Chemotherapy-related cognitive impairment (CRCI) remains poorly understood in terms of the mechanisms of cognitive decline. Neural hyperactivity has been reported on average in cancer survivors, but it is unclear which patients demonstrate this neurophenotype, limiting precision medicine in this population. We evaluated a retrospective sample of 80 breast cancer survivors and 80 non-cancer controls, age 35-73, for which we had previously identified and validated three data-driven, biological subgroups (biotypes) of CRCI. We measured neural activity using the z-normalized percent amplitude of fluctuation from resting state functional magnetic resonance imaging (MRI). We tested established, quantitative criteria to determine if hyperactivity can accurately be considered compensatory. We also calculated brain age gap by applying a previously validated algorithm to anatomic MRI. We found that neural activity differed across the three CRCI biotypes and controls (F = 13.5, p < 0.001), with Biotype 2 demonstrating significant hyperactivity compared to the other groups (p < 0.004, corrected), primarily in prefrontal regions. Alternatively, Biotypes 1 and 3 demonstrated significant hypoactivity (p < 0.02, corrected). Hyperactivity in Biotype 2 met several of the criteria to be considered compensatory. However, we also found a positive relationship between neural activity and brain age gap in these patients (r = 0.45, p = 0.042). Our results indicated that neural hyperactivity is specific to a subgroup of breast cancer survivors and, while it seems to support preserved cognitive function, it could also increase the risk of accelerated brain aging. These findings could inform future neuromodulatory interventions with respect to the risks and benefits of up or downregulation of neural activity.

The authors have declared no competing interest.

This research was supported by the National Institutes of Health (AG078411 to MMM and R01CA172145, R01CA226080, and DP2OD004445 to SRK). The sponsor was not involved in any aspects of this study.

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The studies involving humans were approved by Stanford University Institutional Review Board. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

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