Neoplasms

Nervous System Diseases

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Brain Neoplasms

This group will undergo a working memory training program (Training A). The children will receive individual memory training based on the computer program Cogmed RM and will be supervised by trained neuropsychologists. Its efficacy in the use with children with cancer has been recently published. The children will undergo 25 training sessions "online"; each session takes about 45 minutes and consists of a selection of various tasks that target the different aspects of working memory.

This group will receive a physical training that can be executed at home (Training B). The training will be based on xbox Kinect games and comprise games and activities such as jump'n'run games, physical training, and dance activities. One training session will last approximately 45 minutes and will be performed 3 days a week over a period of 8 weeks (in total 25 sessions).

This group will serve as a waiting control group and will receive either the physical or the working memory training program after completion of the Neuropsychological Assessment II

(Training Details already described above)

Working Memory Training

Physical Training

Kurt Leibundgut, MD Prof

Cancer survival comes at a price: pediatric cancer survivors have a high risk for a wide range of cognitive difficulties, particularly survivors of cancer involving the central nervous system (CNS, e.g., brain tumors \[BT\]) are prone to neurocognitive impairments in areas such as executive functions, working memory, attention, memory, visuospatial and motor skills, processing speed as well as language. The aim of this interdisciplinary longitudinal study is to extend empirical knowledge on training and transfer effects in children with a history of cancer. It is hypothesized that early cognitive and physical interventions affect the remediation of pediatric cancer survivors in terms of cognitive functions. These changes are further hypothesized to be associated with white matter changes.

Aims and Hypotheses:

The overall purpose of this study is threefold: first, this study aims to deepen the knowledge about particular patterns of long-term cognitive impairment in pediatric cancer survivors. Understanding the nature of cognitive deficits in this population will be helpful for developing tailored therapeutic strategies. Second, the availability of well-designed child-friendly evidence-based training is of major clinical relevance to prevent school problems and further decline of cognitive functions. Third, the detection of training-induced neuronal changes in white-matter structure will give insight into the functional plasticity of the child's brain. In addition, training-induced changes in white matter would build strong evidence for the effect of the particular intervention.

The following hypotheses will be assessed in particular in the present study:

1. Children with history of brain tumors (BT) show particular problems in memory and attention, resulting in a general deficit in several cognitive areas. Children with a history of cancer without involvement of the CNS show fewer problems than children with a history of cancer with BT in the same cognitive domains but more problems than healthy control children.
2. Standardized working memory training leads to improvement of working memory performance. Transfer of the training effect especially to the areas of executive functions, memory and attention is expected.
3. Physical training leads to improvement of coordination, endurance and motor strength. A transfer to several cognitive areas (i.e. executive functions) and physical self-concept is expected.
4. After working memory training and physical training, the white matter structure of the patients will show significant changes in fractional anisotropy. There will also be changes in functional connectivity.
5. Neuropsychological effects of training will still be present after 6 months post training for both experimental groups.

All comparisons will be carried out on an individual level (intra-individual level, primary objective) as well as on an inter-individual level (between-groups comparisons, secondary objective). The level of significance is set to α = 0.05.

Participants:

Cancer Survivors: Researchers will include 150 children and adolescents aged 7-16 years who received an initial diagnosis of cancer with / without CNS (central nervous system) involvement in the past 10 years and terminated their treatment (surgery, radiation, and / or chemotherapy) at least 12 months prior to their participation in the study. Cancer survivors will be recruited at two different specialized pediatric units in Switzerland. In order to minimize the heterogeneity of the sample, children with a history of cancer without CNS involvement and only surgical removal of the tumor without subsequent radiation and / or chemotherapy will be excluded from the study. Because of the increased likelihood of drop-out of children with a history of cancer in a longitudinal study, more than the statistically required quantity of participants (\> 25 children per group) will be recruited to reach sufficient statistical power.

Healthy Controls: 40 healthy children and adolescents (matched for age and gender) will be included in the first assessment and serve as a healthy control sample. They will be recruited mainly via their siblings, who are included in the cancer survivor group and also from personal acquaintances among hospital staff and the study collaborators.

