Julie Tseng’s research while affiliated with SickKids and other places

Background While exercise training and metformin treatment have demonstrated preliminary cognitive improvements in pediatric brain tumor (PBT) survivors, the neuronal mechanisms underlying their cognitive improvements are unclear. Diffusion‐weighted metrics (e.g., fractional anisotropy [FA]) are commonly used to evaluate remyelination, but magnetization transfer imaging is thought to be more sensitive to myelin plasticity. Methods We compared white matter changes after exercise and metformin interventions by evaluating magnetization transfer ratio (MTR) and FA changes in irradiated PBT survivors who completed either an exercise (NCT01944761) or metformin pilot trial (NCT02040376) (30 participants: exercise n = 11, metformin n = 12, and control n = 7). Then, we explored correlations between MTR and cognitive outcomes. Results There were significant MTR changes in three brain regions (right forceps minor in both interventions, right inferior and superior longitudinal fasciculi in the exercise group), but no significant FA changes. MTR increases occurred in the right forceps minor in the exercise and metformin groups compared with the control group ( p < 0.033), and in the superior longitudinal fasciculus in the exercise group compared with the control group ( p = 0.016). Preliminary correlations between MTR and cognitive changes were not significant after correcting for multiple comparisons. Conclusions Our results suggest that 12 weeks of exercise or metformin intervention may promote remyelination in PBT survivors in brain regions involved in memory and executive function, and there may be differences in the brain regions affected by each intervention. This work sets the stage for larger clinical trials to identify definitive differences in MTR and validate their association with cognition.

Demyelination disrupts the transmission of electrical signals in the brain and affects neurodevelopment in children with disorders such as multiple sclerosis and myelin oligodendrocyte glycoprotein-associated disorders. Although cognitive impairments are prevalent in these conditions, some children maintain cognitive function despite substantial structural injury. These findings raise an important question: in addition to the degenerative process, do compensatory neural mechanisms exist to mitigate the effects of myelin loss? We propose that a multi-dimensional approach integrating multiple neuroimaging modalities, including diffusion tensor imaging, magnetoencephalography and eye-tracking, is key to investigating this question. We examine the structural and functional connectivity of the default mode and executive control networks due to their significant roles in supporting higher-order cognitive processes. As cognitive proxies, we examine saccade reaction times and direction errors during an interleaved pro- (eye movement towards a target) and anti-saccade (eye movement away from a target) task. 28 typically developing children, 18 children with multiple sclerosis and 14 children with myelin oligodendrocyte glycoprotein-associated disorders between 5 and 18.9 years old were scanned at the Hospital for Sick Children. Tractography of diffusion MRI data examined structural connectivity. Intracellular and extracellular microstructural parameters were extracted using a white matter tract integrity model to provide specific inferences on myelin and axon structure. Magnetoencephalography scanning was conducted to examine functional connectivity. Within groups, participants had longer saccade reaction times and greater direction errors on the anti- versus pro-saccade task; there were no group differences on either task. Despite similar behavioural performance, children with demyelinating disorders had significant structural compromise and lower bilateral high gamma, higher left-hemisphere theta and higher right-hemisphere alpha synchrony relative to typically developing children. Children diagnosed with multiple sclerosis had greater structural compromise relative to children with myelin oligodendrocyte glycoprotein-associated disorders; there were no group differences in neural synchrony. For both patient groups, increased disease disability predicted greater structural compromise, which predicted longer saccade reaction times and greater direction errors on both tasks. Structural compromise also predicted increased functional connectivity, highlighting potential adaptive functional reorganisation in response to structural compromise. In turn, increased functional connectivity predicted faster saccade reaction times and fewer direction errors. These findings suggest that increased functional connectivity, indicated by increased alpha and theta synchrony, may be necessary to compensate for structural compromise and preserve cognitive abilities. Further understanding these compensatory neural mechanisms could pave the way for the development of targeted therapeutic interventions aimed at enhancing these mechanisms, ultimately improving cognitive outcomes for affected individuals.

Improving cognitive sequelae in children treated for brain tumours (CTBT) requires accessible interventions. While instructor-led exercise in a hospital setting is efficacious, it is not extended to communities. Objectives We aimed to (i) develop a website with educational resources/tools for community health and fitness professionals (HFP) to deliver exercise for CTBT in community settings to improve cognition and (ii) assess its usability by community HFP. It was hypothesized that the website would be learnable, clear, satisfactory and efficient to deliver exercise. Methods A scoping review determined the state of eHealth resources to support exercise for CTBT and identified knowledge and resource gaps. Three focus groups with HFP who served cancer survivors in hospital or community settings (n = 13) identified user needs; content analysis identified themes. Gaps from the scoping review and themes from focus groups informed website content. A questionnaire assessed its usability by community HFP (n = 4). Descriptive statistics inferred the website's learnability, clarity, satisfaction and efficiency. Open-ended responses identified issues. Results The scoping review revealed a lack of eHealth resources supporting exercise to improve cognition in CTBT and education for HFP to deliver exercise. Six themes were identified in the focus groups. HFP rated the website as sufficiently learnable, clear, satisfactory and efficient. Two minor issues were reported and addressed. Conclusion The website marks one of the first eHealth resources to increase accessibility of intervention to improve cognitive sequelae and ultimately quality of life in CTBT. HFP also gain access to education and tools to deliver exercise in community settings.

