Primary Outcomes

Description: The GoStop Impulsivity Paradigm measures the ability to inhibit an already initiated response. A number of five digits are presented on a computer screen for 500ms followed by a 500ms blackout. A second number then appears for 500ms followed by a 500ms blackout. If the numbers are identical the mouse button has to be pressed before the second number disappeared. However, the response has to be with-held if a "Stop" signal appeared; that is the second number was identical but changed from black to red. If the two numbers were different then no response was required.

Measure: Go Stop Impulsivity Paradigm

Time: Change from before to after supplementation for three months

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Description: This is test of the tendency to respond in an aggressive manner. A series of cartoons are presented that present an intentionally frustrating situation. The participant reports what he or she would say in that situation. Blind the responses are assessed in terms of the extent to which the responses are aggressive in matter Note that the use of two primary outcomes reflects the aim of the study to contrast performance and questionnaire measures

Measure: Rosenzweig Picture Frustration Test

Time: Change from before to after supplementation for three months

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Secondary Outcomes

Description: The Buss-Perry Aggression Questionnaire assesses four aspects of aggressive behavior: physical aggression, verbal aggression, anger and hostility. Participants rank statements about their temperament using a 7-point Likert scale ranging from 1 (extremely uncharacteristic of me) to 7 (extremely characteristic of me).

Measure: Buss Perry Aggression Scale

Time: Change from before to after supplementation for three months

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Description: The Perceived Stress Scale assesses the extent to which stressful thoughts and feeling had been experienced during the last month. For example: "In the last month, how often have you been upset because of something that happened unexpectedly?" The participant responded on a scale ranging from 0 = Never to 4 = Very Often. An overall score is calculated.

Measure: Perceived Stress Scale

Time: Change from before to after supplementation for three months

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Description: A measure of the subjects ability to forgo initial reward for a later larger reward. The subject can choose to wait for a reward and get more points or alternatively respond more quickly and get fewer points sooner. The longer a subject waits the higher the reward; that the more points are earned. A mouse click began the task and a second resulted in a reward. Two counters display the most recent and cumulative reward over a 20 minute session. Subject are able to infer that responses at a faster rate earn smaller rewards.

Measure: Single Key Impulsivity Paradigm

Time: Change from before to after supplementation for three months

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Description: Polymorphisms associated with the metabolism and receptors of dopamine and serotonin will be related to the response to micro-nutrient supplementation

Measure: General Health Questionnaire

Time: Further analysis of existing data - considers changes from baseline to three months

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Primary Outcomes

Description: Each structural MRI session has ca. 27-30 min of scan time. Investigation of long-lasting changes in cortical and sub-cortical networks after training. How do psychological traits and certain brain structures predict individual differences in training effects.

Measure: Changes in several structural MRI measures (MRI-based cortical thickness, mprage; T1-mapping, mp2rage; automatic amygdala volumetry; tensor-based morphometry, Diffusion Tensor Imaging; Flair)

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: The measure is part of the MRI session and lasts for ca. 15-25 min. Goal is the Investigation of dynamic changes of functional MRI signals during affective and cognitive tasks in order to test the correlation of functional and structural network changes after training. How do psychological traits and certain brain structures predict individual differences in training effects. All cohorts: after T0 only "Generation" part of paradigm. TC1, TC2 and RCC1: not assessed at T1.

Measure: Changes in functional magnetic resonance imaging (fMRI) measure: Regulation and Generation of Emotions (RAGE)

Time: TC1, TC2, RCC1: Changes from T0 to T2 (T0 + 26 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months);

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Description: The measure is part of the MRI session and lasts for ca. 7 min. Goal is the Investigation of dynamic changes of functional MRI signals during resting state in order to test the correlation of functional and structural network changes after training. How do psychological traits and certain brain structures predict individual differences in training effects.

Measure: Changes in functional magnetic resonance imaging (fMRI) measure: Resting State measurement

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: The measure is part of the MRI session and lasts ca. 15 min. Goal is the Investigation of dynamic changes of functional MRI signals during affective tasks in order to test the correlation of functional and structural network changes after training. How do psychological traits and certain brain structures predict individual differences in training effects.

Measure: Changes in functional magnetic resonance imaging (fMRI) measure: Emotional Anticipation (EmoAnt)

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: The measure is part of the session and lasts ca. 20 min. Goal is the Investigation of dynamic changes of functional MRI signals during a pain perception task in order to test the correlation of functional and structural network changes after training. How do psychological traits and certain brain structures predict individual differences in training effects.

Measure: Changes in functional magnetic resonance imaging (fMRI) measure: Modulation of pain perception

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: The measure is part of the MRI session and lasts 15 min. Goal is the Investigation of dynamic changes of functional MRI signals during an attention and orienting task in order to test the correlation of functional and structural network changes after training. How do psychological traits and certain brain structures predict individual differences in training effects.

Measure: Changes in functional magnetic resonance imaging (fMRI) measure: Cued flanker task (CueFla), an attention and orienting task

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: The measure is part of the MRI session and lasts ca. 35-40 min. Goal is the Investigation of dynamic changes of functional MRI signals during a theory of mind and social cognition task in order to test the correlation of functional and structural network changes after training. How do psychological traits and certain brain structures predict individual differences in training effects.

Measure: Changes in functional magnetic resonance imaging (fMRI) measure: a Theory of Mind and Social Cognition task (the EmpaToM)

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: ] Examination of the diurnal cortisol profile (awakening, day timeline): on two weekdays, subjects collect saliva samples during the day (7 timepoints, each ca. 3 min). This will be coordinated with the experience sampling via the smartphones.

Measure: Changes in stress physiology: "diurnal cortisol profile"

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: People sit quietly and no specific task given. We will use "Biopac MP150 Bionomadix" for measurement of autonomic activity (inferred from heart rate variability) by measuring a 3-point ECG in the chest area, as well as electrodermal activity (on the fingertips of the left index and middle finger), and breathing.

Measure: Changes in autonomic nervous system functions: Physiological Resting Baseline (electrocardiogram (ECG), electrodermal activity (EDA), and breathing)

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Part of the Virtual Reality Session (ca. 40 min): In a virtual world, we will look at attention and change detection in an unknown environment with emotional stimuli. It will happen on the same day as the MRI measurements and will be measured by counting the amount of changes of the virtual environment that could be detected. Behavioral measures will be combined with physiological data assessment during the test.

Measure: Changes in a Virtual Reality Setting: The Panopticon --> attention and change detection

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Part of the Virtual Reality Session (ca. 40 min): In a virtual world, we will look at changes in social distance. It will happen on the same day as the MRT measurements and will be measured by detecting the preferred proximity to avatars within the virtual worlds. Behavioral measures will be combined with physiological data assessment during the test.

Measure: Changes in a Virtual Reality Setting: The Crowded Room --> changes in social distance to avatars

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Part of the Virtual Reality Session (ca. 40 min): In a virtual world, we will look at changes in approach and avoidance behavior in terms of affective preferences of available affective stimuli. It will happen on the same day as the MRT measurements and will be measured by detecting the amount of exploratory behavior (approaching, examining objects with neutral or emotional content). Behavioral measures will be combined with physiological data assessment during the test.

Measure: Changes in a Virtual Reality Setting: The Affect Gallery --> changes in affective preferences

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Part of the Virtual Reality Session (ca. 40 min): In a virtual world, we will look at changes in acute stress reactions to aversive affective stimuli (e.g., ground shaking, bugs, sudden loud noise, angry avatars). It will happen on the same day as the MRT measurements. Behavioral measures will be combined with physiological data assessment during the test.

Measure: Changes in a Virtual Reality Setting: Room 101 --> acute stress reactions

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: In this task, two stimuli are presented consecutively (e.g., a pattern with horizontal lines). The two stimuli differ slightly and the participants are asked to identify the differences (e.g., length or direction of the lines). The difference between the two stimuli gradually decreases with each round. The point, at which the participants cannot distinguish between the two stimuli is called the perceptional sensitivity. After each round, the participants are asked to assess their level of certainty regarding their answers. All computer tasks are divided into 6 blocks and participants completed one block per week (1 hour each).

Measure: Computer-based experiment: Changes in the Inhibition and Alerting task (Stop-Signal-Reaction Time task).

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: The participants are presented with 4, 6 or 8 letters, which they have to remember over a short period of time (about 2 seconds). Then they are presented with another letter and are asked to state whether or not that letter was part of the set of letters presented beforehand. After each round, the participants are asked to assess their level of certainty regarding their answers. All computer tasks are divided into 6 blocks and participants completed one block per week (1 hour each).

Measure: Computer-based experiment: Changes in Working Memory Performance

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: The cognitive and affective flexibility is measured in this task. Participants are asked to complete comparable cognitive and affective task-switching tasks respectively. We use a task-cueing paradigm in which participants have to judge different stimuli. These stimuli are cognitive or affective in nature. The dependent variable is reaction time and accuracy in so-called "shift" or "no-shift" rounds, i.e. rounds which either have the same task as the round before ("no-shift") or rounds, which consist of a new task ("shift"). All computer tasks are divided into 6 blocks and participants completed one block per week (1 hour each).

Measure: Computer-based experiment: Changes in the Task Emotional Switching Paradigm

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Participants are asked to judge the similarity of a number of adjectives which describe emotional states. Using network analysis and multi-dimensional scaling, the data regarding the proximity of the adjectives are transformed in a depiction of the emotional-concept networks of the participant. All computer tasks are divided into 6 blocks and participants completed one block per week (1 hour each).

Measure: Computer-based experiment: Changes in the Emotional Granularity task

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Participants watch a number of short clips (max. 15 sec) of news programs or documentaries. These clips have either neutral or have emotional (negative) content. After watching a clip participants report on their emotional state and on how much compassion they feel. Additionally, we will use physiological data assessment of the following parameters during the task: respiration frequency (belt in the chest / abdominal area) heart rate (3-point ECG in the chest area) EDA

Measure: Changes in autonomic nervous system functions and computer experiment: Changes in the Socio-affective Video Task (SoVT)

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: In this computer-based task, participants see a person standing in a room, in which oval-shaped objects can be seen on the walls. The participants are asked to report on how many of these objects can be seen from their own perspective and how many objects the person in the room is able to see. All computer tasks are divided into 6 blocks and participants completed one block per week (1 hour each).

