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Mi Sook Jung, PhD, RN University of Michigan

Altered Neurocognitive Responses in Women Treated with Adjuvant Chemotherapy for Breast Cancer: A Functional MRI Analysis of the Impact of Fatigue. Mi Sook Jung, PhD, RN University of Michigan. Supported by NIH, NINR, R01 NR010939 ( Cimprich B, PI). Co-Authors. Askren MK, PhD

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Mi Sook Jung, PhD, RN University of Michigan

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  1. Altered Neurocognitive Responses in Women Treated with Adjuvant Chemotherapy for Breast Cancer: A Functional MRI Analysis of the Impact of Fatigue Mi Sook Jung, PhD, RN University of Michigan Supported by NIH, NINR, R01 NR010939 (Cimprich B, PI)

  2. Co-Authors • Askren MK, PhD • Research Scientist, Integrated Brain Imaging Center, University of Washington • Berman MG, PhD • Post-doc Fellow, Rotman Research Institute at Baycrest, University of Toronto • Hayes DF, MD • Professor, Department of Internal Medicine, University of Michigan • Zhang M, PhD • Assistant Professor, Department of Biostatistics, University of Michigan • Ossher L, MSc • Doctoral candidate, Department of Psychology, University of Michigan • Peltier S, PhD • Functional MRI Lab. Assistant Research Scientist, Biomedical Engineering, University of Michigan • Noll DC, PhD • Ann and Robert H. Lurie Professor, Biomedical Engineering, University of Michigan • Therrien B, PhD, RN, FAAN • Associate Professor Emerita, School of Nursing, University of Michigan • Reuter-Lorenz PA, PhD • Professor, Department of Psychology, University of Michigan • Cimprich B, PhD, RN, FAAN (PI) • Associate Professor Emerita, School of Nursing, University of Michigan

  3. Cognitive Deficits in Breast Cancer • Common distressing symptom: incidence rate up to 75% in chemotherapy-treated breast cancer patients and survivors (Wefel & Schagen, 2012) • Features: difficulties in attention, working memory, processing speed, and executive function (Boykoff et al, 2009) • Mild to moderate changes in cognitive function with considerable impact on effective functioning and quality of life (Boykofffetal, 2009; Reid-Arndt et al, 2010)

  4. Current State of Research • Various definitions of cognitive deficits • Variable methods, multiple measures, some measures assess more than one domain • Often lack cognitive neuroscience underpinnings to make sense of findings • True incidence and underlying causative brain mechanisms remain unclear. fMRI is a powerful tool! (Cimprich et al, 2010; Wefel et al, 2011; Wefel & Schagen, 2012)

  5. Fatigue • Fatigue can be both determinant and outcome of reduced cognitive function. • Fatigue has been significantly associated with post-treatment cognitive deficits measured by neuropsychological tests in women with breast cancer (Reid-Arndt et al, 2010; Vearncombe et al, 2011) • Greater fatigue has been associated with less frontal perfusion and increased neurocognitive effort in individuals with multiple sclerosis and chronic fatigue syndrome (Genova et al, 2011)

  6. Specific Aims • To determine whether alterations in basic processes of attention and working memory occur over time in women treated with chemotherapy for breast cancer • To examine the association between fatigue and neurocognitive responses over time

  7. Design Note. adj. CTX=adjuvant chemotherapy, Rad TX=radiation therapy, M=month, Y=year

  8. Participants (N=97) * < .01

  9. Measures • During fMRI scanning • Verbal Working Memory Task (VWMT) (Nelson et al, 2003; Cimprich et al, 2010) • Following scanning • Attentional Function Index (AFI)(Cimprich, 1992) • Functional Assessment of Cancer Therapy–Fatigue (FACT-F) (Cella et al, 2010)

  10. x v j k s j Verbal Working Memory Task; includes low, medium and high demand conditions; Response is Y/N whether probe present in current memory set. d m p Scan Test Procedures r p l + + S P + presented for 1500ms 3000ms delay interval presented for 1500ms No Low demand No Medium demand No High demand Yes Z D J X

  11. Task Performance Chemotherapy group was less accurate over time Demand: F (2,188) = 37.82, p < .001 Group: F (2,94) = 3.24 p < .05 Error rates (Pre-treatment) (Post-treatment)

  12. AFI Time: F (1,94) = 7.97, p < .01 Chemotherapy group reported more difficulties in cognitive function over time p < .01 AFI mean score Pre-treatment Post-treatment

