Brain gray matter reduction and premature brain aging after breast cancer chemotherapy: a longitudinal multicenter data pooling analysis.

Brain gray matter (GM) reductions have been reported after breast cancer chemotherapy, typically in small and/or cross-sectional cohorts, most commonly using voxel-based morphometry (VBM). There has been little examination of approaches such as deformation-based morphometry (DBM), machine-learning-based brain aging metrics, or the relationship of clinical and demographic risk factors to GM reduction. This international data pooling study begins to address these questions. Participants included breast cancer patients treated with (CT+, n = 183) and without (CT-, n = 155) chemotherapy and noncancer controls (NC, n = 145), scanned pre- and post-chemotherapy or comparable intervals. VBM and DBM examined GM volume. Estimated brain aging was compared to chronological aging. Correlation analyses examined associations between VBM, DBM, and brain age, and between neuroimaging outcomes, baseline age, and time since chemotherapy completion. CT+ showed longitudinal GM volume reductions, primarily in frontal regions, with a broader spatial extent on DBM than VBM. CT- showed smaller clusters of GM reduction using both methods. Predicted brain aging was significantly greater in CT+ than NC, and older baseline age correlated with greater brain aging. Time since chemotherapy negatively correlated with brain aging and annual GM loss. This large-scale data pooling analysis confirmed findings of frontal lobe GM reduction after breast cancer chemotherapy. Milder changes were evident in patients not receiving chemotherapy. CT+ also demonstrated premature brain aging relative to NC, particularly at older age, but showed evidence for at least partial GM recovery over time. When validated in future studies, such knowledge could assist in weighing the risks and benefits of treatment strategies.

Brain connectivity tracks effects of chemotherapy separately from behavioral measures.

Several studies in cancer research have suggested that cognitive dysfunction following chemotherapy, referred to in lay terms as "chemobrain", is a serious problem. At present, the changes in integrative brain function that underlie such dysfunction remain poorly understood. Recent developments in neuroimaging suggest that patterns of functional connectivity can provide a broadly applicable neuromarker of cognitive performance and other psychometric measures. The current study used multivariate analysis methods to identify patterns of disruption in resting state functional connectivity of the brain due to chemotherapy and the degree to which the disruptions can be linked to behavioral measures of distress and cognitive performance. Sixty two women (22 healthy control, 18 patients treated with adjuvant chemotherapy, and 22 treated without chemotherapy) were evaluated with neurocognitive measures followed by self-report questionnaires and open eyes resting-state fMRI scanning at three time points: diagnosis (M0, pre-adjuvant treatment), 1 month (M1), and 7 months (M7) after treatment. The results indicated deficits in cognitive health of breast cancer patients immediately after chemotherapy that improved over time. This psychological trajectory was paralleled by a disruption and later recovery of resting-state functional connectivity, mostly in the parietal and frontal brain regions. Mediation analysis showed that the functional connectivity alteration pattern is a separable treatment symptom from the decreased cognitive health. Current study indicates that more targeted support for patients should be developed to ameliorate these multi-faceted side effects of chemotherapy treatment on neural functioning and cognitive health.

Cognitive dysfunction and symptom burden in women treated for breast cancer: a prospective behavioral and fMRI analysis.

Neural dysfunction and cognitive complaints are associated with chemotherapy for breast cancer although trajectory and contributory factors remain unclear. We prospectively examined neurocognition using fMRI and self-reported cognitive, physical and psychological symptoms in women treated with adjuvant chemotherapy over one year. Patients treated with (n = 28) or without (n = 34) chemotherapy for localized breast cancer and healthy controls (n = 30) performed a Verbal Working Memory Task (VWMT) during fMRI and provided self-reports at baseline (pre-adjuvant treatment), five- (M5) and 12-months (M12). Repeated measures ANOVA and multivariable regression determined change over time and possible predictors (e.g., hemoglobin, physical symptoms, worry) of VWMT performance, fMRI activity in the frontoparietal executive network, and cognitive complaints at M12. Trajectories of change in VWMT performance for chemotherapy and healthy control groups differed significantly with the chemotherapy group performing worse at M12. Chemotherapy patients had persistently higher spatial variance (neural inefficiency) in executive network fMRI-activation than both other groups from baseline to M12. Cognitive complaints were similar among groups over time. At M12, VWMT performance and executive network spatial variance were each independently predicted by chemotherapy treatment and their respective baseline values, while cognitive complaints were predicted by baseline level, physical symptoms and worry. Executive network inefficiency and neurocognitive performance deficits pre-adjuvant treatment predict cognitive dysfunction one-year post-baseline, particularly in chemotherapy-treated patients. Persistent cognitive complaints are linked with physical symptom severity and worry regardless of treatment. Pre-chemotherapy interventions should target both neurocognitive deficits and symptom burden to improve cognitive outcomes for breast cancer survivors.

