Cerebral hyporesponsiveness and cognitive impairment 10 years after chemotherapy for breast cancer

Abstract

Chemotherapy is associated with cognitive impairment in a subgroup of breast cancer survivors, but the neural circuitry underlying this side effect is largely unknown. Moreover, long-term impairment has not been studied well. In the present study, functional magnetic resonance imaging (fMRI) and neuropsychological testing were performed in breast cancer survivors almost 10 years after high-dose adjuvant chemotherapy (chemo group, n = 19) and in breast cancer survivors for whom chemotherapy had not been indicated (control group, n = 15). BOLD activation and performance were measured during an executive function task involving planning abilities (Tower of London) and a paired associates task for assessment of episodic memory. For the chemo group versus the control group, we found hyporesponsiveness of dorsolateral prefrontal cortex in the Tower of London, and of parahippocampal gyrus in the paired associates task. Also, the chemo group showed significantly impaired planning performance and borderline significantly impaired recognition memory as compared to findings in the control group. Whole-brain analyses demonstrated hyporesponsiveness of the chemo versus the control group in very similar regions of bilateral posterior parietal cortex during both the Tower of London and the paired associates task. Neuropsychological testing showed a relatively stable pattern of cognitive impairment in the chemo group over time. These results indicate that high-dose adjuvant chemotherapy is associated with long-term cognitive impairments. These impairments are underpinned by (a) task-specific hyporesponsiveness of dorsolateral prefrontal cortex and parahippocampal gyrus, and (b) a generalized hyporesponsiveness of lateral posterior parietal cortex encompassing attentional processing.

Figure 1

Tower of London (ToL). In the planning condition (A), subjects saw a starting configuration together with a target configuration with the instruction to “count the number of steps” required to achieve the target configuration. One bead could be moved at a time and only when there was no other bead on top. Two possible answers were shown. Subjects had to press the button corresponding to the side (left or right) of the screen where the correct answer was presented. In the baseline condition (B), subjects had to count the total number of yellow and blue beads. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 2

Paired Associates task. During associative learning, subjects indicated whether the depicted person matched the interior design by indicating “resident” or “visitor.” In the low level baseline, subjects made a left or right button press according to the direction of the arrows. In the high level baseline, subjects indicated whether they were looking at two identical pictures of a person or an interior design. Outside the scanner, subjects indicated whether they had seen the stimulus pair during scanning or not (recognition task). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 3

Tower of London (ToL). A: BOLD activations for the Active > Baseline contrast for breast cancer survivors after chemotherapy (Chemo) and breast cancer survivors without chemotherapy (Control), FDR corrected at P < 0.05; B: group interactions showing hyporesponsiveness of the chemo group versus the control group. Left: bilateral DLPFC (ROI analysis shown at P < 0.05), right: bilateral PPC (whole brain analysis shown at P < 0.01). Vertical bars show T‐values. C: Contrast estimates with 90% confidence intervals for group interactions at left DLPFC and right PPC (MNI coordinates −48, 6, 39 and 39, −60, 54, respectively). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 4

Paired associates task. A: BOLD activations for the Associative learning > Low‐level baseline contrast for breast cancer survivors after chemotherapy (Chemo) and breast cancer survivors without chemotherapy (Control), FDR corrected at P < 0.05. B: group interactions showing hyporesponsiveness of the chemo group versus the control group. Left: bilateral PHG (ROI analysis shown at P < 0.05), right: bilateral PPC (whole brain analysis shown at P < 0.01). Vertical bars show T‐values. C: Contrast estimates with 90% confidence intervals for group interactions at right PHC and right PPC (MNI coordinates 21, −39, −6 and 42, −60, 54, respectively). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 5

Regression analyses of performance with BOLD activation for the chemo group. A. Tower of London. Regression of performance with BOLD activation in right DLPFC (MNI coordinates 48, 24, 30, Z‐value = 3.52, P < 0.001, r = 0.77); B. Memory encoding/retrieval. Regression of memory recognition performance with BOLD activation during associative learning in left PHG (MNI coordinates −27, −18, −27, Z‐value = 3.61, P < 0.001, r = 0.79.