Paper “Central mechanisms of itch: a systematic literature review and meta-analysis”

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Video randomization and mixing

In order to produce ten minutes long videos, clips were mixed together in a pseudo-random manner. None of the clips could be presented twice in the same video. In order to minimize the habituation and expectation the duration of the clips were shortened and chosen randomly between
40 secs and 80 sec. Overall, two kinds of videos were produced, one for the primary experiment which included both control and scratching conditions. And another one mixed for the final experiment including just the scratching action.
The video for primary experiment included both scratching and tapping actions in a manner that none of these two actions happened exactly after each other. In order to gather the information about the scratching, both its severity and location, this video made appear two questions at some Figure 1: Location of the scratching or tapping sites a) Thigh area b) Forearm area c) Neck d)Abdomen area regular time-points onto the clips (each 3 min). The first one was a schema of the human body, with areas of the human body in three different colors (green for the head, yellow for torso and arms, and blue for legs.). A schema was included in the questions, to help subjects identify in which region the itch sensation was induced (Figure 2). This figure was prepared in order to register the information during the MRI session too, hence the four-color configuration. The color
red was reserved for the “no itch” condition.
Another visual question was a visual rating scale for measuring the itch severity, this figure is presented in Figure 3. As the body schema, this figure was adopted for the MRI machine too, therefore the four-color arrangement. Blue for no itch at all, yellow for mild itch, green for moderate itch, and red for worst imaginable itch. A detailed timeline of this video is presented in Figure 4, in it, the itch stimulus was presented in red while the neutral condition was in white. The width of the block represents the duration of the stimulus. Each 3 min one of the schemas (itch location and itch intensity) was presented to the subjects. Table 2 contains the exact location of this stimulus.

Administrative procedure

This stage of the experiment was carried out in the dermatology department of Morvan Hospital of CHRU Brest. All the experiments were done in the same room. This room was calm far away from any possible noise. And finally, all the distracting objects were removed from the room. The temperature of this room was controlled, we tried it to be the same for all the subjects. We also tried to have the same illumination for all the subjects. After small greeting, subjects were sited in front of a monitor, facing the researcher. This insured that they monitor had hidden the researcher’s face and researcher’s face could not distract them. After that subjects were informed about their rights and the goal of the experiments. In order to control for any unwanted nocebo and placebo effects, the examiner read a standardized text for all the participants, this text is presented in the 7.4. After that subjects sign a detailed standardized consent form. The consent form has been already presented and approved by local ethical comity (CPP Ouest 6 – CPP926, IDRCB: 2015-A01900- 49, Jan. 5th, 2016). A version of this form can be found in section 7.5. Subjects were free to withdraw from the experiment at any moment.

Video Watching

In this stage, subjects watched the video. In order to measure itch levels and to be sure that the video is effective, we measure the itch levels using a verbal rating scale (VRS). The researcher explained the VRS to the subjects and asked them about their VRS levels before the start of the video. Then the subjects watched the video. In 5 min mark researcher stopped the video to some moments (normally 10-20 sec) and asked for the VRS levels. At last another VRS was measured after the end of the video.
During the video, subjects were instructed to focus on video normally in the same manner as watching the television. And they were prohibited to speak to the researcher or use any mobile phone. During the video scratching the itch was not permitted in order to prepare the subjects for the MRI machine in which movement should be minimal.


Responding to questionnaires

In the last stage of the first season, subjects responded to three questionnaires. The first one was Edinburgh Oldfield laterality question. For this questionnaire, researchers asked the first three questions and filled the form, then the questionnaire was given to the subjects and they themselves fill the remaining items. Each item had 2 points which were given to left or right based on the laterality of that item in daily life. Assuming the sum of all the right side scores is D and sum of all the scores in the left is G, the final value of this questionnaire calculated by equation 2. If the value of Oldfield value was positive subject consider right-handed, and they would consider lefthanded if Oldfield value was negative. All the Oldfield values close to zero means that the subject is ambiguous. 𝑂𝑙𝑑𝑓𝑖𝑒𝑙𝑑 = 𝐷 − 𝐺 𝐷 + 𝐺 ∗ 100 ( 2 ).
The next questionnaire was the Big Five. For this form subjects were instructed to score all the items from 1 to 5. Then each of five personality traits was calculated by the formulas ( 3 ) to ( 7 ). In these formulas, the denotation Q1 means the scores that subjects have given to question 1, while denotation R1 means the reverse of the subject’s response. (1 replaced with 5 ; and so on for 4:2 ; 3:3 ; 2:4 ; 1:5).