Elucidating how adaptive and maladaptive changes to the structural connectivity of brain networks influences neural synchrony, and how this structure–function coupling impacts cognition is an important question in human neuroscience. This study assesses these links in the default mode and executive control networks during resting state, a visual-motor task, and through computational modeling in the developing brain and in acquired brain injuries. Pediatric brain tumor survivors were used as an injury model as they are known to exhibit cognitive deficits, structural connectivity compromise, and perturbations in neural communication. Focusing on information processing speed to assess cognitive performance, we demonstrate that during the presence and absence of specific task demands, structural connectivity of these critical brain networks directly influences neural communication and information processing speed, and white matter compromise has an indirect adverse impact on reaction time via perturbed neural synchrony. Further, when our experimentally acquired structural connectomes simulated neural activity, the resulting functional simulations aligned with our empirical results and accurately predicted cognitive group differences. Overall, our synergistic findings further our understanding of the neural underpinnings of cognition and when it is perturbed. Further establishing alterations in structural–functional coupling as biomarkers of cognitive impairments could facilitate early intervention and monitoring of these deficits.

BACKGROUND Exercise training and metformin treatment may improve cognition after cranial irradiation in pediatric brain tumors (PBT), but the neuronal mechanisms underlying the effect of these interventions remains unknown. Magnetization transfer imaging (MTI) is an imaging technique that may be sensitive to white matter microstructure – including myelin. METHODS In this work, we analyzed changes in magnetization transfer ratio (MTR) over a 12-week period in irradiated PBT survivors who participated in pilot clinical trials entailing 12 weeks of exercise training (exercise group, n=17), or metformin treatment (n=12). Pre- and post-intervention assessment included MRI scanning and neurocognitive tests. A no intervention control group, (n=7) was also included and seen before and after a 12 week period of time. We used a longitudinal Tract-Based Spatial Statistics (TBSS) approach to analyze differences in MTR across the 12 weeks in the three groups, using as covariates: age at baseline, sex, handedness, age at diagnosis and delay from diagnosis. Then we performed correlations between mean MTR changes and behavioral outcomes. RESULTS Clusters of significant increase in MTR were observed in the right temporal lobe in the exercise group after intervention and in the right minor forceps in the metformin group after treatment. These changes respectively correlated with higher performance in free recall score in exercise group and with higher performances in inhibitory control and attention in metformin group. There was no difference in MTR changes between groups nor within the control group. DISCUSSION This exploratory work suggests either a 12-week period of exercise training or metformin may promote myelination in PBT survivors in brain regions. These changes appear to be associated with improved memory and executive function, two core domains of neurocognitive deficit in this population.

Background The microstructural damage underlying compromise of white matter following treatment for paediatric brain tumours is unclear. We use multi-modal imaging employing advanced diffusion (DTI) and magnetization transfer (MTI) MRI methods to examine chronic microstructural damage to white matter in children and adolescents treated for paediatric brain tumour. Notably, MTI may be more sensitive to macromolecular content, including myelin, than DTI. Methods Fifty patients treated for brain tumours (18 treated with surgery +/- chemotherapy and 32 treated with surgery followed by cranial-spinal radiation; time from diagnosis to scan ~ 6 years) and 45 matched healthy children completed both MTI and DTI scans. Voxelwise and region of interest approaches were employed to compare white matter microstructure metrics (Magnetization Transfer Ratio (MTR); DTI - FA, RD, AD, MD) between patients and healthy controls. Results MTR was decreased across multiple white matter tracts in patients when compared to healthy children, p<0.001. These differences were observed for both patients treated with radiation and those treated with only surgery, p<0.001. We also found that children and adolescents treated for brain tumours exhibit decreased FA and increased RD/AD/MD compared to their healthy counterparts in several white matter regions, ps < 0.02. Finally, we observed that MTR and DTI metrics were related in multiple white matter tracts in patients, ps < .01, but not healthy control children. Conclusions Our findings provide evidence that the white matter damage observed in patients years after treatment of pediatric posterior fossa tumors, likely reflects myelin disruption.

