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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

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)


Mi sook jung phd rn university of michigan

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


Mi sook jung phd rn university of michigan

  • 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)


Mi sook jung phd rn university of michigan

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)


Mi sook jung phd rn university of michigan

  • 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)


Mi sook jung phd rn university of michigan

  • 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


Design

Design

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


Participants n 97

Participants (N=97)

* < .01


Measures

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)


Scan test procedures

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


Task performance

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)


Mi sook jung phd rn university of michigan

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


Mi sook jung phd rn university of michigan

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


Mi sook jung phd rn university of michigan

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


Mi sook jung phd rn university of michigan

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)


Mi sook jung phd rn university of michigan

Linear Mixed Models

VMWT Performance: Error rate

Cognitive Difficulty: AFI


Mi sook jung phd rn university of michigan

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)


Mi sook jung phd rn university of michigan

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)


Summary

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.


Mi sook jung phd rn university of michigan

  • 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.


Conclusion

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.


Mi sook jung phd rn university of michigan

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.


Mi sook jung phd rn university of michigan

Thank you!


Mri acquisition

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


Response times

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)


Mi sook jung phd rn university of michigan

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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