Alterations in brain activation during working memory processing associated with breast cancer and treatment: a prospective functional magnetic resonance imaging study

Abstract

Purpose: To prospectively examine alterations in working memory (WM) -associated brain activation related to breast cancer and treatment by using functional magnetic resonance imaging.

Patients and methods: Patients treated with chemotherapy (CTx+; n = 16) or without chemotherapy (CTx-; n = 12) and healthy controls (n = 15) were scanned during an n-back task at baseline (after surgery but before radiation, chemotherapy, and/or antiestrogen treatment), 1 month after completion of chemotherapy (M1), and 1 year later (Y1), or at yoked intervals for CTx- and controls. SPM5 was used for all image analyses, which included cross-sectional between-group and group-by-time interaction and longitudinal within-group analyses, all using a statistical threshold of 0.001.

Results: At baseline, patients with cancer showed increased bifrontal and decreased left parietal activation compared with controls. At M1, both cancer groups showed decreased frontal hyperactivation compared with controls, with increased hyperactivation at Y1. These cross-sectional findings were confirmed by group-by-time interaction analyses, which showed frontal activation decreases from baseline to M1 in patients compared with controls. Within-group analyses showed different patterns of longitudinal activation change by treatment group (CTx+ or CTx-), with prominent alterations in the frontal lobes bilaterally.

Conclusion: Significant frontal lobe hyperactivation to support WM was found in patients with breast cancer. Superimposed on this background, patients showed decreased frontal activation at M1, with partial return to the previously abnormal baseline at Y1. These functional changes correspond to frontal lobe regions where we previously reported structural changes in this cohort and provide prospective, longitudinal data that further elucidate mechanisms underlying cognitive effects related to breast cancer and its treatment.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

N-back performance data. Task performance data by group for low (0-back and 1-back) and high (2-back and 3-back) working memory load. Note pattern of decreased performance at 1 month after chemotherapy completion (M1) or yoked interval with recovery at 1 year after M1 visit (Y1) in patients with breast cancer treated with chemotherapy (CTx positive). CTx negative, patients not treated with chemotherapy; HC, healthy control.

Fig 2.

Baseline between-group differences in activation (3-back > 0-back contrast). Before adjuvant treatment, patients with breast cancer showed (A, B) hyperactivation of frontal regions bilaterally and (C, D) decreased left parietal activation compared with healthy controls (HCs), and patients treated with chemotherapy (CTx positive) showed (E) greater right frontal activation than those who did not receive chemotherapy (CTx negative; Pcrit [voxel-wise critical significance threshold] = .001; cluster extent [k] = 10).

Fig 3.

Interaction analyses showing between-group differences in brain activation from baseline to 1 month after completion of chemotherapy (M1; 3-back > 0-back contrast). (A) Decreased activation from baseline to M1 in patients with breast cancer treated with chemotherapy (CTx positive) compared with healthy controls (HCs). (B) Decreased activation from baseline to M1 in patients not receiving chemotherapy (CTx negative) compared with HCs. (C) Increased activation from baseline to M1 in CTx-positive patients compared with HCs. (D) Increased activation from baseline to M1 in CTx-positive patients compared with CTx-negative patients (Pcrit [voxel-wise critical significance threshold] = .001; cluster extent [k] = 10).

Fig 4.

Alterations in brain activation over time (3-back > 0-back contrast). (A) Brain activation decrease in patients with breast cancer treated with chemotherapy (CTx positive) from baseline to 1 month after chemotherapy completion (M1) with return to baseline levels of hyperactivation at 1 year after M1 visit (Y1), displayed over atlas template. (B) Activation pattern at left frontal peak displayed in (A) shown graphically for all groups at all time-points (MNI coordinates −38, 44, 6; cluster means extracted by using MarsBaR version 0.42). These frontal changes in CTx-positive patients overlapped with regions of gray matter change following the same pattern of change over time as illustrated in (C), in which brain activation change is shown in yellow, gray matter change is shown in blue, and the intersection of activation and gray matter change is shown in green (displayed by using MRIcroGL [http://www.cabiatl.com/mricrogl/]; Pcrit [voxel-wise critical significance threshold] = .001; cluster extent [k] = 10). CTx negative, not treated with chemotherapy; HC, healthy control.

Fig A1.

Mean activation map for 3-back > 0-back for all groups at all time-points showing the typical working memory activation pattern, including bilateral frontal, parietal, and cerebellar regions (Pcrit [voxel-wise critical significance threshold] = .05). This map was used as an explicit mask for all subsequent imaging analyses.