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From OncoLog, September 2013, Vol. 58, No. 9

Advances in Neuroimaging Help Unveil the Mechanisms of Chemobrain

By Jill Delsigne 

Graphic: Models using composite data from functional magnetic resonance images

Models using composite data from functional magnetic resonance images obtained from multiple breast cancer survivors after chemotherapy show regions of the brain that were hyperactivated during a memory recall task (orange-red). The areas of hyperactivation were broadly distributed throughout the left and right hemispheres and the lateral (top row) and mesial (bottom row) cortexes. Image courtesy of Shelli Kesler, Ph.D., Stanford University Medical Center.

Chemobrain, a catchall term for the cognitive dysfunction and neurophysiological changes produced by chemotherapy toxicity, is an important quality-of-life issue for cancer survivors.

“Cognitive dysfunction associated with cancer and cancer therapy directly impacts our patients and their families,” said Jeffrey Wefel, Ph.D., an associate professor in the Department of Neuro-Oncology at The University of Texas MD Anderson Cancer Center.

Because the symptoms of chemobrain reported by patients resemble those of other disorders, such as depression, patients may be misdiagnosed with a mood disorder. Chemobrain, however, is not a psychological but a physiological disorder. Using state-of-the-art neuroimaging technology, researchers are exploring the underlying mechanisms of chemotherapy-related cognitive dysfunction, and understanding these mechanisms could lead to screening techniques or treatments for chemobrain.

Researchers led by Dr. Wefel reported in 2004 the first prospective, longitudinal study of chemobrain. Before then, chemobrain had been reported only in case reports and retrospective studies. The results of Dr. Wefel’s study demonstrated that chemobrain impairs memory, executive function, attention, and information processing speed. Having uncovered the functions affected by chemobrain, Dr. Wefel has since focused his research on finding the physiological causes of chemobrain.

Visualizing brain activity

Using structural and functional neuroimaging technology, researchers are beginning to understand the mechanisms of chemobrain and to detect chemotherapy-related cognitive dysfunction, which tends to be subtle. Functional magnetic resonance imaging (fMRI), which measures neural activity in the brain, can provide insight into how the brains of patients treated with chemotherapy function differently than those of cancer patients receiving other treatments.

According to Dr. Wefel, the emphasis in this area of research has expanded beyond merely characterizing the nature and prevalence of chemotherapy-related neurotoxicity. He and other researchers are using fMRI to find correlations between cognitive function and changes in brain morphology, brain functional activity patterns, and inflammatory cytokines as well as examining genetic risk factors that predispose patients to this neurotoxicity.

Structural imaging

Dr. Wefel’s research builds on knowledge gained from studies that employed other modalities, including standard MRI, which provides high-resolution snapshots of the brain that can be used to determine the volumes of white and gray matter. As of 2012, only 12 structural imaging studies in patients with chemobrain had been published. These studies showed volume reductions in both white and gray matter up to 10 years following the completion of chemotherapy and suggested that white matter may be particularly sensitive to damage. One study found permanent, long-term (after an average 21-year follow-up) reductions in total brain volume and gray matter in breast cancer patients who had received standard dosages of adjuvant chemotherapy.

Photo: Dr. Jeffrey Wefel
“We need to recognize the magnitude of these issues, the frequency of cognitive dysfunction across many cancer patient groups, and the profound effects of cognitive dysfunction on our patients’ lives.”

– Dr. Jeffrey Wefel

Changes in brain structure associated with chemotherapy correspond to the cognitive changes found on neuropsychological testing. For example, in one study, worse performance on cognitive tests of attention and verbal memory correlated with lower fractional anisotropy (a sign of brain injury) in frontal, parietal, and occipital white matter tracts on diffusion tensor MRI, a modality that enables visualization of the microstructure of the white matter.

Functional imaging


Studies employing fMRI—which analyzes the dynamic patterns of neural activity while a patient engages in specific mental tasks—to assess the effects of chemobrain have shown physiological evidence of the condition’s cognitive symptoms. One study found decreased activity in the prefrontal cortex during a memory-encoding task in breast cancer survivors 3 years after they completed chemotherapy. Another study found that breast cancer survivors who had finished chemotherapy 5 years earlier (on average) had decreased left caudal lateral prefrontal activity, which corresponded to the decreased executive function experienced by these survivors.

fMRI studies have also shown how the brain compensates for the dysfunction produced by chemotherapy. “In patients with chemobrain, it takes more brain to do the same amount of work,” said Charles Cleeland, Ph.D., a professor in and chair of the Department of Symptom Research. In one study of a pair of monozygotic twins—a healthy twin and one who had breast cancer and received chemotherapy—fMRI showed that the chemotherapy-treated twin had increased task activation in the bilateral frontal and bilateral parietal brain regions when performing the easiest tasks. In other words, to accomplish even a simple task, the chemotherapy-treated twin’s brain had to engage more working memory circuitry. This compensation may help explain why some patients report symptoms of chemobrain but still perform within normal limits on cognitive tests. At some point, however, as the tasks increase in difficulty, these compensatory strategies might be inadequate.

Assessing functional neural networks

fMRI also reveals the ways in which chemotherapy changes neural networks during resting states, when the brain is not engaged in a specific mental task. Dr. Wefel recently collaborated with a research group at Stanford University in a functional neuroimaging study that showed disruptions in the default mode network (DMN) connectivity of breast cancer patients after chemotherapy. The DMN, one of the most studied resting state networks, is believed to function in implicit learning, autobiographical memory retrieval, prospection, and other internally focused processes.

