The impact of mindfulness on functional brain connectivity and peripheral inflammation in breast cancer survivors with cognitive complaints

Simple Summary Cognitive impairment is a common side effect of cancer treatment and impacts the quality of life of cancer survivors. As there is currently no golden standard for the treatment of cancer-related cognitive impairment (CRCI), we investigated the potential of a mindfulness-based intervention to impact the underlying mechanisms of CRCI. Breast cancer survivors with cognitive complaints (n = 117) were randomly assigned to a mindfulness, physical training, or waitlist control group. Resting state functional MRI data and serum blood samples were collected and compared before and after the intervention. We could not identify differences between the groups in resting state functional connectivity. However, the functional organization of attention-, salience- and executive functioning-related neural networks differed between both intervention groups and the waitlist control group. Additionally, physical training could alter therapy-induced immune deregulation. In conclusion, physical training had the most pronounced effects on functional network organization and biomarkers of inflammation, two mechanisms that might be involved in CRCI. Background: Cancer-related cognitive impairment (CRCI) has been linked to functional brain changes and inflammatory processes. Hence, interventions targeting these underlying mechanisms are needed. In this study, we investigated the effects of a mindfulness-based intervention on brain function and inflammatory profiles in breast cancer survivors with CRCI. Methods: Female breast cancer survivors reporting cognitive complaints (n = 117) were randomly assigned to a mindfulness-based intervention (n = 43), physical training (n = 36), or waitlist control condition (n = 38). Region-of-interest (ROI) and graph theory analyses of resting state functional MRI data were performed to study longitudinal group differences in functional connectivity and organization in the default mode, dorsal attention, salience, and frontoparietal network. Additionally, bead-based immunoassays were used to investigate the differences in inflammatory profiles on serum samples. Measures were collected before, immediately after and three months post-intervention. Results: No ROI-to-ROI functional connectivity changes were identified. Compared to no intervention, graph analysis showed a larger decrease in clustering coefficient after mindfulness and physical training. Additionally, a larger increase in global efficiency after physical training was identified. Furthermore, the physical training group showed a larger decrease in an inflammatory profile compared to no intervention (IL-12p70, IFN-& gamma;, IL-1 & beta;, and IL-8). Conclusion: Both mindfulness and physical training induced changes in the functional organization of networks related to attention, emotion processing, and executive functioning. While both interventions reduced functional segregation, only physical training increased functional integration of the neural network. In conclusion, physical training had the most pronounced effects on functional network organization and biomarkers of inflammation, two mechanisms that might be involved in CRCI

Proton therapy of a pregnant patient with nasopharyngeal carcinoma

Background and purpose: Radiotherapy during pregnancy is rarely administered due to lack of data and practical challenges. This is the first detailed report of proton therapy as cancer treatment for a pregnant patient with nasopharyngeal carcinoma. Materials and methods: Pencil beam scanning proton therapy was prescribed to a pregnant patient to a total dose of 70 Gy (RBE) to the therapeutic CTV and 54.25 Gy to the prophylactic CTV, delivered in 35 fractions with a simultaneous integrated boost technique. Results: Phantom measurements showed a thirty-fold decrease in fetal radiation dose when using proton compared to photon therapy, with a total fetal dose of 5.5 mSv for the complete proton treatment, compared to 185 and 298 mSv for the photon treatment with and without lead shielding, respectively. After adminstering proton therapy during pregnancy, at 39 weeks of gestation, a healthy boy with a birthweight on the 83th percentile was delivered. Pediatric follow-up at 2 months of age of the offspring showed normal growth and age-adequate motor development with no signs of neurological problems. MR follow-up of the tumor 3 months after the end of treatment showed complete remission. Conclusion: This case demonstrates the potential of proton therapy for treatment during pregnancy. Compared to photon therapy, proton therapy can significantly limit fetal dose, while simultaneously offering a more optimized treatment to the patient

Effects of prenatal exposure to cancer treatment on neurocognitive development: an MRI and ERP study

