Building the Path to Resilience in Preterm Infants: Mindfulness-based Intervention

Study Overview
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Brief Summary
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Yearly 15 million babies worldwide are born too soon. 10% of these preterm births occur very early before 32 weeks of gestation and these newborns are at high risk for neurodevelopmental disorders later in life. Neurocognitive disorders now touch 27% of the European population, and 5% or 3.3 million children suffer from social and learning difficulties, including attention-deficit hyperactivity disorders and autism, whose rates are increasing and prematurity contributes to this rise. Cognition, and socio-emotional competence are based on intact brain structure and functions that are formed early in development, both pre- and post-natally, and are heavily influenced by environment. Ramon y Cajal in his studies on the making of the brain clearly stated: The total arborisation of a neuron represents the graphic history of conflicts suffered during its developmental life. Understanding how environment affects early brain development and defining timing and mode of early interventions to enhance brain development in high risk populations, such as preterm infants, is currently acknowledged as a fundamental endeavor for the scientific community (see guidelines of the National Scientific Council for the Developing Child). Interventions to improve and maintain cognitive and socio-emotional skills are to become an essential tool of medical care for high-risk infants. The goal of this study is to test the impact of a Mindfulness-based intervention - considered to target brain networks previously described as affected by prematurity and improve socio-emotional and executive functions. Mindfulness based intervention (intentional self-regulation of attention) will be performed in 10-13 year old preterm children, both from our prior studied preterm cohorts. Overall, our planned research will fill an important gap in our theoretical understanding of the brain vulnerability linked to prematurity. Even more importantly, the compelling issue of how to build cognitive and emotional resilience in preterm children will be addressed by preventing the onset of difficulties and reducing them with appropriate interventions.

Official Title
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Building the Path to Resilience in Preterm Infants: a Neuroimaging Investigation of the Impact of Multisensory and Neurocognitive Interventions Concern: Mindfulness-based Intervention

Conditions
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Preterm Birth, Cognitive Dysfunction, Behavioral Problem

Intervention / Treatment
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* Behavioral: Mindfulness-based intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: born before 32 gestational weeks Exclusion Criteria: severe sensory or physical disabilities (cerebral palsy, blindness, hearing loss) intelligence quotient below 70 not French speaking

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: For young adolescents enrolled in the randomised controlled trial design, families were randomised either to the intervention group or the waiting group. Participants enrolled in the RCT completed three assessments at three different time points: Time 1, Time 2, Time 3. Participants from the intervention group participated in Mindfulness-based intervention between Time 1 and Time 2. Participants from the waiting group took part in the Mindfulness-based intervention between Time 2 and Time 3.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention group (RCT)<br>Participants from the intervention group participated in the mindfulness-based intervention between Time 1 and Time 2. | Behavioral: Mindfulness-based intervention<br>* Mindfulness-based intervention: The proposed MBI was designed based on well-known MBI programs including Mindfulness-Based Stress Reduction and Mindfulness-Based Cognitive Therapy and adapted to adolescents' needs and language. The program consisted of 8 weekly sessions in groups of up to 8 participants, lasting 1h30. Two MBI groups were offered per week (Wednesdays and Fridays) and participants had the possibility to choose the most convenient day for them. Two instructors were present for each group throughout the intervention.For each session one theme was addressed, such as attention and the stabilisation of the focus of attention, bodily sensations, breath, emotions, thoughts, compassion, stress, stress reactivity and coping strategies.<br>|