The suppression of scale-free fMRI brain dynamics across three different sources of effort: aging, task novelty and task difficulty.

There is growing evidence that fluctuations in brain activity may exhibit scale-free ("fractal") dynamics. Scale-free signals follow a spectral-power curve of the form P(f ) ∝ f(-ß), where spectral power decreases in a power-law fashion with increasing frequency. In this study, we demonstrated that fractal scaling of BOLD fMRI signal is consistently suppressed for different sources of cognitive effort. Decreases in the Hurst exponent (H), which quantifies scale-free signal, was related to three different sources of cognitive effort/task engagement: 1) task difficulty, 2) task novelty, and 3) aging effects. These results were consistently observed across multiple datasets and task paradigms. We also demonstrated that estimates of H are robust across a range of time-window sizes. H was also compared to alternative metrics of BOLD variability (SDBOLD) and global connectivity (Gconn), with effort-related decreases in H producing similar decreases in SDBOLD and Gconn. These results indicate a potential global brain phenomenon that unites research from different fields and indicates that fractal scaling may be a highly sensitive metric for indexing cognitive effort/task engagement.

Assessment of Cognitive Impairment and Complaints in Individuals With Colorectal Cancer.

PURPOSE/OBJECTIVES: To assess cognitive function in individuals with colorectal cancer (CRC) and identify factors associated with cognitive effects.
 DESIGN: Cross-sectional, comparative design.
. SETTING: Midwest hospital.
. SAMPLE: Men and women with (n = 50) and without (n = 50) CRC. 
 METHODS: Comparative and regression analyses were performed to assess the relationship between cognition and CRC.
 MAIN RESEARCH VARIABLES: Attention, cognitive control, and memory function were assessed with neuropsychological tests and self-report.
. FINDINGS: Compared to healthy volunteers, individuals with CRC performed worse and reported more problems on tasks requiring attention and cognitive control (p < 0.05). After controlling for covariates, poorer performance on tasks of attention and cognitive control was associated (p < 0.001) with having CRC, older age, and less education. In contrast, poorer perceived attention and cognitive control were associated (p < 0.001) with greater fatigue but not CRC. 
 CONCLUSIONS: Individuals with CRC are vulnerable to cognitive problems. In addition, older age, less education, and fatigue can increase risk for worse cognitive performance and self-reported cognition.
 IMPLICATIONS FOR NURSING: Cognitive problems can profoundly affect an individual's ability to function in everyday life and cope with cancer. Nurses should assess for cognitive problems in patients with CRC and intervene to reduce distress.

Scale-free brain dynamics under physical and psychological distress: pre-treatment effects in women diagnosed with breast cancer.

Stressful life events are related to negative outcomes, including physical and psychological manifestations of distress, and behavioral deficits. Patients diagnosed with breast cancer report impaired attention and working memory prior to adjuvant therapy, which may be induced by distress. In this article, we examine whether brain dynamics show systematic changes due to the distress associated with cancer diagnosis. We hypothesized that impaired working memory is associated with suppression of "long-memory" neuronal dynamics; we tested this by measuring scale-free ("fractal") brain dynamics, quantified by the Hurst exponent (H). Fractal scaling refers to signals that do not occur at a specific time-scale, possessing a spectral power curve P(f)∝ f(-ß); they are "long-memory" processes, with significant autocorrelations. In a BOLD functional magnetic resonance imaging study, we scanned three groups during a working memory task: women scheduled to receive chemotherapy or radiotherapy and aged-matched controls. Surprisingly, patients' BOLD signal exhibited greater H with increasing intensity of anticipated treatment. However, an analysis of H and functional connectivity against self-reported measures of psychological distress (Worry, Anxiety, Depression) and physical distress (Fatigue, Sleep problems) revealed significant interactions. The modulation of (Worry, Anxiety) versus (Fatigue, Sleep Problems, Depression) showed the strongest effect, where higher worry and lower fatigue was related to reduced H in regions involved in visuospatial search, attention, and memory processing. This is also linked to decreased functional connectivity in these brain regions. Our results indicate that the distress associated with cancer diagnosis alters BOLD scaling, and H is a sensitive measure of the interaction between psychological versus physical distress.