About 1 in 1000 pregnancies is complicated by maternal cancer, a diagnosis which confronts families and caregivers with difficult medical and ethical decisions, with potential long-lasting consequences for both mother and child. While studies have indicated reassuring outcomes for the child after different therapies during pregnancy, subtle differences in birthweight, cardiac functioning and neuropsychological outcome have raised questions on the long-term effects of prenatal exposure to maternal cancer and its treatment. The main aim of this thesis is to provide solid data on the long-term effects of prenatal exposure to cancer and its treatment on neurocognitive development, with particular focus on the use of chemotherapy during pregnancy. Furthermore, we want to explore which treatment-related and secondary factors might play a role in the observed neurodevelopmental effects. For instance, many children are born preterm after cancer-complicated pregnancies, which has been associated with lower IQ scores and an increased risk of behavioral and neurocognitive problems. Advanced multimodal neuroimaging techniques, measuring different functional and structural characteristics of the brain, are used to investigate the multifaceted nature of neurodevelopment in these children. This information is then combined with data on mother and child from the International Network on Cancer, Infertility and Pregnancy (INCIP) registration and follow-up studies, in order to relate neuroimaging findings to the oncological and obstetrical history, as well as to the neuropsychological outcome. First, we investigated the impact of chemotherapy on brain volume in a longitudinal cohort of 121 young and older, non-pregnant, women with breast cancer, of whom 72 treated with chemotherapy, alongside 59 controls. We observed age-dependent cognitive decline and white matter volume expansion, potentially caused by chemotherapy-induced neuroinflammatory processes, with younger patients showing less cognitive decline and more white matter volume increase. These results suggest the younger brain to have a neuroprotective response to chemotherapy-induced neurotoxicity. Next, we applied event-related potentials to evaluate the development of executive functioning in 20 nine-year-old children who were prenatally exposed to chemotherapy, comparing with controls who where matched on a 1:1 ratio based on age, sex and gestational age at birth. We found children with prenatal chemotherapy exposure to have an impacted development of response inhibition and spatial attention. Moreover, both prenatal chemotherapy exposure and prematurity were found to affect neurocognitive processes of conflict monitoring. These findings indicate that cancer and/or chemotherapy during pregnancy might indeed impact neurodevelopment of the child, not limited to the effect of prematurity. Finally, multimodal MRI techniques were used to assess structural and functional brain development of 42 children born to cancer-complicated pregnancies, compared to matched controls. Cancer during pregnancy was associated with local differences in grey and white matter structure, but was not found to significantly affect functional connectivity or brain organization. While platinum derivatives showed an increased impact on gyrification of the left superior temporal gyrus, chemotherapy during pregnancy in general was not associated with a worse outcome. In summary, the work of this thesis describes a subtle impact of maternal cancer and its treatment on neurodevelopment of the child at the age of nine years. Although we, as well as others, observed the neurotoxic impact of chemotherapy in cancer patients, chemotherapy during pregnancy showed only a limited effect on the neurodevelopment of the child. Secondary mechanisms, such as the psychosocial impact of a cancer diagnosis during pregnancy, might have large contributions to the observed neurodevelopmental differences, and have to be explored in future research. Balancing the benefits of treating cancer during pregnancy against the subtle neurocognitive impact observed in this thesis, the current data favour cancer treatment during pregnancy, including chemotherapy, when clinically indicated.publisher: Elsevier articletitle: Effects of prenatal exposure to cancer treatment on neurocognitive development, a review journaltitle: NeuroToxicology articlelink: http://dx.doi.org/10.1016/j.neuro.2016.02.013 content_type: article copyright: © 2016 Elsevier B.V. All rights reserved.nrpages: 11status: publishe

Structural brain changes after a mindfulness-based intervention in breast cancer survivors with cognitive complaints