Design The present study is designed as a randomized stratified controlled trial including two intervention groups, one waiting group (children with a history of cancer \[both CNS+ and CNS-\] and a healthy control group (matched for age and gender). Some children of the patient group will be allocated to a waiting-control group to determine the training effects (their training starts later on). After random assignment to the respective conditions, the interventional material (XBOX or computer), will be installed at the participants home. Thereby, a supervised first training session will take place. The executive functions before and after as well as more details on the effects of a single intervention session (on enjoyment, arousal etc.) will be examined. Subsequently, the respective group will either follow a standardized, computerized working memory training or a physical training. Neuropsychological assessment will be carried out before the intervention / training and re-performed with all participants at the end of the memory training or physical training and at 6 months posttraining. Structural and functional imaging will be performed prior and shortly after working memory training and physical training. A 3 Tesla whole body MRI system will be used (Siemens; Erlangen, Germany). Anatomical imaging will be obtained using a sequence for T1 weighted structural brain imaging with whole brain coverage. Structural connectivity images will be acquired by using a q-ball sequence, functional connectivity will be measured by using a multiband echo planar imaging sequence (MB EPI). Pre- and post-processing of the structural data will be performed using SPM8 (Welcome Departement of Imaging Neuroscience, London) and MATLAB programs (MATLAB version 8.2). In order to perform functional connectivity analyses, the CONN fMRI connectivity toolbox 13.1 (Whitfield-Gabrieli \& Nieto-Castanon, 2012) is used. The fractional anisotropy maps are provide by the Siemens software and can be directly used for further statistical evaluation.

Interventions:

All 150 participants with a history of cancer will be randomly but in a stratified manner assigned to 3 groups (group A, B and C) (see Fig.1).

Training A: Group A (n1= 25 CNS+, n2 = 25 CNS-) will undergo working memory training program. The children will receive individual memory training based on the computer program Cogmed RM (Klingberg et al., 2005) and will be supervised by trained neuropsychologists. Its efficacy in the use with children with cancer has been recently published (e.g. Hardy et al., 2012). The children will undergo 25 training sessions "online"; each session takes about 45 minutes and consists of a selection of various tasks that target the different aspects of working memory. The difficulty level of the training is always adjusted based on the user's performance. The children will perform the memory training program at home over a period of 8 weeks. The child and a licensed Cogmed RM coach (neuropsychologist) will review and monitor the results of each day's training online. In an initial session at the Hospital (Zurich or Bern) the Cogmed RM coach plans and structures the training together with the child and the parents. The coach will provide weekly supervision and feedback on the child's performance and progress via phone call to the child's home. In the closing session with the child and the parents, the training experience will be reviewed .

Training B: Group B (n1= 25 CNS+, n2 = 25 CNS-) will receive a physical training that can be executed at home. The training will be based on xbox Kinect games (e.g. Shape Up) and comprise games and activities such as jump'n'run games, physical training, and dance activities. All material will be provided by the Inselspital Bern. One training session will last approximately 45 minutes and will be performed 3days a week over a period of 8 weeks.

Group C (n1= 25 CNS+, n2 = 25 CNS-) will serve as a waiting control group and will receive either the physical or the working memory training program after completion of the Neuropsychological Assessment II.

Efficacy of Cognitive and Physical Trainings in Pediatric Cancer Survivors

The primary endpoint in this study will be the participant's scores in executive functions based on the model of Miyake et al. (2000) which will be assessed using two different subtests: The subtest Block Recall from the Working Memory Test Battery for Children, WMTB-C (Pickering \& Gathercole, 2001) and the Color-Word Interference Test from the Delis-Kaplan Executive Function System™ (D-KEFS™, (Delis, Kaplan, \& Kramer, 2001).These tests will be administered at each neuropsychological testing, specifically, before and after the training intervention. It is expected to find a statistically significant amelioration in performance after the intervention (effect size f = 0.14 at a level of significance of α =0.05).

Insel Gruppe AG, University Hospital Bern

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

The investigator will be randomizing participants to complete Cogmed training on an iPad.

The investigator will be randomizing participants to complete Cogmed training in Virtual Reality.

Participants will complete five sessions of the Cogmed training program on an iPad. Participants will complete sessions over the course of one to two weeks while on campus for radiotherapy. Each session will take place in the Psychology Clinic and consist of 15 to 20 minutes of Cogmed training.

Cognitive training via iPad

Participants will complete five sessions of the Cogmed training program within virtual reality. Participants will complete sessions over the course of one to two weeks while on campus for radiotherapy. Each session will take place in the Psychology Clinic and consist of 15 to 20 minutes of Cogmed training.