Measure: Computer-based experiment: Changes in the "Visual Spatial Perspective Taking Task" by Samson

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: In this task, a number of visual stimuli are presented consecutively for short periods of time (about 100ms). The relevant stimuli are embedded in a number of distractor-stimuli. The participants are asked to report on the number of perceived relevant stimuli. They are also supposed to identify them. All computer tasks are divided into 6 blocks and participants completed one block per week (1 hour each).

Measure: Computer-based experiment: Changes in the "Emotional Attentional Blink" paradigm

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: In this computer-based game, participants have to find their way through a labyrinth and solve little tasks on their way. They are under the impression, that there is another participant playing with them. The participant's readiness to share resources, necessary to complete the game, is measured. All computer tasks are divided into 6 blocks and participants completed one block per week (1 hour each).

Measure: Computer-based experiment: Changes in the "Trust Game"

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: There are two parts to this game: 2nd person punishing and 3rd person punishing. In the 2nd person punishing game, there are two players. One Player (player A) has a larger amount of money at her disposal, than the other player (player B). The player with the larger amount of money can decide how she wants to split the money between herself and the other player. Then player B can decide whether he wants to punish player A by taking money from player A while using his own money (for each unit of money she spends three three units are taken from the other player). After two rounds, the tasks of the players are reversed. In the 3rd person punishing game, the participants watch the interaction of anonymous players A and B. After each round, the participant can decide whether or not to punish the player, who split the money. All computer tasks are divided into 6 blocks and participants completed one block per week (1 hour each).

Measure: Computer-based experiment: Changes in the "Punishing Game"

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: In this game, participants can decide how they split a set amount of money between themselves and an anonymous player. All computer tasks are divided into 6 blocks and participants completed one block per week (1 hour each).

Measure: Computer-based experiment: Changes in the "Dictator Game"

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: In a first step, participants are asked to cluster 30 positive or negative personality traits around their depicted self in such a way, that the spatial closeness or distance reflects, how much they identify with the trait. In a second step, they are asked to choose selected items and pile them. The height of the stack then is thought to reflect the complexity of the self. All computer tasks are divided into 6 blocks and participants completed one block per week (1 hour each).

Measure: Computer-based experiment: Changes in the "Self-complexity Task"

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: In the first part of this task, participants are asked to judge adjectives regarding a) whether they apply to themselves, b) whether they apply to a famous person (e.g., Angela Merkel), or c) whether they meet linguistic criteria (e.g., whether they are written in capital letters). In the second part, participants are asked to identify the adjectives, which had been presented in the first part. All computer tasks are divided into 6 blocks and participants completed one block per week (1 hour each).

Measure: Computer-based experiment: "Self-reference Task"

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Aim of this measure is to access the amount and content of spontaneously generated cognition. Main focus is "day dreaming" or "mind wandering" that occurs, when our minds drift off, while working on a task. In this measure, subjects are asked to work on two little, rather boring PC-based exercises (1. choice reaction time task (CRT); 2. working memory (WM) task). During selective queries, they are then asked for the content and valence of their thoughts ("thought probe"). All computer tasks are divided into 6 blocks and participants completed one block per week (1 hour each).

Measure: Computer-based experiment: Changes in the "Mind-wandering task"

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: This economic game assesses the participant's willingness to donate to selected charity groups. In this game, they receive a certain amount of money and can decide, if and how much they would like to contribute. All computer tasks are divided into 6 blocks and participants completed one block per week (1 hour each).

Measure: Computer-based experiment: Changes in "Donation Task"; willingness to make donations in the economic computer experiment.

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Participants divide money between themselves and close friends, strangers, or enemies. All computer tasks are divided into 6 blocks and participants completed one block per week (1 hour each).

Measure: Computer-based experiment: "Social Discounting" Task

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Subjects are asked to silently count their heart beats in five intervals [15, 25, 35, 45, 55], presented in a random order, and note the counted number.

Measure: Changes in interoception: Heart Beat Perception Task

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Local Power (LP), as short term estimate of high frequency heart rate variability is reported to the subjects. They observe a ball on a computer screen, which ascends in accordance with their LP. Goal is to make the ball rise. We will use the "Biopac MP150 Bionomadix" for measurement of respiration frequency (belt in the chest / abdominal area) as well as ECG and electrodermal activity.

Measure: Changes in autonomic nervous system functions: Local Power Biofeedback and Heart Rate Biofeedback

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: TSST: a standardized stress test, that induces stress in the laboratory. Here, cortisol and alpha-amylase are analyzed from saliva (Department of Biological and Clinical Psychology, Trier University), oxytocin (Max-Planck-Institute for Psychiatry, Munich) as well as the inflammatory markers Interleukin-6 (IL-6), brain-derived neurotrophic factor (BDNF) and C-reactive protein (CRP) are analysed from blood (Aghia Sophia Children's Hospital, Department of Clinical Biochemistry) and heart rate and heart rate variability (HRV) are assessed as adjunct measurement. Stress-related questionnaires will be filled out during the TSST as well.

Measure: Stress Physiology: "Trier Social Stress Test" (TSST)

Time: Because it includes elements of deception, the TSST is only done once: Participants will either do the TSST at T0, T1, or T2

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Description: Heart rate, body movement,respiratory frequency and heart rate variability are being measured during two meditation sessions in each training block (week 3 and 13). We use the non-invasive "Zephyr BioHarness 3 multi-sensor-device", which comes with a chest belt. After the meditation session, subjects are asked to answer a 5-item questionnaire.

Measure: Changes in autonomic nervous system functions: "Physiological Signature of Meditation states"

Time: Only in TC1, TC2, TC3: Changes from T1, to T2, to T3; week 3 and 13 of each module.

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Description: During each measurement time point, blood samples will be collected from each subject and stored at -80 degrees Celsius. The aim is to test if the training leads to reduced shortening of the telomeres, the probes are sent to the Blackburn lab of UCLA in San Francisco, USA. Additionally, a complete blood count is drawn. Not aiming in diagnostic directions, the goal is to assess the status of neutrophils, lymphocytes, and monocytes in the probes. These are thought to be general markers of immune activity and are inspected in relation to telomere length. Blood counts will be assessed by a lab in Leipzig, Germany.

Measure: Changes telomere length (+ number of neutrophils, lymphocytes, and monocytes)

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Once during the training for each subject, before and directly after a 2h "Perspective" or "Affect" training session, a blood sample will be drawn and stored at -80 degrees celsius. To analyze blood levels of oxytocin, probes are sent to the Max-Planck-Institut für Psychiatrie, Munich, Germany (Department of Prof. Rainer Landgraf). The same procedure was done pre and post the TSST session.

Measure: Training induced short-term changes in oxytocin blood level (pre/post Meditation)

Time: Changes pre/post a "Perspective" or "Affect" training session during T1, T2, or T3; Week 12 of Training (i.e. for arm one: between 11/21/13 - 12/23/13 or 3/3/14 - 4/5/14; for arm two: between 1/20/14 - 2/20/14 or 5/2/14 - 5/24/14). Pre/Post TSST

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Description: 10 ml blood samples will be drawn. Plasma levels of interleukin-6, brain-derived neurotrophic factor (BDNF), C-reactive protein (CRP) will be assessed. They are sent to the "First Dept of Pediatrics, Director, Division of Endocrinology, Metabolism and Diabetes, University of Athens Medical School, Aghia Sophia Children's Hospital, Athens, Greece" for analysis.

Measure: Changes in amount of plasma levels (blood samples) of interleukin-6, brain-derived neurotrophic factor, C-reactive protein.

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months); Pre/Post TSST

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Description: All cohorts: • weekly questions via online platform, concerning: actual affective condition, actual activity, actual thoughts, social closeness, quality of sleep (administered once a week via short questions online, duration 2-4 min.). TC1, TC2, TC3: • questions via online platform before and after all core training exercise participants perform at home; duration is ca. 2-4 min, concerning: actual effects and experiences after daily mental training practice. All cohorts: • experience- sampling via smartphones, concerning: valance and arousal of current emotional state using "single item affect grid" method. Current activity and situation. Current thoughts. Amount of significant or stressful events since last sampling and how positive or negative or stressful was this event. How did you cope with this event. (7-10 times for 2 consecutive days for each cohort at T0-T4).

Measure: Changes in "subjective experience sampling by smartphones or by means of an internet platform"

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Secondary Outcomes

Description: above: w=weeks, m=months. Administration of the questionnaire via an online platform. It assesses effortful control, extraversion, frustration, inhibitory control, negative affect, sadness, sociability, etc. TC1 and TC2 participants will not fill out the questionnaire at time point T2.

Measure: Questionnaire: Changes in "Adult temperament questionnaire (ATQ)"

Time: TC1, TC2: Changes from T0 to T1 (T0 + 13 w), to T3 (T2 + 13 w), to T4 (T3 + 4.5 or 10 m). RCC1, RCC2: from T0 to T1 (T0 + 13 w), to T2 (T1 + 13 w), to T3 (T2 + 13 w), to T4 (T3 + 4.5 or 10 m). TC3: from T0 to T1 (T0 + 13 w), to T2 (T1 + 4.5 or 10 m).

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Description: Administration of the German questionnaire via an online platform. It assesses symptoms of attentional deficits, attention deficit hyperactivity disorder (ADHD), hyperactivity.

Measure: Questionnaire: Change in "ADHS-Selbstbeurteilungsfragebogen (ADHS-SB)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses non-judgmental acceptance of experience, awareness of experience, and mindfulness.

Measure: Questionnaire: Change in "FFA Freiburger Fragebogen zur Achtsamkeit".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses awareness, describing, non-judging of experiences, non-reactivity, observing, mindfulness. This questionnaire is also filled out by the observers of participants.

Measure: Questionnaire: Change in questionnaire "Five Facets Mindfulness Questionnaire (FFMQ)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses different facets of interoceptive awareness.

Measure: Questionnaire: Change in "Multidimensional Assessment of Interoceptive Awareness (MAIA)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses self-compassion, self-kindness, self-judgment, over-identification, mindfulness, isolation, and common humanity.

Measure: Questionnaire: Change in "Self-Compassion Scale" by Kristin Neff (SCS).

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses serenity, i.e. low arousal positive affect. TC1 and TC2 participants will not fill out the questionnaire at time point T2 and T3.

Measure: Questionnaire: Change in "The Short Affect intensity scale (only serenity subscale) (SAIS)".

