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Altered Arousal Regulation, Fatigue, and Processing Speed after Childhood Brain Tumor Radiotherapy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Clinical and translational research in pediatric oncology.ORCID iD: 0000-0002-1388-1826
Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.ORCID iD: 0000-0002-4310-3224
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Pediatric brain tumor survivors (PBTS) often experience fatigue and slowed processing speed after radiotherapy (RT). White matter loss and network alterations have been reported, but associations between pupil dilation, fatigue, processing speed and RT doses to organs at risk (OARs) remain unclear. Pupillometry reflects autonomic nervous system activity and may serve as a biomarker of arousal and cognitive control. This study assessed pupil dilation and fatigue in PBTS, and associations with processing speed and RT doses to OARs in PBTS. 

Methods: Twenty-one PBTS (mean age = 23 y), assessed 8–20 y after RT, and 50 age-matched controls (mean age = 26 y) completed a visual attention task with eye tracking. Pupil dilation was measured in response to unexpected auditory cues and during an anti-saccade task. Group differences were analyzed with independent t-tests (Cohen´s d). Associations between RT doses, pupil dilation, fatigue and processing speed were examined within the PBTS group. 

Results: PBTS showed greater pupil dilation to auditory cues and higher fatigue than controls (medium to large effects). Within PBTS, altered pupil dilation during anti-saccades correlated with higher fatigue and higher RT doses to the cerebellum and vermis. Fatigue was associated with slower processing speed and higher RT doses to the frontal lobes and optic nerves. Processing speed was strongly associated with higher RT doses to several OARs.

Conclusion: PBTS showed altered arousal regulation, fatigue, and slower processing speed associated with RT dose. Pupillometry and fatigue measures can complement neuropsychological assessment and may guide targeted rehabilitation.

Keywords [en]
Brain tumor, radiotherapy, fatigue, pupil dilatation, processing speed
National Category
Pediatrics Cancer and Oncology
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-577668OAI: oai:DiVA.org:uu-577668DiVA, id: diva2:2032652
Funder
Swedish Childhood Cancer Foundation, PR2018-0042, TJ018-0046
Note

Gustaf Ljungman and Johan Kundin Kleberg share senior authorship.

Available from: 2026-01-27 Created: 2026-01-27 Last updated: 2026-01-27
In thesis
1. Pediatric Brain Tumor Survivors after Radiotherapy: Long-Term Neurocognitive Outcomes, Oculomotor Function, and Arousal
Open this publication in new window or tab >>Pediatric Brain Tumor Survivors after Radiotherapy: Long-Term Neurocognitive Outcomes, Oculomotor Function, and Arousal
2026 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pediatric brain tumor survivors (PBTS) are at increased risk of long-term neurocognitive late effects, particularly following radiotherapy (RT), with processing speed being one of the domains most commonly impaired. The developing brain is particularly vulnerable to RT, and long-term neuropsychological follow-up is therefore recommended. Most studies addressing this topic have primarily focused on prescribed dose, planning target volume (PTV), and whole-brain radiotherapy (WBRT) dose, whereas the association between mean radiation dose to organs at risk (OAR) and neurocognitive outcomes remains insufficiently explored. Although neurocognitive functioning is routinely assessed through standardized neuropsychological testing, eye-tracking measures—including eye movements and pupillometry—may serve as sensitive complementary indicators of attention, processing speed, arousal, and executive functioning.

This thesis investigated neurocognitive outcomes in relation to different RT dose measures, including PTV dose and mean RT dose to established and potential new OAR, using both neuropsychological assessment and eye-tracking metrics. Additional clinical risk factors were also explored. Both retrospective and prospective studies of PBTS treated with RT between 2003-2015 were included. Neurocognitive function was assessed before, after, and 8–20 years post-RT. Long-term outcomes were related to RT dose parameters, and eye-tracking and fatigue were compared with age-matched controls.

Neurocognitive impairments were present prior to RT and became more prevalent with increasing time after treatment. Higher PTV dose was associated with lower working memory performance. Higher mean RT doses to several established and potential new OAR were associated with lower intelligence quotient and processing speed, as well as impaired oculomotor performance, altered pupil responses, and higher fatigue. WBRT and larger tumor size were also linked to poorer outcomes. 

In conclusion, the findings from this thesis show that PBTS are at elevated risk of long-term neurocognitive, oculomotor, and arousal-related difficulties following RT. Mean RT dose to OAR provides valuable information on radiation-related impairment beyond PTV dose. These findings underscore the need of structured neuropsychological follow-up. They further demonstrate the value of mean RT dose metrics an eye-tracking measures in evaluating radiation-related neurocognitive outcomes and guiding targeted treatment and rehabilitation strategies.  

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2026. p. 83
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 2229
Keywords
Pediatric brain tumor, radiotherapy, organs at risk, mean dose, neurocognition, processing speed, fatigue, eye-tracking, pupillometry
National Category
Pediatrics Cancer and Oncology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-577656 (URN)978-91-513-2726-6 (ISBN)
Public defence
2026-03-13, Universitetshuset, sal IV, Biskopsgatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Funder
Swedish Childhood Cancer Foundation, PR2013-0062,PR2018-0042, TJ2018-0046
Available from: 2026-02-19 Created: 2026-01-27 Last updated: 2026-02-20

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Söderström, HelenaBrocki, KarinMartinsson, UllaIsacsson, UlfLundin Kleberg, JohanLjungman, Gustaf

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