The functional connectivity landscape of the human brain.

Functional brain networks emerge and dissipate over a primarily static anatomical foundation. The dynamic basis of these networks is inter-regional communication involving local and distal regions. It is assumed that inter-regional distances play a pivotal role in modulating network dynamics. Using three different neuroimaging modalities, 6 datasets were evaluated to determine whether experimental manipulations asymmetrically affect functional relationships based on the distance between brain regions in human participants. Contrary to previous assumptions, here we show that short- and long-range connections are equally likely to strengthen or weaken in response to task demands. Additionally, connections between homotopic areas are the most stable and less likely to change compared to any other type of connection. Our results point to a functional connectivity landscape characterized by fluid transitions between local specialization and global integration. This ability to mediate functional properties irrespective of spatial distance may engender a diverse repertoire of cognitive processes when faced with a dynamic environment.

Neuromarkers of fatigue and cognitive complaints following chemotherapy for breast cancer: a prospective fMRI investigation.

The aim of this study is to use functional magnetic resonance imaging (fMRI) to prospectively examine pre-treatment predictors of post-treatment fatigue and cognitive dysfunction in women treated with adjuvant chemotherapy for breast cancer. Fatigue and cognitive dysfunction often co-occur in women treated for breast cancer. We hypothesized that pre-treatment factors, unrelated to chemotherapy per se, might increase vulnerability to post-treatment fatigue and cognitive dysfunction. Patients treated with (n = 28) or without chemotherapy (n = 37) and healthy controls (n = 32) were scanned coincident with pre- and one-month post-chemotherapy during a verbal working memory task (VWMT) and assessed for fatigue, worry, and cognitive dysfunction. fMRI activity measures in the frontoparietal executive network were used in multiple linear regression to predict post-treatment fatigue and cognitive function. The chemotherapy group reported greater pre-treatment fatigue than controls and showed compromised neural response, characterized by higher spatial variance in executive network activity, than the non-chemotherapy group. Also, the chemotherapy group reported greater post-treatment fatigue than the other groups. Linear regression indicated that pre-treatment spatial variance in executive network activation predicted post-treatment fatigue severity and cognitive complaints, while treatment group, age, hemoglobin, worry, and mean executive network activity levels did not predict these outcomes. Pre-treatment neural inefficiency (indexed by high spatial variance) in the executive network, which supports attention and working memory, was a better predictor of post-treatment cognitive and fatigue complaints than exposure to chemotherapy per se. This executive network compromise could be a pre-treatment neuromarker of risk, indicating patients most likely to benefit from early intervention for fatigue and cognitive dysfunction.

Cognitive deficits in Korean women treated with chemotherapy for breast cancer.

BACKGROUND: Cognitive deficits have been reported as detrimental side effects in chemotherapy-treated breast cancer patients and survivors. Korean women treated for breast cancer may experience unrecognized cognitive deficits related to their treatment. However, no research has examined cognitive test performance in chemotherapy-treated Korean breast cancer survivors. OBJECTIVE: The objectives of this study were 2-fold: (1) to examine differences in occurrence and severity of cognitive deficits in Korean women treated with adjuvant chemotherapy for breast cancer as compared with a control group of women without breast cancer and (2) to examine the relationship of selected demographic and cultural factors with cognitive test performance. METHODS: Sixty-four Korean women, 32 women treated for localized breast cancer and 32 healthy controls, were enrolled. Breast cancer participants were assessed with established cognitive measures within 4 months after chemotherapy, and healthy controls, within 6 months after negative screening mammography. RESULTS: The breast cancer group showed a significantly higher occurrence and greater severity of cognitive deficits than controls did. Importantly, older age, less education, greater collectivist tendency, and greater childrearing burden were reliably associated with poorer attention and working memory test performance. CONCLUSIONS: Cognitive deficits were found in chemotherapy-treated Korean women with moderate to large effect sizes compared with controls. Cultural characteristics contributed to worse cognitive performance. IMPLICATIONS FOR PRACTICE: Healthcare providers should recognize that Korean women may be highly vulnerable to cognitive deficits. Cultural factors also need to be considered when assessing cognitive function and designing therapeutic interventions to counteract negative cognitive outcomes.

