Brain Activity Associated With Attention Deficits Following Chemotherapy for Childhood Acute Lymphoblastic Leukemia

Abstract

Background: The impact of contemporary chemotherapy treatment for childhood acute lymphoblastic leukemia on central nervous system activity is not fully appreciated.

Methods: Neurocognitive testing and functional magnetic resonance imaging (fMRI) were obtained in 165 survivors five or more years postdiagnosis (average age = 14.4 years, 7.7 years from diagnosis, 51.5% males). Chemotherapy exposure was measured as serum concentration of methotrexate following high-dose intravenous injection. Neurocognitive testing included measures of attention and executive function. fMRI was obtained during completion of two tasks, the continuous performance task (CPT) and the attention network task (ANT). Image analysis was performed using Statistical Parametric Mapping software, with contrasts targeting sustained attention, alerting, orienting, and conflict. All statistical tests were two-sided.

Results: Compared with population norms, survivors demonstrated impairment on number-letter switching (P < .001, a measure of cognitive flexibility), which was associated with treatment intensity (P = .048). Task performance during fMRI was associated with neurocognitive dysfunction across multiple tasks. Regional brain activation was lower in survivors diagnosed at younger ages for the CPT (bilateral parietal and temporal lobes) and the ANT (left parietal and right hippocampus). With higher serum methotrexate exposure, CPT activation decreased in the right temporal and bilateral frontal and parietal lobes, but ANT alerting activation increased in the ventral frontal, insula, caudate, and anterior cingulate.

Conclusions: Brain activation during attention and executive function tasks was associated with serum methotrexate exposure and age at diagnosis. These findings provide evidence for compromised and compensatory changes in regional brain function that may help clarify the neural substrates of cognitive deficits in acute lymphoblastic leukemia survivors.

© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

Functional magnetic resonance imaging (fMRI) brain activation for the continuous performance task (CPT) and the three anterior cingulate cortex (ANT) attentional networks. Images are displayed in neurological convention. All the activation maps had thresholds that were set at P < .001 (uncorrected) with an extent of 5 voxels for visualization. CPT > fixation (red): right cerebellum, bilateral insula, left thalamus, right midfrontal, left fronto-parietal, and right anterior cingulate cortices. Alerting network (center cue > no cue; pink): right midtemporal and bilateral fronto-parietal cortices. Orienting network (spatial cue > center cue; blue): the right lingual gyrus and bilateral occipital cortex. Conflict network (incongruent > congruent; green): bilateral insula, bilateral temporo-occipital, and right frontal cortices. ANT = attention network task; CPT = continuous performance task.

Figure 2.

Brain areas showing statistically significant correlations with clinical risk factors. Images are displayed in neurological convention. All the activation maps are shown with thresholds set at P < .001 (uncorrected) and extent of 5 voxels for visualization. Activation maps revealed neural correlates of altered brain function. Continuous performance task activation decreased in survivors diagnosed at a younger age in bilateral superior temporal and bilateral parietal cortices (red) and decreased with methotrexate area under the curve (MTX AUC) in the bilateral midfrontal, parietal, and right middle temporal areas (green). Conflict-related activity decreased in survivors diagnosed at younger ages in the left parietal lobe and right hippocampus (blue). Alerting-related activity increased with MTX AUC in the bilateral frontal, caudate nuclei, left putamen, and anterior cingulate cortex (pink). CPT = continuous performance task; MTX AUC = methotrexate area under the curve.

Figure 3.

Schematic representation of associations between brain activity and clinical risk factors in long-term survivors of acute lymphoblastic leukemia (ALL). Decreased activation in younger survivors could imply a compromised task involvement. Increased activity in prefrontal and subcortical brain regions during the attention network task (ANT; pink) and decreased activity in parietal and temporal regions during the continuous performance task (CPT; green) were both associated with higher methotrexate exposure and may suggest increased effortful processing as a method to compensate for inefficiency in posterior brain regions in patients at highest risk for attention deficits. Red: CPT–age at diagnosis; blue: conflict–age at diagnosis; green: CPT–methotrexate AUC; pink: alerting-methotrexate AUC. CPT = continuous performance task; MTX AUC = methotrexate area under the curve.