Time: TC1, TC2: Changes from T0 to T1 (T0 + 13 w), to T4 (T3 + 4.5 or 10 m). RCC1, RCC2: from T0 to T1 (T0 + 13 w), to T2 (T1 + 13 w), to T3 (T2 + 13 w), to T4 (T3 + 4.5 or 10 m). TC3: from T0 to T1 (T0 + 13 w), to T2 (T1 + 4.5 or 10 m). w=weeks; m=months

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Description: Administration of the questionnaire via an online platform. It assesses compassion for others, common humanity, disengagement, indifference towards others, kindness towards others, mindfulness, separation.

Measure: Questionnaire: Change in "Compassion scale - How I typically act towards others (COSN)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses empathic concern, empathic distress and ability to take other's perspective. This questionnaire is also filled out by observers of the participants.

Measure: Questionnaire Participants and Observer: Change in "Interpersonal Reactivity Index (IRI)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses active, reactive and safe/warm positive affect.

Measure: Questionnaire: Change in "Types of Positive Affect (TTPAS)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses fear of compassion from others or for self.

Measure: Questionnaire: Change in "Fears of Compassion Scales (FOCS)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: above: w=weeks, m=months Administration of the questionnaire via an online platform. It assesses impulsivity, affective instability, relationships, abandonment, quasi-psychotic states, self image, emptiness, anger, suicide, borderline personality traits. TC1 and TC2 participants will not fill out the questionnaire at time point T2.

Measure: Questionnaire: Change in "Borderline Personality Questionnaire (BPQ)".

Time: TC1, TC2: Changes from T0 to T1 (T0 + 13 w), to T3 (T2 + 13 w), to T4 (T3 + 4.5 or 10 m). RCC1, RCC2: from T0 to T1 (T0 + 13 w), to T2 (T1 + 13 w), to T3 (T2 + 13 w), to T4 (T3 + 4.5 or 10 m). TC3: from T0 to T1 (T0 + 13 w), to T2 (T1 + 4.5 or 10 m).

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Description: above: w=weeks, m=months Administration of the questionnaire via an online platform. It assesses narcissism, exhibitionism, entitlement, authority, superiority, exploitativeness, self-sufficiency, vanity. TC1 and TC2 participants will not fill out the questionnaire at time point T2.

Measure: Questionnaire: Change in "Narcissistic Personality Inventory (NPI)".

Time: TC1, TC2: Changes from T0 to T1 (T0 + 13 w), to T3 (T2 + 13 w), to T4 (T3 + 4.5 or 10 m). RCC1, RCC2: from T0 to T1 (T0 + 13 w), to T2 (T1 + 13 w), to T3 (T2 + 13 w), to T4 (T3 + 4.5 or 10 m). TC3: from T0 to T1 (T0 + 13 w), to T2 (T1 + 4.5 or 10 m).

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Description: Administration of the questionnaire via an online platform. It assesses regulation via catastrophizing, positive refocusing, or blaming others strategy (self-blame, acceptance, rumination, positive refocus, planning refocus, planning refocus, positive reappraisal, perspective, catastrophizing, other blame)

Measure: Questionnaire: Change in "Cognitive Emotion Regulation Questionnaire (CERQ)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: above: w=weeks, m=months, T2 (T1+ 13 weeks), T3 (T2 + 13 weeks) Administration of the questionnaire via an online platform. It assesses several coping strategies. TC1 and TC2 participants will fill out a shorter version at time point T2 and T3. This questionnaires is also filled out by observers of participants.

Measure: Questionnaire Participants and Observers: Change in "Brief COPE" inventory.

Time: TC1, TC2: Changes from T0 to T1 (T0 + 13 w) and at T4 (T3 + 4.5 or 10 m). Short version at T2 and T3; RCC1, RCC2: from T0 to T1 (T0 + 13 w), to T2, to T3, to T4 (T3 + 4.5 or 10 m). TC3: from T0 to T1 (T0 + 13 w), to T2 (T1 + 4.5 o

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Description: Administration of the questionnaire via an online platform. It assesses expressivity of negative and positive emotions, and strength of expression impulse. TC1 and TC2 participants will not fill out the questionnaire at time point T2 and T3.

Measure: Questionnaire: Change in "Berkeley Expressivity Questionnaire (BEQ)".

Time: TC1, TC2: Changes from T0 to T1 (T0 + 13 w), to T4 (T3 + 4.5 or 10 m). RCC1, RCC2: from T0 to T1 (T0 + 13 w), to T2 (T1 + 13 w), to T3 (T2 + 13 w), to T4 (T3 + 4.5 or 10 m). TC3: from T0 to T1 (T0 + 13 w), to T2 (T1 + 4.5 or 10 m). w=weeks; m=months

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Description: Administration of the questionnaire via an online platform. It assesses range of experience emotions, and differentiation of experienced emotions.

Measure: Questionnaire: Change in "Range and Differentiation of Emotion Scale (RDEES)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses tendency to choose decisions that maximize other's output.

Measure: Questionnaire: Change in "An Instrument to Measure Social Value Orientation (SVO) " by van Lange et al.

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses internally focussed emotion regulation of positive and negative affect. TC1 and TC2 participants will not fill out the questionnaire at time point T2 and T3.

Measure: Questionnaire: Change in "Emotion Regulation of Others and Self (EROS)".

Time: TC1, TC2: Changes from T0 to T1 (T0 + 13 w), to T4 (T3 + 4.5 or 10 m). RCC1, RCC2: from T0 to T1 (T0 + 13 w), to T2 (T1 + 13 w), to T3 (T2 + 13 w), to T4 (T3 + 4.5 or 10 m). TC3: from T0 to T1 (T0 + 13 w), to T2 (T1 + 4.5 or 10 m). w=weeks; m=months

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Description: Administration of the questionnaire via an online platform. It assesses compassionate and self-image goals.

Measure: Questionnaire: Change in "Friendship, Compassionate and Self-Image Goals Scale".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses the degree to which people's self-concepts center on moral traits.

Measure: Questionnaire: Change in "Self Importance of Moral Identity Scale".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses global awareness and understanding of others and attempts and endeavours to understand the perspective ot others.

Measure: Questionnaire: Change in "Self Dyadic Perspective-Taking Scale and Other Dyadic Perspective Taking Scale (SDPT /ODPT )".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses the tendency to perceive oneself as interdependent with others or as an independent person.

Measure: Questionnaire: Change in "Self Construal Scale".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses the tendency to behave in a prosocial way (help and support others). This questionnaire is also filled out by observers of participants.

Measure: Questionnaire Participants and Observers: Change in "Prosocialness Scale" by Capara.

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses self reported self attitudes using an open-ended response format beginning with: "Who am I...".

Measure: Questionnaire: Change in "Twenty Statement Test (TST)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses tendency to value own advantage over moral principles.

Measure: Questionnaire: Change in "The Machiavellianism Scale".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses personality traits such as neuroticism, extraversion, openness, agreeableness, conscientiousness, aesthetic interests, negative affect, sociability, etc.

Measure: Questionnaire: Change in "NEO Fünf Faktoren Inventar (NEO FFI)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses rumination, magnification and helplessness regarding pain.

Measure: Questionnaire: Change in "Pain Catastrophizing Questionnaire (PCS)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses uncertainty intolerance, paralysis by uncertainty, negative affect by uncertainty and increased vigilance by uncertainty.

Measure: Questionnaire: Change in "Unsicherheitstoleranz-Skala (Uncertainty Intolerance, UI-18)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses work dissatisfaction, excessive demands at work, lack of social recognition, social isolation, chronic concern, chronic stress, and social tensions etc.

Measure: Questionnaire: Change in "Trier Inventory for Chronic Stress (TICS)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses the degree to which situations in one's life are appraised as stressful.

Measure: Questionnaire: Change in "Perceived Stress Scale (PSS-10)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses paternal and maternal care and overprotection.

Measure: Questionnaire: Change in "Parental Bonding Inventory (PBI)".

Time: TC1, TC2, RCC1, RCC2, TC3: T0 only

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Description: Administration of the German questionnaire via an online platform. It assesses general well-being, tiredness, emotional reactivity, sensory problems, gastrointestinal problems, nose/throat irritation, tension, pain, and cardiovascular problems.

Measure: Questionnaire: Change in "Freiburger Beschwerdeliste (FBL)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses sleep habits and sleep quality.

Measure: Questionnaire: Change in "Pittsburgh Sleep Inventory (PSQI)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses hope for success and control, fear of rejection and failure or losing control, and hope for affiliation.

Measure: Questionnaire: Change in "Multi Motive Grid (MMG)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses overall psychological well-being, emotional and social well-being, etc.

Measure: Questionnaire: Change in "Mental Health Continuum short form (MHC-SF)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses satisfaction with one's life. This questionnaire is also filled out by observers of participants.

Measure: Questionnaire Participants and Observers: Change in "Satisfaction with Life Scale (SWLS)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses severity of depression, affective and somatic symptoms of depression.

Measure: Questionnaire: Change in "Becks Depression Inventory (BDI-2)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses ego-resiliency.

Measure: Questionnaire: Change in "Ego Resiliency Scale (ER-89)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses anxiety and avoidance. TC1 and TC2 will not fill out this questionnaire at time point T2 and T3.

Measure: Questionnaire: Change in "Experiences in Close Relationships - revised (ECR-RD)".

Time: TC1, TC2: Changes from T0 to T1 (T0 + 13 w), to T4 (T3 + 4.5 or 10 m). RCC1, RCC2: from T0 to T1 (T0 + 13 w), to T2 (T1 + 13 w), to T3 (T2 + 13 w), to T4 (T3 + 4.5 or 10 m). TC3: from T0 to T1 (T0 + 13 w), to T2 (T1 + 4.5 or 10 m). w=weeks; m=months

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Description: Administration of the questionnaire via an online platform. It assesses lonliness.

Measure: Questionnaire: Change in "UCLA Lonliness Scale".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses positive and negative affect in the last weeks.

Measure: Questionnaire: Change in "Positive Affect Negative Affect Schedule (PANAS)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses positive and negative emotions. This questionnaire was assessed on a weekly basis.

Measure: Questionnaire: Change in "modified Differential Emotions Scale (mDES)".

Time: Weekly; TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses difficulties in identifying and describing emotions, as well as an externally oriented thinking style.

Measure: Questionnaire: Change in "Toronto Alexithymia Scale (TAS-20)"

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of a paper & pencil version of the POMS mood scale, for each subject on that day, when they do the TSST stress test. It assesses mood states.

Measure: Questionnaire: Change in "Profile of Mood States - 2nd Edition (POMS-2)".

Time: Only once per participant during the TSST

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Description: Administration of a paper & pencil version, for each subject on that day, when they do the TSST stress test. It assesses state anxiety.