  13. Whole Brain Analyses Chemotherapy Radiation therapy Healthy control The chemotherapy group fail to activate frontal regions prior to treatment A B A. Pre-treatment High > Low B. Post-treatment High > Low 6.4 3.4 -3.4 -6.4

  14. Fatigue Time: F (1,92) = 7.01, p < .01 Group: F (2,92) = 5.94, p < .01 Chemotherapy group reported higher fatigue p < .05 FACT-F mean score Pre-treatment Post-treatment

  15. Fatigue and Cognitive Function Higher fatigue related to worse cognitive function r = .21 p < .05 r = -.59 p < .001 Error rates in high demand (Post-treatment) AFI mean scores (Post-treatment) Fatigue (post-treatment) Fatigue (post-treatment)

  16. Linear Mixed Models VMWT Performance: Error rate Cognitive Difficulty: AFI

  17. Frontal region activation r = -.24 p < .05 Pre-treatment LIFG activation related to fatigue prior to treatment Fatigue (pre-treatment) LeftInferior Frontal Gyrus (LIFG) activation High > Low (CV)

  18. Frontal region activation r = -.21 p < .05 Pre-treatment LMFG activation related to change in fatigue Change in fatigue Left Middle Frontal Gyrus (LMFG) activation High > Low (CV)

  19. Summary • Overall, when compared with other groups, women treated with adjuvant chemotherapy: • showed poorer test performance pre- and post-treatment • reported more cognitive dysfunction and higher fatigue over time. • In the radiation therapy group, performance and fatigue levels fell between chemotherapy and healthy control groups. • However, across all groups and time points higher fatigue was associated with poorer performance and more difficulties in cognitive function.

  20. Imaging working memory: • Patient groups showed no activation differences pre- and post-treatment; • Importantly, pre-treatment failure to activate left frontal regions during working memory task was associated with higher fatigue over time.

  21. Conclusion • In a longitudinal assessment of “chemo brain”, reduced neurocognitive responses were revealed even before treatment. • Vulnerability to negative outcomes of cognitive function is not limited to only women treated with chemotherapy for breast cancer. • Fatigue and reduced neurocognitive responses may be significantly interlinked. Early detection of cognitive vulnerability before treatment may reduce negative outcomes and improve wellbeing following treatment.

  22. Key References • Boykoff N Moieni M, & Subramanian SK (2009) Confronting chemobrain: an in-depth look at survivors' reports of impact on work, social networks, and health care response. J Cancer Surviv 3 (4):223-232. • Cella D, Lai JS, & Stone A (2010). Self-reported fatigue: one dimension or more? Lessons from the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire. Supportive Care in Cancer, 19(9), 1441-1450. • Cimprich B, Reuter-Lorenz PA, Nelson,J et al (2010). Prechemotherapy alterations in brain function in women with breast cancer. Journal of Clinical and Experimental Neuropsychology, 32(3), 324-331. • Genova HM, Wylie GR, & DeLuca J (2011). Neuroimaging o fatigue, 369-381. In Brain Imaging in Behavioral Medicine and Clinical Neuroscience. • Wefel JS & Schagen SB (2012) Chemotherapy-related cognitive dysfunction. CurrNeurolNeurosci Rep 12 (3):267-275. • Reid-Arndt SA, Hsieh C, & Perry MC (2010) Neuropsychological functioning and quality of life during the first year after completing chemotherapy for breast cancer. Psychooncology 19 (5):535-544.

  23. Thank you!

  24. MRI Acquisition MR Acquisition: GE Signa 3T T2* spirals, TR = 1500 ms, TE = 30 ms, flip angle = 70°, 25 slices, 3.75 x 3.75 x 5 mm, FOV = 24 cm T1 SPGR, TR = 9 ms, TE = 1.8 ms, flip angle = 15°, slice thickness = 1.2 mm, FOV = 25 cm

  25. Response Times Demand: F (2,188) = 124.03, p < .001 Time: F (1,94) = 6.73, p < .05 Response times similar in all groups * Response time (ms) * * * (Pre-treatment) (Post-treatment) * p < .05, Paired t-test (pre- vs. post-treatment)

  26. Fatigue and Cognitive Function r = .10 p > .1 r = .21 p < .05 Higher fatigue related to worse cognitive function over time Error rates in high demand (Pre-treatment) Error rates in high demand (Post-treatment) r = -.54 p < .001 r = -.59 p < .001 AFI (Pre-treatment) AFI (Post-treatment) Fatigue (Pre-treatment) Fatigue (Post-treatment)

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