| Experimental: Waiting group (RCT)<br>Participants from the waiting group took part in the mindfulness-based intervention between Time 2 and Time 3. | Behavioral: Mindfulness-based intervention<br>* Mindfulness-based intervention: The proposed MBI was designed based on well-known MBI programs including Mindfulness-Based Stress Reduction and Mindfulness-Based Cognitive Therapy and adapted to adolescents' needs and language. The program consisted of 8 weekly sessions in groups of up to 8 participants, lasting 1h30. Two MBI groups were offered per week (Wednesdays and Fridays) and participants had the possibility to choose the most convenient day for them. Two instructors were present for each group throughout the intervention.For each session one theme was addressed, such as attention and the stabilisation of the focus of attention, bodily sensations, breath, emotions, thoughts, compassion, stress, stress reactivity and coping strategies.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Affect Recognition (NEPSY-II; Korkman, Kirk, and Kemp (2007) | The affect recognition subtest assesses the ability to recognise facial emotional expressions (happy, sad, anger, fear, disgust, and neutral) from photographs of children's faces in several matching tasks. In the first task, the participant selected one of the four faces that depicted the same emotion as a child's face at the top of the page. In a second task, the participant selected two photographs of faces that displayed the same affect from a selection of four photographs. Finally, the participant examined a photograph of a child's face for 5 seconds, and then from memory, selected two photographs that matched the same emotion as the face previously shown. Standardised scores will be used. Higher scores mean better outcomes. | Assessment at Time 1 (pre-intervention for learning group; pre-treatment as usual for waiting group) | 
| Affect Recognition (NEPSY-II; Korkman, Kirk, and Kemp (2007) | The affect recognition subtest assesses the ability to recognise facial emotional expressions (happy, sad, anger, fear, disgust, and neutral) from photographs of children's faces in several matching tasks. In the first task, the participant selected one of the four faces that depicted the same emotion as a child's face at the top of the page. In a second task, the participant selected two photographs of faces that displayed the same affect from a selection of four photographs. Finally, the participant examined a photograph of a child's face for 5 seconds, and then from memory, selected two photographs that matched the same emotion as the face previously shown. Standardised scores will be used. Higher scores mean better outcomes. | Assessment at Time 2 (immediately after the intervention for learning group; pre-intervention for waiting group) | 
| Affect Recognition (NEPSY-II; Korkman, Kirk, and Kemp (2007) | The affect recognition subtest assesses the ability to recognise facial emotional expressions (happy, sad, anger, fear, disgust, and neutral) from photographs of children's faces in several matching tasks. In the first task, the participant selected one of the four faces that depicted the same emotion as a child's face at the top of the page. In a second task, the participant selected two photographs of faces that displayed the same affect from a selection of four photographs. Finally, the participant examined a photograph of a child's face for 5 seconds, and then from memory, selected two photographs that matched the same emotion as the face previously shown. Standardised scores will be used. Higher scores mean better outcomes. | Assessment at Time 3 (3 months post-intervention for learning group; immediately after the intervention for waiting group) | 
| Theory of Mind (NEPSY-II; Korkman et al. (2007)) | The theory of mind subtest measures understanding of mental functions and other people's perspectives. In the first task, questions are asked to the participant about different verbal scenarios measuring understanding of beliefs, intentions, others' thoughts, ideas and comprehension of figurative language. In the second task, participants have to match facial emotional expressions, from photographs of children's faces, to a scenario. The total raw score willl be age-adjusted. Higher scores mean better outcomes. | Assessment at Time 1 (pre-intervention for learning group; pre-treatment as usual for waiting group) | 
| Theory of Mind (NEPSY-II; Korkman et al. (2007)) | The theory of mind subtest measures understanding of mental functions and other people's perspectives. In the first task, questions are asked to the participant about different verbal scenarios measuring understanding of beliefs, intentions, others' thoughts, ideas and comprehension of figurative language. In the second task, participants have to match facial emotional expressions, from photographs of children's faces, to a scenario. The total raw score willl be age-adjusted. Higher scores mean better outcomes. | Assessment at Time 2 (immediately after the intervention for learning group; pre-intervention for waiting group) | 
