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Brain Changes in Pediatric OSA

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ClinicalTrials.gov Identifier: NCT05368077
Recruitment Status : Recruiting
First Posted : May 10, 2022
Last Update Posted : June 30, 2022
Sponsor:
Information provided by (Responsible Party):
Rajesh Kumar, PhD, University of California, Los Angeles

Study Description
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Brief Summary:
Obstructive sleep apnea (OSA) is highly prevalent in children and is often caused by overgrowth of the child's adenoids and/or tonsils. Consequently, adenotonsillectomy (removal of the tonsils and adenoids) is the most common treatment of OSA in children, although just the tonsils or adenoids may be removed depending on the case. As well, OSA in children is often associated with cognitive dysfunction and mood issues, suggesting brain changes due to the condition. However, the link between brain changes, cognitive and moods issues, and OSA in children has not been thoroughly explored. Therefore, this study aims to examine brain changes, cognition and mood in pediatric OSA subjects compared to controls as well as before and after removal of the adenoids and/or tonsils. This study hopes to enroll 70 subjects, ages 7-12 years, 35 healthy controls and 35 subjects diagnosed with OSA and scheduled for an adenoidectomy and/or tonsillectomy. Control subjects will schedule one visit to UCLA and OSA subjects will schedule two. Upon the first visit, all subjects will undergo cognitive, mood and sleep questionnaires and MRI scanning. That will be the duration of the controls' participation in the study; however, OSA subjects will return 6 months later (after their adenoidectomy and/ or tonsillectomy) to repeat the same procedures. Sleep quality, mood, cognition and brain images will be compared between OSA and controls and between OSA subjects before surgery and after surgery.

Condition or disease Intervention/treatment Phase
Pediatric Obstructive Sleep Apnea Procedure: Adenotonsillectomy Not Applicable

Detailed Description:
Pediatric obstructive sleep apnea (OSA) is a common and progressive syndrome accompanied by severe cognition, mood, and daytime behavioral issues, as well as poor school performance, presumably stemming from compromised neural tissue, induced by intermittent hypoxia and perfusion changes. However, it is unclear whether the brain tissue injury is in acute or chronic condition, and whether myelin is preferentially affected than axons, an essential step to understand, since interventions for neural repair/recovery differ for acute vs chronic and myelin vs axonal injury. Also, it is unclear whether accompanying brain changes in pediatric OSA have functional consequences, resulting to cognitive or mood deficits. In addition, intermittent hypoxia triggers a cascade of injurious processes affecting endothelial cells, but unclear whether regional cerebral blood flow (CBF) is reduced in pediatric OSA. Treatment methods for pediatric OSA include tonsillectomy and/or adenoidectomy, and it is unclear whether brain tissue changes, regional CBF, and neural responses to cognitive challenge improve post-treatment. Using diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI)-based procedures, acute and chronic tissue changes and axonal status and myelin integrity can be assessed. Regional brain CBF can be assessed by validated arterial spin labeling (ASL) imaging, and regional neural activity to cognitive challenge can be examined with blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (MRI). Thus, using 35 treatment-naïve, pediatric OSA and 35 control children, the specific aims are to; determine the nature and types of brain tissue injury, using DTI and DKI measures, in untreated pediatric OSA over healthy controls; identify regional brain CBF, using ASL imaging, and neural responses to cognitive challenge, using BOLD functional MRI in pediatric OSA over healthy children; assess cognitive (by the differential ability scale II and NEPSY II) and emotion functions (by the child behavior checklist) in pediatric OSA compared to control children, and examine relationships between brain injury and cognitive and emotion dysfunctions in pediatric OSA; and examine whether brain tissue changes, reduced CBF, and altered neural responses to cognitive challenge reverse, and cognition and mood signs improve after adenotonsillectomy at 6 months in pediatric OSA. In summary, the nature and types of brain injury, regional CBF changes, and neural responses to cognitive challenge, and whether brain tissue changes, altered CBF, and diminished neural responses, as well as mood and cognitive functions recover after adenotonsillectomy in pediatric OSA will be examined. Evaluation of pathological characteristics is essential to assess the mechanisms of damage, and to suggest intervention strategies before and after surgery. The findings will also help guide potential treatments to rescue/restore brain tissue (e.g., nonsteroidal anti-inflammatory drugs) and improve CBF that could be implemented to benefit cognitive and mood health, and improve academic performance in pediatric OSA.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Brain Changes in Pediatric Obstructive Sleep Apnea
Actual Study Start Date : May 14, 2022
Estimated Primary Completion Date : April 30, 2023
Estimated Study Completion Date : July 31, 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: 35 Pediatric Obstructive Sleep Apnea
The investigators will also determine whether brain tissue changes, reduced CBF, and altered neural responses to cognitive challenge reverse, and cognition and mood signs improve after standard surgical procedure "adenotonsillectomy" for breathing condition at 6 months in pediatric OSA.
 Procedure: Adenotonsillectomy
Adenotonsillectomy is a standard surgical procedure for pediatric OSA treatment, which involves removal of hypertrophied tonsils and adenoids.