In March 2020, C.T., a kind, bright, and friendly young woman underwent surgery for a midline tumor involving her septum pellucidum and extending down into her fornices bilaterally. Following tumor diagnosis and surgery, C.T. experienced significant memory deficits: C.T.'s family reported that she could remember things throughout the day, but when she woke up in the morning or following a nap, she would expect to be in the hospital, forgetting all the information that she had learned before sleep. The current study aimed to empirically validate C.T.'s pattern of memory loss and explore its neurological underpinnings. On two successive days, C.T. and age-matched controls watched an episode of a TV show and took a nap or stayed awake before completing a memory test. Although C.T. performed numerically worse than controls in both conditions, sleep profoundly exacerbated her memory impairment, such that she could not recall any details following a nap. This effect was replicated in a second testing session. High-resolution MRI scans showed evidence of the trans-callosal surgical approach's impact on the mid-anterior corpus callosum, indicated that C.T. had perturbed white matter particularly in the right fornix column, and demonstrated that C.T.'s hippocampal volumes did not differ from controls. These findings suggest that the fornix is important for processing episodic memories during sleep. As a key output pathway of the hippocampus, the fornix may ensure that specific memories are replayed during sleep, maintain the balance of sleep stages, or allow for the retrieval of memories following sleep.

Episodic memory involves personal experiences paired with their context. The Medial Temporal, Posterior Medial, Anterior Temporal, and Medial Prefrontal networks have been found to support the hippocampus in episodic memory in adults. However, there lacks a model that captures how the structural and functional connections of these networks interact to support episodic memory processing in children. Using diffusion‐weighted imaging, magnetoencephalography, and memory tests, we quantified differences in white matter microstructure, neural communication, and episodic memory performance, respectively, of healthy children (n = 23) and children with reduced memory performance. Pediatric brain tumor survivors (PBTS; n = 24) were used as a model, as they exhibit reduced episodic memory and perturbations in white matter and neural communication. We observed that PBTS, compared to healthy controls, showed significantly (p < 0.05) (1) disrupted white matter microstructure between these episodic memory networks through lower fractional anisotropy and higher mean and axial diffusivity, (2) perturbed theta band (4–7 Hz) oscillatory synchronization in these same networks through higher weighted phase lag indices (wPLI), and (3) lower episodic memory performance in the Transverse Patterning and Children's Memory Scale (CMS) tasks. Using partial‐least squares path modeling, we found that brain tumor treatment predicted network white matter damage, which predicted inter‐network theta hypersynchrony and lower verbal learning (directly) and lower verbal recall (indirectly via theta hypersynchrony). Novel to the literature, our findings suggest that white matter modulates episodic memory through effect on oscillatory synchronization within relevant brain networks. Research Highlights Investigates the relationship between structural and functional connectivity of episodic memory networks in healthy children and pediatric brain tumor survivors Pediatric brain tumor survivors demonstrate disrupted episodic memory, white matter microstructure and theta oscillatory synchronization compared to healthy children Findings suggest white matter microstructure modulates episodic memory through effects on oscillatory synchronization within relevant episodic memory networks

BACKGROUND It is crucial to develop effective and accessible interventions to improve cognitive sequelae in children treated for brain tumours (CTBT), as their impact on functional outcomes is significant. Instructor-led exercise training in a hospital setting is safe, feasible and efficacious to promote cognitive improvements in patients, however, most receive their post-treatment rehabilitative care in the community. eHealth is well positioned to support the delivery of community interventions. OBJECTIVE We aimed to i) develop a website that provides educational resources/tools for health and fitness professionals (HFP) to deliver exercise training to CTBT in the community with the goal of improving cognitive outcomes and ii) assess the website’s usability by community HFP. It was hypothesized that the website would be rated as learnable, clear, satisfactory and efficient to train on and deliver exercise training to CTBT in the community. METHODS A scoping review of academic literature, and publicly and commercially available eHealth resources was conducted. The scoping review determined the state of eHealth resources to support exercise training for CTBT and identify knowledge and resource gaps. Three focus groups were conducted with HFP with expertise serving cancer survivors in hospital (n=5) and community (n=8) settings to identify user needs and preferences. Content analysis identified themes. Gaps identified in the scoping review and themes from focus groups informed content that was integrated into the website build. Usability by community HFP (n=4) was assessed using a questionnaire (multiple choice, Likert-type, and open-ended questions). Descriptive statistics inferred elements of the website deemed sufficiently learnable, clear, satisfactory and efficient, and aspects with issues requiring modification. The mode of each multiple choice and Likert-type response was calculated to determine the value that appeared most often. Open ended responses identified issues. RESULTS The scoping review revealed a lack of eHealth resources to support exercise training to improve cognitive sequelae in CTBT and education for professionals to deliver training. Six themes were identified in the focus groups: instructor experience, instructor training, training on the intervention, venue considerations/suitability, exercise session planning and feedback. HFP reported the website to be sufficiently learnable, clear, satisfactory and efficient. Two minor issues were reported and addressed: a desire for discussion of appropriate language when instructing and correspondence between website activities and visual tools. CONCLUSIONS The development and usability testing of the website marks one of the first eHealth resources to increase accessibility of interventions typically delivered in a hospital setting to improve cognitive sequelae in CTBT. It also provides professionals the necessary education/tools for delivery in the community and provision of exercise intervention designed to improve cognitive outcomes. This website would afford an increase in the number of patients with access to interventions that promote cognitive improvement and ultimately enhance quality of life.