| Theory of Mind (NEPSY-II; Korkman et al. (2007)) | The theory of mind subtest measures understanding of mental functions and other people's perspectives. In the first task, questions are asked to the participant about different verbal scenarios measuring understanding of beliefs, intentions, others' thoughts, ideas and comprehension of figurative language. In the second task, participants have to match facial emotional expressions, from photographs of children's faces, to a scenario. The total raw score willl be age-adjusted. Higher scores mean better outcomes. | Assessment at Time 3 (3 months post-intervention for learning group; immediately after the intervention for waiting group) | 
| Flanker Visual Filtering Task (Christ, Kester, Bodner, & Miles, 2011) | The Flanker Visual Filtering Task was used to assess attentional control and information processing speed. Each trial showed a horizontal row of five fish. The participant was asked to respond as quickly as possible to whether the central fish was facing to the left or right. Congruent trials were the ones with all five fish in the horizontal row pointing in the same direction and incongruent trials were the ones with the four distracting fishes pointing in the opposite direction of the central target fish. Reaction time of the congruent condition and of the incongruent condition were used to assess information processing speed, and the inhibition score (reaction time in incongruent conditions - reaction time in congruent conditions) was used as a measure of attentional control. Higher scores (reaction time) mean worse outcomes. | Assessment at Time 1 (pre-intervention for learning group; pre-treatment as usual for waiting group) | 
| Flanker Visual Filtering Task (Christ, Kester, Bodner, & Miles, 2011) | The Flanker Visual Filtering Task was used to assess attentional control and information processing speed. Each trial showed a horizontal row of five fish. The participant was asked to respond as quickly as possible to whether the central fish was facing to the left or right. Congruent trials were the ones with all five fish in the horizontal row pointing in the same direction and incongruent trials were the ones with the four distracting fishes pointing in the opposite direction of the central target fish. Reaction time of the congruent condition and of the incongruent condition were used to assess information processing speed, and the inhibition score (reaction time in incongruent conditions - reaction time in congruent conditions) was used as a measure of attentional control. Higher scores (reaction time) mean worse outcomes. | Assessment at Time 2 (immediately after the intervention for learning group; pre-intervention for waiting group) | 
| Behaviour Rating Inventory of Executive Function, parent questionnaire (BRIEF; Gioia, Isquith, Guy, and Kenworthy (2000)) | Executive competences of young adolescents were assessed using the Behaviour Rating Inventory of Executive Function - parent questionnaire version (BRIEF) evaluating attention, hyperactivity and impulsivity in everyday life. The BRIEF comprises 86 items over two standardised subscales, the Behavioural Regulation Index (BRI) and the Metacognition Index (MI), as well as a global score called the Global Executive Composite (GEC). These 3 scores will be used as a measure of executive function in daily life. Higher scores mean worse outcomes. | Assessment at Time 1 (pre-intervention for learning group; pre-treatment as usual for waiting group) | 
| Behaviour Rating Inventory of Executive Function, parent questionnaire (BRIEF; Gioia, Isquith, Guy, and Kenworthy (2000)) | Executive competences of young adolescents were assessed using the Behaviour Rating Inventory of Executive Function - parent questionnaire version (BRIEF) evaluating attention, hyperactivity and impulsivity in everyday life. The BRIEF comprises 86 items over two standardised subscales, the Behavioural Regulation Index (BRI) and the Metacognition Index (MI), as well as a global score called the Global Executive Composite (GEC). These 3 scores will be used as a measure of executive function in daily life. Higher scores mean worse outcomes. | Assessment at Time 2 (immediately after the intervention for learning group; pre-intervention for waiting group) | 
| Behaviour Rating Inventory of Executive Function, parent questionnaire (BRIEF; Gioia, Isquith, Guy, and Kenworthy (2000)) | Executive competences of young adolescents were assessed using the Behaviour Rating Inventory of Executive Function - parent questionnaire version (BRIEF) evaluating attention, hyperactivity and impulsivity in everyday life. The BRIEF comprises 86 items over two standardised subscales, the Behavioural Regulation Index (BRI) and the Metacognition Index (MI), as well as a global score called the Global Executive Composite (GEC). These 3 scores will be used as a measure of executive function in daily life. Higher scores mean worse outcomes. | Assessment at Time 3 (3 months post-intervention for learning group; immediately after the intervention for waiting group) | 
