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

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.

[1]  P. Jacobsen,et al.  Identifying clinically meaningful fatigue with the Fatigue Symptom Inventory. , 2008, Journal of pain and symptom management.

[2]  H. Jim,et al.  Cognitive functioning in breast cancer survivors: A controlled comparison , 2009, Cancer.

[3]  C. Bielajew,et al.  Cognitive effects of chemotherapy in post‐menopausal breast cancer patients 1 year after treatment , 2009, Psycho-oncology.

[4]  Michael E. Phelps,et al.  Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy , 2007, Breast Cancer Research and Treatment.

[5]  G. Lyman,et al.  Measurement of Fatigue in Cancer Patients: Development and Validation of the Fatigue Symptom Inventory , 1998, Quality of Life Research.

[6]  Sterling C. Johnson,et al.  Hormone effects on fMRI and cognitive measures of encoding: Importance of hormone preparation , 2006, Neurology.

[7]  J. Weis,et al.  Cognitive deficits as long‐term side‐effects of adjuvant therapy in breast cancer patients: ‘subjective’ complaints and ‘objective’ neuropsychological test results , 2009, Psycho-oncology.

[8]  R. Theriault,et al.  ‘Chemobrain’ in breast carcinoma? , 2004, Cancer.

[9]  Paul C. Fletcher,et al.  Physiological variation in estradiol and brain function: A functional magnetic resonance imaging study of verbal memory across the follicular phase of the menstrual cycle , 2008, Hormones and Behavior.

[10]  Andrew J Saykin,et al.  Mild cognitive impairment: conceptual issues and structural and functional brain correlates. , 2003, Seminars in clinical neuropsychiatry.

[11]  D. Weinberger,et al.  Modulation of cognition-specific cortical activity by gonadal steroids: a positron-emission tomography study in women. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[12]  H. Yamasue,et al.  Prefrontal Cortex and Amygdala Volume in First Minor or Major Depressive Episode After Cancer Diagnosis , 2006, Biological Psychiatry.

[13]  A. Saykin,et al.  Nicotinic versus muscarinic blockade alters verbal working memory-related brain activity in older women. , 2008, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[14]  Andra M. Smith,et al.  Pre-Chemotherapy Differences in Visuospatial Working Memory in Breast Cancer Patients Compared to Controls: An fMRI Study , 2011, Front. Hum. Neurosci..

[15]  A. Saykin,et al.  Brain structure and function differences in monozygotic twins: possible effects of breast cancer chemotherapy. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  B. Collins.  Acute and Late Onset Cognitive Dysfunction Associated With Chemotherapy in Women With Breast Cancer: Wefel JS, Saleeba AK, Buzdar AU, et al (The Univ of Texas M D Anderson Cancer Ctr, Houston) Cancer 116:3348-3356, 2010 , 2011 .

[17]  Joel Kramer,et al.  A metaanalysis of studies of the effects of cancer chemotherapy on various domains of cognitive function , 2005, Cancer.

[18]  D. Veltman,et al.  Cerebral hyporesponsiveness and cognitive impairment 10 years after chemotherapy for breast cancer , 2011, Human brain mapping.

[19]  C. Bielajew,et al.  A Meta-Analysis of the Neuropsychological Effects of Adjuvant Chemotherapy Treatment in Women Treated for Breast Cancer , 2006, The Clinical neuropsychologist.

[20]  M. Lux,et al.  Cognitive function during neoadjuvant chemotherapy for breast cancer , 2007, Cancer.

[21]  S. Kesler,et al.  Regional Brain Activation during Verbal Declarative Memory in Metastatic Breast Cancer , 2009, Clinical Cancer Research.

[22]  Cecil R. Reynolds,et al.  A demographically based index of premorbid intelligence for the WAIS—R. , 1984 .

[23]  D. Grosshans,et al.  Catechol-O-Methyltransferase Genotype Modulates Cancer Treatment-Related Cognitive Deficits in Breast Cancer Survivors: Small BJ, Rawson KS, Walsh E, et al (Univ of South Florida, Tampa, FL; Univ of Kentucky College of Medicine, Lexington; et al) Cancer 117:1369-1376, 2011§ , 2011 .

[24]  I. Tannock,et al.  Cancer and cancer-therapy related cognitive dysfunction: an international perspective from the Venice cognitive workshop. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[25]  D. Yurgelun-Todd,et al.  Estrogen therapy selectively enhances prefrontal cognitive processes: a randomized, double-blind, placebo-controlled study with functional magnetic resonance imaging in perimenopausal and recently postmenopausal women , 2006, Menopause.

[26]  Andrew J. Saykin,et al.  Cognitive function in breast cancer patients prior to adjuvant treatment , 2008, Breast Cancer Research and Treatment.

[27]  Yutaka Matsuoka,et al.  Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy , 2007, Cancer.

[28]  C. Spielberger.  State‐Trait Anxiety Inventory , 2010 .

[29]  Andrew J. Saykin,et al.  Candidate mechanisms for chemotherapy-induced cognitive changes , 2007, Nature Reviews Cancer.

[30]  A. Saykin,et al.  Brain activation patterns associated with working memory in relapsing-remitting MS , 2004, Neurology.