Cognitive training via virtual reality

Heather Conklin, PhD

Andrew Heitzer, PhD, ABPP-CN

The objective of this study is to estimate the feasibility and acceptability of cognitive training in the virtual reality setting with children undergoing radiotherapy for brain tumors. To achieve this goal, the investigators plan to study children undergoing radiotherapy for brain tumors randomly assigned to cognitive training administered via an iPad or virtual reality. Both groups will also participate in cognitive testing and exams using functional near infrared spectroscopy (fNIRS) pre- and post-intervention. The questions to be investigated are:

1. Will cognitive training via virtual reality be feasible and acceptable for children undergoing radiotherapy for brain tumors as indicated by participation rates, adherence and frequency of side effects?
2. Will cognitive training via virtual reality provide neurocognitive benefits?
3. Will there be predictable changes in brain activity as measured by neuroimaging?

Findings from this study will be used to develop a larger, definitive trial with direct potential to improve cognitive outcomes for children treated for cancer using a safe and effective alternative to desktop- or laptop-based computerized cognitive interventions with great promise for improving quality of life.

The objectives of this study are:

Primary Objective:

• To estimate the participation rate, intervention adherence, and side effects of cognitive training in the virtual reality setting with children undergoing radiotherapy for brain tumors.

Secondary Objectives:

* To estimate the effect size of change in cognitive outcomes associated with cognitive training in the virtual reality setting relative to cognitive training on an iPad.
* To evaluate patterns of cortical activation (oxygenated and deoxygenated hemoglobin responses) pre- and post- cognitive training in the virtual reality setting and on an iPad.

The investigators will use a randomized, single blind (psychology examiner), parallel group design (cognitive training via iPad versus virtual reality) to test hypotheses about behavioral and neurophysiological changes associated with cognitive training in childhood cancer survivors. The investigators will recruit patients who are being treated for a BT with radiotherapy. Patients will participate in study sessions in the Psychology Clinic during routine visits to St. Jude for radiotherapy. fNIRS studies will be conducted with participants randomized to both the virtual reality and iPad groups pre- and post- Cogmed training sessions. The time period between pre- and post-cognitive assessments will be 2 to 4 weeks for both virtual reality and iPad groups.

Participants will be enrolled until 30 patients initiating radiotherapy for a BT are evaluable, with approximately 20 randomized to the virtual reality group and 10 to the iPad group. The investigators expect to recruit and screen up to 45 patients to ascertain 30 eligible participants.

Enrollment and assessment will be completed approximately 18 months after the study begins. Imaging data will be processed approximately two years after the study begins, and study findings will be disseminated within three years after the study begins.

Data management and statistical analysis will be provided locally by the Department of Psychology, the Neuroimaging Division of Radiological Sciences and the Biostatistics Department at St. Jude Children's Research Hospital

Cognitive Training in the Virtual Reality Setting With Children Undergoing Radiotherapy for Brain Tumors

The participation rate of this study (i.e., how many patients agree to participate/how many patients are approached for participation) and its 90% Blyth-Still-Casella exact binomial confidence intervals will be estimated for all participants.

The completion of cognitive training sessions is defined as completion of four out of five planned sessions. The rate of completion of cognitive training sessions and its 90% Blyth-Still-Casella exact binomial confidence intervals will be estimated for all participants, and separately for virtual reality and iPad administration groups.

Summary statistics, including counts and percentages of side effects/cyber sickness symptoms will be provided at pre-, immediate-, and 1-hour post-cognitive training for participants completing training via the iPad or virtual reality.

To estimate the effect size of change in cognitive outcomes associated with cognitive training in the virtual reality setting relative to cognitive training on an iPad. The effect size of the change in cognitive outcomes is defined as the difference in group means/standard deviation (e.g., Cohen's d). The effect size will be calculated separately for change in cognitive outcomes for cognitive training in the virtual reality setting or on iPad. The effect size of the difference of the change between two groups will also be estimated.

To evaluate patterns of cortical activation (oxygenated hemoglobin response) pre- and post- cognitive training on the iPad and in the virtual reality setting. The effects of VR and iPad based cognitive training will be assessed by n-back and grid-based spatial working memory tasks in conjunction with fNIRS brain imaging of the prefrontal cortex.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Efficacy of Cognitive and Physical Trainings in Pediatric Cancer Survivors	NCT02749877	Pediatric Cance...	Working Memory ... Physical Traini...	7 Years - 16 Years	Insel Gruppe AG, University Hospital Bern
Cognitive Training in the Virtual Reality Setting With Children Undergoing Radiotherapy for Brain Tumors	NCT05947045	Brain Tumor	Cognitive train... Cognitive train...	8 Years - 22 Years	St. Jude Children's Research Hospital

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