Pretreatment worry and neurocognitive responses in women with breast cancer.

UNLABELLED: [Correction Notice: An Erratum for this article was reported in Vol 33(3) of Health Psychology (see record 2014-07787-001). The name of author Misook Jung was misspelled as Mi Sook Jung. All versions of this article have been corrected.] OBJECTIVE: Altered cognitive function has been associated with breast cancer treatment, particularly adjuvant chemotherapy, but the underlying neuropsychological mechanisms are not yet understood. Recent research indicates that compromised attention and working memory can exist before adjuvant treatment, implicating psychological distress, such as worry, as a possible contributor to observed alterations in cognitive function. We hypothesized that worry associated with breast cancer diagnosis might influence neurocognitive responses before any adjuvant therapy. DESIGN: Fifty women, 25 due to receive chemotherapy and 25 due to receive radiation therapy, participated in the study. Women performed a verbal working memory task during functional magnetic resonance imaging scanning to assess neurocognitive responses before any adjuvant treatment and to test the relationship of such responses with self-reports of worry. RESULTS: Although prechemotherapy participants showed significantly higher levels of worry compared with preradiation participants, higher worry, across both groups, was related to altered brain function. Specifically, increased worry was associated with reduced demand-related deactivation in default-mode regions, such as the precuneus/posterior cingulate. Reduced demand-related deactivation was critically related to worse behavioral performance, which was partially mediated by worry. CONCLUSION: Worry appears to be a significant contributor to neurocognitive dysfunction independent of adjuvant treatment for breast cancer. These results suggest that alterations in cognitive function may develop before any chemotherapy treatment and that worry about cancer diagnosis may contribute to reports of "chemo brain" during treatment. Psychological interventions aimed at mitigating worry may help to alleviate cognitive dysfunction associated with life-threatening illness such as breast cancer.

Cognitive function and breast cancer: promise and potential insights from functional brain imaging.

Altered cognitive function can be a distressing side effect of cancer and its treatment. Women diagnosed and treated for breast cancer often report problems with memory, concentration, and other cognitive abilities that can pose significant barriers to full resumption of family, job, and social roles. Despite considerable neuropsychological research, many unanswered questions remain about cancer-related cognitive deficits and the underlying neural bases. Functional magnetic resonance imaging (fMRI) measures brain activation associated with different mental states and has significantly advanced our understanding of cognitive function and dysfunction in healthy and clinical populations. However, to date the application of fMRI to the study of cognitive function in breast cancer is limited. The current review addresses the potential importance of this method for understanding the neurocognitive effects of breast cancer disease and treatment. Along with reviewing published fMRI studies on breast cancer to date, we discuss potential major contributions of this method which include: (a) delineating components of cognitive function and underlying neural processes most affected by cancer and its treatment, (b) uncovering compensatory processes and their limits, (c) identifying altered resting state networks that may relate to subjective complaints and longer term outcomes, and (d) clarifying the relationship between pre-treatment alterations in brain activity and longer term neural and behavioral outcomes. Finally, we pose questions for future research that can be optimally addressed by integrating fMRI and other imaging modalities to clarify the nature and causes of "chemo brain" and guide interventions to improve cognitive function and the quality of breast cancer survivorship.

Study of dyadic communication in couples managing prostate cancer: a longitudinal perspective.