The DMN normally deactivates during task performance, but in patients with chemobrain, the DMN does not deactivate as much as it should; this may be associated with slower response times and errors.

According to Dr. Wefel’s research, altered DMN connectivity could be a promising biomarker for cognitive dysfunction after chemotherapy. His research compared the DMN connectivity in breast cancer survivors who had undergone chemotherapy with that in survivors who were treated without chemotherapy and that in healthy controls. The patterns of DMN connectivity revealed by fMRI could distinguish survivors who had undergone chemotherapy from both other groups with 90%–91% accuracy. Disrupted DMN connectivity also is one of the more promising imaging biomarkers of mild cognitive impairment in aging.

Functional near-infrared spectroscopy

In addition to fMRI, functional near-infrared spectroscopy (fNIS) may hold promise in the study of chemobrain. Whereas fMRI measures the magnetic properties of hemoglobin to detect the variations in blood flow and in the distribution of oxygenated and deoxygenated hemoglobin that occur to meet the oxygen needs of active neurons, fNIS measures the light absorption by molecules at two or more wavelengths to estimate the changes in hemoglobin concentration. This imaging modality is less expensive and requires less restriction of movement than fMRI. And unlike fMRI, fNIS does not take place in a small chamber, an attribute that can lead some patients to experience claustrophobia during MRI examinations. The advantages of fNIS—especially its portability and affordability—may facilitate longitudinal study of chemobrain and its effects as patients age.

Current research

Photo: Dr. Charles Cleeland
“It is important to recognize that chemobrain has physiological causes; it is not a psychological disorder.”

– Dr. Charles Cleeland

Dr. Wefel is in the midst of conducting a longitudinal study of multimodal imaging, genetic profiling, and neuropsychological assessment approaches for chemobrain at MD Anderson. His group is also researching biomarkers that might identify women with breast cancer who are at increased risk for developing chemobrain. If a biomarker could identify high risk for chemobrain before a patient undergoes chemotherapy, the patient could be closely monitored or other treatment options might be considered. Also, identifying a high-risk population would allow physicians to study interventions aimed at preventing neurotoxicity.

Dr. Wefel’s study will include a comprehensive panel of neuropsychological tests and structural MRI and fMRI studies (including measures of both gray and white matter volume, white matter integrity, neural connectivity, resting state and task-based functional activity, and multivoxel spectroscopy to examine alterations in neurometabolites) both before and after women receive chemotherapy. Importantly, this research will focus on women 60 years and older, as most of the 53 studies of chemobrain in breast cancer patients to date have not assessed the cognitive effects of chemotherapy in older patients. Dr. Wefel hypothesizes that cancer and cancer therapy may accelerate the aging process and abnormal age-associated cognitive decline.

Of the 26 longitudinal studies of chemobrain, only four have included patients older than 60 years, despite the fact that more than half of women diagnosed with breast cancer are in this age group. Given the excellent survival rates for breast cancer patients, it is becoming increasingly important to research how chemotherapy affects cognitive ability as patients age.

In one study that used fMRI to measure network alterations in the brains of breast cancer patients who had undergone chemotherapy, the authors concluded that several of the network alterations they observed resembled the patterns that have been reported in studies of cognitive decline during normal aging. This study suggested that chemotherapy can accelerate the aging of the brain, but more research is necessary to produce definitive results.

Unknown mechanisms, undefined therapies

Because the mechanisms of chemobrain are not yet fully understood, few specific pharmaceutical treatments for this condition are available. However, neuropsychologists within the Section of Neuropsychology in MD Anderson’s Department of Neuro-Oncology provide a number of intervention services, which include cognitive compensatory strategy training, training in the use of cognitive prostheses (i.e., electronic devices that extend the capacity for cognition or perception), counseling to facilitate adjustment and adaptation, energy conservation plans to maximize cognitive efficiency, work modifications, and disability and capacity determination.

Recent evidence has suggested that a computerized neuroplasticity-based cognitive exercise program, meditation, and neuropsychological rehabilitation can improve cognition, reduce stress, and enhance quality of life. In addition, stimulants, such as methylphenidate, appear to be beneficial in patients with certain profiles of cognitive dysfunction and fatigue.

According to Dr. Wefel, physicians should not ignore the symptoms of chemobrain. “Neuropsychological services will need to be a cornerstone of comprehensive cancer care for many patients,” he said. “We need to recognize the magnitude of these issues, the frequency of cognitive dysfunction across many cancer patient groups, and the profound effects of cognitive dysfunction on our patients’ lives.”

Dr. Cleeland added, “It is important to recognize that chemobrain has physiological causes; it is not a psychological disorder. The worst thing you can say to a cancer patient with this disorder is, ‘it’s all in your head.’”

FURTHER READING

Jean-Pierre P. Integrating functional near-infrared spectroscopy in the characterization, assessment, and monitoring of cancer and treatment-related neurocognitive dysfunction. Neuro-Image. 2013 Jul 3. [Epub ahead of print]

Kesler SR, Wefel JS, Hosseini SMH, et al. Default mode network connectivity distinguishes chemotherapy-treated breast cancer survivors from controls. Proc Natl Acad Sci USA. 2013;110:11600–11605.

Wefel JS, Lenzi R, Theriault RL, et al. The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial. Cancer. 2004;100:2292–2299.

Wefel JS, Schagen SB. Chemotherapy-related cognitive dysfunction. Curr Neurol Neurosci Rep. 2012;12:267–275.

For more information, call Dr. Charles Cleeland at 713-745-3470 or Dr. Jeffrey Wefel at 713-563-0514.

Other articles in OncoLog, September 2013 issue:

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