ObjectivesCancer-related cognitive impairment (CRCI) is a common side effect of breast cancer treatment and has been linked to structural brain abnormalities. As previous research showed that mindfulness-based interventions (MBI) might alter brain structure, we hypothesized that MBI can induce structural brain recovery after chemotherapy in breast cancer survivors with cognitive complaints.MethodFemale breast cancer survivors reporting cognitive complaints (n = 117) were randomly assigned to a mindfulness (n = 43), physical training (n = 36), or waitlist control condition (n = 38). Multimodal MRI was used to investigate differences between groups in gray matter volume changes using a voxel-based morphometry analysis, and white matter structure using a fixel-based whole-brain and tract-based analysis.ResultsNinety-five participants completed structural MRI scans before the intervention, immediately after, and 3 months post-intervention. Comparing MBI to the waitlist control group, results showed an increase in gray matter volume in the right primary motor cortex immediately after MBI compared to baseline. Tract-based analysis showed small regional differences within the corpus callosum between both intervention groups and the waitlist controls. No differences in the whole-brain white matter or between MBI and physical training could be identified.ConclusionsThis study showed that MBI may be associated with subtle short-term structural brain changes in a region involved in the control of voluntary movements and pain processing, which might indirectly impact cognitive functioning. However, no long-term effects were found, suggesting that longer interventions might be needed to widely affect brain structure and associated CRCI. Nonetheless, MBI might show promise as a non-invasive intervention in the context of CRCI.PreregistrationThe study was registered at clinicaltrial.gov (NCT03736460)

Correction to:Structural brain changes after a mindfulness-based intervention in breast cancer survivors with cognitive complaints

ObjectivesCancer-related cognitive impairment (CRCI) is a common side effect of breast cancer treatment and has been linked to structural brain abnormalities. As previous research showed that mindfulness-based interventions (MBI) might alter brain structure, we hypothesized that MBI can induce structural brain recovery after chemotherapy in breast cancer survivors with cognitive complaints.MethodFemale breast cancer survivors reporting cognitive complaints (n = 117) were randomly assigned to a mindfulness (n = 43), physical training (n = 36), or waitlist control condition (n = 38). Multimodal MRI was used to investigate differences between groups in gray matter volume changes using a voxel-based morphometry analysis, and white matter structure using a fixel-based whole-brain and tract-based analysis.ResultsNinety-five participants completed structural MRI scans before the intervention, immediately after, and 3 months post-intervention. Comparing MBI to the waitlist control group, results showed an increase in gray matter volume in the right primary motor cortex immediately after MBI compared to baseline. Tract-based analysis showed small regional differences within the corpus callosum between both intervention groups and the waitlist controls. No differences in the whole-brain white matter or between MBI and physical training could be identified.ConclusionsThis study showed that MBI may be associated with subtle short-term structural brain changes in a region involved in the control of voluntary movements and pain processing, which might indirectly impact cognitive functioning. However, no long-term effects were found, suggesting that longer interventions might be needed to widely affect brain structure and associated CRCI. Nonetheless, MBI might show promise as a non-invasive intervention in the context of CRCI.PreregistrationThe study was registered at clinicaltrial.gov (NCT03736460)

A BIDS compliant automated CSD fiber tracking pipeline for presurgical white matter mapping

Abstract accepted for Oral presentation. Presented 05/10/2019status: Published onlin

Virtual brain grafting: Enabling whole brain parcellation in the presence of large lesions