OBJECTIVE: Cancer patients and partners often report inadequate communication about illness-related issues, although it is essential for mutual support and informal caregiving. This study examined the patterns of change in dyadic communication between patients with prostate cancer and their partners, and also determined if certain factors affected their communication over time. METHOD: Using multilevel modeling, this study analyzed longitudinal data obtained from a randomized clinical trial with prostate cancer patients and their partners, to examine their communication over time. Patients and partners (N=134 pairs) from the usual-care control group independently completed baseline demographic assessment and measures of social support, uncertainty, symptom distress, and dyadic communication at baseline, and 4-, 8-, and 12-month follow-ups. RESULTS: The results indicated that (1) patients and partners reported similar levels of open communication at the time of diagnosis. Communication reported by patients and partners decreased over time in a similar trend, regardless of phase of illness; (2) phase of illness affected couples' open communication at diagnosis but not patterns of change over time; and (3) couples' perceived communication increased as they reported more social support, less uncertainty, and fewer hormonal symptoms in patients. Couples' demographic factors and general symptoms, and patients' prostate cancer-specific symptoms did not affect their levels of open communication. CONCLUSIONS: Perceived open communication between prostate cancer patients and partners over time is affected by certain baseline and time-varying psychosocial and cancer-related factors. The results provide empirical evidence that may guide the development of strategies to facilitate couples' interaction and mutual support during survivorship.

Assessing longitudinal quality of life in prostate cancer patients and their spouses: a multilevel modeling approach.

PURPOSE: This study aimed at examining the relationship between quality of life (QOL) in prostate cancer (PCa) patients and partners and how baseline demographics, cancer-related factors, and time-varying psychosocial and symptom covariates affect their QOL over time. METHODS: Guided by a modified Stress-Coping Model, this study used multilevel modeling to analyze longitudinal data from a randomized clinical trial that tested a family-based intervention to improve QOL in couples managing PCa. Patients and partners from the usual-care control group (N = 134 dyads) independently completed the measurements at baseline, and at 4-, 8-, and 12-month follow-ups. RESULTS: Correlations of QOL between patients and partners over time were small to moderate. Patients' lower education level, partners' older age, higher family income, and localized cancer at baseline were associated with better QOL in couples. Over time, couples' QOL improved as their social support and cancer-related dyadic communication increased and as couples' uncertainty, general symptoms, and patients' prostate cancer-related sexual and hormonal symptoms decreased. CONCLUSIONS: Evidence indicates that couples' QOL during cancer survivorship is affected by multiple contextual factors (e.g., baseline demographics and time-varying psychosocial factors and symptoms). Intervention research is needed to explore comprehensive strategies to improve couples' QOL during the continuum of PCa survivorship.

The Attentional Function Index--a self-report cognitive measure.

OBJECTIVE: Cognitive assessment in individuals with cancer requires both measured performance on neuropsychological tests and self-report of effectiveness in functioning. Few instruments are available to assess the perceived impact of cognitive alterations on daily functioning in individuals treated for cancer. In this study, we investigated the psychometric properties of a theoretically based instrument, and the Attentional Function Index (AFI), designed to measure perceived effectiveness in common activities requiring attention and working memory, particularly the ability to formulate plans, carry out tasks, and function effectively in daily life. METHODS: Women (N=172), ages 27-86 years, completed the questionnaire before primary treatment for early stage breast cancer. Construct validity was established using exploratory principal component factor analysis with varimax rotation. RESULTS: A 13-item instrument emerged with 3 subscales, namely effective action, attentional lapses, and interpersonal effectiveness, which explained 74.69% of total variance. The internal consistency coefficients (Cronbach's α) were 0.92 for the total instrument, and ranged from 0.80 to 0.92 for the 3 subscales. Further examination of validity indicated that the scores on the AFI (1) showed expected correlations with established measures of ability to concentrate, cognitive failures, states of confusion, and mental fatigue, and (2) could distinguish differences in perceived cognitive functioning between younger and older age groups. AFI scores were not significantly associated with years of education or presence of comorbid conditions. CONCLUSION: The brief AFI has demonstrated usefulness for assessment of perceived cognitive functioning in populations with life-threatening and chronic illness, such as breast cancer.

Prechemotherapy alterations in brain function in women with breast cancer.