| Strength and Difficulties Questionnaire, parent questionnaire (SDQ; Goodman (2001)) | The SDQ parent questionnaire assess overall behaviour problems, emotional symptoms, hyperactivity and inattention, peer relationship problems, and prosocial behaviour. It rates participant's behaviour over the previous 6 months. The SDQ is scored on a Likert scale and includes 25 items, providing a Total Difficulties score. The Total Difficulties score will be use as a score of behavioural functionning in daily life. Higher scores mean worse outcomes. | Assessment at Time 1 (pre-intervention for learning group; pre-treatment as usual for waiting group) | 
| Strength and Difficulties Questionnaire, parent questionnaire (SDQ; Goodman (2001)) | The SDQ parent questionnaire assess overall behaviour problems, emotional symptoms, hyperactivity and inattention, peer relationship problems, and prosocial behaviour. It rates participant's behaviour over the previous 6 months. The SDQ is scored on a Likert scale and includes 25 items, providing a Total Difficulties score. The Total Difficulties score will be use as a score of behavioural functionning in daily life. Higher scores mean worse outcomes. | Assessment at Time 2 (immediately after the intervention for learning group; pre-intervention for waiting group) | 
| Strength and Difficulties Questionnaire, parent questionnaire (SDQ; Goodman (2001)) | The SDQ parent questionnaire assess overall behaviour problems, emotional symptoms, hyperactivity and inattention, peer relationship problems, and prosocial behaviour. It rates participant's behaviour over the previous 6 months. The SDQ is scored on a Likert scale and includes 25 items, providing a Total Difficulties score. The Total Difficulties score will be use as a score of behavioural functionning in daily life. Higher scores mean worse outcomes. | Assessment at Time 3 (3 months post-intervention for learning group; immediately after the intervention for waiting group) | 
| KIDSCREEN-27 - Self-reported questionnaire (Robitail et al., 2007) | The KIDSCREEN-27 is a self-reported questionnaire providing an index of health-related quality of life in children and adolescents. This instrument scored on a Likert scale and includes 27 items, providing a total score. The total score will be used as a measure of quality of life. Higher scores mean better outcomes. | Assessment at Time 1 (pre-intervention for learning group; pre-treatment as usual for waiting group) | 
| KIDSCREEN-27 - Self-reported questionnaire (Robitail et al., 2007) | The KIDSCREEN-27 is a self-reported questionnaire providing an index of health-related quality of life in children and adolescents. This instrument scored on a Likert scale and includes 27 items, providing a total score. The total score will be used as a measure of quality of life. Higher scores mean better outcomes. | Assessment at Time 2 (immediately after the intervention for learning group; pre-intervention for waiting group) | 
| KIDSCREEN-27 - Self-reported questionnaire (Robitail et al., 2007) | The KIDSCREEN-27 is a self-reported questionnaire providing an index of health-related quality of life in children and adolescents. This instrument scored on a Likert scale and includes 27 items, providing a total score. The total score will be used as a measure of quality of life. Higher scores mean better outcomes. | Assessment at Time 3 (3 months post-intervention for learning group; immediately after the intervention for waiting group) | 
| Social Goal Scale - Self-reported questionnaire (SGS; Patrick, Hicks, and Ryan (1997)) | The SGS is a self-reported questionnaire providing an index of social responsiveness and of goals setting which ultimately gets you involve with some social work. This instrument scored on a Likert scale and includes 11 items providing one total score that will be used as a measure of social goal. Higher scores mean better outcomes. | Assessment at Time 1 (pre-intervention for learning group; pre-treatment as usual for waiting group) | 
| Social Goal Scale - Self-reported questionnaire (SGS; Patrick, Hicks, and Ryan (1997)) | The SGS is a self-reported questionnaire providing an index of social responsiveness and of goals setting which ultimately gets you involve with some social work. This instrument scored on a Likert scale and includes 11 items providing one total score that will be used as a measure of social goal. Higher scores mean better outcomes. | Assessment at Time 2 (immediately after the intervention for learning group; pre-intervention for waiting group) | 
| Social Goal Scale - Self-reported questionnaire (SGS; Patrick, Hicks, and Ryan (1997)) | The SGS is a self-reported questionnaire providing an index of social responsiveness and of goals setting which ultimately gets you involve with some social work. This instrument scored on a Likert scale and includes 11 items providing one total score that will be used as a measure of social goal. Higher scores mean better outcomes. | Assessment at Time 3 (3 months post-intervention for learning group; immediately after the intervention for waiting group) | 
