Introduction

Improved cancer treatments have resulted in longer survival of childhood cancer patients 1, 2. However, many survivors show difficulties in working memory, attention, cognitive switching, and visuospatial distortion, which have been attributed to chemotherapies used3-5 (ca. chemobrain). Although chemobrain has been well studied in breast cancer survivors, it has not been adequately studied in pediatric cancer patients. This study tested the hypothesis that chemotherapy-treated pediatric cancer survivors show reduced regional brain volumes and cortical thickness when compared to age-matched controls.

Methods

Fifteen chemotherapy-treated childhood cancer survivors diagnosed with a non-central nervous system cancer before the age of 18 and seventeen healthy age-matched controls were studied. Exclusions included prior cranial radiation therapy, known neuropsychiatric disorders, or contraindications for MRI. To evaluate for memory, attention and fine motor skills, subjects underwent the NEPSY-II, Purdue Pegboard and N-back working-memory tasks (0-back and 2-back paradigm). Parents also completed the Behavioral Rating Inventory of Executive Functioning (BRIEF) Parental Rating. Subjects completed a 3D-MPRAGE MRI at 3T (TR=2300ms, TE=3.24ms, FOV=223x223 mm, thk=0.87mm, and 0.9x0.9x0.9mm). Structural volumes were normalized to MNI space, and segmented using tissue probability maps. Voxel-based morphometry (VBM) and cortical thickness analysis were performed using CAT12 toolbox for SPM. Subcortical volumetric analysis was performed using FSL FIRST. Statistical and correlation analysis were performed using SPSS.

Results

Compared to controls, patients showed smaller total-brain volume (T=-2.1, p=0.043), gray-matter (T=-2.2, p=0.03), and white-matter (T=-2.1, p=0.046) volumes. VBM analysis showed smaller gray-matter volume in patients in the right orbitofrontal area (T=-5.1, p=0.001), right anterior prefrontal cortex (T=-4.8, p=0.001), and right supramarginal gyrus (T=-4.5, p=0.030) compared to controls. Cortical thickness analysis showed thinning of the right temporal pole (T=-6.2, p=0.002) and thickening of the right parahippocampal gyrus in the patient group. Patients revealed reduced volume in the right thalamus (T=-4.01, p=0.001), left thalamus (T=-4.6, p<0.001), and left nucleus accumbens (T=-3.2, p=0.004). On the working-memory task, patients had fewer correct responses and more incorrect and no-responses than controls. They also had longer response times on all trials compared to controls. The number of correct answers positively correlated with total brain volume (R2=0.459, p=0.018) and white-matter volume (R2=0.453, p=0.023) while the number of incorrect negatively correlated with total brain volume (R2=-0.424, p=0.031) and white-matter volume (R2=0.424, p=0.031). The number of no-response trials negatively correlated with the right thalamus volume (R2=-0.366, p=0.006) and the left nucleus accumbens volume (R2=-0.730, p<0.001). Patients showed deficits by NEPSY-II and Purdue Pegboard scores but none by BRIEF total score or sub-scores compared to normative data. However, these results did not significantly correlate with differences in regional brain volumes or cortical thicknesses.

Discussion

The anterior prefrontal cortex and supramarginal gyrus are involved in working memory function, albeit distinct components, as demonstrated by individuals with damage to these areas 7,8,9. The orbitofrontal area is associated with higher order reasoning and decision making8 while the thalamus is one of the major relay stations in the brain. These areas are involved in working memory, decision-making, and the relaying and processing of information. It is conceivable that they play some role in poorer working memory performance given the correlations observed between decreased global brain and white matter volumes with inferior performance on the working memory task. The right temporal pole also showed reduced cortical thickness which may be significant given that it is involved in memory retrieval, something known to be deficient in childhood cancer survivors 10. Alternatively, the cortical thickening of the right parahippocampal gyrus, which is known to be involved in memory encoding and retrieval, was increased in patients. Although it may seem contradictory, this cortical thickening may be associated with increased effort in memory and coordination tasks reported by chemobrain patients. There are only a handful of other studies on volumetric changes in pediatric cancer survivors. Neurocognitive scores measuring working memory and inhibition were correlated with the volumes of the amygdala, 11. No papers documented changes in cortical thickness.

Conclusion

Chemotherapy in pediatric cancer survivors likely caused changes in regional brain volumes and cortical thickness consistent with problems that survivors face with working memory and cognitive function.

Acknowledgements

No acknowledgement found.

References

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