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Neural Correlates of Sleep Recovery Following Melatonin Treatment for Pediatric Concussion: a Randomized Control Trial

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Neural Correlates of Sleep Recovery Following Melatonin Treatment for Pediatric Concussion: a Randomized Control Trial medRxiv preprint doi: https://doi.org/10.1101/2020.08.02.20166918; this version posted August 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Neural correlates of sleep recovery following melatonin treatment for pediatric concussion: a randomized control trial Kartik K. Iyer1, Andrew Zalesky2 , Luca Cocchi3 , Karen M. Barlow1,4,5,6 1Child Health Research Centre, Faculty of Medicine, The University of Queensland, Brisbane, Australia. 2Melbourne Neuropsychiatry Centre & Department of Biomedical Engineering, The University of Melbourne, Australia. 3QIMR Berghofer Medical Research Institute, Clinical Brain Networks group, Australia. 4Department of Neurology, Queensland Children’s Hospital, Brisbane, Australia. 5Alberta Children's Hospital Research Institute, Calgary, Canada. 6University of Calgary, Calgary, Canada. Corresponding author: Dr Kartik K. Iyer Corresponding author’s address: Child Health Research Centre, Faculty of Medicine, The University of Queensland, Brisbane, Australia. Corresponding author’s phone and fax: +61 7 3069 7522 Corresponding author’s e-mail address: [email protected] Keywords: mild traumatic brain injury, concussion, brain connectivity, sleep, melatonin ABSTRACT Evidence-based treatments for children with persistent post-concussion symptoms (PPCS) are few and limited. Common PPCS complaints such as sleep disturbance and fatigue could be ameliorated via the supplementation of melatonin, which has significant neuroprotective and anti-inflammatory properties. This study aims to identify neural correlates of melatonin treatment with changes in sleep disturbances and clinical recovery in a pediatric cohort with PPCS. We examined structural and functional neuroimaging (MRI) in 62 children with PPCS in a randomized, double-blind, placebo- controlled trial of 3mg or 10mg of melatonin (NCT01874847). The primary outcome was the total youth self-report Post-Concussion Symptom Inventory (PCSI) score after 28 days of treatment. Secondary outcomes included the change in the sleep domain PCSI score and sleep-wake behavior (assessed using wrist-worn actigraphy). Whole-brain analyses of (i) functional connectivity (FC) of resting-state fMRI, and (ii) structural grey matter (GM) volumes via voxel-based morphometry were assessed immediately before and after melatonin treatment and compared to placebo in order to identify neural effects of melatonin treatment. Increased FC of posterior default mode network (DMN) regions with visual, somatosensory and dorsal networks was detected in the melatonin groups over time. FC increases also corresponded with reduced wake periods (r=-0.27, p=0.01). Children who did not recover (n=39) demonstrated significant FC increases within anterior DMN and limbic regions compared to those that did recover (i.e. PCSI scores returned to pre-injury level n=23) over time, (p=0.026). Increases in GM volume within the posterior cingulate cortex were found to correlate with reduced wakefulness after sleep onset (r=-0.32, p=0.001) and sleep symptom improvement (r=0.29, p=0.02). Although the melatonin treatment trial was negative and did not result in PPCS recovery (with or without sleep problems), the relationship between melatonin and improvement in sleep parameters were linked to changes in function-structure within and between brain regions interacting with the DMN. 1 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.08.02.20166918; this version posted August 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . INTRODUCTION Traumatic brain injuries (TBI) in children are one of the most common causes of neurological morbidity and mortality worldwide.1 Most children sustain a mild TBI (mTBI), and more than 25% of these children will develop persistent post-concussion symptoms (PPCS) at one-month post-injury.2, 3 Children with PPCS commonly experience a cluster of physical, psychological and behavioral symptoms. One of the most common complaints is the presence of sleep disturbances and difficulty maintaining regular sleep-wake rhythms.4, 5 The neural effects of these ongoing sleep disturbances in TBIs, which include insomnia, pleiosomnia, and fatigue, alongside headaches, dizziness and irritability common to PPCS are associated with changes in brain structure and function during