Outcome Measures
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Primary Outcome Measures :
  1. Brain tissue changes between baseline and after adenotonsillectomy. [ Time Frame: 6 months ]
    The investigators will examine whether brain tissue changes reverse after adenotonsillectomy in pediatric obstructive sleep apnea subjects. The investigators will use diffusion tensor imaging based mean diffusivity and diffusion kurtosis imaging based mean kurtosis measures to examine brain tissue changes; both procedures examine brain tissue integrity with mean diffusivity showing reduced and mean kurtosis indicating increased values in acute tissue changes, and with mean diffusivity showing increased and mean kurtosis showing reduced values in chronic tissue changes.

  2. Regional brain cerebral blood flow changes between baseline and after adenotonsillectomy. [ Time Frame: 6 months ]
    Using arterial spin labeling magnetic resonance imaging, the investigators will assess if regional cerebral blood flow improves after standard obstructive sleep apnea surgery in pediatric subjects. The cerebral blood flow values reduce with hypo-perfusion and increase with hyper-perfusion.

  3. Neural response changes before and after adenotonsillectomy. [ Time Frame: 6 months ]
    Using functional magnetic resonance imaging, the investigators will examine whether neural responses in brain cognitive control sites to arithmetic cognitive challenge will improve after adenotonsillectomy compared to baseline in pediatric obstructive sleep apnea subjects.

  4. Cognitive symptoms examination after adenotonsillectomy surgery. [ Time Frame: 6 months ]
    The investigators will examine cognitive symptom changes after adenotonsillectomy in pediatric obstructive sleep apnea subjects. The investigators will use the Differential Ability Scale II for cognition evaluation. The Differential Ability Scale II scores range from 30-170, with reduced values indicating impaired cognition (General Conceptual Ability score <90, abnormal; General Conceptual Ability score > 90-170, normal).

  5. Cognition assessment after adenotonsillectomy in pediatric obstructive sleep apnea patients. [ Time Frame: 6 months ]
    The investigators will assess cognition changes after adenotonsillectomy in pediatric obstructive sleep apnea subjects. The investigators will use the NEuroPSYchological Assessment II for cognition examination. The NEuroPSYchological Assessment II scores will be lower with impaired cognition (Scaled score <8, abnormal; Scaled score 8-19, normal).

  6. Mood changes after adenotonsillectomy surgery. [ Time Frame: 6 months ]
    The investigators will examine mood changes after adenotonsillectomy in pediatric obstructive sleep apnea subjects using the Child Behavior Checklist. The Child Behavior Checklist scores will be higher with mood symptoms in pediatric obstructive sleep apnea compared to control children (t-scores, 65-69 borderline; >70 clinical).


Eligibility Criteria
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Ages Eligible for Study:   7 Years to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

OSA

  • Pediatric OSA subjects will be in the age range 7-12 years (upper and lower age limit will be chosen to avoid developmental-related brain changes and potential requirement of anesthesia for brain MRI)
  • Have a diagnosis of at least moderate OSA (AHI>5 events/hour) via overnight polysomnography at a sleep laboratory
  • Without obesity (≥95th percentile BMI for age and sex) to avoid perioperative issues
  • No treatment for the breathing condition
  • Undergoing for adenotonsillectomy.

Control subjects

  • Healthy children
  • Age-range from 7-12 years (within ±3 months)
  • Sex- and BMI-matched (±2 kg/m2) to pediatric OSA
  • No medications for brain disorders
  • Without any diagnosed neurological condition

Exclusion Criteria:

  • Previous history of diagnosed psychiatric diseases (depression and other brain disorders that may introduce brain injury)
  • Cystic fibrosis, concussion, and presence of space-occupying brain lesions
  • Metallic or electronic implants and other MRI-specific exclusion criteria
Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05368077


Contacts
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Contact: Rajesh Kumar, PhD 310-206-1679 rkumar@mednet.ucla
Contact: Bhaswati Roy, PhD 310-825-1808 broy@mednet.ucla.edu