Measure: Questionnaire: Change in "STAI -X1 State, State Trait Anxiety Inventory".

Time: Only once per participant during the TSST

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Description: Administration of a paper & pencil version of a measure for the visualisation of body sensations following Fox et al. (2012). The measure will be administered at the start and the end of the first training block, the "presence block". The start of the presence block for arm one will be: Aug. 19th 2013 till Sept. 19th 2013. The start of the presence block for arm two will be: Okt. 7th 2013 till Okt. 30th 2013.

Measure: Questionnaire: Change in "Subjective Sensory Sensitivity questionnaire" following Fox et al. (2012)".

Time: Changes during the Presence Module (beginning and end of Module).

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Description: above: w=weeks, m=months; Administration of the questionnaire via an online platform. It assesses the noticing of body sensations. TC1 and TC2 will not fill out this questionnaire at time point T2

Measure: Questionnaire: Change in "Private Body Consciousness subscale of the Body Consciousness Questionnaire (PBCS)".

Time: TC1, TC2: Changes from T0 to T1 (T0 + 13 w), to T3 (T2 + 13 w), to T4 (T3 + 4.5 or 10 m). RCC1, RCC2: from T0 to T1 (T0 + 13 w), to T2 (T1 + 13 w), to T3 (T2 + 13 w), to T4 (T3 + 4.5 or 10 m). TC3: from T0 to T1 (T0 + 13 w), to T2 (T1 + 4.5 or 10 m).

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Description: Administration of questionnaire via online platform. The scale is answered by observers of participants only. It assesses responsiveness to partner's disclosure of positive events.

Measure: Questionnaire - Observer only: Change in "Perceived Responsiveness Scale (12 items)" filled out by observers.

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months)

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Description: Administration of questionnaire via online platform. The scale is answered by observers of participants only. It assesses positive reactions of partner by several subscales.

Measure: Questionnaire - Observer only: Change in "Capitalization" by Gable et al., 2004 filled out by observers

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months)

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Description: Administration of questionnaire via online platform. The scale is answered by observers of participants only. It assesses degrees to which respondent agrees with partner, do activities together, or satisfaction with partner.

Measure: Questionnaire - Observer only: Change in "Dyadic Adjustment Scale (DAS)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months)

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Description: Administration of questionnaire via online platform. The scale is answered by observers of participants only. It assesses personality traits such as emotional stability, openness, conscientiousness, agreeableness, extraversion. This questionnaire has also been used for matching the cohorts into their respective groups.

Measure: Questionnaire - Observer: Change in "Ten Item Personality Scale (TIPI-10)"

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months)

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Description: Administration of questionnaire via online platform. The scale is answered by observers of participants only. It assesses the feelings of closeness to others

Measure: Questionnaire - Observer only: Change in "Inclusion of Other in the Self Scale (IOS)"

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months)

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Description: During each measurement time point, the subjects are asked for small hair samples from the back of their head. It will be sent to a cooperating lab in Dresden to assess long-term stress by analyzing the the amount of cortisol in hair samples.

Measure: Stress physiology: Changes in "Long-term cortisol levels from hair samples"

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Analyze the connection between gene variants, personality traits, training effects, behavior, brain activation. Arginine-vasopressin-receptor gene; microsat. Polym., RS1 and RS3 oxytocin-receptor gene; rs53576 catechol-O-methyltransferase gene, rs4680 serotonin-transporter 5HTTPLR gene (SCL6A4, S/L Allele and rs25531) monoamine-oxidase A gene (rs6323) mu-opioid-receptor gene (rs6323) neuropeptide Y (NPY); rs5573, rs5574, rs16139, rs16147 tryptophan hydroxylase-2 gene (rs4570625) Gene for a-subunit of L-type calcium channel Cav1.2; CACNA1C gene (rs1006737) Gene for a-subunit of nico. acetylch. receptor channel, CHRNA4 gene (rs1044396) Deletion mutation of a-2-beta adrenoreceptor gene Cannabinoid-receptor 1 gene (CNR1); rs6454674, rs806380, rs806377, rs1049353 Dopamine D4 Receptor gene (DRD4); rs1800955, VNTR Exon 3 repeat allele Dicarboxylate/amino acid cation sodium transporter (DAT1); rs27072, VNTR repeat allele

Measure: Assessment of gene variants / polymorphisms

Time: Blood samples are taken once during T0

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Description: Administration of the questionnaire via an online platform. It assesses affiliation tendency and rejection sensitivity.

Measure: Questionnaire: Change in "Affiliation Tendency and Rejection Sensitivity Scales"

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses self-reported fidgeting and mind-wandering behavior.

Measure: Questionnaire: Change in "Spontaneous Activity Questionnaire (SAQ)"

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses self-reported deliberate and spontaneous mind wandering behavior.

Measure: Questionnaire: Change in "Spontaneous and Deliberate Mind Wandering Scales (MDD, MDS)"

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses subscales of personality traits such as warmth, gregariousness, assertiveness, activity, seeking excitement, positive emotions, and extraversion.

Measure: Questionnaire: Change in "Subscales from the NEO Persönlichkeitsinventar nach Costa and McCrae - revised version (NEO-PI-R)"

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses the tendency to respond in a socially desirable way.

Measure: Questionnaire: Change in "Soziale Erwünschtheits-Skala-17 (SES-17)"

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Description: Administration of the questionnaire via an online platform. It assesses trait anxiety. It was used of screening possible participants for the study.

Measure: Questionnaire: Change in "State-Trait Anxiety Inventory (STAI-X2; STAI-Trait)".

Time: TC1, TC2, RCC1, RCC2: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 13 weeks), to T3 (T2 + 13 weeks), to T4 (T3 + 4.5 months or 10 months). TC3: Changes from T0 to T1 (T0 + 13 weeks), to T2 (T1 + 4.5 months or 10 months)

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Other Outcomes

Description: German Paper/Pencil questionnaire that assesses psychopathological occurences in family members.

Measure: Questionnaire: "Psychopathologie der Familie / Psychopathology in family members".

Time: Only once per participants at time point T0

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Description: The d2 Test is a timed test of selective attention/concentration. In response to the discrimination of similar visual stimuli, the test measures processing speed, rule compliance, and quality of performance, allowing estimation of individual attention and concentration performance. It was used of matching participants into cohorts.

Measure: Questionnaire - Matching: Score of "Test d2 - Revision (d2R)" attention task.

Time: 2 months before T0 and during initial proband screening phase of the project, each subject takes the d2 test in paper & pencil version..

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Description: The TIPI is designed to assess the constellation of traits defined by the Five Factor Theory of Personality. It was used of matching participants into cohorts.

Measure: Questionnaire - Matching: Score of "Ten Item Personality Inventory (TIPI-10)" personality test.

Time: 2 months before T0 and during initial proband screening phase of the project, each subject fills out this questionnaire at the online recruiting webpage via secure connection.

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Description: Administration of the questionnaire via an online platform. It assesses overall psychological well-being, emotional and social well-being, etc. It was used of matching participants into cohorts.

Measure: Questionnaire - Matching: Score of "Mental Health Continuum short form (MHC-SF)".

Time: 2 months before T0 and during initial proband screening phase of the project, each subject fills out this questionnaire at the online recruiting webpage via secure connection.

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Description: Administration of the questionnaire via an online platform. It assesses compassion for others, common humanity, disengagement, indifference towards others, kindness towards others, mindfulness, separation. It was used of matching participants into cohorts.

Measure: Questionnaire - Matching: Score of "Compassion scale - How I typically act towards others (COSN)".

Time: 2 months before T0 and during initial proband screening phase of the project, each subject fills out this questionnaire at the online recruiting webpage via secure connection.

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Description: Administration of the questionnaire via an online platform. It assesses the degree to which situations in one's life are appraised as stressful. It was used of matching participants into cohorts. This questionnaire is also filled out by observers of participants.

Measure: Questionnaire - Matching/Observers: Score of "Perceived Stress Scale (PSS-10)".

Time: 2 months before T0 and during initial proband screening phase of the project, each subject fills out this questionnaire at the online recruiting webpage via secure connection.

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Description: Administration of the questionnaire via an online platform. It assesses awareness, describing, non-judging of experiences, non-reactivity, observing, mindfulness. This questionnaire is also filled out by the observers of participants. It was used of matching participants into cohorts.

Measure: Questionnaire - Matching/Observer: Score of "Five Facets of Mindfulness Questionnaire (FFMQ)".

Time: 2 months before T0 and during initial proband screening phase of the project, each subject fills out this questionnaire at the online recruiting webpage via secure connection.

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Description: German Paper/Pencil Questionnaire that assesses Non-verbal Intelligence.

Measure: Questionnaire: Score of "Grundlagenintelligenztest Skala 2- Revision without WS/ZF-R" (Intelligence Test)

Time: 2 months before T0 and during initial proband screening phase of the project, each subject fills out this questionnaire at the online recruiting webpage via secure connection.

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Description: On a voluntary basis and with written consent, conducted qualitative interviews with some of the participants, where they are able to describe the subjective experience of the whole training. The interviews will be video-taped with the consent of the participants. We will be using depth-interview techniques that assess not only what the subjects experience but also how they process it. Interviews will be done by a interview specialist with a degree in Psychology and Philosophy. The data will be treated in accordance with data protection laws. In further publications, all statements of the subjects will be anonymized, the tapes will be erased after transcription. In case they agreed to be video-taped, the material will potentially be used for a video documentation of the whole ReSource Project.

Measure: Qualitative Elicitation Interviews and Interviews about subjective Experience during the study (1-2 hours)

Time: only TC1, TC2, or TC3: Voluntarily, possible during each Training Module

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Description: Administration of the questionnaire via an online platform. It assesses self-compassion, self-kindness, self-judgment, over-identification, mindfulness, isolation, and common humanity. It was used of matching participants into cohorts.

Measure: Questionnaire - Matching: Score in "Self-Compassion Scale" by Kristin Neff (SCS).

Time: 2 months before T0 and during initial proband screening phase of the project, each subject fills out this questionnaire at the online recruiting webpage via secure connection.

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Description: Administration of the questionnaire via an online platform. It assesses mild to severe depression. It was used of screening possible participants for the study

Measure: Questionnaire - Screening/Matching: "Major Depression Inventory (ICD-10, MDI)"

Time: Screening procedure of each participant before matching into cohorts

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Description: Administration of the questionnaire via an online platform. It assesses difficulties in describing emotions, tendency to focus attention externally, alexithymia, identification of emotions. It was used of screening possible participants for the study.

