NIA Neuroeconomics Workshop Scott Huettel, Duke University Neuroimaging the Aging Brain: Methodological Insights from Cognitive Neuroscience

NIA Neuroeconomics Workshop Scott Huettel, Duke University

Neuroimaging the Aging Brain: Methodological Insights from Cognitive Neuroscience


Major Themes: Methodology and Function

How do neuroimaging methods change when studying elderly adults?

Are there general principles underlying functional changes in the elderly brain, and how can those principles be addressed using neuroimaging?


I. Methodological Changes


Overview of Methodological Changes in Neuroimaging

• Functional MRI (fMRI)• MRI Volumetrics• Diffusion Tensor Imaging (DTI)• Task Logistics

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Overview of Methods in Cognitive NeuroscienceNeuronal activity vs. Metabolism

Key idea: distinguish changes in our measure from changes in function.


Neuronal Activity: Signaling and Integration Local field potentials (LFPs) reflect the summed activity of many neurons


The fMRI Blood-Oxygenation-Level-Dependent (BOLD) ResponseIncreased neuronal activity results in increased MR (T2*) signal

BASELINE

ACTIVE


Neuronal origins of the fMRI Hemodynamic ResponseThe fMRI BOLD response is predicted by dendritic activity (LFPs)

Adapted from Logothetis et al. (2002)


Age-Related Changes in Cerebrovascular SystemStructural changes that may have functional consequences

• Thickening of vessel walls• Hypertension• Venous occlusions• Changes in capillary structure• Reduced blood flow• Reduced oxygen consumption

(CMRO2)Fang (1976)


Do these Structural Changes Influence the fMRI BOLD Signal?

Time since stimulus onset (sec)

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BO

LD S

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nge

~1%

Huettel et al. (2001)


Do these Structural Changes Influence the fMRI BOLD Signal?Probably not… No… and Yes

Huettel et al. (2001)

BOLD Amplitude

BOLD Refractory Effects

BOLD Signal-Noise Ratio

YE

Y

E

Y

E

Y1E1

Y2E2

Two of three studies report that BOLD amplitude is similar in young

(Y) and elderly (E) adults.

Two studies report that the BOLD signal has similar refractory

properties (i.e., to multiple events in rapid succession) in young and

elderly adults.

Two studies report that the BOLD signal has reduced signal-noise

ratio (SNR) in elderly adults.

D’Esposito et al. (1999)Buckner et al. (2000)

Y1

E1

Y2

E2

Y E E/Y


How does Increased Noise affect fMRI Analyses?Simulations show clear effects on spatial extent

Huettel et al., 2001

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SNR = 0.10

SNR = 0.15

SNR = 0.25

SNR = 1.00

SNR = 0.52 (Young)

SNR = 0.35 (Old)

Number of Trials Averaged

Num

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of S

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Age-related differences in how much of the brain is activated may reflect differences in SNR, not cognition.


Conclusions: Aging and BOLD fMRIEffects not in principle, but for practice

• FMRI is a hemodynamic measure

• Aging causes cardiovascular changes

• BOLD response form unchanged with age

• BOLD response SNR decreased with age

• Problematic for between-group comparisons

• Suggestion: Group by Condition testing


Structural Changes in the Elderly Brain: Gray MatterDifferent brain regions exhibit different patterns of lifespan change

Data from Raz et al. (2004); figure from Hedden & Gabrieli (2004)

These effects are attributable primarily to loss of synaptic density (secondarily, to cell death).

Image courtesy Gregory McCarthy


Structural Changes in the Elderly Brain: White MatterMeasurement using diffusion tensor imaging (DTI)

Fractional Anisotropy (FA)

FA ~ 0FA ~ 1


White Matter Maps: Diffusion Tensor MapsDiffusion tends to be less anisotropic in elderly adults

OlderYounger


DTI: White-Matter Changes with Aging Reduced Fractional Anisotropy

Genu

Region of Interest

FA

Older Younger

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SFG PCF PV FFGALC Splenium PAR

Key fiber tracts in the human brain

Data from Madden et al. (2004)

White matter integrity, assessed in central voxels,

decreases in the elderly


DTI: White-Matter Changes with Aging Reduced Fractional Anisotropy

Data from Madden et al. (2004)

Different white matter tracts mediate performance in

young and elderly.