| Self-Compassion Scale - Short form - Self-reported questionnaire (SCS; Raes, Pommier, Neff, and Van Gucht (2011)) | The SCS is a self-reported questionnaire comprising 12 items, which produces a total global score. The total global score will be used as a measure of self compassion. Higher scores mean better outcomes. | Assessment at Time 1 (pre-intervention for learning group; pre-treatment as usual for waiting group) | 
| Self-Compassion Scale - Short form - Self-reported questionnaire (SCS; Raes, Pommier, Neff, and Van Gucht (2011)) | The SCS is a self-reported questionnaire comprising 12 items, which produces a total global score. The total global score will be used as a measure of self compassion. Higher scores mean better outcomes. | Assessment at Time 2 (immediately after the intervention for learning group; pre-intervention for waiting group) | 
| Self-Compassion Scale - Short form - Self-reported questionnaire (SCS; Raes, Pommier, Neff, and Van Gucht (2011)) | The SCS is a self-reported questionnaire comprising 12 items, which produces a total global score. The total global score will be used as a measure of self compassion. Higher scores mean better outcomes. | Assessment at Time 3 (3 months post-intervention for learning group; immediately after the intervention for waiting group) | 
| Letter-Number Sequencing (WISC-IV; Wechsler (2003)) | The letter-number sequencing is a working memory task. Sequences of number and letters are read to the participant, and he/she is then asked to re-sequence the numbers in numerical order from lowest to highest and then to sequence the letters in alphabetical order. Standardised total scores will be used as a measure of working memory. Higher scores mean better outcomes. | Assessment at Time 1 (pre-intervention for learning group; pre-treatment as usual for waiting group) | 
| Letter-Number Sequencing (WISC-IV; Wechsler (2003)) | The letter-number sequencing is a working memory task. Sequences of number and letters are read to the participant, and he/she is then asked to re-sequence the numbers in numerical order from lowest to highest and then to sequence the letters in alphabetical order. Standardised total scores will be used as a measure of working memory. Higher scores mean better outcomes. | Assessment at Time 2 (immediately after the intervention for learning group; pre-intervention for waiting group) | 
| Letter-Number Sequencing (WISC-IV; Wechsler (2003)) | The letter-number sequencing is a working memory task. Sequences of number and letters are read to the participant, and he/she is then asked to re-sequence the numbers in numerical order from lowest to highest and then to sequence the letters in alphabetical order. Standardised total scores will be used as a measure of working memory. Higher scores mean better outcomes. | Assessment at Time 3 (3 months post-intervention for learning group; immediately after the intervention for waiting group) | 
| Tempo Test Rekenen (De Vos, 1992) | The Tempo Test Rekenen is an arithmetic test consisting of 200 arithmetic number fact problems presented in five rows (one row with addition, one row with subtraction, one row with division, one row with multiplication, and one mixed problem row). Within each row, the problems increase in difficulty. Participant are asked to solve as many items as possible within 1 min per row. The total raw score will be age-adjusted for each participant and used as a measure of arithmetic competences. Higher scores mean better outcomes. | Assessment at Time 1 (pre-intervention for learning group; pre-treatment as usual for waiting group) | 
| Tempo Test Rekenen (De Vos, 1992) | The Tempo Test Rekenen is an arithmetic test consisting of 200 arithmetic number fact problems presented in five rows (one row with addition, one row with subtraction, one row with division, one row with multiplication, and one mixed problem row). Within each row, the problems increase in difficulty. Participant are asked to solve as many items as possible within 1 min per row. The total raw score will be age-adjusted for each participant and used as a measure of arithmetic competences. Higher scores mean better outcomes. | Assessment at Time 2 (immediately after the intervention for learning group; pre-intervention for waiting group) | 
| Tempo Test Rekenen (De Vos, 1992) | The Tempo Test Rekenen is an arithmetic test consisting of 200 arithmetic number fact problems presented in five rows (one row with addition, one row with subtraction, one row with division, one row with multiplication, and one mixed problem row). Within each row, the problems increase in difficulty. Participant are asked to solve as many items as possible within 1 min per row. The total raw score will be age-adjusted for each participant and used as a measure of arithmetic competences. Higher scores mean better outcomes. | Assessment at Time 3 (3 months post-intervention for learning group; immediately after the intervention for waiting group) | 