Table of contents :

List of the Abbreviations
Table of figures
Table of tables
1 Introduction
1.1 Itch
1.1.1 Central mechanisms of itch
1.2 Itch induction
1.2.1 Histamine
1.2.2 Non-histaminergic itch
1.2.3 Physically-induced itch
1.2.4 Contagious itch (audio-visual itch)
1.3 Pain
1.4 Scratching
1.5 Itchy diseases
1.6 Imaging techniques
1.6.1 Electroencephalography
1.6.2 Magnetoencephalography
1.6.3 Near-infrared spectroscopy
1.6.4 Positron emission tomography
1.6.5 fMRI
1.7 MRI analysis
1.7.1 Preprocessing
1.7.2 Network-based statistic
1.8 Behavioral and psychological evaluations
1.8.1 Itch severity measurements
1.8.2 Edinburgh Oldfield
1.8.3 Big five
1.8.4 Empathy
2 Material and methods
2.1 Video production
2.1.1 Subjects
2.1.2 Procedure
2.1.3 Video randomization and mixing
2.2 Preliminary experiments
2.2.1 Subjects
2.2.2 Procedure
2.3 Main experiments
2.3.1 Subjects
2.3.2 Inclusion call
2.3.3 First season
2.3.4 MRI season
2.4 Data analysis
2.4.1 Statistical analysis
2.4.2 Prepressing fMRI
2.4.3 NBS connectivity pipeline
2.4.4 CAN-ICA
2.4.5 TBBS Pipeline
2.4.6 VBM pipeline
2.5 Meta-analysis
2.5.1 Screening and eligibility cheek
2.5.2 Inclusion criteria
2.5.3 Meta-analysis
3 Results
3.1 Preliminary experiments results
3.1.1 VAS time profile
3.1.2 Scratching allowed vs not allowed
3.1.3 Number of scratchings vs self-rated itch intensity
3.1.4 Location
3.2 First session (behavioral and VRS)
3.2.1 Behavioral
3.2.2 Verbal rating scores
3.2.3 VRS vs behavioral factors
3.3 NBS results
3.3.1 First 10 min vs Second 10 min
3.3.2 Healthy vs Psoriasis
3.3.3 Healthy vs Urticaria
3.4.1 Healthy
3.4.2 Psoriasis
3.5 TBSS
3.5.1 Healthy vs Psoriasis
3.5.2 Healthy vs Urticaria
3.6 VBM
3.7 Heartbeat
3.8 Meta-analysis
3.8.1 Included studies
3.8.2 Subtraction based studies (itch matrix)
3.8.3 Itch correlation
3.8.4 Reduction
3.8.5 AD
4 Discussion
4.1 Preliminary experiments
4.2 Behavioral and VRS data of the main experiments
4.3 TBSS results
4.4 NBS
4.5 ICA
4.6 VBM
4.7 Hearth beat
4.8 Meta-analysis
4.9 Limitations and Perspectives
5 Conclusions
6 References
7 Appendixes and supplementary material
7.1 Image rights waiver form
7.2 Recruitment posters
7.2.1 Poster 1
7.2.2 Poster 2
7.3 Inclusion form
7.4 Standard text
7.5 Standardized consent
7.6 MRI questionnaire
7.7 Edinburgh Oldfield
7.8 Empathy questionnaire
7.9 Big five questionnaire
7.10 Normality tests results
7.10.1 Normality test of VAS levels for the preliminary experiments
7.10.2 Normality test of behavioral factors
7.10.3 Normality test of VRS of the main experiments
7.10.4 Normality test for the heartbeat
7.11 Complementary graphs
7.11.1 Bar graph of VRS levels
7.12 Results of the other papers
7.13 Automated Anatomical Labeling
8 Publications and papers
8.1 Poster presentation “journée des jeunes chercheurs (UBO)”
8.2 Poster presentation “Journée de l’École Doctorale”
8.3 Poster presentation ESDR
8.3.1 Indexed abstract (Journal of Investigative Dermatology)
8.3.2 Presented Poster
8.4 Conference presentation (JDP)
8.5 Paper “Central mechanisms of itch: a systematic literature review and meta-analysis” …
8.6 Paper “Functional and anatomical brain connectivity in psoriasis patients and healthy controls: A pilot brain imaging study after exposure to mentally-induced itch”
8.7 Paper “Itch processing in the brain” .


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