Logistical Changes Differences in experimental procedures

• Reduced tolerance for time in scanner

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Elderly adults, in our experience, generally tolerate sessions of 60-75 minutes – with substantial individual variation. Younger adults tolerate sessions of 75-90

minutes. Head motion is more extensive in the elderly.Y

oung

Elderly




• Reduced sensory abilities





• Reduced performance on many tasks

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NST = nonsingleton target ; ST = singleton target

Excerpts from Madden et al. (2004a, 2004b, 2006)






• Biased sample selection


The “Super Elderly” Performance, on many scales, approximates or exceeds the young

Excerpts from Madden et al. (2004a, 2004b)

Is the typical elderly adult someone who

is college-educated,

has no significant health problems,

is taking only minimal medication,

and has a vocabulary (etc.) similar to a Duke undergraduate?


Logistical Changes Differences in experimental procedures for elderly subjects




• Biased sample selection

• Different motivation for participating

Excerpt from Hertwig & Ortmann (2001)

? ?


II. Functional Changes


Overview of Functional Changes

• Memory

• Control processes

• Emotion and affect

• Reward evaluation

Theme I: Selective and Non-selective deficits

Theme II: Functional compensation

?


Selective Deficits: Memory Aging has greater effects on recollection (hippocampally mediated)

Cabeza et al., 2006

Elderly: Attenuation of recollection-based

activation in hippocampus. Elderly:

Enhancement of familiarity-based

activation in rhinal cortex.


Non-Selective Deficits: EmotionSimilar regions, but less extensive activation, in the elderly

Wright et al., 2006

< Tessitore et al., 2005


Compensation: MemoryElderly adults recruit additional regions to maintain performance

Cabeza et al., 2002a

In a memory retrieval task, elderly adults who perform similarly to young adults (Old-High) show increased activation in left PFC,

compared to elderly adults with impaired performance.


Compensation: Memory (and other)Frontal compensation is a robust phenomenon

Cabeza, 2002; Cabeza et al., 2004

The reductions in asymmetry are found both when hemispheric specialization is based on process (e.g., memory retrieval / encoding) and when based on stimulus domain (e.g., verbal / spatial working memory).


Compensation: Attention Increased frontal activation in elderly adults under divided attention

Madden et al., 1997

Divided minus Central

Younger Adults Older Adults

F S W

H M D

B T G

N Z L

T R J

Q T Y


Compensation: Executive Control Elderly adults recruit additional, non-prefrontal regions

Madden et al., 2004

Posano et al., 2005

Younger adults: Prefrontal Cortex

Elderly adults: Thalamus/BG

Elderly adults: Parietal Cortex


Compensation: Methodological Caveats fMRI provides information about what’s active, not what’s not active

Cabeza, 2002


Selective Deficits, Compensation: Reward systems?

Almost nothing known… hence, this meeting.


Acknowledgments

Faculty collaborators, discussed projects• David Madden • Roberto Cabeza• Len White• Gregory McCarthy

External support• NIMH (Huettel)• NINDS (McCarthy)• NIA (Madden, Cabeza)

neuroeconomics.duke.edu

Current Laboratory Members• Alexandru Avram • J. Neil Bearden• Jacqui Detwiler • Erin Douglas• Wilko Schultz-Mahlendorf• Mark Sutherland• Dharol Tankersley• Bethany Weber

Recommended Readings:• Cabeza, Nyberg, & Park (2005). Cognitive Neuroscience of Aging. Oxford Univ. Press• Hedden & Gabrieli (2004). Nature Reviews Neuroscience• D’Esposito, Deouell, & Gazzaley (2003). Nature Reviews Neuroscience

All uncredited figures from:• Huettel, Song, & McCarthy (2004). Functional Magnetic Resonance Imaging

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NIA Neuroeconomics Workshop Scott Huettel, Duke University Neuroimaging the Aging Brain: Methodological Insights from Cognitive Neuroscience