[31]  S. Schagen,et al.  Persistent neurocognitive problems after adjuvant chemotherapy for breast cancer. , 2008, Clinical breast cancer.

[32]  Andrew J Saykin,et al.  Cholinergic enhancement of frontal lobe activity in mild cognitive impairment. , 2004, Brain : a journal of neurology.

[33]  Andrew J. Saykin,et al.  Increased brain activation during working memory in cognitively intact adults with the APOE ε4 allele , 2006 .

[34]  L. Radloff.  The CES-D Scale , 1977 .

[35]  Willem Boogerd,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 , 2012, Human brain mapping.

[36]  S. Rodenhuis,et al.  Late effects of adjuvant chemotherapy on cognitive function: a follow-up study in breast cancer patients. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[37]  M. Albert,et al.  Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD , 2005, Neurology.

[38]  Andrew J. Saykin,et al.  Differential Working Memory Load Effects after Mild Traumatic Brain Injury , 2001, NeuroImage.

[39]  A. Saykin,et al.  The relationship of APOE genotype to neuropsychological performance in long‐term cancer survivors treated with standard dose chemotherapy , 2003, Psycho-oncology.

[40]  M. Dodd,et al.  A prospective longitudinal study of chemotherapy-induced cognitive changes in breast cancer patients , 2011, Supportive Care in Cancer.

[41]  A. Saykin,et al.  Brain activation during working memory 1 month after mild traumatic brain injury , 1999, Neurology.

[42]  Ruth O'Hara,et al.  Prefrontal cortex and executive function impairments in primary breast cancer. , 2011, Archives of neurology.

[43]  Yoshiharu Kim,et al.  Structure of orbitofrontal cortex and its longitudinal course in cancer-related post-traumatic stress disorder , 2007, Neuroscience Research.

[44]  Bruce E Compas,et al.  Neuropsychological effects of treatments for adults with cancer: A meta-analysis and review of the literature , 2003, Journal of the International Neuropsychological Society.

[45]  William J Jagust,et al.  Estrogen- and tamoxifen-associated effects on brain structure and function , 2004, NeuroImage.

[46]  T. Dietrich,et al.  Effects of Blood Estrogen Level on Cortical Activation Patterns during Cognitive Activation as Measured by Functional MRI , 2001, NeuroImage.

[47]  P. McGuire,et al.  A study of visuospatial working memory pre- and post-Gonadotropin Hormone Releasing Hormone agonists (GnRHa) in young women , 2008, Hormones and Behavior.

[48]  Andrew J Saykin,et al.  Mechanisms of working memory dysfunction after mild and moderate TBI: evidence from functional MRI and neurogenetics. , 2006, Journal of neurotrauma.

[49]  S. Allan,et al.  A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer , 2006, British Journal of Cancer.

[50]  A. Leemans,et al.  Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[51]  P. Fletcher,et al.  Gonadotropin hormone releasing hormone agonists alter prefrontal function during verbal encoding in young women , 2007, Psychoneuroendocrinology.

[52]  A. Saykin,et al.  Cognition and Cancer: Brain imaging investigation of chemotherapy-induced neurocognitive changes , 2008 .

[53]  Andrew J. Saykin,et al.  Gray matter reduction associated with systemic chemotherapy for breast cancer: a prospective MRI study , 2010, Breast Cancer Research and Treatment.

[54]  H. Jim,et al.  Catechol‐O‐methyltransferase genotype modulates cancer treatment‐related cognitive deficits in breast cancer survivors , 2011, Cancer.

[55]  K. Hermelink.  Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer , 2011, Cancer.

[56]  Andrew J Saykin,et al.  Mechanisms of chemotherapy-induced cognitive disorders: neuropsychological, pathophysiological, and neuroimaging perspectives. , 2003, Seminars in clinical neuropsychiatry.

[57]  J. Zubieta,et al.  Enhanced neuroactivation during verbal memory processing in postmenopausal women receiving short-term hormone therapy. , 2009, Fertility and sterility.

[58]  A. Saykin,et al.  Increased brain activation during working memory in cognitively intact adults with the APOE epsilon4 allele. , 2006, The American journal of psychiatry.

[59]  J. Savard,et al.  Cognitive impairments associated with breast cancer treatments: results from a longitudinal study , 2008, Breast Cancer Research and Treatment.

[60]  Douglas C. Noll,et al.  Prechemotherapy alterations in brain function in women with breast cancer , 2010, Journal of clinical and experimental neuropsychology.

[61]  L. Katz,et al.  Effect of Estrogen on Brain Activation Patterns in Postmenopausal Women During Working Memory Tasks , 1999 .

[62]  S. Pal,et al.  Cognitive changes associated with endocrine therapy for breast cancer. , 2010, Maturitas.

[63]  Andrew J Saykin,et al.  Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[64]  Thomas E. Nichols,et al.  Impact of combined estradiol and norethindrone therapy on visuospatial working memory assessed by functional magnetic resonance imaging. , 2006, The Journal of clinical endocrinology and metabolism.

[65]  Jean-Luc Anton,et al.  Region of interest analysis using an SPM toolbox , 2010 .