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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)


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


  • 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)


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)


  • 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)


  • 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



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)


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


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


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


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)


Linear Mixed Models

VMWT Performance: Error rate

Cognitive Difficulty: AFI


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)


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.


  • 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.


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.



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)


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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