Measure: Questionnaire - Screening/Matching: "Toronto Alexithymia Scale (TAS-20)".

Time: Screening procedure of each participant before matching into cohorts

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Description: Administration of the questionnaire via an online platform. It assesses trait anxiety. It was used of screening possible participants for the study.

Measure: Questionnaire - Screening/Matching: "State-Trait Anxiety Inventory (STAI-X2; STAI-Trait)"

Time: Screening procedure of each participant before matching into cohorts

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Description: Administration of the questionnaire via an online platform. It assesses psychological health and drug abuse. It was used of screening possible participants for the study.

Measure: Questionnaire- Screening: "Patient Health Questionnaire - D (PHQ-D)

Time: Screening procedure of each participant before matching into cohorts

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Description: Interview with possible participants. It assesses psychological disorders. It was used of screening possible participants for the study.

Measure: Screening - Interview: DIA-X for Axis II psychiatric disorders of DSM-IV and clinical interviews for personality disorders (SCID-II)

Time: Screening procedure of each participant before matching into cohorts

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Description: Interview with possible participants. It assesses psychological disorders. It was used of screening possible participants for the study.

Measure: Screening - Interview: DIA-X for Axis I psychiatric disorders of DSM-IV

Time: Screening procedure of each participant before matching into cohorts

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Primary Outcomes

Description: Complete absence of any nausea and/or vomiting (including retching) in a previously nauseated or vomiting patient within 24 hours after administration of the study treatment.

Measure: Treatment efficacy of Dexamethasone for established PONV

Time: 24 hour follow up

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Secondary Outcomes

Description: Free from PONV during the first 6 hours

Measure: Short term efficacity

Time: 6 hours

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Description: Number of patients staying PONV free after rescue antiemetic during the first 24 postoperative hours

Measure: PONV free after rescue antiemtic

Time: 24 hour follow up

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Description: quality of sleep during the first postoperative night (numerical rating scale ranging from 0 = no sleep at all to 10 = excellent sleep)

Measure: Quality of sleep

Time: 24 hour follow up

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Description: any minor or major adverse effects during 24h.

Measure: Minor or major adverse effects

Time: 24 hour follow up

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Primary Outcomes

Description: Weekly mean pain index computed as the arithmetic mean of daily pain index values during the week prior to randomization and prior to each study visit. Daily pain index is computed as pain intensity (0-100 numeric rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable") multiplied by pain duration (0-100 percentage scale where percent = "percent of waking day you had facial pain") as reported in the Daily Symptom Diary and divided by 100. The pain index range is from 0 to 100. A higher score means a worse outcome.

Measure: Change in the Weekly Mean Pain Index After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Secondary Outcomes

Description: Weekly mean pain intensity computed as the arithmetic mean of daily pain intensity values during the week prior to randomization and prior to each study visit. Daily pain intensity is measured on 0-100 numeric rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable") as reported in the Daily Symptom Diary. A higher score means a worse outcome.

Measure: Change in the Weekly Mean Pain Intensity After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Weekly mean pain duration computed as the arithmetic mean of daily pain duration values during the week prior to randomization and prior to each study visit. Daily pain duration is measured on 0-100 percentage scale where percent = "percent of waking day you had facial pain" as reported in the Daily Symptom Diary. A higher score means a worse outcome.

Measure: Change in the Weekly Mean Pain Duration After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: The SF-McGill Pain Questionnaire contains 4 affective descriptors rated on a 0-3 scale where 0 = "none," 1 = "mild," 2 = "moderate," and 3 = "severe." The item scores are summed to yield a total score ranging from 0 to 12. A higher score means a worse outcome.

Measure: Change in the SF-McGill Pain Questionnaire Affective Component After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: The SF-McGill Pain Questionnaire contains 11 sensory descriptors rated on a 0-3 scale where 0 = "none," 1 = "mild," 2 = "moderate," and 3 = "severe." The item scores are summed to yield a total score ranging from 0 to 33. A higher score means a worse outcome.

Measure: Change in the SF-McGill Pain Questionnaire Sensory Component After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Self-reported present intensity of facial pain at the moment of assessment scored on a descriptive scale where 1 = "no pain' and 6 = "excruciating pain." A higher score means worse outcome.

Measure: Change in the SF-McGill Pain Questionnaire Present Facial Pain Intensity After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Self-reported average facial pain intensity for the last week scored on 0-100 numerical rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable". A higher score means a worse outcome.

Measure: Change in the SF-McGill Pain Questionnaire Weekly Average Facial Pain Intensity After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Self-reported average facial pain duration for the last week scored on 0-100 percentage scale where percent = "percent of waking day you had facial pain". A higher score means a worse outcome.

Measure: Change in the SF-McGill Pain Questionnaire Weekly Average Facial Pain Duration After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Self-reported average fatigue for the last week scored on 0-100 numerical rating scale where 0 = "no fatigue" and 100 = "the greatest imaginable." A higher score means a worse outcome.

Measure: Change in the SF-McGill Pain Questionnaire Weekly Fatigue After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Individuals were classified into 6 chronic pain grades: 0 = no pain; I = low pain intensity and low pain-related disability; IIa = high pain intensity and low pain-related disability; IIb = high pain intensity and high activity interference; III = moderate pain-related disability; and IV = severe pain-related disability. For analyses, this variable was dichotomized: grades 0-IIa were combined in one category and all higher grades in another. A higher grade means a worse outcome.

Measure: Number of Participants Stratified Per Graded Chronic Pain Scale (GCPS) Grade After 9 Weeks of Treatment

Time: Visit 4 (study day 63 +/-7)

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Description: The JFLS contains 20 items that measure limitations across mastication, vertical jaw mobility, and verbal/emotional expression rated on a 0-10 scale where 0 = "no limitation" and 10 = "severe limitation." The Global Score is computed as the mean response for all items and ranges from 0 to 10. A higher score means a worse outcome.

Measure: Change in the Jaw Functional Limitation Scale (JFLS) Global Score After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: The HIT-6 contains 6 items and assesses headache-related disability by the frequency of daily activity limitations ranging from "never" to "always." The 6 item scores are summed to yield a global score ranging from 36 to 78. A higher score means a worse outcome.

Measure: Change in the Headache Impact Test (HIT-6) Global Score After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: The PSQI has 19 items grouped into 7 component scores, each weighted equally on a 0-3 scale, The 7 component scores are summed to yield a global PSQI score, which has a range of 0-21. A higher score means a worse outcome.

Measure: Change in the Pittsburgh Sleep Quality Index (PSQI) Global Score After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: The PGIC scale assesses patient overall change in the severity of illness following treatment. Participants rate how they feel now compared with how they felt before receiving study drug on a 7-point scale where 0 = "No change or condition has got worse" and 6 = "A great deal better." A higher score means a better outcome. For analyses, this variable was dichotomized: scores from 0 to 3 were combined in one category of "No" (no significant improvement) and scores from 4 to 6 were combined in another category of "Yes" (significant improvement with the study treatment).

Measure: Number of Participants Stratified Per Dichotomized Score From the Patient Global Impression of Change (PGIC) Scale After 9 Weeks of Treatment

Time: Visit 4 (study day 63 +/-7)

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Description: The PSS assesses the frequency of 14 sources of stress on a scale from 0 = "never" to 4 = "very often." The item scores are summed to yield a global score ranging from 0 to 56. A higher score means a worse outcome.

Measure: Change in the Perceived Stress Scale (PSS) Global Score After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: The HADS is a 14-item assessment of anxiety (7 items) and depression (7 items) using the relative frequency of symptoms over the past week, rated on a 4-point scale ranging from 0 = "not at all" to 3 = "very often indeed". Responses are summed to provide separate scores for anxiety and depression with a range from 0 to 21. A higher score means a worse outcome.

Measure: Change in the Hospital Anxiety and Depression Scale (HADS) Depression Score After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: The HADS is a 14-item assessment of anxiety (7 items) and depression (7 items) using the relative frequency of symptoms over the past week, rated on a 4-point scale ranging from 0 = "not at all" to 3 = "very often indeed". Responses are summed to provide separate scores for anxiety and depression with a range from 0 to 21. A higher score means a worse outcome.

Measure: Change in the Hospital Anxiety and Depression Scale (HADS) Anxiety Score After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: The SCL-90R Somatization Scale is a 12-item assessment of somatic symptom distress over the past 7 days rated from 0 = "not at all" to 4 = "extremely." The scale score is computed as the mean for all items. The score range is from 0 to 4. A higher score means a worse outcome.

Measure: Change in the Symptom Checklist 90-Revised (SCL-90R) Somatization Scale Score After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: The SF-12v2 contains 7 questions assessing 8 domains of functioning and well-being rated from: "excellent" to "poor" (for general health); "yes, limited a lot" to "no, not limited at all" (for functional level); and "all of the time" to "none of the time" (for emotional state). These 8 domains can be further summarized into a physical component summary (PCS) and a mental component summary (MCS). summary (MCS). The range for each component is 0-100 and a higher score means a better outcome.

Measure: Change in the SF-12 Health Survey v2 (SF-12v2) Physical Component Summary (PCS) After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: The SF-12v2 contains 7 questions assessing 8 domains of functioning and well-being rated from: "excellent" to "poor" (for general health); "yes, limited a lot" to "no, not limited at all" (for functional level); and "all of the time" to "none of the time" (for emotional state). These 8 domains can be further summarized into a physical component summary (PCS) and a mental component summary (MCS). The range for each component is 0-100 and a higher score means a better outcome.

Measure: Change in the SF-12 Health Survey v2 (SF-12v2) Mental Component Summary (MCS) After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Temperature values, measured in degrees Celsius, from 4 examiner-applied contact heat stimuli will be averaged to measure the experimental thermal pain threshold (temperature at which pain is first perceived). The range was 32-50 degrees Celsius and a higher value means a better outcome.

Measure: Change in Thermal Pain Threshold After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Temperature values, measured in degrees Celsius, from 4 examiner-applied contact heat stimuli will be averaged to measure the experimental thermal pain tolerance (temperature at which pain can no longer be tolerated). The range was 32-50 degrees Celsius and a higher value means a better outcome.

Measure: Change in Thermal Pain Tolerance After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Pressure values, measured in kilopascals (kPa), from up to 5 experimental pressure stimuli, bilaterally applied to the area of temporalis muscle, are averaged to obtain a single pressure pain threshold value per anatomical site. The range is 0-500 kPa and a higher value means a better outcome.

