Functional connectivity changes in attention-related networks of childhood leukemia survivors

Charlotte Sleurs¹, Iris Elens², Jurgen Lemiere¹, Thibo Billiet³, Dorothée Vercruysse⁴, Patricia Bijttebier⁵, Marina Danckaerts², Rudi D'Hooghe⁶, Ron Peeters³, Stefan Sunaert³, Anne Uyttebroeck¹, Stefaan Van Gool⁷, and Sabine Deprez³

¹Pediatric Hemato-Oncology, UZ Leuven, Leuven, Belgium, ²Child and Adolescent Psychiatry, UZ Leuven, Leuven, Belgium, ³Radiology, UZ Leuven, Leuven, Belgium, ⁴Gynaecological Oncology, UZ Leuven, Leuven, Belgium, ⁵School Psychology and Child and Adolescent Development, KU Leuven, Leuven, Belgium, ⁶Biological Psychology, KU Leuven, Leuven, Belgium, ⁷Pediatric Hemato-Oncology, University Hospital, Aachen, Germany

Synopsis

Neurocognitive sequelae in childhood leukemia survivors are often related to attentional disfunctioning. We investigated whether altered functional brain connectivity might explain neurocognitive sequelae in childhood leukemia survivors. Resting state fMRI was investigated, by using ROI-based connectivity comparisons as well as dual regression analysis at whole-brain level. We demonstrated that the Default Mode Network (DMN) and Inferior Temporal Gyrus, was less functionally connected in childhood leukemia survivors compared to controls. This suggests an altered coherence between activity of the DMN and Fronto-Parietal Network (FPN). Finally, based on this specific connectivity we could predict clearly reduced cognitive flexibility of the patients.

PURPOSE

High dose methotrexate (MTX) is associated with neurocognitive sequelae in childhood leukemia survivors. Still, the underlying mechanisms remain enigmatic. Altered functional brain connectivity might offer an explanation. Previous research indicated that the default mode network (DMN) and fronto-parietal network (FPN) are involved in cognitive flexibility1. The goal of this study was to compare resting state functional connectivity (RSFC) between childhood leukemia survivors and control participants, within and between these networks.

METHODS

We acquired Rs-fMRI in survivors (n=35) ( [1.5:16yrs] since treatment, no cranial irradiation), and healthy age-matched controls (n=35). RSFC was examined using two analyses.

(1) For each network, connectivity (i.e. temporal correlation) matrices were constructed between spherical regions of interest (ROIs), based on earlier MNI coordinates ². Unpaired T-tests were used to compare RSFC between patients and controls.

(2) Secondly, independent component analysis (ICA) yielded sample-specific DMN and FPN masks. Through dual regression analysis, we assessed RSFC between each network and the rest of the brain. Both analyses were Bonferroni-corrected.

Finally, with a regression analysis we linked survivor’s RSFC to subjective cognitive complaints (Cognitive Failure Questionnaire), and objectively measured cognitive flexibility (subtask of the Amsterdam Neuropsychological Tasks) in. Socio-economic status (SES), age and relative MTX-dose were included as covariates.

RESULTS

ROI-based analyses showed differences within the FPN, at uncorrected level (Figure 1). However, these effects disappeared after Bonferroni-correction (p<.05). By contrast, dual regression analysis resulted in a significant lower connectivity in survivors between DMN and the inferior temporal gyrus (ITG), located in the FPN (p<.05) (Figure 2). This effect even remained after Bonferroni & multiple-voxel-correction. What is more, this specific connectivity correlated significantly with patient's impaired cognitive flexibility (p=.019), but not with their subjective complaints (p=.253).

CONCLUSION

Dual Regression Analysis showed that the DMN and ITG was less functionally connected in childhood leukemia survivors compared to controls, suggesting a modified coherence between the DMN and FPN. Furthermore, we showed that this connectivity at whole-brain level was related to reduced patient’s cognitive flexibility.

Acknowledgements

No acknowledgement found.

References

[1] Spreng, R. N., Sepulcre, J., Turner, G. R., Stevens, W. D., & Schacter, D. L. (2013). Intrinsic architecture underlying the relations among the default, dorsal attention, and frontoparietal control networks of the human brain. Journal of cognitive neuroscience, 25(1), 74-86.

[2] Watanabe, T., Hirose, S., Wada, H., Imai, Y., Machida, T., Shirouzu, I., ... & Masuda, N. (2013). A pairwise maximum entropy model accurately describes resting-state human brain networks. Nature communications, 4, 1370.

Figures

Figure 1. Uncorrected comparisons between region-of-interest (ROI)-based connectivity in the DMN (controls (group1) vs. survivors (group2)). Stronger connections in survivor group are indicated in blue, whereas stronger connections in the control group are indicated in red.

Figure 2. Uncorrected comparisons between region-of-interest (ROI)-based connectivity in the FPN (controls (group1) vs. survivors (group2)). Stronger connections in survivor group are indicated in blue, whereas stronger connections in the control group are indicated in red.

Figure 3. Result of the Dual Regression analysis: The Default Mode Network estimated by the ICA, is shown in orange. The region that is functionally stronger connected with the DMN for control participants than survivors, is depicted in blue (located in the ITG).

Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)

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