recovery.6-12 In examining neural changes during pediatric PPCS recovery, fMRI connectivity studies have highlighted the significance of altered patterns of communications within brain regions comprising the default mode (DMN) and executive networks.11-15 In typically developing cohorts, sleep-related problems in children and adolescents are known to compromise the efficiency and connectivity of key nodes of the DMN, such as the posterior cingulate cortex (PCC).16, 17 Reports on changes to grey matter following PPCS, however, remain scarce. A recent pediatric study reported increased anisotropic diffusion in cortical and subcortical grey matter structures in thalamic and temporal cortices at 4-months post-injury.8 Though these findings highlight that changes in brain activity occur during recovery, little is known about the relationship of specific symptoms with structure-function alterations during recovery from PPCS. Adding to this literature, we recently reported that, in children with mTBI and PPCS, persisting sleep disturbance and fatigue are linked to decreases in functional connectivity and grey matter volumes within the posterior and anterior regions of the DMN one month following the injury.9 Given these evidences, the relationship between symptom resolution and brain network reorganization is likely to reveal important insights into the role of neuroplasticity and likelihood for recovery. Pharmacological and non-pharmacological treatments that seek to the alleviate PPCS are limited, often yielding mixed results.18 The supplementation of neuroprotective agents such as melatonin could help ameliorate common sleep and fatigue complaints present in individuals with PPCS, and in turn, help reduce overall symptom burden and improve brain functions during recovery. Previous studies which have examined increased sleep disturbances in TBI cohorts19-22 have indicated that decreased melatonin production is strongly associated with reduced sleep efficiency, overall sleep quality and increased wake periods after sleep onset (WASO). Further studies in children and adolescents with sleep-wake disorders and related fatigue, have shown that melatonin treatment can improve sleep onset, increase sleep duration and reduce daytime sleepiness,23 whilst improving other physical complaints such as post-traumatic headaches following a head injury.24 However, evidences linking melatonin treatment with improved sleep and brain network response is less understood in TBI-related cohorts. In consideration of existing evidences and prior work, the present study investigates the neural effects of melatonin as a treatment for children with PPCS and whether changes to anatomical and functional brain markers observed before and after treatment were associated with improvement in sleep parameters. Analyses of structural and functional MRI were performed in a randomized, double-blind, placebo-controlled clinical trial of melatonin in a pediatric PPCS cohort over a 4-week period, with neuroimaging obtained before and after treatment.25 A whole-brain connectomics approach was employed to ascertain treatment effects in conjunction with change in sleep parameters. This study hypothesized that, following melatonin treatment, associated changes in whole-brain grey matter and functional connectivity would enhance compensatory functions of the DMN and be positively associated with improvement in sleep parameters and overall recovery. METHODS Study design and participants 2 medRxiv preprint doi: https://doi.org/10.1101/2020.08.02.20166918; this version posted August 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . This study was a single-center, randomized, double-blind, placebo-controlled trial of melatonin administered in children (ages 8 to 18 years) with PPCS at 4 to 6 weeks post-injury, conducted at Alberta Children’s Hospital (NCT01874847) and has been reported previously.25 The clinical trial was conducted in accordance with Good Clinical Practice guidelines and enrollment occurred between February 2014 and April 2017. Participants were excluded if (1) they had had a previous concussion within 3-months; (2) a Glasgow Coma Scale (GCS) scores less than 13; (3) significant medical history including any subjects taking medications that were likely to affect neuroimaging and/or sleep; and (4) inability to complete questionnaires and/or neuropsychological evaluation. Participants who enrolled in the trial were also invited to participate in neuroimaging (MRI) scanning before and after treatment concurrent with completion of
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