Measure: Change in Pressure Pain Threshold at Temporalis Muscle After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Pressure values, measured in kilopascals, from up to 5 experimental pressure stimuli, bilaterally applied to the area of masseter muscle, will be averaged to obtain a single pressure pain threshold value per anatomical site.

Measure: Change in Pressure Pain Threshold at Masseter Muscle After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/- 7)

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Description: Pressure values, measured in kilopascals, from up to 5 experimental pressure stimuli, bilaterally applied to the area of temporomandibular joint, will be averaged to obtain a single pressure pain threshold value per anatomical site.

Measure: Change in Pressure Pain Threshold at Temporomandibular Joint After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Pressure values, measured in kilopascals, from up to 5 experimental pressure stimuli, bilaterally applied to the area of trapezius muscle, will be averaged to obtain a single pressure pain threshold value per anatomical site.

Measure: Change in Pressure Pain Threshold at Trapezius Muscle After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Pressure values, measured in kilopascals, from up to 5 experimental pressure stimuli, bilaterally applied to the area of lateral epicondyle, will be averaged to obtain a single pressure pain threshold value per anatomical site.

Measure: Change in Pressure Pain Threshold at Lateral Epicondyle After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Measured at TMD exam. A higher value means a better outcome.

Measure: Change in Pain-free Jaw Opening After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Measured at TMD exam. A higher value means a better outcome.

Measure: Change in Maximum Unassisted Jaw Opening After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Measured at TMD exam. A higher value means a better outcome.

Measure: Change in Maximum Assisted Jaw Opening After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Average of 3 repeated measures taken with a 2-minute interval.

Measure: Change in Systolic Blood Pressure After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Average of 3 repeated measures taken with a 2-minute interval.

Measure: Change in Diastolic Blood Pressure After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Average of 3 repeated measures taken with a 2-minute interval.

Measure: Change in Heart Rate After 9 Weeks of Treatment

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Other Outcomes

Description: Weekly mean pain index computed as the arithmetic mean of daily pain index values during the week prior to randomization and prior to each study visit. Daily pain index is computed as pain intensity (0-100 numeric rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable") multiplied by pain duration (0-100 percentage scale where percent = "percent of waking day you had facial pain") as reported in the Daily Symptom Diary, divided by 100. The pain index range is from 0 to 100. A higher score means a worse outcome. The pain index was stratified per number of catechol-O-methyltransferase (COMT) Low Pain Sensitive (LPS) haplotypes.

Measure: Change in the Weekly Mean Pain Index After 9 Weeks of Treatment Stratified Per Number of COMT LPS Haplotypes

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Description: Weekly mean pain index computed as the arithmetic mean of daily pain index values during the week prior to randomization and prior to each study visit. Daily pain index is computed as pain intensity (0-100 numeric rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable") multiplied by pain duration (0-100 percentage scale where percent = "percent of waking day you had facial pain") as reported in the Daily Symptom Diary, divided by 100. The pain index range is from 0 to 100. A higher score means a worse outcome. The pain index was stratified per number of catechol-O-methyltransferase (COMT) valine alleles at single nucleotide polymorphism (SNP) rs4680.

Measure: Change in the Weekly Mean Pain Index After 9 Weeks of Treatment Stratified Per Number of COMT Valine Alleles at rs4680

Time: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

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Primary Outcomes

Description: Startle and PPI are assessed using 42 trials of 6 types: a 118 decibels (dB) (A) 40 ms noise alone, and the same "pulse" preceded 10, 20, 30, 60, or 120 ms by a prepulse 16 dB over a 70 dB(A) background. Startle amplitude, habituation, latency and latency facilitation are tested, and are used to interpret drug and subgroup effects on %PPI. Primary dependent measure: AMPH effects on %PPI.

Measure: Prepulse inhibition (PPI)

Time: 5 years

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Secondary Outcomes

Description: The MCCB includes 10 tests assessing 7 cognitive domains". In "low baseline" HS, AMPH primarily increased speed of processing (SP) and attention/ vigilance (A/V), but some gains were evident in all domains except visual learning (30). Total test time is 1-1.5h. The primary dependent measures will be AMPH effects on SP and A/V T-scores; secondary and exploratory measures will include T-scores for both spatial (Wechsler Spatial Span) and verbal (Letter-Number Span) working memory, as well as T-scores for the other cognitive domains.

Measure: MATRICS Consensus Cognitive Battery Performance (MCCB)

Time: 5 years

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Description: Sensory discrimination learning module: Sound "Sweeps" of adaptive auditory processing exercises: 1) parameters (e.g. inter-stimulus interval, stimulus duration) are established for subjects to maintain 80% correct responses in each stimulus set, and 2) task difficulty increases systematically and parametrically as performance improves. On screen and test days, subjects complete 1h of TCT. Analytic software yields the dependent measures: subjects' across-session improvement score, processing speed percentile and total number of levels completed.

Measure: Targeted Cognitive Training (TCT): PositScience, Inc.

Time: 5 years

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Primary Outcomes

Description: pain scale; from 0 to 10; score 0: no pain, score 10: unbearable pain

Measure: Visual Analog Scale (VAS)

Time: change from baseline (1st menstrual phase, before tDCS) at one month (2nd menstrual phase, with tDCS), change from baseline (1st menstrual phase, before tDCS) at two months (3rd menstrual phase)

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Description: Resting-state functional magnetic resonance imaging (rs-fMRI) is a well established method of functional magnetic resonance imaging (fMRI) that is used to evaluate regional interactions in the brain that occur in a resting (task-negative) state, when a subject is not performing an explicit task. Functional connectivity is the connectivity between brain regions that share functional properties, it can be defined as the correlation between spatially remote neurophysiological events, expressed as the neural networks of brain.

Measure: Functional connectivity of rs-fMRI Imaging

Time: change from baseline (before tDCS, before 2nd menstrual phase) at one week (after tDCS completion), change from baseline (before tDCS, before 2nd menstrual phase) at four weeks (before the 3rd menstrual phase)

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Secondary Outcomes

Description: To assess the threshold of thermal sensation (cold, cold-pain, heat, heat-pain; from 0 to 50 centigrade temperature), according to the established protocol of an ascending limit approach for heat pain and a descending limit approach for cold pain.

Measure: Quantitative sensory testing (QST)

Time: change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase)

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Description: To assess anxious symptoms; from 20 to 80; score 20: not anxious, score 80: extremely anxious

Measure: Spielberger State-Trait Anxiety Inventory (STAI)

Time: change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase)

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Description: To assess anxious symptoms; from 0 to 63; score 0: not anxious, score 63: extremely anxious

Measure: Beck Anxiety Inventory (BAI)

Time: change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase)

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Description: To assess depressive symptoms; from 0 to 63; score 0: not depressed, score 63: extremely depressed

Measure: Beck Depression Inventory (BDI)

Time: change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase)

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Description: To assess pain-maladaptive psychological status; from 0 to 52; score 0: not pain Catastrophizing , score 52: extremely pain Catastrophizing

Measure: Pain Catastrophizing Scale (PCS)

Time: change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase)

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Description: To assess pain status; from 0 to 78; score 0: not painful, score 78: extremely painful

Measure: Long-form McGill Pain Questionnaire (MPQ)

Time: change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase)

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Description: To assess quality of life; he SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. From 0 to 100; score 0: equivalent to maximum disability, score 100: no disability.

Measure: Short-Form Health Survey (SF-36)

Time: change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase)

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Description: To assess testosterone, progesterone, estrogen

Measure: Blood Hormones Measurement

Time: change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase)

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Description: To genotype the single nucleotide polymorphism genotyping (i.e., BDNF Val66Met polymorphism (rs6265), COMT Val158Met polymorphism (rs4680), OPRM1 (rs1799971), 5HTR2A (rs6313), SLC6A4 (rs25531)) from blood specimen

Measure: Genotyping

Time: baseline

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Description: To assure blinding efficacy; Patients do self-assessment about whether they receive real tDCS or sham tDCS. Assessment questionnaire:1 or 0. 1: real tDCS; 0: sham tDCS.

Measure: Efficacy of tDCS blinding

Time: At 1 months after tDCS intervention

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Primary Outcomes

Description: pain scale; from 0 to 10; score 0: no pain, score 10: unbearable pain

Measure: Visual Analog Scale (VAS)

Time: change from baseline (1st menstrual phase, before tDCS) at one month (2nd menstrual phase, with tDCS), change from baseline (1st menstrual phase, before tDCS) at two months (3rd menstrual phase)

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Description: Somatosensory evoked magnetic fields (SEFs) is a well established magnetoencephalographic (MEG) cortical response evoked by electric stimulation. SEFs to experimental pain stimulation using electrical stimulator applied on the skin over the trajectory of median nerve will be used to evaluate pain-evoked cortical response.

Measure: Somatosensory evoked magnetic fields to experimental pain

Time: change from baseline (before tDCS, before 2nd menstrual phase) at one week (after tDCS completion), change from baseline (before tDCS, before 2nd menstrual phase) at four weeks (before the 3rd menstrual phase)

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Secondary Outcomes

Description: To assess the threshold of thermal sensation (cold, cold-pain, heat, heat-pain; from 0 to 50 centigrade temperature), according to the established protocol of an ascending limit approach for heat pain and a descending limit approach for cold pain.

Measure: Quantitative sensory testing (QST)

Time: change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase)

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Description: To assess anxious symptoms; from 20 to 80; score 20: not anxious, score 80: extremely anxious

Measure: Spielberger State-Trait Anxiety Inventory (STAI)

Time: change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase)

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Description: To assess anxious symptoms; from 0 to 63; score 0: not anxious, score 63: extremely anxious

Measure: Beck Anxiety Inventory (BAI)

Time: change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase)

---

Description: To assess depressive symptoms; from 0 to 63; score 0: not depressed, score 63: extremely depressed

Measure: Beck Depression Inventory (BDI)

Time: change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase)

---

Description: To assess pain-maladaptive psychological status; from 0 to 52; score 0: not pain Catastrophizing , score 52: extremely pain Catastrophizing

Measure: Pain Catastrophizing Scale (PCS)

Time: change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase)

---

Description: To assess pain status; from 0 to 78; score 0: not painful, score 78: extremely painful

Measure: Long-form McGill Pain Questionnaire (MPQ)

Time: change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase)

---

Description: To assess quality of life; he SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. From 0 to 100; score 0: equivalent to maximum disability, score 100: no disability.