| Flanker Visual Filtering Task (Christ, Kester, Bodner, & Miles, 2011) | The Flanker Visual Filtering Task was used to assess attentional control and information processing speed. Each trial showed a horizontal row of five fish. The participant was asked to respond as quickly as possible to whether the central fish was facing to the left or right. Congruent trials were the ones with all five fish in the horizontal row pointing in the same direction and incongruent trials were the ones with the four distracting fishes pointing in the opposite direction of the central target fish. Reaction time of the congruent condition and of the incongruent condition were used to assess information processing speed, and the inhibition score (reaction time in incongruent conditions - reaction time in congruent conditions) was used as a measure of attentional control. Higher scores (reaction time) mean worse outcomes. | Assessment at Time 3 (3 months post-intervention for learning group; immediately after the intervention for waiting group) | 
| Reality Filtering Task (Liverani et al., 2017; Schnider, 2018) | The Reality Filtering task child-adapted version was used to assess recognition memory and orbitofrontal reality filtering. It consisted of a continuous recognition task composed of two runs with the same picture set but arranged in different order. Accuracy of the second run (D2) and Temporal Context Confusion index (TCC as defined by Schnider, 2018) measures reality filtering. Higher scores mean better outcomes. | Assessment at Time 1 (pre-intervention for learning group; pre-treatment as usual for waiting group) | 
| Reality Filtering Task (Liverani et al., 2017; Schnider, 2018) | The Reality Filtering task child-adapted version was used to assess recognition memory and orbitofrontal reality filtering. It consisted of a continuous recognition task composed of two runs with the same picture set but arranged in different order. Accuracy of the second run (D2) and Temporal Context Confusion index (TCC as defined by Schnider, 2018) measures reality filtering. Higher scores mean better outcomes. | Assessment at Time 2 (immediately after the intervention for learning group; pre-intervention for waiting group) | 
| Reality Filtering Task (Liverani et al., 2017; Schnider, 2018) | The Reality Filtering task child-adapted version was used to assess recognition memory and orbitofrontal reality filtering. It consisted of a continuous recognition task composed of two runs with the same picture set but arranged in different order. Accuracy of the second run (D2) and Temporal Context Confusion index (TCC as defined by Schnider, 2018) measures reality filtering. Higher scores mean better outcomes. | Assessment at Time 3 (3 months post-intervention for learning group; immediately after the intervention for waiting group) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neuroimaging acquisition | (i) High resolution structural T1-weighted MP-RAGE (Magnetization Prepared Rapid Gradient Echo) sequence. (ii) Functional images were T2*-weighted with a multislice gradient-echo-planar imaging (EPI) sequence, including Resting-State fMRI data for which participants were asked to lie still with their eyes closed and engage into mind wandering and task-related activation paradigm (Flanker Visual Filtering Task, Reality Filtering task, Emotion Regulation task used to assessed emotional regulation functions (Samson, Kreibig, Soderstrom, Wade, & Gross, 2016) and the Recognition of Emotions in Contextual Scene task used to assessed facial emotional expression recognition based on contextual cues (Theurel et al., 2016)). (iii) Diffusion-weighted imaging (DWI) sequences were acquired with 1.3 mm3 isotropic voxels with four different shells. | pre-intervention (Time 1 for learning group; Time 2 for wainting group) | 
| Neuroimaging acquisition | (i) High resolution structural T1-weighted MP-RAGE (Magnetization Prepared Rapid Gradient Echo) sequence. (ii) Functional images were T2*-weighted with a multislice gradient-echo-planar imaging (EPI) sequence, including Resting-State fMRI data for which participants were asked to lie still with their eyes closed and engage into mind wandering and task-related activation paradigm (Flanker Visual Filtering Task, Reality Filtering task, Emotion Regulation task used to assessed emotional regulation functions (Samson, Kreibig, Soderstrom, Wade, & Gross, 2016) and the Recognition of Emotions in Contextual Scene task used to assessed facial emotional expression recognition based on contextual cues (Theurel et al., 2016)). (iii) Diffusion-weighted imaging (DWI) sequences were acquired with 1.3 mm3 isotropic voxels with four different shells. | immediately after the intervention (Time 2 for learning group; Time 3 for wainting group) |