Duration | Average duration of the participant's pauses in milliseconds | Three years | 
| Minimal self | Measure on the Multidimensional Assessment of Interoceptive Awareness - Version 2; Min = 0, max =185; Higher score is a better outcome | Three years | 
| Narrative self | Measure on the Tennessee Self Concept Scale - Short Form, Present; Min = 21, max = 105; Higher score is a better outcome | Three years | 
| Visual episodic memory performance | Measure on the Family Pictures from Wechsler Memory Scale-III (standardized score) | Three years | 
| Current emotional state before the task | Measure on the Mood Visual Analogue Scale; Min = 0, max = 100; Higher score is a better outcome | Three years | 
| Embodiment | Measure on the Embodiment Questionnaire; Min = -3, max = 3; Higher score is a better outcome | Three years | 
| Presence | Measure on the Igroup Presence Questionnaire; Min = -42, max = 42; Higher score is a better outcome | Three years | 
| Cybersickness | Measure on the Simulator Sickness Questionnaire; Min = 0, max = 48; Higher score is a worse outcome | Three years | 
| Current emotional state after the task | Measure on the Mood Visual Analogue Scale; Min = 0, max = 100; Higher score is a better outcome | Three years | 
| Recognition task: What 1 | Proportion of hits (number of recognised events divided by total number of events) (in percents) | Three years | 
| Recognition task: What 2 | Proportion of false alarms (number of falsely recognised lures divided by total number of lures) (in percents) | Three years | 
| Recognition task: What 3 | Hit mean reaction time (in seconds) | Three years | 
| Recognition task: What 4 | False alarm mean reaction time (in seconds) | Three years | 
| Recognition task: When | Proportion of correct When answers (number of correct When answers divided by number of hits) (in percents) | Three years | 
| Recognition task: Where | Proportion of correct Where answers (in percents) | Three years | 
| Recognition task: Source | Proportion of correct Source answers (in percents) | Three years | 
| Recognition task: Binding What-When-Where | Mean of (What + When + Where) (in percents) | Three years | 
| Recognition task: Binding What-When-Where-Source | Mean of (What + When + Where + Source) (in percents) | Three years | 
| Recognition task: Referent | Proportion of correct Referent answers (in percents) | Three years | 
| Recognition task: Remember/Know | Mean (a score between 0 and 100) | Three years | 
| Recognition task: Perspective | Mean (a score between 0 and 100) | Three years | 
| Recognition task: Vivacity | Mean (a score between 0 and 100) | Three years | 
| Recognition task: Fidelity | Mean (a score between 0 and 100) | Three years | 
| Recognition task: Emotional intensity | Mean (a score between 0 and 100) | Three years | 
| Recognition task: Strength of associated bodily sensations | Mean (a score between 0 and 100) | Three years | 
| Recognition task: Episodic self-reference | Mean (a score between 0 and 100) | Three years | 
| Recognition task: Semantic self-reference | Mean (a score between 0 and 100) | Three years | 
| Free recall: What | Proportion of recalled events (in percents) | Three years | 
| Free recall: When | Proportion of correct When answers (in percents) | Three years | 
| Free recall: Where | Proportion of correct Where answers (in percents) | Three years | 
| Free recall: Source | Proportion of correct Source answers (in percents) | Three years | 
| Free recall: Binding What-When-Where | Mean of (What + When + Where) (in percents) | Three years | 
| Free recall: Binding What-When-Where-Source | Mean of (What + When + Where + Source) (in percents) | Three years | 
| Free recall: Referent | Proportion of correct Referent answers (in percents) | Three years | 
| Free recall: Objective details | Mean number of objective details | Three years | 
| Free recall: Subjective details | Mean number of subjective details | Three years | 
| Free recall: Remember/Know 1 | Proportion of Remember answers (in percents) | Three years | 
| Free recall: Remember/Know 2 | Proportion of Know answers (in percents) | Three years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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electroencephalography, at risk mental state, ultra high risk, first episode psychosis, schizophrenia, autism spectrum disorder, EEG microstates, polysomnography, sensorimotor integration, prosody, hypnosis