Measure: Short-Form Health Survey (SF-36)

Time: change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase)

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Description: To assess testosterone, progesterone, estrogen

Measure: Blood Hormones Measurement

Time: change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase)

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Description: To genotype the single nucleotide polymorphism genotyping (i.e., BDNF Val66Met polymorphism (rs6265), COMT Val158Met polymorphism (rs4680), OPRM1 (rs1799971), 5HTR2A (rs6313), SLC6A4 (rs25531)) from blood specimen

Measure: Genotyping

Time: baseline

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Description: To assure blinding efficacy; Patients do self-assessment about whether they receive real tDCS or sham tDCS. Assessment questionnaire:1 or 0. 1: real tDCS; 0: sham tDCS.

Measure: Efficacy of tDCS blinding

Time: At 1 months after tDCS intervention

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Primary Outcomes

Description: Edinburgh Postnatal Depression Scale. Score range: 0-30. Higher scores indicate more symptoms of postpartum depression. Total group

Measure: Depressive symptoms

Time: Week 3-6 postpartum

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Description: Score on the Hamilton 17-item depression scale. Score range: 0-52. Higher scores indicate more depressive symptoms. Assessed in imaging group

Measure: Depressive symptoms

Time: Week 3-6 postpartum

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Description: 116 a priori defined gene transcripts, which where differentially expressed in third trimester of women who later developed perinatal depression with postpartum onset relative to pregnant women who did not and to other depressed (reference Mehta et al, 2014, Psychological Medicine) and confirmed to be coupled to estrogen fluctuations (Mehtaet al. 2018 British Journal of Psychiatry) will be evaluated in the total group. Also DNA methylation of the genes of these transcripts will be determined and analysed in terms of their predictive value (above chance) for perinatal depression.

Measure: Gene transcript and DNA methylation markers of estrogen sensitivity

Time: Prior to caesarean section

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Description: Latent variable construct of brain 5-HT4R level based on quantification of 5-HT4R binding from 11C-SB207145 positron emission tomography in primary volumes of interest; neocortex, nucleus caudatus, putamen and hippocampus. Assessed in imaging group.

Measure: Cerebral serotonin 4 receptor binding postpartum

Time: Week 3-6 postpartum

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Description: Assessed in total group

Measure: CSF levels of GABA

Time: On day of caesarean section

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Description: Assessed in total group

Measure: CSF levels of serotonin metabolite (5-HIAA)

Time: On day of caesarean section

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Description: Cortisol awakening response, area under the curve with respect to baseline from 0 to 60 minutes from awakening.

Measure: Cortisol awakening response

Time: Week 3-6 postpartum

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Description: Provides an estimate of cortisol exposure up to 6 months prior to delivery, total group

Measure: Hair cortisol level mothers

Time: On day of caesarean section.

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Description: Provides an estimate of fetal cortisol exposure, infants from total group

Measure: Hair cortisol level newborns

Time: Day 0-5 postpartum.

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Description: Hippocampal brain volume (including hippocampus) from structural MRI, imaging group.

Measure: Hippocampal volumes

Time: Week 3-6 postpartum.

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Description: fMRI (BOLD response) based assessment of brain activity in response to reward, relative to non-reward, stimuli. Assessed in imaging cohort

Measure: functional MRI response to reward

Time: Week 3-6 postpartum.

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Description: rsfMRI based spontaneous co-fluctuations in low frequency BOLD signal, (functional connectivity). Assessed with rsfMRI scan in the resting state, i.e. non-goal oriented spontaneous thought and awake. Assessed in imaging group.

Measure: Resting state functional connectivity MRI

Time: Week 3-6 postpartum

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Description: Change in epigenetic SERT status from late pregnancy to postpartum week 3-6.

Measure: Change in epigenetic SERT status

Time: From just before delivery to 3-6 weeks postpartum

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Description: Composite measure of hsCRP, TNF-α, IL-6, IL-18 and IL-10 levels, total group

Measure: Concentration of inflammatory markers, i.e hsCRP and immunoactive cytokines, in peripheral blood

Time: At week 3-6

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Description: fMRI (BOLD response) based assessment of brain activity to emotionally salient, relative to neutral, stimuli. Assessed in imaging cohort.

Measure: functional MRI response to emotional faces

Time: Week 3-6 postpartum.

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Secondary Outcomes

Description: Score on the Hamilton 17-item depression scale. Score range: 0-52. Higher scores indicate more depressive symptoms. Assessed in imaging group

Measure: Depressive symptoms

Time: Day 3-5 postpartum

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Description: Score on the Hamilton 17-item depression scale. Score range: 0-52. Higher scores indicate more depressive symptoms. Assessed in imaging group

Measure: Depressive symptoms

Time: Week 12 postpartum

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Description: Edinburgh Postnatal Depression Scale. Score range: 0-30. Higher scores indicate more symptoms of postpartum depression. Assessed in total group

Measure: Depressive symptoms

Time: Day 3-5 postpartum

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Description: Edinburgh Postnatal Depression Scale. Score range: 0-30. Higher scores indicate more symptoms of postpartum depression. Assessed in all

Measure: Depressive symptoms

Time: 6 months postpartum

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Description: Assessed in total group

Measure: CSF levels of serotonin

Time: On day of caesarean section

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Description: Assessed in total group

Measure: CSF levels of dopamine metabolites

Time: On day of caesarean section

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Description: Assessed in total group

Measure: CSF levels of noradrenaline metabolites

Time: On day of caesarean section

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Description: Composite measure of IFN-c, IFN-alfa TNF-alfa og IL-6, in total group

Measure: CSF levels of inflammatory markers

Time: On day of caesarean section

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Description: Estradiol level in peripheral blood, total group

Measure: Estradiol level

Time: Prior to caesarean section.

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Description: Estradiol level peripheral blood, total group

Measure: Estradiol level

Time: At week 3-6 postpartum.

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Description: Estradiol change pre- to postpartum, peripheral blood total group

Measure: Change in estradiol level

Time: From baseline (caesarean section to week 3-6 postpartum)

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Description: Progesterone level in peripheral blood

Measure: Progesterone level

Time: Prior to caesarean section.

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Description: Progesterone level in peripheral blood

Measure: Progesterone level

Time: At week 3-6 postpartum.

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Description: Progesterone change pre- to postpartum, peripheral blood total group

Measure: Change in progesterone level

Time: From baseline (caesarean section to week 3-6 postpartum)

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Description: Allopregnanolone level in peripheral blood

Measure: Allopregnanolone level

Time: Prior to caesarean section.

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Description: Allopregnanolone level in peripheral blood

Measure: Allopregnanolone level

Time: At week 3-6 postpartum.

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Description: Change in allopregnanolone level in peripheral blood

Measure: Change in allopregnanolone level

Time: From baseline (caesarean section to week 3-6 postpartum)

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Description: Cortisol change pre- to postpartum, peripheral blood total group

Measure: Change in cortisol level

Time: From baseline (caesarean section to week 3-6 postpartum)

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Description: Cortisol awakening response, area under the curve with respect to baseline from 0 to 60 minutes from awakening.

Measure: Cortisol awakening response

Time: Week 12 postpartum

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Description: Cortisol awakening response, area under the curve with respect to baseline from 0 to 60 minutes from awakening.

Measure: Cortisol awakening response

Time: Prior to caesarean section

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Description: Change in cortisol awakening response, from caesarean section to 3-6 weeks postpartum.

Measure: Change in cortisol awakening response

Time: ´From baseline (caesarean section to week 3-6 postpartum)

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Description: Methylation status for the SERT gene, total group

Measure: DNA methylation of the SERT gene

Time: Prior to caesarean section

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Description: DNA Methylation status for the SERT gene, total group

Measure: DNA methylation of the SERT gene

Time: Week 3-6 postpartum

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Description: Methylation status for the FK506-binding protein 51 (FKBP5) gene, total group

Measure: DNA methylation of the FK506-binding protein 51 (FKBP5) gene

Time: Prior to caesarean section.

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Description: Methylation status for the FK506-binding protein 51 (FKBP5) gene, total group

Measure: DNA methylation of the FK506-binding protein 51 (FKBP5) gene

Time: Week 3-6 postpartum

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Description: Change in methylation status for the FK506-binding protein 51 (FKBP5) gene from late pregnancy to postpartum week 3-6.

Measure: Change in DNA methylation of the FK506-binding protein 51 (FKBP5) gene

Time: From baseline (caesarean section to week 3-6 postpartum)

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Description: Methylation status for the glucocorticoid receptor gene, total group

Measure: DNA methylation of the glucocorticoid receptor gene

Time: Prior to caesarean section.

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Description: Methylation status for the glucocorticoid receptor gene, total group

Measure: DNA methylation of the glucocorticoid receptor gene

Time: Week 3-6 postpartum

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Description: Change in methylation status for the glucocorticoid receptor gene from late pregnancy to postpartum week 3-6.

Measure: Change in DNA methylation of the glucocorticoid receptor gene

Time: From baseline (caesarean section to week 3-6 postpartum)

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Description: Methylation status for the COMT gene, total group

Measure: DNA methylation of the COMT gene

Time: Prior to caesarean section.

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Description: Methylation status for the COMT gene, total group

Measure: DNA methylation of the COMT gene

Time: Week 3-6 postpartum

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Description: Change in methylation status for the COMT gene from just before delivery to 3-6 weeks postpartum

Measure: Change in DNA methylation of the COMT gene

Time: From baseline (caesarean section to week 3-6 postpartum)

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Description: Methylation status for the MAO-A gene, total group

Measure: DNA methylation of the MAO-A gene

Time: Prior to caesarean section.

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Description: Change in methylation status for the MAO-A gene, total group

Measure: Change in DNA methylation of the MAO-A gene

Time: From baseline (caesarean section to week 3-6 postpartum)

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Description: Methylation status for the MAO-A gene, total group

Measure: DNA methylation of the MAO-A gene

Time: Week 3-6 postpartum

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Description: Methylation status for the oxytocin receptor gene, total group

Measure: DNA methylation of the oxytocin receptor gene

Time: Prior to caesarean section.

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Description: Methylation status for the oxytocin receptor gene, total group

Measure: DNA methylation of the oxytocin receptor gene

Time: Week 3-6 postpartum

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Description: Change in methylation status for the oxytocin receptor gene, total group

Measure: Change in DNA methylation of the oxytocin receptor gene

Time: From baseline (caesarean section to week 3-6 postpartum)

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Description: Methylation status for the oxytocin gene, total group

Measure: DNA methylation of the oxytocin gene

Time: Prior to caesarean section.

