Brain structure, working memory and response inhibition in childhood leukemia survivors

Abstract

Introduction: Survival rates for children with acute lymphoblastic leukemia (ALL) approach 95%. At the same time, there is growing concern that chemotherapy causes alterations in brain development and cognitive abilities. We performed MRI measurements of white and gray matter volume to explore how variation in brain structure may be related to cognitive abilities in ALL survivors and healthy controls.

Methods: The sample included 24 male ALL survivors who had completed contemporary treatment 3-11 years prior, and 21 age- and sex-matched controls. Participants were between 8 and 18 years old. Working memory and motor response inhibition were measured with the N-Back and Stop Signal Tasks (SST), respectively. Participants underwent 3T structural MRI to assess white and gray matter volumes overall, lobe-wise, and in cortical and atlas-identified subcortical structures. Mental health was assessed with the Child Behavioral Checklist.

Results: ALL survivors performed more poorly on measures of working memory and response inhibition than controls. Frontal and parietal white matter, temporal and occipital gray matter volume, and volumes of subcortical white and gray matter structures were significantly reduced in ALL survivors compared with controls. Significant structure-function correlations were observed between working memory performance and volume of the amygdala, thalamus, striatum, and corpus callosum. Response inhibition was correlated with frontal white matter volume. No differences were found in psychopathology.

Conclusions: Compared with controls, a reduction in volume across brain regions and tissue types, was detectable in ALL survivors years after completion of therapy. These structural alterations were correlated with neurocognitive performance, particularly in working memory. Confirming these observations in a larger, more representative sample of the population is necessary. Additionally, establishing the time course of these changes-and the treatment, genetic, and environmental factors that influence them-may provide opportunities to identify at-risk patients, inform the design of treatment modifications, and minimize adverse cognitive outcomes.

Keywords: acute lymphoblastic leukemia; cognitive late effects; magnetic resonance imaging.

Figure 1

Schematic representations of the N‐Back and Stop Task. In the N‐back task (A), the participant hits “enter” if the displayed letter meets criterion, or “space” otherwise. For the 0‐back, “enter” is required whenever a particular letter (“z”) is shown. For the 1‐back and 2‐back, “enter” is required when the letter matches one shown 1‐ or 2‐times previously

Figure 2

Consort diagram. The diagram indicates the number of participants at each step of the study, and which were included in analyses. Where participants or data were excluded, the reason is listed

Figure 3

CBCL and YSR results. The distribution of CBCL (left) and YSR (right) T scores on DSM‐oriented scales in controls (pink) and ALL survivors (blue) are shown in box‐and‐whisker plots. The dotted red lines represent the cutoff at which scores are considered clinically relevant. Several individuals in both groups score above the “normal” range, but there is no significant difference between groups

Figure 4

N‐Back and Stop Task results. Performance on the N‐Back (Panel a) and Stop Task (Panel b) in controls (pink) and ALL survivors (blue). The graphs show means with 95% confidence limits. In Panel a, the N‐Back condition is plotted on the x‐axis and target accuracy on the y‐axis. ALL survivors (blue) made significantly more errors than controls (pink) in the 1‐back and 2‐back conditions (p = .0009 and .01 respectively). In Panel b, the groups are plotted on the x‐axis and response inhibition is plotted on the y‐axis. For response inhibition, lower scores represent better performance. ALL survivors (blue) were significantly slower on this this task compared with controls (pink) (p < .01). The asterisks mark significant differences between groups

Figure 5

White matter in ALL survivors and controls. Panel a: Lobe‐wise, normalized white matter volume in ALL survivors (blue) and controls (pink). Regions are listed on the x‐axis, along with the reference volume for controls in parentheses (used for normalization). Normalized volume is on the y‐axis. Means and 95% confidence intervals of the means are shown. Frontal and parietal white matter were significantly reduced in ALL survivors compared with controls (q < 0.1). Panel b: Deformation‐based morphometry results. The heatmaps represent change in volume between ALL survivors and controls, ranging from 0 to 20% difference (shown in regions with q < 0.1). Throughout subcortical regions, ALL survivors had significantly lower volume than did controls. Panel c: Atlas‐based analyses of subcortical differences between ALL survivors and controls were used to quantify volume in individual structures. Volume differences between ALL survivors and controls were significant for the corpus collasum (genu and rostrum) and the internal capsule (q < 0.1). Panel d: For each atlas structure, the relationship between age and volume were modeled. Shown is the left posterior corona radiata volume (lpCR) across ALL survivors (green = standard‐risk treatment; blue = high‐risk treatment) and controls (pink), showing on average a lower volume in ALL survivors. Panel e: Summary statistics (means and 95% confidence intervals) after normalization for age show decreased volume of subcortical white matter structures in ALL survivors (blue) relative to controls (pink). A complete list of comparisons is provided in Table 2. lpCR = Left posterior corona radiata; lCCG = left cingulum along cingulate gyrus; lsLF = left superior longitudinal fasciculus; lpCR = Left posterior corona radiata; lALIC = left anterior limb of the internal capsule; Total CC = total corpus callosum volume

Figure 6

Gray matter volume in ALL survivors and controls. Panel a: Lobe‐wise, normalized cortical volume in controls (pink) and ALL survivors. Regions are listed on the x‐axis, along with reference volume for controls in parentheses. Normalized volume is on the y‐axis. Means and 95% confidence intervals are shown. Temporal and occipital cortical volume were significantly reduced in ALL survivors compared with controls (q = 0.09). Panel b: Relationship between age and right amygdala volume across ALL survivors (green = standard‐risk treatment; blue = high‐risk treatment) and controls (pink), showing an average volume decrease in ALL survivors. Panel e: Summary statistics (means and 95% confidence intervals) for normalized volume of subcortical gray matter structures in ALL survivors (blue) and controls (pink). A complete list of comparisons is provided in Table 2. rAMY  =  right amygdala; lGP  = left globus pallidus; lST  = left striatum; rTH  = right thalamus

Figure 7

Regional brain structure and cognitive abilities. Panels a–d show correlations between subcortical volume measurements (right amygdala, right thalamus, left striatum and corpus collasum, respectively), and target accuracy on the 1‐back across ALL survivors (green = standard‐risk treatment; blue = high‐risk treatment) and controls (pink) (all significant correlations at q < 0.1). In panel e, the right frontal white matter volume is shown as correlated with response inhibition (p = .04, uncorrected). All measures are age‐corrected