Despite clinical reports of cognitive deficits associated with cancer chemotherapy, the underlying brain mechanisms are not clear. This research examined selective attention and working memory using functional magnetic resonance imaging (fMRI) in women before chemotherapy for localized breast cancer. Patients were tested with an established selective attention and working memory task during fMRI. Compared with healthy controls, patients showed (a) bilateral brain activation in high-demand task conditions with recruitment of additional components of attention/working memory circuitry, and (b) less accurate and slower task performance. Results indicate compromised cognitive functioning before any chemotherapy and raise key questions for further research.

Breast cancer survivorship program: testing for cross-cultural relevance.

Taking CHARGE, a theory-based self-management program, was developed to assist women with survivorship concerns that arise after breast cancer treatment. Few such programs have been evaluated for cultural relevance with diverse groups. This study determined the utility and cultural relevance of the program for African American (AA) breast cancer survivors. Two focus groups were held with AA women (n = 13), aged 41 to 72 years, who had completed primary treatment. Focus group participants assessed the program content, format, materials, and the self-regulation process. Content analysis of audiotapes was conducted using an open, focused coding process to identify emergent themes regarding program relevance and topics requiring enhancement and/or further emphasis. Although findings indicated that the program's content was relevant to participants' experiences, AA women identified need for cultural enhancements in spirituality, self-preservation, and positive valuations of body image. Content areas requiring more emphasis included persistent fatigue, competing demands, disclosure, anticipatory guidance, and age-specific concerns about body image/sexuality. Suggested improvements to program materials included portable observation logs, additional resources, more photographs of younger AA women, vivid colors, and images depicting strength. These findings provide the basis for program enhancements to increase the utility and cultural relevance of Taking CHARGE for AA survivors and underscore the importance of evaluating interventions for racially/ethnically diverse groups.

Worry and the formation of cognitive representations of illness in individuals undergoing surgery for suspected lung cancer.

Worry involving repetitive thoughts about threats and concerns is prevalent when confronted with a life-threatening illness such as cancer. Worry may contribute to the formation of negative cognitive representations of illness that can have a detrimental effect on behavioral and adaptive outcomes. The study examined for the first time (a) the relationship between worry and early formation of cognitive representations of illness in individuals with suspected lung cancer over the presurgical and postsurgical period and (b) associations between worry and anxiety, sex, age, and educational level. Correlational statistical analyses were used to assess worry and cognitive representations in 42 individuals before lung surgery and again 3 weeks postsurgery. Higher worry was significantly related to more threatening content in multiple illness domains. Repeated-measures analysis of variance using high- and low-worry strata showed significant interactions between worry and time on certain illness domains indicating that high worry was associated with increased threat and negative contents in cognitive representations of illness over time. Multiple regression analyses showed that trait anxiety was the only significant predictor of worry in a regression model including age, sex, education, and anxiety before surgery. Findings suggest that higher worry at time of diagnosis is associated with the development of negative and more threatening contents in cognitive representations of illness in individuals with suspected lung cancer.

The influence of developmental life stage on quality of life in survivors of prostate cancer and their partners.

INTRODUCTION: Although prostate cancer is prevalent, little information is available on how it affects couples' quality of life (QOL) according to their age cohort. The purpose of this study was to examine how quality of life, self-efficacy and appraisal of the illness experience vary among men with prostate cancer and their partners according to age cohort: middle age (50-64); young-old (65-74); and old-old (75-84). Using an Adult Developmental and Family Stress framework, this study focuses on how normative (developmental stage) and non-normative stressors (prostate cancer) may affect a couple's ability to adapt. METHODS: A descriptive, comparative design was used to examine age-related differences in quality of life and selected psychosocial variables in 69 men with prostate cancer and their spouses. Cross-sectional data were obtained using standardized instruments with adequate reliability and validity. ANCOVA and MANCOVA were used to determine differences among age groups. RESULTS: Findings indicated that patients who were ages 65-74 had better QOL and higher self-efficacy than patients ages 50-64 and less negative appraisal of illness than the other two groups. Spouses ages 50-64 reported the most distress related to sexual changes in their husbands. Spouses in both the middle age and old-old group had more bother related to hormone therapy than the young-old spouses. IMPLICATIONS FOR CANCER SURVIVORS: Findings suggest that interventions should be tailored to dyads' developmental life stage. Younger and older prostate cancer survivors and their partners may benefit from tailored interventions designed to improve their quality of life and confidence in managing their treatment outcomes during the survivorship period.