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Description: Methylation status for the oxytocin gene, total group

Measure: DNA methylation of the oxytocin gene

Time: Week 3-6 postpartum

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Description: Change methylation status for the oxytocin gene, total group

Measure: Change in DNA methylation of the oxytocin gene

Time: From baseline (caesarean section to week 3-6 postpartum)

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Description: Composite measure of hsCRP, TNF-α, IL-6, IL-18 and IL-10 levels, total group

Measure: Systemic inflammation peripheral blood hsCRP and immunoactive cytokines

Time: Prior to caesarean section.

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Description: Change in composite measure of hsCRP, TNF-α, IL-6, IL-18 and IL-10 levels, total group

Measure: Change in systemic inflammation peripheral blood hsCRP and immunoactive cytokines

Time: From baseline (caesarean section to week 3-6 postpartum

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Description: Family History Assessment Module (OS-FHAM). Number of first degree relatives with a history of depressive episodes or bipolar disorder. Total group.

Measure: Self reported family history of mood disorders

Time: Day 3-5 postpartum or before

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Description: Barratt Impulsiveness Scale (BIS-11), self-reported. Range: 30-120. Total group.

Measure: Self reported impulsiveness score

Time: Day 3-5 postpartum or before

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Description: NEO-PI-R - Revised NEO Personality Inventory, self-reported. Participants may score 20-80 for each of the personality traits: openness, conscientiousness, extraversion, agreeableness, and neuroticism. The higher the score, the more prominent is the personality trait. Total group.

Measure: Self reported Neuroticism score from NEO personality questionnaire

Time: Day 3-5 postpartum or before

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Description: Parental bonding instrument (PBI), both parents, self-reported. Total group.

Measure: Self reported parental bonding quality

Time: Day 3-5 postpartum or before

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Description: Perceived Stress Scale (PSS), range 0-40, a score of 0 indicates no perceived stress. Total group.

Measure: Self-reported perceived stress

Time: Day 3-5 postpartum

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Description: Perceived Stress Scale (PSS), range 0-40, a score of 0 indicates no perceived stress. Total group.

Measure: Self-reported perceived stress

Time: Week 3-6 postpartum

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Description: Change in Perceived Stress Scale (PSS), range 0-40, a score of 0 indicates no perceived stress. Total group.

Measure: Change in self-reported perceived stress

Time: Change from day 3-5 to week 3-6 postpartum

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Description: Snaith-Hamilton Pleasure Scale (SHAPS), range 0-14, a score of 0 indicates no self-reported anhedonia. Total group.

Measure: Self-reported anhedonia

Time: Day 3-5 postpartum

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Description: Snaith-Hamilton Pleasure Scale (SHAPS), range 0-14, a score of 0 indicates no self-reported anhedonia. Total group.

Measure: Self-reported anhedonia

Time: Week 3-6 postpartum

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Description: Change in Snaith-Hamilton Pleasure Scale (SHAPS) score, range 0-14, a score of 0 indicates no self-reported anhedonia. Total group.

Measure: Change in self-reported anhedonia

Time: Change from day 3-5 to week 3-6 postpartum

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Description: Rumination Response Scale (RRS), range 22-88, a score of 22 indicates no ruminative symptoms. Total group.

Measure: Self-reported rumination

Time: Day 3-5 postpartum

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Description: Rumination Response Scale (RRS), range 22-88, a score of 22 indicates no ruminative symptoms. Total group.

Measure: Self-reported rumination

Time: Week 3-6 postpartum

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Description: Change in Rumination Response Scale (RRS) score, range 22-88, a score of 22 indicates no ruminative symptoms. Total group.

Measure: Change in elf-reported rumination

Time: Change from day 3-5 to week 3-6 postpartum

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Description: Profile of Mood States (POMS), range 0-260, a score of 0 indicates no mood disturbance. Total group.

Measure: Self-reported mood

Time: Day 3-5 postpartum

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Description: Profile of Mood States (POMS), range 0-260, a score of 0 indicates no mood disturbance. Total group.

Measure: Self-reported mood

Time: Week 3-6 postpartum

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Description: Change in Profile of Mood States (POMS) score, range 0-260, a score of 0 indicates no mood disturbance. Total group.

Measure: Change in self-reported mood

Time: Change from day 3-5 to week 3-6 postpartum

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Description: Pittsburgh Sleep Quality Index (PSQI), range 0-21, a score of 0 indicates a healthy sleep quality. Total group.

Measure: Self-reported sleep quality

Time: Day 3-5 postpartum

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Description: Pittsburgh Sleep Quality Index (PSQI), range 0-21, a score of 0 indicates a healthy sleep quality. Total group.

Measure: Self-reported sleep quality

Time: Week 3-6 postpartum

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Description: Change in Pittsburgh Sleep Quality Index (PSQI), range 0-21, a score of 0 indicates a healthy sleep quality. Total group.

Measure: Change in self-reported sleep quality

Time: Change from day 3-5 to week 3-6 postpartum

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Description: Brief symptom Inventory-53 item (BSI-53), range 0-212, increasing score means worsening of symptoms.Total group.

Measure: Self-reported psychiatric symptoms

Time: Day 3-5 postpartum

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Description: Brief symptom Inventory-53 item (BSI-53), range 0-212, increasing score means worsening of symptoms.Total group.

Measure: Self-reported psychiatric symptoms

Time: Week 3-6 postpartum

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Description: Change in Brief symptom Inventory-53 item (BSI-53) score, range 0-212, increasing score means worsening of symptoms.Total group.

Measure: Change in self-reported psychiatric symptoms

Time: Change from day 3-5 to week 3-6 postpartum

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Description: WHO-5 well-being index, range 0-100, low score means less well-being. Total group.

Measure: Self-reported well-being

Time: Day 3-5 postpartum

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Description: WHO-5 well-being index, range 0-100, low score means less well-being. Total group.

Measure: Self-reported well-being

Time: Week 3-6 postpartum

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Description: Change in WHO-5 well-being index, range 0-100, low score means less well-being. Total group.

Measure: Change in self-reported well-being

Time: Change from day 3-5 to week 3-6 postpartum

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Description: State Trait Anxiety Inventory (STAI-AD-D), state and trait subscales each have a range of 20-80, 20 means no anxiety. Total group.

Measure: Self-reported anxiety

Time: Day 3-5 postpartum

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Description: State Trait Anxiety Inventory (STAI-AD-D), state subscale range 20-80, 20 means no anxiety. Total group.

Measure: Self-reported anxiety

Time: Week 3-6 postpartum

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Description: Change in State Trait Anxiety Inventory (STAI-AD-D) score, state subscale range 20-80, 20 means no anxiety. Total group.

Measure: Change in self-reported anxiety

Time: Change from day 3-5 to week 3-6 postpartum

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Description: Obsessive-Compulsive Inventory (OCI) score, self-reported, range 0-72, higher scores indicate more symptoms. Total group.

Measure: Self-reported obsessive and compulsive symptoms

Time: Day 3-5

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Description: Obsessive-Compulsive Inventory (OCI) score, self-reported, range 0-72, higher scores indicate more symptoms. Total group.

Measure: Self-reported obsessive and compulsive symptoms

Time: Week 3-6 postpartum

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Description: Change in Obsessive-Compulsive Inventory (OCI) score, self-reported, range 0-72, higher scores indicate more symptoms. Total group.

Measure: Change in self-reported obsessive and compulsive symptoms

Time: Change from day 3-5 to week 3-6 postpartum

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Description: Performance on Simple Reaction Time, in imaging cohort.

Measure: Performance on Simple Reaction Time

Time: Week 3-6 postpartum

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Description: Gray matter brain volume prefrontal cortex and anterior cingulate cortex

Measure: Gray matter brain volume prefrontal cortex and anterior cingulate cortex

Time: At week 3-6 postpartum

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Description: Composite measure of serotonin, tryptophan og tryptofan hydroxylase levels relative to 5-HIAA, in placenta sample. Infants from total group

Measure: Serotonergic turnover in placenta

Time: At delivery.

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Description: 11-beta-hydroxysteroid dehydrogenase type 2 activity in placenta. Infants from total group

Measure: 11-beta-hydroxysteroid dehydrogenase type 2 activity in placenta

Time: At delivery

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Description: Composite measure of methylation status for the FKBP5, glucocorticoid receptor, 11-beta hydroxysteroid dehydrogenase type 2 genes. Infants from total group

Measure: Methylation status of genes relevant for stress-hormone regulation in placenta

Time: At delivery

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Description: Composite measure of the methylation status for monoamine oxidase, serotonin receptor and serotonin transporter genes. Infants from total group

Measure: Methylation status of genes related to serotonergic signaling in placenta

Time: At delivery

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Description: Composite measure of methylation status and gene transcript profiles of Glucocorticoid receptor, FKBP5, oxytocin and oxytocin receptors, Brain-derived neurotrophic factor (BDNF) genes. Assessed in blood from umbilical cord blood sample from infants, total group.

Measure: Methylation status and gene transcript profiles of relevance for early brain development and stress regulation in newborn infants

Time: At delivery.

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Other Outcomes

Description: val158met (rs4680) status, binary variable, i.e. "val/val, val/met" vs "met/met" variants

Measure: COMT-genotype (rs4680) variant, i.e met/met vs other polymorphisms

Time: Prior to caesarean section.

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Description: BDNF val66met (rs6265) status, binary variable, i.e. "val/val" versus "met-carrier" status

Measure: BDNF genotype (rs6265) status, i.e. val/val versus met-carrier variants

Time: Prior to caesarean section.

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Description: 5-HTTLPR genotype status (binary), i.e. high-expressing LALA vs low-expressing (S or LG) variants, based on SLC6A4, i.e. L or S variants, and further subtyping on rs25531 haplotype L(A)L(A) vs LGLA, LGLG or variants containing as S as specified above.

Measure: 5-HTT genotype status, i.e LALA vs low-expressing (S or LG) variants

Time: Prior to caesarean section.

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Description: In house interview based on Kennerley Maternity Blues Questionnaire, range: 0-28, higher score indicates more severe postpartum blues symptoms. High blues score is associated with greater risk for perinatal depression at week 3-6.

Measure: Postpartum blues symptoms

Time: Day 3-5 postpartum.

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Description: In house interview based on Stein's Maternity Blues Scale, range 0-26. High blues score is associated with greater risk for perinatal depression at week 3-6.

Measure: Postpartum blues symptoms

Time: Day 3-5 postpartum.

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