Locations
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United States, California
UCLA Recruiting
Los Angeles, California, United States, 90095
Contact: Rajesh Kumar, PHD    310-825-1808    rkumar@mednet.ucla.edu   
Contact: Megan Carrier, MSHA    303-801-8961    mcarrier@mednet.ucla.edu   
Principal Investigator: Rajesh Kumar, PHD         
Sponsors and Collaborators
University of California, Los Angeles
  Study Documents (Full-Text)

Documents provided by Rajesh Kumar, PhD, University of California, Los Angeles:
Informed Consent Form  [PDF] April 5, 2021

More Information
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Additional Information:

Publications:
Ehlert, L., Roy, B., Sahib, A., Song, X., Singh, S., Townsley, M., Kang, D.W., Aysola, R., Wen, E., Woo, M.A., Harper, R.M. & Kumar, R. Diffusion tensor imaging shows brain tissue changes before and after positive airway pressure treatment in patients with obstructive sleep apnea. Society for Neuroscience Annual Meeting, Washington, DC, USA, 2017.
Sahib, A., Roy, B., Song, X., Singh, S., Aysola, R., Kang, D.W., Woo, M.A. & Kumar, R. Brain axonal and myelin changes after positive airway pressure treatment in patients with obstructive sleep apnea. Joint Annual Meeting International Society for Magnetic Resonance in Medicine, Paris, France, 2018.
Keith, T.Z., Low, J.A., Reynolds, M.R., Patel, P.G. & Ridley, K.P. Higher-order factor structure of the differential ability scales-II: consistency across ages 4 to 17. Psychology in the Schools 47: 676-697, 2010.
Achenbach, T.M. The child behavior checklist and related instruments. In: The use of psychological testing for treatment planning and outcomes assessment, 2nd ed, edited by. Mahwah, NJ, US: Lawrence Erlbaum Associates Publishers, 1999, p. 429-466.
Ellis, E.M., Zarndt, R., Ho, B., Hopkins, S. & Powell, F.L. Effects of non-steroid anti-inflammatory drugs on the human hypoxic ventilatory response and acclimatization. The FASEB Journal 26: 1150.1152- 1150.1152, 2012.
Ehlert, L., Roy, B., Sahib, A.K., Song, X., Singh, S., Townsley, M., Kang, D.W., Aysola, R., Wen, E., Woo, M.A., Harper, R.M. & Kumar, R. Diffusion tensor imaging shows brain tissue changes before and after positive airway pressure treatment in patients with obstructive sleep apnea. Society for Neuroscience Annual Meeting, Washington, D.C., 2017.
Paruthi, S. Evaluation of suspected obstructive sleep apnea in children. Edited by A.G. Hoppin, 2019.
Rubinstein, B.J. & Baldassari, C.M. An Update on the management of pediatric obstructive sleep apnea. Curr Treat Options Pediatr 1: 211-223, 2015.
Elliott, C.D. Differential Ability Scales : introductory and technical handbook. San Antonio: Psychological Corp: Harcourt Brace Jovanovich, 1990.
Achenbach TM, R.L. Manual for the ASEBA school-based forms and profiles. Burlington: University of Vermont, Research Center for Children , Youth and Families, 2001.
Barmpoutis, A. & Jiachen, Z. Diffusion kurtosis imaging: robust estimation from DW-MRI using homogeneous polynomials. 2011 IEEE International Symposium on Biomedical Imaging: From Nano to Macro, Chicago, IL: 262-265, 2011.

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Responsible Party: Rajesh Kumar, PhD, Professor, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT05368077    
Other Study ID Numbers: IRB#21-000408
First Posted: May 10, 2022    Key Record Dates
Last Update Posted: June 30, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Once the findings have been published, the MRI data (devoid of individual identifiers) will be placed on a read-only anonymous file transfer protocol (ftp) server, with access in the conventional fashion by email ID. Investigators, who request access to the data, will e-mail us with an academic e-mail address and provide a description of their proposed project/purpose. Access to the data will be given to requesting investigator, as long as project does not require personal identifiable information. Such storage represents a substantial commitment of capacity, since the data are expected to require several terabytes. The MRI data (both pre- and post-surgery at 6 months), cognition and mood scores, and OSA disease severity from the same population will be especially valuable to the field, as it is rare to have from patients with pediatric OSA.
Supporting Materials: Clinical Study Report (CSR)
Time Frame: One year after study completion.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Sleep Apnea Syndromes
Sleep Apnea, Obstructive
Apnea
Respiration Disorders
Respiratory Tract Diseases
 Sleep Disorders, Intrinsic
Dyssomnias
Sleep Wake Disorders
Nervous System Diseases