Brain atlases and templates are at the heart of neuroimaging analyses, for which they facilitate multimodal registration, enable group comparisons and provide anatomical reference. However, as atlas-based approaches rely on correspondence mapping between images they perform poorly in the presence of structural pathology. Whilst several strategies exist to overcome this problem, their performance is often dependent on the type, size and homogeneity of any lesions present. We therefore propose a new solution, referred to as Virtual Brain Grafting (VBG), which is a fully-automated, open-source workflow to reliably parcellate magnetic resonance imaging (MRI) datasets in the presence of a broad spectrum of focal brain pathologies, including large, bilateral, intra- and extra-axial, heterogeneous lesions with and without mass effect. The core of the VBG approach is the generation of a lesion-free T1-weighted input image which enables further image processing operations that would otherwise fail. Here we validated our solution based on Freesurfer recon-all parcellation in a group of 10 patients with heterogeneous gliomatous lesions, and a realistic synthetic cohort of glioma patients (n=100) derived from healthy control data and patient data. We demonstrate that VBG outperforms a non-VBG approach assessed qualitatively by expert neuroradiologists and Mann-Whitney U tests to compare corresponding parcellations (real patients U(6,6) = 33, z = 2.738, P < .010, synthetic-patients U(48,48) = 2076, z = 7.336, P < .001). Results were also quantitatively evaluated by comparing mean dice scores from the synthetic-patients using one-way ANOVA (unilateral VBG = 0.894, bilateral VBG = 0.903, and non-VBG = 0.617, P < .001). Additionally, we used linear regression to show the influence of lesion volume, lesion overlap with, and distance from the Freesurfer volumes of interest, on labelling accuracy. VBG may benefit the neuroimaging community by enabling automated state-of-the-art MRI analyses in clinical populations using methods such as FreeSurfer, CAT12, SPM, Connectome Workbench, as well as structural and functional connectomics. To fully maximize its availability, VBG is provided as open software under a Mozilla 2.0 license (https://github.com/KUL-Radneuron/KUL_VBG). Graphical abstract Image, graphical abstract Download : Download high-res image (208KB)Download : Download full-size image (A) shows T1 images from two patients with gliomatous lesions. VBG is a lesion replacement/filling workflow with one approach for unilateral lesions (uVBG) and one for bilateral lesion (bVBG). (B) shows the lesion filling and recon-all combination selected, (C) & (D) show the output, tissue segmentations (C) and whole brain parcellations (D). If VBG is not used (non-VBG) recon-all may quit without generating a parcellation (hard failure) shown on the lower left, or finish with some errors (soft failures) in the parcellations shown on the lower right. However, using either VBG method allows recon-all to complete where it had previously failed and also improves parcellation quality. (PAT = patient, VBG = virtual brain grafting, uVBG = unilateral VBG, bVBG = bilateral VBG

Cortical thinning and altered functional brain coherence in survivors of childhood sarcoma

High-dose chemotherapy is increasingly evidenced to be neurotoxic and result in long-term neurocognitive sequelae. However, research investigating grey matter alterations in childhood cancer patients remains limited. As childhood sarcoma patients receive high-dose chemotherapy, we aimed to investigate cortical brain alterations in adult survivors. We analyzed high-resolution structural (T1-weighted) MRI and resting-state functional MRI (rsfMRI), to derive structural and functional cortical information in survivors of childhood sarcoma, treated with high-dose intravenous chemotherapy (n = 33). These scans were compared to age- and gender- matched controls (n = 34). Cortical volume and thickness were investigated using voxel-based morphometry and vertex-wise surface-based morphometry. Brain regions showing significant group differences in volume or thickness were implemented as seeds of interest to estimate their resting state co-activity with other areas (i.e. functional coherence). We explored whether structural measures were associated with potential risk factors, such as age at diagnosis, and cumulative doses of chemotherapeutic agents (methotrexate, ifosfamide). Finally, we investigated the link between functional regional strength, neurocognitive assessments and daily life complaints. In patients relative to controls we observed lower grey matter volumes in cerebellar and frontal areas, as well as frontal cortical thinning. Cerebellar volume and orbitofrontal thickness appeared dose- and age-related, respectively. Cortical thickness of the parahippocampal area appeared lower, only if the group comparison was not adjusted for depression. This region specifically showed lower functional coherence, which was associated with lower processing speed. This study suggests cortical thinning as well as decreased functional coherence in survivors of childhood sarcoma, which could be important for both long-term attentional functioning and emotional distress in daily life. Frontal areas might be specifically vulnerable during adolescence.status: publishe

The effect of prenatal chemotherapy exposure on functional brain development: a prospective case-control functional MRI study.

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