Chemobrain Part 2: The Science Behind Chemobrain


Part 2 of my 3-part series focuses on the evidence behind chemobrain and how chemotherapy may impair cognition.

The first part of this blog focused on the basics of chemobrain. This section will focus on the science behind chemobrain, including the interpretation of imaging studies and the mechanisms by which chemotherapy may impair cognition. The third and final section will concentrate on how nurses can use this information to help patients cope with chemobrain.

What's the Science Behind Chemobrain? Is There Any Hard Evidence for It? Although breast cancer patients have been reporting symptoms of cognitive impairment for many years, the first scientific studies began appearing in the mid-1990s. Some of the first studies began exploring the impact of particular protocols, such as CMF, on cognition. But as studies progressed, it seemed that more questions arose than were being resolved. There were so many confounding factors, such as age, hormonal status, baseline cognitive performance, educational level, genetic predisposition, comorbidities that impact oxygenation, depression, anxiety, fatigue, pain, anemia, time since treatment, and dietary factors. How would it be possible to control for all those factors?

Thankfully, advances in neuroimaging have provided us with information that has moved the field forward. Functional MRI (fMRI) studies have documented that:

  • Chemotherapy results in both cerebral functional and structural changes,
  • The alterations correlated with complaints regarding impaired cognition and performance,
  • The alterations persist over time.

In an early study exploring functional changes in the brain due to chemotherapy, Ferguson et al9 had twin 60 year-old females, one of whom had been treated with chemotherapy, perform a series of tasks while undergoing an fMRI. The resulting images documented areas of hyperactivity in the chemotherapy-treated twin relative to the untreated twin, which the authors interpreted as areas of deficits due to chemotherapy.

Findings of several functional brain imaging studies have been reviewed by Reuter-Lorenz and Cimprich,10 and relative to “controls,” individuals treated with chemotherapy have been found to exhibit functional differences, including both areas of hyper- and hypoactivity during tasks, as well as differences in brain activity while the brain is at rest.

In addition, structural differences have been noted as well. de Ruiter et al11 compared brain images of women with breast cancer, some of whom received chemotherapy and some did not, and found decreases in volume and density of both white and grey matter in the group treated with chemotherapy. Chemotherapy-related reductions in grey matter have also been correlated with impairment in cognitive abilities.12

How Exactly Does Chemotherapy Affect the Brain? Merriman et al13 have constructed a model detailing a proposed mechanism by which cancer treatment may lead to cognitive changes: Cancer treatment (chemotherapy but also including surgery, radiation treatment, and hormonal therapy) combined with other clinical factors (inflammation, stress, fatigue, comorbidities, and co-occurring symptoms) lead to cytokine dysregulation, hormonal changes, and neurotransmitter dysfunction. This process, which may be moderated by baseline cognitive function, genetic variations and age, combine to create cognitive changes.

Fardell et al14 have put forth another model in which chemotherapy increases oxidative stress and inflammation, and decreases brain vascularization, neurogenesis and growth factors and catecholamines. These processes combine to decrease hippocampal function, leading to impaired learning and memory, and decrease frontal cortex function, which hinders executive function (planning and decision-making).


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  • Ferguson RJ, McDonald BC, Saykin AJ, et al: Brain structure and function differences in monozygotic twins: Possible effects of breast cancer chemotherapy. J Clin Oncol. 2007;25:3866-3870,
  • Reuter-Lorenz PA, Cimprich B: Cognitive function and breast cancer: Promise and potential insights from functional brain imaging. Breast Cancer Res Treat. 2013;137:33-43.
  • de Ruiter MB, Reneman L, Boogerd W, et al: Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: Converging results from multimodal magnetic resonance imaging. Human Brain Mapping. 2012;33:2971-2983,
  • McDonald BC, Conroy SK, Smith DJ, et al: Frontal gray matter reduction after breast cancer chemotherapy and association with executive symptoms: A replication and extension study. Brain Behav Immun. 2013;30:S117-S125.
  • Merriman JD, Von Ah D, Miaskowski C, et al: Proposed mechanisms for cancer- and treatment-related cognitive changes. Sem Oncol Nursing. 2013;29:260-269.
  • Fardel JE, Varcy J, Johnston IN, et al: Chemotherapy and cognitive impairment: Treatment options. Clin Pharmacol Ther. 2011;90:366-376.

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