Impact of non-CNS childhood cancer on resting-state connectivity and its association with cognition

Janine S Spitzhüttl, Martin Kronbichler, Lisa Kronbichler, Valentin Benzing, Valerie Siegwart, Manuela Pastore-Wapp, Claus Kiefer, Nedelina Slavova, Michael Grotzer, Claudia M Roebers, Maja Steinlin, Kurt Leibundgut, Regula Everts, Janine S Spitzhüttl, Martin Kronbichler, Lisa Kronbichler, Valentin Benzing, Valerie Siegwart, Manuela Pastore-Wapp, Claus Kiefer, Nedelina Slavova, Michael Grotzer, Claudia M Roebers, Maja Steinlin, Kurt Leibundgut, Regula Everts

Abstract

Introduction: Non-central nervous system cancer in childhood (non-CNS CC) and its treatments pose a major threat to brain development, with implications for functional networks. Structural and functional alterations might underlie the cognitive late-effects identified in survivors of non-CNS CC. The present study evaluated resting-state functional networks and their associations with cognition in a mixed sample of non-CNS CC survivors (i.e., leukemia, lymphoma, and other non-CNS solid tumors).

Methods: Forty-three patients (off-therapy for at least 1 year and aged 7-16 years) were compared with 43 healthy controls matched for age and sex. High-resolution T1-weighted structural magnetic resonance and resting-state functional magnetic resonance imaging were acquired. Executive functions, attention, processing speed, and memory were assessed outside the scanner.

Results: Cognitive performance was within the normal range for both groups; however, patients after CNS-directed therapy showed lower executive functions than controls. Seed-based connectivity analyses revealed that patients exhibited stronger functional connectivity between fronto- and temporo-parietal pathways and weaker connectivity between parietal-cerebellar and temporal-occipital pathways in the right hemisphere than controls. Functional hyperconnectivity was related to weaker memory performance in the patients' group.

Conclusion: These data suggest that even in the absence of brain tumors, non-CNS CC and its treatment can lead to persistent cerebral alterations in resting-state network connectivity.

Keywords: childhood cancer survivors; cognitive late-effects; non-CNS childhood cancers; resting-state networks; rs-fMRI analysis.

Conflict of interest statement

All authors confirm that they do not have any conflict of interests.

© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.

Figures

FIGURE 1
FIGURE 1
Between‐group differences in region‐to‐region functional connectivity for the contrast “patients > controls”,p < .05 (FDR‐corrected), two‐sided. Red lines indicate stronger functional connectivity in patients than controls. Bluelinesindicate weaker functional connectivity in patients than controls. FDR, false discovery rate; L, left hemisphere; R, right hemisphere (using radiologists' convention)
FIGURE 2
FIGURE 2
Significant correlations between functional connectivity and verbal memoryand between functional connectivity and age in patients. Verbal memory (panel a) and age (panel b) are represented on thex‐axis. Region‐to‐region functional connectivities (Fisher'sZcorrelation coefficients) are represented on they‐axis. Panel (a): Relationship between verbal memory and functional connectivity between the right parahippocampal gyrus and the right parietal operculuminpatients (red) and controls (blue). Panel (b): Relationship between age and functional connectivity between the right parahippocampal gyrus and the right parietal operculuminpatients (red) and controls (blue). The red and blue lines represent the linear fits,the shaded areas represent the 95% CIs
FIGURE 3
FIGURE 3
Significant correlations between functional connectivity and cognitiveperformancein controls. Processing speed (panel a) and nonverbal intelligence(IQ; panel b) are represented on thex‐axis. Region‐to‐region functional connectivities (Fisher'sZcorrelation coefficients) are represented on they‐axis. Panel (a): Relationship between processing speed and functional connectivity between the frontal‐medial cortex and the right supramarginal gyrus across patients (red) and controls (blue). Panel (b): Relationship between nonverbal IQ and functional connectivity between the default mode network (lateral parietal area) and the cerebellum across patients (red) and controls (blue). The red and blue lines represent the linear fits and the shaded regions illustrate the 95% CIs

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